Macrocyclic compounds with farnesyltransferase inhibitory activity

Abstract

The present invention relates to macrocyclic compounds of any one of formula (I), or pharma- ceutically acceptable forms thereof, pharmaceutical compositions containing them, processes for their preparation, and methods of using them to treat cancers dependent on famesylated proteins.

Description

[Technical field]

[0001] 1. Cross reference 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 aforementioned related applications is incorporated herein by reference in its entirety.

[0002] 2.Technical Field The present invention relates to macrocyclic compounds and pharmaceutical compositions comprising them that are useful in the treatment of cancers dependent on farnesylated proteins. The present invention also relates to methods for preparing such macrocyclic compounds and pharmaceutical compositions comprising them. The present invention also relates to the use of such macrocyclic compounds and pharmaceutical compositions comprising them in methods for inhibiting farnesyltransferase and in methods for treating cancers dependent on farnesylated proteins. [Background technology]

[0003] 3.Background technology Activated Ras oncogenes are often identified in cancerous tumors, and transformed Ras proteins are involved in the proliferation of cancer cells. The protein products of the Ras oncogenes, Ras proteins, are small GTPases that are important in signal transduction, cell growth, and cell proliferation. Shields, JM, et al., Trends Cell Biol. 2000, 10, 147-154. Ras proteins must associate (or bind) with the inner surface of the plasma membrane to transduce extracellular signals that can lead to the proliferation of cancer cells. In order to bind to the plasma membrane of cells and transduce extracellular signals, Ras proteins must undergo several post-translational modifications, including farnesylation of a cysteine ​​in the C-terminal CAAX box (C represents cysteine, A represents an aliphatic amino acid, and X represents any amino acid). Rowinsky, EK, et al., J. Clin. Oncol. 1999, 17, 3631-3652. The enzyme farnesyltransferase (FTase) recognizes the CAAX motif and farnesylates the Ras protein (transferring the 15-carbon farnesyl isoprenoid from farnesyl diphosphate to a cysteine ​​residue). Once farnesylated, the Ras protein can associate with the cell membrane. Inhibition of farnesyltransferase represents a pathway that would thereby block Ras protein cell membrane binding and reduce cell proliferation in cancer cells, and may provide potential clinical benefit to cancer patients. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Shields, JM, et al.,Trends Cell Biol.2000,10,147-154 [Non-Patent Document 2] Rowinsky,EK,et al.,J.Clin.Oncol.1999,17,3631-3652 Summary of the Invention [Means for solving the problem]

[0005] 4. Summary of the Invention In one embodiment, a compound of formula (I): [ka] or a pharma- ceutically acceptable form thereof, wherein The dashed line is A 1 and A 2 A single or double bond between A 1 However, independently, N and NR 1a , C.R. 1b or -C(=O)-; A 2 However, independently, N and NR 2a , C.R. 2b or -C(=O)-; A 3 But independently, CR 3 or N, A 4 But, CR 8 or N, A 5 and A 6 However, each independently, CR 8 Or N or A 5 and A 6 But together, O, NR 9 , or S, W is C 6-12 aryl or 5-12 membered heteroaryl, each of which is selected from 1-4 R 4 is optionally substituted with a substituent; Y is a bond or linker having a length of up to 6 atoms; Z is C 6-12 aryl or 5-12 membered heteroaryl, each of which is selected from 1-4 R 5 is optionally substituted with a substituent; R 1a and R 2a Each independently, R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10 R 11 , -S(O) p R 9 , or -S(O) 2 NR 10 R 11 and R 1b , R 2b , R 3 , R 5 , and R 8 each occurrence independently represents R9 , -OR 9 , Haro, CN, NO 2 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 9 , -S(O) p R 9 , -S(O) 2 NR 10 R 11 , or -NR 10 S(O) 2 NR 10 R 11 and R 4 is, in each occurrence, independently, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkoxy, C 1-6 Heteroalkoxy, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, -NR 14 R 15 , C 6-12 aryl, or 5-12 membered heteroaryl; R 4 Each C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkoxy, C 1-6 Heteroalkoxy, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, C 6-12 aryl, or 5-12 membered heteroaryl, optionally independently selected from halo, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 substituted with 1, 2, 3, 4, 5, or 6 substituents selected from haloalkoxy, and (O); R 6 But, CN,R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 OR 9 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 9 , -NR 10 C(NR 10 )NR 10 R 11 , -S(O) p R 9 , -S(O) 2 NR 10 R 11 , or -NR10 S(O) 2 NR 10 R 11 and R 7 But, Hello, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 9 , -S(O) p R 9 , -S(O) 2 NR 10 R 11 , and -NR 10 S(O) 2 NR 10 R 11 is a 5-12 membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 9 may, in each occurrence, independently represent hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 aryl, or 5-12 membered heteroaryl; R 9 Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl is optionally independently selected from halo, hydroxy, CN, NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, (O), -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)OR 12 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 12 , -NR 10 C(O)OR 12 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 12 , -S(O) p R 12 , -S(O) 2 NR 10 R 11 , and -NR 10 S(O) 2 NR 10 R 11 and is substituted with 1, 2, 3, 4, 5, or 6 substituents selected from R 10 and R 11 is, in each occurrence, independently, hydrogen, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 6-12 aryl, or 5-12 membered heteroaryl, or each of which, together with the N to which it is attached, combines to form a 3-6 membered heterocycloalkyl; R 10 and R 11 Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 6-12 Aryl or 5-12 membered heteroaryl is optionally independently selected from halo, hydroxy, CN, NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, (O), -C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -OC(O)OR 13 , -C(O)NR 14 R 15 , -NR 14 R 15 , -NR 14 C(O)R 13 , -NR 14 C(O)OR 13 , -NR 14 C(O)NR 14 R 15 , -NR 14 S(O) 2 R13 , -S(O) p R 13 , -S(O) 2 NR 14 R 15 , and -NR 14 S(O) 2 NR 14 R 15 and is substituted with 1, 2, 3, 4, 5, or 6 substituents selected from R 12 may, in each occurrence, independently represent hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 aryl, or 5-12 membered heteroaryl; R 12 Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl is optionally independently selected from halo, hydroxy, CN, NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, (O), -C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -OC(O)OR 13 , -C(O)NR10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 13 , -NR 10 C(O)OR 13 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 13 , -S(O) p R 13 , -S(O) 2 NR 10 R 11 , and -NR 10 S(O) 2 NR 10 R 11 and is substituted with 1, 2, 3, 4, 5, or 6 substituents selected from R 13 may, in each occurrence, independently represent hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; R 14 and R 15 is, in each occurrence, independently, hydrogen, hydroxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, or C 1-6 alkoxy, or each taken together with the N to which it is attached forms a 3- to 6-membered heterocycloalkyl; Provided herein are compounds, or pharma- ceutically acceptable forms thereof, wherein 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): [ka] During the ceremony, W 1 , W 2 , W 3 , and W 4 are each independently N or CR 4 or W 1 and W 2 But together, O, NR 4A , or S, or W 2 and W 3 But together, O, NR 4A , or S, Z 1 , Z 2 , Z 3 , and Z 4 are each independently N or CR 5 or Z 2 and Z 3 But together, O, NR 5A , or S, or Z 3 and Z 4 But together, O, NR 5A , or S, R 4A and R 5A are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 aryl, or 5-12 membered heteroaryl; R 4A and R 5A Each C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 aryl, or 5-12 membered heteroaryl, optionally independently selected from halo, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 the compound is substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from haloalkoxy, and (O); or a pharma- ceutically acceptable form thereof.

[0007] In certain embodiments, the compound of formula (I) is a compound of formula (III): [ka] During the ceremony, W 1 , W 2 , W 3 , and W 4 are each independently N or CR 4 or W 1 and W 2 But together, O, NR 4A , or S, or W 2 and W 3 But together, O, NR 4A , or S, Z 1 , Z 2 , Z 3 , and Z 4 are each independently N or CR 5 or Z 2 and Z 3 But together, O, NR 5A , or S, or Z 3 and Z 4 But together, O, NR5A , or S, R 4A and R 5A are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 aryl, or 5-12 membered heteroaryl; R 4A and R 5A Each C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 aryl, or 5-12 membered heteroaryl, optionally independently selected from halo, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 the compound being substituted with 1, 2, 3, 4, 5, or 6 substituents selected from haloalkoxy, and (O); or a pharma- ceutically acceptable form thereof.

[0008] In certain embodiments, the compound of formula (I) is a compound of formula (IV): [ka] During the ceremony, W 1 , W 2 , W 3 , and W 4 are each independently N or CR 4 or W 1 and W 2 But together, O, NR4A , or S, or W 2 and W 3 But together, O, NR 4A , or S, Z 1 , Z 2 , Z 3 , and Z 4 are each independently N or CR 5 or Z 2 and Z 3 But together, O, NR 5A , or S, or Z 3 and Z 4 But together, O, NR 5A , or S, R 4A and R 5A are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 aryl, or 5-12 membered heteroaryl; R 4A and R 5A Each C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 aryl, or 5-12 membered heteroaryl, optionally independently selected from halo, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 the compound being substituted with 1, 2, 3, 4, 5, or 6 substituents selected from haloalkoxy, and (O); or a pharma- ceutically acceptable form thereof.

[0009] In certain embodiments, the compound of formula (I) is a compound of formula (V): [ka] During the ceremony, W 1 , W 2 , W 3 , and W 4 are each independently N or CR 4 or W 1 and W 2 But together, O, NR 4A , or S, or W 2 and W 3 But together, O, NR 4A , or S, Z 1 , Z 2 , Z 3 , and Z 4 are each independently N or CR 5 or Z 2 and Z 3 But together, O, NR 5A , or S, or Z 3 and Z 4 But together, O, NR 5A , or S, R 4A and R 5A are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 aryl, or 5-12 membered heteroaryl; R 4A and R 5A Each C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 aryl, or 5-12 membered heteroaryl, optionally independently selected from halo, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 the compound being substituted with 1 to 6 substituents independently selected from haloalkoxy, and (O); or a pharma- ceutically acceptable form thereof.

[0010] In certain embodiments, the compound of formula (I) is a compound of formula (VI): [ka] During the ceremony, W 1 , W 2 , W 3 , and W 4 are each independently N or CR 4 or W 1 and W 2 But together, O, NR 4A , or S, or W 2 and W 3 But together, O, NR 4A , or S, Z 1 , Z 2 , Z 3 , and Z 4 are each independently N or CR 5 or Z 2 and Z 3 But together, O, NR 5A , or S, or Z 3 and Z 4 But together, O, NR5A , or S, R 4A and R 5A are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 aryl, or 5-12 membered heteroaryl; R 4A and R 5A Each C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 aryl, or 5-12 membered heteroaryl, optionally independently selected from halo, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 the compound being substituted with 1 to 6 substituents independently selected from haloalkoxy, and (O); or a pharma- ceutically acceptable form thereof.

[0011] In certain embodiments, provided herein are compounds of formula (I), (II), (III), or (IV), or compounds of formula (V) or (VI), where 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 a ZYW orientation, where Z refers to Z or a Z-containing ring, and W refers to W or a W-containing ring, as applicable in formula (I), (II), (III), or (IV), or formula (V) or (VI), and subformulas thereof. In certain embodiments, Y is C 1-6 Alkylene, with one or more -CH 2 - is optionally, independently, -O-, -C(O)-, -N(R 10 )-, -N(R 10 )C(O)-, -C(O)N(R 10 )-, -N(R 10 )C(O)N(R 11 )-, -S(O) p -, -N(R 10 )S(O) 2 -, -S(O) 2 N(R 10 )-, or -N(R 10 )S(O) 2 N(R 11 In certain embodiments, Y is replaced by -(CR 16 R 17 ) q -, -(CR 16 R 17 ) m O(CR 16 R 17 ) n -, -(CR 16 R 17 ) m C(O)(CR 16 R 17 ) n -, -(CR 16 R 17 ) m N(R 10 )(CR 16 R 17 ) n-, -(CR 16 R 17 ) m N(R 10 )C(O)(CR 16 R 17 ) n -, -(CR 16 R 17 ) m C(O)N(R 10 )(CR 16 R 17 ) n -, -(CR 16 R 17 ) m N(R 10 )C(O)N(R 11 )(CR 16 R 17 ) n -, -(CR 16 R 17 ) m S(O) p (CR 16 R 17 ) n -, -(CR 16 R 17 ) m N(R 10 )S(O) 2 (CR 16 R 17 ) n -, -(CR 16 R 17 ) m S(O) 2 N(R 10 )(CR 16 R 17 ) n - or -(CR 16 R 17 ) m N(R 10 )S(O) 2 N(R 11 )(CR 16 R 17 ) n - and During the ceremony, R 16 and R 17 each occurrence independently represents hydrogen, halo, hydroxy, CN, NO 2 , C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkoxy, C 1-6 heteroalkoxy, or 3- to 6-membered heterocycloalkoxy, or each of which is combined with the C to which it is attached to form C(O), C 3-6 forming a cycloalkyl or a 3- to 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; 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; Each q is independently an integer of 0, 1, 2, 3, 4, 5, or 6.

[0012] In certain embodiments, a compound of formula (I), (II), (III), or (IV), or a compound of formula (V) or (VI), wherein R 7 is imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, or pyrimidinyl, each of which is selected from halo, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , -NR10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 9 , -S(O) p R 9 , -S(O) 2 NR 10 R 11 , or -NR 10 S(O) 2 NR 10 R 11 Provided herein are compounds optionally substituted with 1 to 4 substituents independently selected from:

[0013] In certain embodiments, a compound of formula (I), (II), (III), or (IV), or formula (V) or (VI), wherein R 6 But, CN,R 9 , -OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -NR 10 R 11 , -NR 10 OR 9 , -NR 10 C(O)R 9 , or -NR 10 C(NR 10 )NR 10 R 11 Provided herein is a compound,

[0014] In certain embodiments, a compound of formula (I), (II), (III), or (IV), or formula (V) or (VI), wherein R 6 But, CN,R 9 , -OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -NR 10 R 11 , -NR 10 OR 9 , or -NR 10 C(O)R 9 Provided herein is a compound,

[0015] In certain embodiments, a compound of formula (I), (II), (III), or (IV), or formula (V) or (VI), wherein R 10 and R 11 together form a divalent radical, e.g., -(CH 2 ) x -, where x=2 to 5, -CH 2 CH 2 OCH 2 CH 2 -, or -CH 2 CH 2 NR 18 CH 2 CH 2 -, wherein R 18 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Provided herein are compounds wherein the heteroaryl is a heteroalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 12-membered heteroaryl.

[0016] In certain embodiments, a compound of formula (I), (II), (III), or (IV), or formula (V) or (VI), wherein R 6 is hydrogen, -CH 3 , Hydroxy, -OCH 3 , -OCD 3 , -NH 2 , -NHCH 3 , or -NH(OCH 3 In some embodiments, the compound is provided herein, wherein R 6 But -NH(CH 2 CH 2 )Cl, -NH(CH 2 CH 2 ) F, or N-linked morpholino.

[0017] In certain embodiments, provided herein is a compound of formula (I), (II), (III), or (IV), or formula (V) or (VI), wherein the compound has a MW of 1,000 g / mol or less. In certain embodiments, the compound has a MW of 900 g / mol or less, 800 g / mol or less, 700 g / mol or less, 600 g / mol or less, or 500 g / mol or less. In certain embodiments, the compound has a MW of 600 g / mol or less. In certain embodiments, the compound has a MW of 500 g / mol or less.

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

[0019] In certain embodiments, the compound of formula (I) is a compound of formula (Ia), or the compound of formula (I) is a compound of formula (Ib), [ka] or a pharma- ceutically acceptable form thereof.

[0020] In certain embodiments, the compound of formula (II) is a compound of formula (IIa), or the compound of formula (II) is a compound of formula (IIb), [ka] or a pharma- ceutically acceptable form thereof.

[0021] In certain embodiments, the compound of formula (II) is a compound of formula (II-1): [ka] or a pharma- ceutically acceptable form thereof.

[0022] In certain embodiments, the compound of formula (II-1) is a compound of formula (IIa-1), or the compound of formula (II-1) is a compound of formula (IIb-1), [ka] or a pharma- ceutically acceptable form thereof.

[0023] In certain embodiments, the compound of formula (II) is a compound of formula (II-2): [ka] or a pharma- ceutically 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), [ka] or a pharma- ceutically acceptable form thereof.

[0025] In certain embodiments, the compound of formula (III) is a compound of formula (IIIa), or the compound of formula (III) is a compound of formula (IIIb): [ka] or a pharma- ceutically acceptable form thereof.

[0026] In certain embodiments, the compound of formula (III) is a compound of formula (III-1): [ka] or a pharma- ceutically acceptable form thereof.

[0027] In certain embodiments, the compound of formula (III-1) is a compound of formula (IIIa-1), or the compound of formula (III-1) is a compound of formula (IIIb-1), [ka] or a pharma- ceutically acceptable form thereof.

[0028] In certain embodiments, the compound of formula (III) is a compound of formula (III-2): [ka] or a pharma- ceutically 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), [ka] or a pharma- ceutically acceptable form thereof.

[0030] In certain embodiments, the compound of formula (III) is a compound of formula (III-3): [ka] or a pharma- ceutically acceptable form thereof.

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

[0033] In certain embodiments, the compound of formula (IV) is a compound of formula (IV-1): [ka] or a pharma- ceutically 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), [ka] or a pharma- ceutically acceptable form thereof.

[0035] In certain embodiments, the compound of formula (IV) is a compound of formula (IV-2): [ka] or a pharma- ceutically 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), [ka] or a pharma- ceutically acceptable form thereof.

[0037] In some embodiments, the compound of formula (V) is a compound of formula (Va) or formula (Vb): [ka] or a pharma- ceutically acceptable form thereof.

[0038] In some embodiments, the compound of formula (V) is a compound of formula (V-1): [ka] or a pharma- ceutically acceptable form thereof.

[0039] In some embodiments, the compound of formula (V-1) is a compound of formula (Va-1) or formula (Vb-1): [ka] or a pharma- ceutically acceptable form thereof.

[0040] In some embodiments, the compound of formula (VI) is a compound of formula (VIa) or formula (VIb): [ka] or a pharma- ceutically acceptable form thereof.

[0041] In some embodiments, the compound of formula (VI) is a compound of formula (VI-1): [ka] or a pharma- ceutically acceptable form thereof.

[0042] In some embodiments, the compound of formula (VI-1) is a compound of formula (VIa-1) or formula (VIb-1): [ka] or a pharma- ceutically acceptable form thereof.

[0043] In certain embodiments, a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2) disclosed herein, e.g., a compound of formula (Ia), (Ib), (IIa), (IIa-1), (IIa-2), (IIb), (IIb-1), (IIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb), (IIIb-1), (IIIb-2), The compound of (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-1), (Va-1), (Vb-1), (VI), (VIa), (VIb), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, is a single enantiomer or a single diastereomer. In certain embodiments, the compounds disclosed herein are single enantiomers. In certain embodiments, the compounds disclosed herein are (R)-enantiomers. In certain embodiments, the compounds disclosed herein have an enantiomeric excess of the (R)-enantiomer of more than 10%, for example, an enantiomeric excess of the (R)-enantiomer 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. In certain embodiments, the compounds disclosed herein are (S)-enantiomers. In certain embodiments, the compounds disclosed herein have an enantiomeric excess of greater than 10% of the (S)-enantiomer, e.g., 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, a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), such as a compound of formula (Ia), (Ib), (IIa), (IIa-1), (IIa-2), (IIb), (IIb-1), (IIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb), (IIIb-1), (IIIb-2), (IVa), (IVa-1), (IVa-2), (IV Disclosed herein is a pharmaceutical composition comprising a compound of formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VI), (VIa), (VIb), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, and a pharma- ceutically acceptable carrier, excipient, or diluent.

[0045] In certain embodiments, a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2) disclosed herein, e.g., a compound of formula (Ia), (Ib), (IIa), (IIa-1), (IIa-2), (IIb), (IIb-1), (IIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb), (IIIb-1), (IIIb-2), A compound of formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VI), (VIa), (VIb), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, is a farnesyltransferase inhibitor. In certain embodiments, the compounds disclosed herein, or a pharma- ceutically acceptable form thereof, are selective farnesyltransferase inhibitors, as compared to inhibition of geranylgeranyltransferase type 1, e.g., geranylgeranyltransferase type 1.

[0046] In certain embodiments, a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2) disclosed herein, e.g., a compound of formula (Ia), (Ib), (IIa), (IIa-1), (IIa-2), (IIb), (IIb-1), (IIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb), (IIIb-1), (IIIb-2), (IVa), (IVa-1), (IVa-2), (I A compound of formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VI), (VIa), (VIb), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, is metabolically stable, e.g., metabolically stable to hepatic metabolism in a subject, e.g., metabolically stable to hepatic metabolism in a human.

[0047] In certain embodiments, a method for inhibiting farnesyl transferase is provided, comprising administering to the patient a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), e.g., a compound of formula (Ia), (Ib), (IIa), (IIa-1), (IIa-2), (IIb), (IIb-1), (IIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb), (IIIb-1), (IIIb-2), (IVa), (IVa-1), (IVa-2), (IVb), (IVb-1), or (IVb-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VI), (VIa), (VIb), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof. In certain embodiments, a method for inhibiting farnesyl transferase is provided, comprising administering to the patient a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), e.g., a compound of formula (Ia), (Ib), (IIa), (IIa-1), (IIa-2), (IIb), (IIb-1), (IIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb), (IIIb-1), (IIIb-2), (I

[0033] Provided herein is a method of administering a compound of Formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VI), (VIa), (VIb), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, with a compound of Formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VI), (VIa), (VIb), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, and a pharma- ceutically acceptable carrier, excipient, or diluent.In certain embodiments, the method of inhibiting farnesyltransferase inhibits the farnesylation of H-Ras protein.In certain embodiments, the H-Ras protein has mutation.In certain embodiments, the method of inhibiting farnesyltransferase inhibits the farnesylation of N-Ras protein.In certain embodiments, the N-Ras protein has mutation.

[0048] In certain embodiments, a method of treating a cancer dependent on a farnesylated protein in a subject includes administering to a subject a therapeutically effective amount of a compound of Formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), such as a compound of Formula (Ia), (Ib), (IIa), (IIa-1), (IIa-2), (IIb), (IIb-1), (IIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb), (IIIb-1), (IIIb-2), (IVa), (IIIb-2), (IIIb), (IIIb-1), (IIIb-2), (IVa), (IIIb-2), (IIIb), (IIIb-1), (IIIb-2), (IVa), (IIIb-2), (IIIb), (IIIb-2), (IIIb), (IIIb-1), (IIIb-2), (IIIb ... Provided herein is a method comprising administering a compound of Formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VI), (VIa), (VIb), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, to a subject suffering from a cancer that is dependent on a farnesylated protein.In certain embodiments, a method of treating a cancer dependent on a farnesylated protein in a subject includes administering to a subject a therapeutically effective amount of a compound of Formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), e.g., Formula (Ia), (Ib), (IIa), (IIa-1), (IIa-2), (IIb), (IIb-1), (IIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb), (IIIb-1), (IIIb-2), (IVa), (IVa-1), (IVa-2), (IV b), (IVb-1), or (IVb-2), or a pharma- ceutically acceptable form thereof, or a pharmaceutical composition comprising a compound of formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VI), (VIa), (VIb), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, and a pharma- ceutically acceptable carrier, excipient, or diluent, to a subject suffering from a 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 a farnesylated H-Ras protein. In certain embodiments, the cancer dependent on a farnesylated protein has an H-Ras protein mutation. In certain embodiments, the cancer dependent on farnesylated protein is head and neck cancer. In certain embodiments, the cancer dependent on farnesylated protein is 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 a cancer dependent on farnesylated protein in a subject, wherein the subject is a human.

[0049] In certain embodiments, a method of treating a cancer dependent on a farnesylated protein in a subject includes administering to a subject a therapeutically effective amount of a compound of Formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), such as a compound of Formula (Ia), (Ib), (IIa), (IIa-1), (IIa-2), (IIb), (IIb-1), (IIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb), (IIIb-1), (IIIb-2), (IVa), (IIIb-2), (IIIb), (IIIb-1), (IIIb-2), (IVa), (IIIb-2), (IIIb), (IIIb-1), (IIIb-2), (IVa), (IIIb-2), (IIIb), (IIIb-2), (IIIb), (IIIb-1), (IIIb-2), (IIIb ... Provided herein is a method comprising administering a compound of Formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VI), (VIa), (VIb), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, to a subject suffering from a cancer that is dependent on a farnesylated protein.In certain embodiments, a method of treating a cancer dependent on a farnesylated protein in a subject includes administering to a subject a therapeutically effective amount of a compound of Formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), e.g., Formula (Ia), (Ib), (IIa), (IIa-1), (IIa-2), (IIb), (IIb-1), (IIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb), (IIIb-1), (IIIb-2), (IVa), (IVa-1), (IVa-2), (IV b), (IVb-1), or (IVb-2), or a pharma- ceutically acceptable form thereof, or a pharmaceutical composition comprising a compound of formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VI), (VIa), (VIb), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, and a pharma- ceutically acceptable carrier, excipient, or diluent, to a subject suffering from a 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 a 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 farnesylated proteins is melanoma, acute myeloid leukemia (AML), thyroid cancer, lung adenocarcinoma, rectal cancer, endometrial cancer, or colorectal cancer. In certain embodiments, provided herein is a method of treating a cancer dependent on farnesylated proteins in a subject, wherein the subject is a human. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0050] 5. MODE FOR CARRYING OUT THEINVENTION In one embodiment, provided herein is a compound having the structure of any one of formulas (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof. In one embodiment, provided herein is a compound having the structure of any one of formulas (V) or (VI), or a pharma- ceutically acceptable form thereof. In one embodiment, provided herein is a compound having the structure of any one of formulas (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof. In one embodiment, provided herein is a compound having the structure of any one of formulas (Va), (Vb), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof. In one embodiment, provided herein is a compound having the structure of any one of formulas (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., formulas (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 pharma- ceutically acceptable form thereof. In one embodiment, provided herein is a compound having the structure of any one of formulas (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof.

[0051] In one embodiment, provided herein is a pharmaceutical composition comprising a compound having the structure of any one of formulas (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, and a pharma- ceutically acceptable carrier, diluent, or excipient. In one embodiment, provided herein is a pharmaceutical composition comprising a compound having the structure of any one of formulas (V) or (VI), or a pharma- ceutically acceptable form thereof, and a pharma- ceutically acceptable carrier, diluent, or excipient. In one embodiment, provided herein is a pharmaceutical composition comprising a compound having the structure of any one of formulas (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound having the structure of any one of formulas (Va), (Vb), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof, and a pharma- ceutically acceptable carrier, diluent, or excipient. In one embodiment, the compound has the structure of any one of formulas (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., (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). Provided herein is a pharmaceutical composition comprising a compound, or a pharma- ceutically acceptable form thereof, or a compound having the structure of any one of formulas (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, and a pharma- ceutically acceptable carrier, diluent, or excipient.

[0052] In another embodiment, a method of treating a cancer dependent on a farnesylated protein is provided, comprising administering to a subject a therapeutically effective amount of a compound having the structure of any one of formulas (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, or a pharmaceutical composition comprising same. In another embodiment, a method of treating a cancer dependent on a farnesylated protein is provided, comprising administering to a subject a therapeutically effective amount of a compound having the structure of formula (V), or (VI), or a pharma- ceutically acceptable form thereof, or a pharmaceutical composition comprising same. In another embodiment, a method of treating a cancer dependent on a farnesylated protein is provided comprising administering to a subject a therapeutically effective amount of a compound having the structure of any one of Formulas (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound having the structure of any one of Formulas (Va), (Vb), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof, or a pharmaceutical composition comprising same. In another embodiment, a method of treating cancer includes administering to a subject a therapeutically effective amount of a compound of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., (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 pharma- ceutically acceptable form thereof, or a compound having the structure of any one of formulas (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, or administering a pharmaceutical composition comprising same.Examples of cancers dependent on farnesylated proteins that can be treated according to the methods of treatment provided herein are described herein.

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

[0054] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this 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 may refer to one sample or to more than one sample.

[0056] As used herein, and unless otherwise indicated, the term "about" or "approximately" refers to 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 terms "administer," "administering," or "administration" refer to the act of delivering or causing to be delivered a compound or pharmaceutical composition to the body of a subject by methods described herein or otherwise known in the art. Administering a compound or pharmaceutical composition includes formulating the compound or pharmaceutical composition to be delivered to the body of a patient. Exemplary administration forms include oral dosage forms, e.g., tablets, capsules, syrups, suspensions; injectable dosage forms, e.g., 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 "administration amount" refers to an amount of a compound or pharmaceutical composition described herein sufficient to achieve the intended use, including but not limited to disease treatment, as set forth below. A therapeutically effective amount can vary depending on the intended use (in vitro or in vivo), or the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The specific dose will vary depending, for example, on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other agents, the timing of administration, the tissue to which it is administered, and the physical delivery system to which it is delivered. In certain embodiments, a therapeutically effective amount is sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with a disease or disorder. The term also refers to an amount of a compound sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, physician, 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 may be known as a "racemic" mixture. The terms "(±)" or "(rac)" are used to indicate a racemic mixture when appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry may be specified according to the Cahn-Ingold-Prelog RS system. When a compound is an enantiomer, the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds of unknown absolute configuration may be specified as (+) or (-) depending on the direction (dextrorotatory or levorotatory) that they rotate the plane of polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of the absolute stereochemistry at each asymmetric atom as (R)- or (S)-. The chemical compounds, pharmaceutical compositions, and methods of the present invention are intended to include all such possible isomers, including racemic mixtures, optically substantially pure forms, and intermediate mixtures. Optically active (R)- and (S)-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 a composition, e.g., a composition that contains 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., the S enantiomer, and 10% of the other enantiomer, e.g., the R enantiomer, is said to have an enantiomeric excess of 80%. ee=(90-10) / 100=80%. In some embodiments, the compounds described herein are mixtures of enantiomers of the compounds and comprise 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 S enantiomer. In other words, in some embodiments, the compounds described herein are mixtures of enantiomers of the compounds and comprise an enantiomeric excess of the S enantiomer over the R enantiomer. In other embodiments, the compounds described herein are mixtures of enantiomers of the compounds and comprise 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 R enantiomer. In other words, in some embodiments, the compounds described herein are mixtures of enantiomers of the compounds and comprise an enantiomeric excess of the R enantiomer over the S enantiomer.

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

[0062] In some embodiments, the compounds are racemic mixtures of (S)- and (R)-isomers. In other embodiments, mixtures of compounds are provided herein in which the individual compounds of the mixture are present predominantly in the (S)- or (R)-isomeric configuration. For example, in some embodiments, the compound mixtures have an (S)-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 (S)-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%, about 99.5% or greater. In some embodiments, the compound mixture has an (S)-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 greater than about 99.5%.

[0063] In other embodiments, the compound mixture has an (R)-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 (R)-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%, 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%, about 99% to about 99.5%, or greater than about 99.5%.

[0064] In other embodiments, the compound mixture contains identical chemical entities except for their stereochemical orientation, i.e., (S)- or (R)-isomers. For example, if a compound disclosed herein has a -CH(R)- unit and R is not hydrogen, then -CH(R)- will have the (S)- or (R)-stereochemical orientation for each of the identical chemical entities (i.e., (S)- or (R)-stereoisomers). In some embodiments, the mixture of identical chemical entities (i.e., a mixture of stereoisomers) is a racemic mixture of (S)- and (R)-isomers. In another embodiment, the mixture of identical chemical entities (i.e., a mixture of stereoisomers) contains predominantly (S)-isomers or predominantly (R)-isomers. For example, in some embodiments, the (S)-isomer in a mixture of identical chemical entities (i.e., a 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%, about 99.5% or more by weight, based on the total weight of the mixture of (S)- and (R)-isomers. In some embodiments, the (S)-isomer in a mixture of identical chemical entities (i.e., a mixture of stereoisomers) is from about 10% to about 99.5%, from about 20% to about 99.5%, from about 30% to about 99.5%, from about 40% to about 99.5%, from about 50% to about 99.5%, from about 55% to about 99.5%, from about 60% to about 99.5%, from about 65% to about 99.5%, The compound is present in an (S)-enantiomeric excess of 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%, about 99% to about 99.5%, or greater than about 99.5%.In other embodiments, the (R)-isomer in a mixture of identical chemical entities (i.e., a mixture of stereoisomers) is present in 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%, about 99.5% or more by weight, based on the total weight of the mixture of (S)- and (R)-isomers. In some embodiments, the (R)-isomer in a mixture of identical chemical entities (i.e., a mixture of stereoisomers) is from about 10% to about 99.5%, from about 20% to about 99.5%, from about 30% to about 99.5%, from about 40% to about 99.5%, from about 50% to about 99.5%, from about 55% to about 99.5%, from about 60% to about 99.5%, from about 65% to about 99.5%, The (R)-enantiomeric excess is present in an amount of 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%, about 99% to about 99.5%, or greater than about 99.5%. The enantiomers may be isolated from the racemic mixture by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and supercritical fluid chromatography (SFC), chiral salt formation and crystallization, or may be prepared by asymmetric synthesis. 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] Additionally, reference to a compound disclosed herein having one or more stereocenters (e.g., the R- or S-enantiomer) without designation of a particular chirality is understood to refer to the compound as a racemic mixture (or mixture of diastereomers), while inclusion of the R- or S-designation is understood to refer to an enantiomeric (or diastereomeric) form of the compound, e.g., an enantiomerically (or diastereomeric) enriched form of the compound, or an enantiomeric excess of the specified enantiomeric form of the compound, in accordance with the above discussion regarding enantiomerically enriched and enantiomeric excess. Representation of a compound with an R- or S-designation is understood to include enantiomerically enriched or enantiomeric excess of the specified enantiomer of the compound, and is not limited to only 100% of a single specified enantiomer of the compound.

[0066] In certain embodiments, the pharma- ceutically acceptable forms are isomers. "Isomers" are different compounds that have the same molecular formula. In some embodiments, isomers can be stereoisomers. In some embodiments, isomers can be tautomers. In some embodiments, isomers can be geometric isomers. "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 and stereoisomers. For example, "isomer" includes geometric double bond cis- and trans-isomers, also referred to as E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof, as included within the scope of this disclosure.

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

[0068] The term "isotopically enriched" refers to compounds identical to those listed herein, but which are isotopically enriched due to the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally 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 may be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 35 Cl, 36 Cl, and 37Cl, each of which is also within the scope of this description. For example, compounds having the structures of the present invention, except for the replacement or enrichment of hydrogen with deuterium or tritium at one or more atoms in the molecule, are within the scope of this disclosure. In one embodiment, isotopically labeled compounds are provided herein having one or more hydrogen atoms replaced or enriched with deuterium. In one embodiment, isotopically labeled compounds are provided herein having one or more hydrogen atoms replaced or enriched with tritium. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes, such as H, can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements). Isotopically labeled disclosed compounds can generally be prepared by replacing an isotopically labeled reagent with a non-isotopically labeled reagent. Isotopically enriched compounds of formula (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, or isotopically enriched compounds of formula (V) or (VI), or a pharma- ceutically acceptable form thereof, such as compounds of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), such as compounds of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as compounds of formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (III Compounds 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 pharma- ceutically acceptable form thereof, may generally be prepared using procedures well known to those skilled in the art by substituting the appropriate isotopically enriched reagent for the non-isotopically enriched reagent.

[0069] When a compound is enriched with deuterium, the ratio of deuterium to hydrogen on the deuterated atoms of the molecule substantially exceeds the naturally occurring deuterium to hydrogen ratio.

[0070]

[0033] The embodiments described herein include isotopically substituted forms of compounds of formula (I), (II), (III), or (IV), or pharma- ceutically acceptable forms thereof, e.g., compounds of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), e.g., compounds of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., compounds of 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 pharma- ceutically acceptable form thereof, or a compound 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 pharma- ceutically acceptable form thereof, wherein the isotopic substitutions have one or more deuterium atoms substituted for one or more hydrogen atoms on one or more atomic members of the compound, or a pharma- ceutically acceptable form thereof. The embodiments described herein include a compound of formula (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, e.g., a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), e.g., a compound of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., a compound of 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 pharma- ceutically acceptable form thereof, or a compound 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 pharma- ceutically acceptable form thereof, wherein the carbon atoms may have 1 to 3 hydrogen atoms optionally replaced with deuterium.

[0071] As used herein, a "pharmaceutically acceptable form" of a compound disclosed herein includes, but is not limited to, pharmaceutically acceptable salts, solvates, isomers, and isotopically substituted (i.e., isotopically labeled derivatives) of a compound of formula (I), (II), (III), or (IV), or a compound of formula (V) or (VI), as disclosed herein, such as, but not limited to, pharmaceutically acceptable salts, solvates, isomers, and isotopically substituted (i.e., isotopically labeled derivatives) of a compound of formula (I), (II), (III), or (IV), or a compound of formula (V) or (VI), as disclosed herein. In one embodiment, pharma- ceutically acceptable forms include, but are not limited to, pharma- ceutically acceptable salts, solvates, isomers, and isotopic substitutions (i.e., isotopically labeled derivatives) of a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a compound of formula (Va), (Vb), (VIa), or (VIb), as disclosed herein, such as, for example, pharma- ceutically acceptable salts, hydrates, stereoisomers, and isotopic substitutions of a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a compound of formula (Va), (Vb), (VIa), or (VIb), as disclosed herein.In one embodiment, pharma- ceutically acceptable forms include, but are not limited to, pharma- ceutically acceptable salts, solvates, isomers, and isotopically substituted (i.e., isotopically labeled) derivatives of a compound of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., 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 formula (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), as disclosed herein. In one embodiment, pharma- ceutically acceptable forms include, but are not limited to, pharma- ceutically acceptable salts, hydrates, stereoisomers, and isotopic substitutes of a compound of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., 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 formula (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), as disclosed herein. One of ordinary skill in the art will recognize that the free and salt forms of the compounds may be in the form of solvates.

[0072] In certain embodiments, the pharma- ceutically acceptable form is a pharma- ceutically acceptable salt. As used herein, the term "pharma- ceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharma- ceutically 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 pharma- ceutically acceptable form is a solvate (e.g., a hydrate). As used herein, the term "solvate" refers to a compound (e.g., a compound, isomer, or isotopic substitution free form, or a pharma- ceutically acceptable salt of any of the foregoing, e.g., a solvate in free form or in pharma- ceutically acceptable salt form) further comprising a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate may be a disclosed compound or a pharma- ceutically acceptable salt thereof. When 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 may include, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. It will be understood that the term "compound" as used herein encompasses compounds and solvates of compounds, as well as mixtures thereof.

[0074] In certain embodiments, the pharma- ceutically acceptable forms are tautomers. As used herein, the term "tautomer" is a type of isomer that includes two or more interconvertible compounds resulting from at least one formal shift of a hydrogen atom and at least one change in valence (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 proton transfer or proton shift tautomerization, which is considered a subset of acid-base chemistry. "Proton transfer tautomerization" or "proton shift tautomerization" involves the transfer of a proton with a change in bond order. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. When tautomerization is possible (e.g., in solution), a chemical equilibrium of the tautomers can be reached. Tautomerization (i.e., the reaction that provides the tautomeric pair) can be catalyzed by an acid or base, or can occur without the action or presence of an external agent. Exemplary tautomers include, but are not limited to, keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different)enamine tautomers.

[0075] In certain embodiments, the pharma- ceutically acceptable form of the compounds disclosed herein does not include the salt forms (i.e., not salts) of the compounds disclosed herein, which may be referred to as free base forms. For example, in one embodiment, the pharma-ceutically acceptable form of the compounds of formula (I), (II), (III), or (IV), or formula (V) or (VI), disclosed herein does not include salt forms, but includes pharma-ceutically acceptable solvates, isomers, and isotopically substituted derivatives (i.e., isotopically labeled derivatives) of the compounds of formula (I), (II), (III), or (IV), or formula (V) or (VI), disclosed herein, including, for example, the salt forms and hydrates, stereoisomers, and isotopically substituted derivatives of the compounds of formula (I), (II), (III), or (IV), or formula (V) or (VI), disclosed herein. In one embodiment, the pharma- ceutically acceptable forms do not include salt forms, but include pharma- ceutically acceptable solvates, isomers, and isotopic substitutions (i.e., isotopically labeled derivatives) of the compounds of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or the compounds of formula (Va), (Vb), (VIa), or (VIb), as disclosed herein, such as the salt forms of the compounds of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or the compounds of formula (Va), (Vb), (VIa), or (VIb), as disclosed herein, as well as hydrates, stereoisomers, and isotopic substitutions.In one embodiment, the pharma- ceutically acceptable form does not include salt forms, but rather pharma- ceutically acceptable solvates, isomers, and isotopic variants (e.g., 1,2,3,4-trimethylsilyl) of a compound of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., 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 formula (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), as disclosed herein. (i.e., isotopically labeled derivatives), and does not include, for example, salt forms, as well as hydrates, stereoisomers, and isotopic substitutions, of the compounds of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., 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 formula (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), as disclosed herein.

[0076] As used herein, the term "pharmaceutical acceptable carrier, excipient, or diluent" refers to a carrier, excipient, or diluent approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, and more specifically 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 pharmaceutical compositions administered intravenously. Saline and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. For example, the term pharmaceutical 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 pharma- ceutical 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 disclosed herein is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0077] Typical compositions and dosage forms include 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, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including, but not limited to, the way the dosage form is administered to a patient and the particular active ingredient in the dosage form. One or more compounds of formula (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, or a compound of formula (V) or (VI), or a pharma- ceutically acceptable form thereof, as described herein, such as a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), such as a compound of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as a compound of formula (IIa-1), (IIb-1), (II Further provided herein are anhydrous pharmaceutical compositions and dosage forms comprising a compound of Formula (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, or a compound of Formula (III-4), (IIIa-4), (IIIb-4), (IIIa-5), (IIIa-6), (IIIa-7), (IIIa-8), (IIIa-9), (IIIa-10), (IIIa-11), (IIIa-12), (IIIa-13), (IIIa-14), (IIIa-15), (IIIa-16), (IIIa-17), (IIIa-18), (IIIa-19), (IIIa-20), (IIIa-21), (IIIa-22), (IIIa-23), (IIIa-24), (IIIa-25), (IIIa-26), (IIIa-27), (IIIa-28), (IIIa-29), (IIIa-30), (IIIa-31), (IIIa-32), (IIIa-33), (IIIa-34), (IIIa-35), (IIIa-36), (IIIa-37), (IIIa-38), (IIIa-39), (IIIa-41), (IIIa-19), (IIIa-19), (IIIa-11), (IIIa-12), (IIIa-13), (IIIa-14), (IIIa-15), (IIIa-16), (IIIa-17), (IIIa-18), (IIIa-19), (IIIa-19), (IIIa-21), (IIIa-22), (IIIa-23), (IIIa-24), (IIIa-25), (IIIa-26), (IIIa-27), (IIIa-28), (IIIa-29), (IIIa-30), (IIIa-3 The compositions and single unit dosage forms can take the form of a solution or syrup (optionally with a flavoring), a suspension (optionally with a flavoring), an emulsion, a tablet (e.g., a chewable tablet), a pill, a capsule, a granule, a powder (optionally for reconstitution), a taste-masked formulation or a sustained release formulation, and the like.

[0078] Pharmaceutical compositions provided herein that are suitable for oral administration can be presented as discrete dosage forms, such as, but not limited to, tablets, caplets, capsules, granules, powders, and liquids. Such dosage forms contain a predetermined amount of active ingredient and can be prepared by pharmaceutical methods 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 a beneficial or desired result, including, but not limited to, a prophylactic benefit. For a prophylactic benefit, the compounds and pharmaceutical compositions disclosed herein can be administered to a patient at risk of developing a particular disease or reporting one or more of the physiological symptoms of a disease or disorder, even if a diagnosis of the disease or disorder cannot be 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 "isomers" includes any and all geometric and stereoisomers. For example, "isomers" includes geometric double bond cis- and trans-isomers, also referred to as E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof, as included within the scope of this disclosure.

[0082] In certain embodiments, the symbol [ka] indicates a bond which may be single or double as described herein.

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

[0084] Substituents around a carbon-carbon double bond may alternatively be designated "cis" or "trans", with "cis" referring to substituents on the same side of the double bond and "trans" referring to substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring may also be designated "cis" or "trans". The term "cis" refers to substituents on the same side of the plane of the ring and the term "trans" refers to substituents on opposite sides of the plane of the ring. Mixtures of compounds in which substituents are disposed both on 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., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals (including commercially relevant mammals such as cows, 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 may be a patient, e.g., a patient with a cancer that is dependent on a farnesylated protein.

[0086] A "therapeutic effect," as that term is used herein, encompasses therapeutic benefits and / or prophylactic benefits 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. These terms refer to an approach to obtain a beneficial or desired result, including, but not limited to, therapeutic benefit. Therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated. Also, therapeutic benefit is achieved by eradicating or ameliorating one or more of the physiological symptoms associated with the underlying disease, such that an improvement is observed in the patient, even though the patient may still be affected by the underlying disease or disorder. For example, when used in relation to a patient with a cancer that is dependent on a farnesylated protein, it refers to the action of reducing the severity of the cancer or slowing or delaying the progression of the cancer, including (a) inhibiting the growth of the cancer or preventing the onset of the cancer, and (b) causing the 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. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. In addition, 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 subrange within that range. For example, "C 1-6 Alkyl" is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0090] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and in some embodiments having 1 to 10 carbon atoms (e.g., C 1 -C 10 Linear or straight chain alkyl refers to an alkyl having no branching, e.g., methyl, ethyl, n-propyl. Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer within 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 this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl refers to any of the C 1 -C 6It is an alkyl group. In some embodiments, the alkyl group has 1-10, 1-6, 1-4, or 1-3 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl, and 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 substituents which include, independently, 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(R a ) 3 , -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(Ra )C(O)N(R a ) 2 , -N(R a )C(NR a )N(R a ) 2 , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a ) 2 (wherein t is 1 or 2), or -OP(=O)(OR a ) 2 And each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which can be optionally substituted as defined herein.

[0091] "Alkenyl" refers to an alkyl group containing at least one double bond and, in some embodiments, 2 to 10 carbon atoms (i.e., C 2 -C 10 "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, having a carbon atom number of 2 to 8 carbon atoms. Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer within the given range, for example, "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 2 to 8 carbon atoms. In other embodiments, an alkenyl comprises 2 to 5 carbon atoms (e.g., C 2 -C 5Alkenyl includes groups that are attached to the parent molecular structure by a single bond, such as, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like. The one or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ) etc. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkenyl groups, as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 Unless stated otherwise in the specification, alkenyl groups are optionally substituted by one or more substituents which may independently be 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(R a ) 3 , -OR a , -SR a , -OC(O)-R a, -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a ) 2 , -N(R a )C(NR a )N(R a ) 2 , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a ) 2 (wherein t is 1 or 2), or -OP(=O)(OR a ) 2 And each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which can be optionally substituted as defined herein.

[0092] "Alkynyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, and in some embodiments having from 2 to 10 carbon atoms (i.e., C 2 -C 10Alkynyl refers to a straight or branched hydrocarbon chain radical group having a carbon atom, such as aryl, aryl, aryls, arylalkyl ... 2 -C 5 Alkynyl is attached to the parent molecular structure by a single bond, and includes, for example, ethenyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise in the specification, alkynyl groups are optionally substituted with one or more substituents which include, independently, 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(R a ) 3 , -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)R a, -N(R a )C(O)N(R a ) 2 , -N(R a )C(NR a )N(R a ) 2 , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a ) 2 (wherein t is 1 or 2), or -OP(=O)(OR a ) 2 And each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which can be optionally substituted as defined herein.

[0093] The term "alkoxy" refers to the group -O-alkyl (in some embodiments containing from 1 to 10 carbon atoms) of straight, branched, cyclic configurations, 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 an alkoxy group containing from 1 to 6 carbons. In some embodiments, C 1 -C 4Alkoxy is an alkoxy group that includes both straight and branched chain alkyls of 1 to 4 carbon atoms. Unless stated otherwise in the specification, alkoxy groups are optionally substituted with one or more substituents that 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(R a ) 3 , -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a ) 2 , -N(R a )C(NR a )N(R a ) 2 , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a ) 2(wherein t is 1 or 2), or -OP(=O)(OR a ) 2 And each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which can be optionally substituted as defined herein. The terms "alkenoxy" and "alkynoxy" mirror the description above for "alkoxy", where the prefix "alk" is replaced with an "alken" or "alkyn", respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein.

[0094] "Aryl" refers to a ring system having 6 to 14 ring atoms (e.g., C) with at least one carbon ring having a conjugated pi-electron system that is aromatic (e.g., having 6, 10, or 14 pi-electrons shared in a cyclic arrangement) (e.g., phenyl, fluorenyl, and naphthyl). 6 -C 14 or C 6 -C 10In one embodiment, a divalent radical formed from a substituted benzene derivative and having a free valence at a ring atom is named as a substituted phenylene radical. In another embodiment, a divalent radical derived from a monovalent monocyclic or polycyclic hydrocarbon radical whose name ends in "-yl" by removing one hydrogen atom from the carbon atom having a free valence is named by adding "-yden" to the name of the corresponding monovalent radical, e.g., a naphthyl group having two points of attachment is referred to as naphthylidene. Whenever it appears herein, a numerical range such as "6-10 aryl" refers to each integer within the given range, e.g., "6-10 ring atoms" means that the aryl group can consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. This term includes monocyclic or fused ring polycyclic (i.e., rings sharing adjacent pairs of ring atoms) groups. Unless otherwise stated in the specification, an aryl moiety can be optionally substituted by one or more substituents which include, independently, 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(R a ) 3 , -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a ) 2 , -N(R a )C(NR a )N(R a ) 2 , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a ) 2 (wherein t is 1 or 2), or -OP(=O)(OR a ) 2 And each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein. In one embodiment, unless otherwise stated, "aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more cycloalkyl or heterocyclyl groups, the points of attachment to the parent molecular structure being on the aryl ring.

[0095] "Cycloalkyl", or alternatively "carbocyclyl", refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated or partially unsaturated. A partially unsaturated cycloalkyl group can be referred to as a "cycloalkenyl" if the carbocyclic ring contains at least one double bond, or as a "cycloalkynyl" if the carbocyclic ring contains at least one triple bond. Cycloalkyl groups are groups having 3 to 10 ring atoms, such as C 3 -C 10Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer within the given range, for example, "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 ring structures that do not contain heteroatoms. The term also includes monocyclic or fused ring polycyclic (i.e., rings that share adjacent pairs of ring atoms) groups. In some embodiments, it includes C 3 -C 8 In some embodiments, it is a cycloalkyl radical. 3 -C 5 Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) etc. 3-8 Examples of carbocyclyl groups include the above-mentioned C 3-6 Carbocyclyl groups, as well as cycloheptyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, etc. 3-10 Examples of carbocyclyl groups include the above-mentioned C 3-8Examples of cycloalkyl groups include carbocyclyl groups, as well as octahydro-1H-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, and the like. Unless stated otherwise in the specification, cycloalkyl groups are optionally substituted by one or more substituents which may independently be 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(R a ) 3 , -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a ) 2 , -N(R a )C(NR a )N(R a ) 2 , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or -OP(=O)(OR a ) 2 And each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein. In one embodiment, unless otherwise stated, "cycloalkyl" or "carbocyclyl" also includes ring systems in which a cycloalkyl or carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups whose points of attachment to the parent molecular structure are on the cycloalkyl or carbocyclyl ring.

[0096] The terms "halo", "halide", or alternatively, "halogen", refer to fluoro, chloro, bromo, or iodo.

[0097] The terms "haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures substituted with one or more halo groups or combinations thereof. In certain embodiments, all hydrogen atoms of an alkyl group are replaced with halo atoms. In certain embodiments, an alkyl group is replaced with 1, 2, 3, 4, 5, or 6 halo atoms. In certain embodiments, an alkyl group is replaced with 1, 2, or 3 halo atoms. In certain other embodiments, an alkyl group is replaced with 2 halo atoms. In certain embodiments, an alkyl group is replaced with 1 halo atom. In certain embodiments, a haloalkyl includes trifluoromethyl, fluoromethyl, perfluoroethyl, or chloromethyl. Certain other embodiments of a haloalkyl include chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, or 1,1,1-trifluoroethanyl. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, where halo is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. 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, having one or more skeletal chain atoms selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, and phosphorus, or combinations thereof. Numeric ranges referring to total chain length include, for example, C 1 -C 4 Heteroalkyl can be provided and in this example can be up to 4 atoms long. For example, -CH 2 OCH 2 CH 3 The radical is "C4 " Heteroalkyl groups are referred to as heteroalkyl, which includes the heteroatom center in describing the atomic chain length. The connection to the parent molecular structure can be through either the heteroatom or a carbon in the heteroalkyl chain. For example, an N-containing heteroalkyl moiety refers to a group in which at least one of the backbone atoms is a nitrogen atom. One or more heteroatom(s) in a heteroalkyl radical can be optionally oxidized. One or more nitrogen atoms, if present, can also be optionally quaternized. For example, heteroalkyl also includes a backbone chain substituted with one or more nitrogen oxide (-O-) substituents. Exemplary heteroalkyl groups include, but are not limited to, ethers, such as methoxyethanyl (-CH 2 CH 2 OCH 3 ), ethoxymethanil (-CH 2 OCH 2 CH 3 ), (methoxymethoxy)ethanyl (-CH 2 CH 2 -OCH 2 OCH 3 ), (methoxymethoxy)methanil (-CH 2 OCH 2 OCH 3 ), and (methoxyethoxy)metanil (-CH 2 OCH 2 CH 2 OCH 3 ), amines, e.g., -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 NHCH 2 CH 3 , -CH 2 N(CH 2 CH 3 )(CH 3The heteroalkyl, heteroalkenyl, and heteroalkynyl groups can each be optionally substituted with one or more substituents, which can be, independently, 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(R a ) 3 , -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a ) 2 , -N(R a )C(NR a )N(R a ) 2 , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a ) 2 (wherein t is 1 or 2), or -OP(=O)(ORa ) 2 And each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which can be optionally substituted as defined herein.

[0099] "Heteroaryl", or alternatively "heteroaromatic", refers to a radical of a 5-18 membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-18 membered heteroaryl"). A heteroaryl polycyclic ring system can contain one or more heteroatoms in one or more rings. Whenever it appears herein, a numerical range such as "5-18" refers to each integer within the given range, for example, "5-18 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, divalent radicals derived from monovalent monocyclic heteroaryl radicals whose names end in "-yl" by removing one hydrogen atom from the atom with the free valence are named by adding "-idene" to the name of the corresponding monovalent radical, e.g., a pyridyl group having two points of attachment is a pyridylidene.

[0100] 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 a heteroaryl radical can be optionally oxidized. One or more nitrogen atoms, if present, can also be optionally quaternized. Heteroaryl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as pyridinyl N-oxide. Heteroaryl is attached to the parent molecular structure through any atom of the ring(s).

[0101] "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, either on the aryl or on the heteroaryl ring, or in which a heteroaryl ring, as defined above, is fused to one or more cycloalkyl or heterocyclyl groups, either on the heteroaryl ring, or in which a heteroaryl ring, as defined above, is fused to one or more cycloalkyl or heterocyclyl groups, either on the heteroaryl ring. For polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment to the parent molecular structure can be on either the ring containing the heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur.

[0102] Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, and benzofuranyl. Zanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-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[1,2-c]pyridazinyl, dibenzyl benzofuranyl, 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-1H-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).

[0103] Unless otherwise stated in the specification, a heteroaryl moiety is optionally substituted by one or more substituents which include, independently, 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(R a ) 3 , -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)ORa , -N(R a )C(O)R a , -N(R a )C(O)N(R a ) 2 , -N(R a )C(NR a )N(R a ) 2 , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a ) 2 (wherein t is 1 or 2), or -OP(=O)(OR a ) 2 And each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which can be optionally substituted as defined herein.

[0104] "Heterocyclyl", "heterocycloalkyl", or "heterocarbocyclyl" each refer to any 3- to 18-membered non-aromatic radical monocyclic or polycyclic moiety containing at least one ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur. Heterocyclyl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and polycyclic ring systems can be fused, bridged, or spiro ring systems. Heterocyclyl polycyclic ring systems can contain one or more heteroatoms in one or more rings. Heterocyclyl groups can be saturated or partially unsaturated. Partially unsaturated heterocycloalkyl groups can be referred to as "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 within the given range, for example, "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, divalent radicals derived from monovalent monocyclic heterocyclyl radicals whose names end in "-yl" by removing one hydrogen atom from the atom having the free valence are named by adding "-ylidene" to the name of the corresponding monovalent radical, for example, a piperidyl group having two points of attachment is a piperidylidene.

[0105] N-containing heterocyclyl moieties refer to non-aromatic groups 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-oxide. Heterocyclyl is attached to the parent molecular structure through any atom of any of the ring(s).

[0106] "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, either on the carbocyclyl or on the heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, either .... In some embodiments, a heterocyclyl group is a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, 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 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, a 5-6 membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1 ring heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur.

[0107] Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyls containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyls containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl, and triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyro[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5, Examples of such aryl groups include, but are not limited to, 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-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, and 1,2,3,4-tetrahydro-1,6-naphthyridinyl.

[0108] Unless otherwise stated in the specification, heterocyclyl moieties are optionally substituted by one or more substituents which include, independently, 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(R a )3 , -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a ) 2 , -N(R a )C(NR a )N(R a ) 2 , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a ) 2 (wherein t is 1 or 2), or -OP(=O)(OR a ) 2 And each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which can be optionally substituted as defined herein.

[0109] "Hydroxyalkyl" refers to a group of the formula -R-(OH) z wherein R is alkyl as defined herein and z is 1 or 2. In one embodiment, hydroxyalkyl is -ROH. In one embodiment, hydroxyalkyl is -CH 2In one embodiment, hydroxyalkyl is -R(OH) 2 It is.

[0110] A "leaving group or atom" is any group or atom that, under reaction conditions, cleaves from a starting material, thus facilitating reaction at a particular site. Suitable non-limiting examples of such groups, unless otherwise specified, include halogen atoms, mesyloxy, o-nitrobenzenesulfonyloxy, p-nitrobenzenesulfonyloxy, trifluoromethyloxy, and tosyloxy groups.

[0111] "Protecting group" has the meaning conventionally associated with organic synthesis, for example, a group that selectively blocks one or more reactive sites in a multifunctional compound, so that a chemical reaction can be selectively carried out on an otherwise unprotected reactive site, and the group can be easily removed after the selective reaction is completed. Various protecting groups are disclosed, for example, in TH Greene and PG M Huts, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, New York (2006), which is incorporated herein by reference in its entirety. For example, a hydroxy-protected form is one in which at least one of the hydroxy groups present in a compound is protected with a hydroxy-protecting group. Similarly, amines and other reactive groups can be similarly protected.

[0112] As used herein, the term "substituted" or "substitution" means that at least one hydrogen present on a group atom (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that upon replacement of the hydrogen results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group may 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 substituents are either the same or different at each position. Unless otherwise stated in the specification, a substituent can be selected from the group consisting of 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(R a ) 3 , -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a ) 2 , -N(R a )C(NR a )N(R a ) 2 , -N(R a)S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a ) 2 (wherein t is 1 or 2), and -OP(=O)(OR a ) 2 and each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein. For example, a cycloalkyl substituent can have a halide substituted on one or more ring carbons, etc. 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.

[0113] 5.1 Compound In some embodiments, the compound is a compound of formula (I), (Ia), or (Ib) as disclosed herein, wherein A 1 is N or NR 1a In some embodiments, the compounds of formula (I), (Ia), or (Ib) disclosed herein, wherein A 2 CR 2b Or -C(=O)-. In some embodiments, A 1 and A 2 The bond between is a single bond, and A 1 is NR 1a And A 2 In some embodiments, A is -C(=O)-. 1 and A 2 The bond between is a double bond, and A 1 is N and A 2 CR 2bIt is.

[0114] In some embodiments, the compound is a compound of formula (I), (Ia), or (Ib) as disclosed herein, wherein: [ka] teeth, [ka] It is.

[0115] In some embodiments, the compound is a compound of formula (I), (Ia), or (Ib) as disclosed herein, wherein: [ka] teeth, [ka] For example, in some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] It is.

[0116] In some embodiments, the compound is a compound of formula (I), (Ia), or (Ib) as disclosed herein, wherein: [ka] teeth [ka] In some embodiments, [ka] teeth, [ka] It is.

[0117] In some embodiments, the compound is a compound of formula (I), (Ia), or (Ib) as disclosed herein, wherein Y and A are each independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 1 , A 2 , and A 3 In some embodiments, the fused ring system containing Y is linked to W in a 1,2-relationship. 1 , A 2 , and A 3 is linked to W in a 1,3-relationship. In some embodiments, W is 6-12 In some embodiments, W is 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 selected from the group consisting of 1, 2, 3, or 4 R 4 In some embodiments, W is substituted with two R 4 In some embodiments, W is substituted with one R 4In some embodiments, R 4 are independently hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkoxy, C 1-6 Heteroalkoxy, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, or -NR 14 R 15 and R 4 Each C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkoxy, C 1-6 Heteroalkoxy, C 3-6 The cycloalkoxy or 3- to 6-membered heterocycloalkoxy is optionally, independently, selected from halo, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, and (O). For example, in some embodiments, R 4 are independently hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, or C 1-6haloalkoxy, R 4 Each C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, or C 1-6 Haloalkoxy is optionally, independently, halo, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 In some embodiments, R is substituted with 1, 2, 3, 4, 5, or 6 substituents selected from haloalkoxy, and (O). 4 are independently hydrogen.

[0118] In some embodiments, the compound is a compound of formula (I), (Ia), or (Ib) as disclosed herein, wherein -(C(R 6 )(R 7 )(A 4 , A 5 , and A 6 In some embodiments, the -(C(R 6 )(R 7 )(A 4 , A 5 , and A 6 In some embodiments, Z is a fused ring system containing C 6-12 In some embodiments, Z is aryl. In some embodiments, Z is phenyl. In some embodiments, Z is 5-12 membered heteroaryl. In some embodiments, Z is pyridyl. In some embodiments, Z is selected from the group consisting of 1, 2, 3, or 4 R 5 In some embodiments, Z is substituted with two R 5 In some embodiments, Z is substituted with one R5 In some embodiments, R 5 is independently hydrogen, halo, or CN. In some embodiments, R 5 is independently hydrogen. In some embodiments, R 5 is independently an electron withdrawing group. In some embodiments, R 5 is independently chloro. In some embodiments, R 5 is independently CN.

[0119] In some embodiments, the compound is a compound of formula (I) or (II) disclosed herein, e.g., a compound of formula (Ia), (Ib), (IIa), or (IIb), or a pharma- ceutically acceptable form thereof, wherein R 1a are independently 9 For example, in some embodiments, R 1a is hydrogen, C 1-6 Alkyl, or C 3-6 Cycloalkyl, C 1-6 Alkyl or C 3-6 Cycloalkyl is optionally independently selected from halo, hydroxy, CN, NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, (O), -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)OR 12 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 12 , -NR 10C(O)OR 12 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 12 , -S(O) p R 12 , and -S(O) 2 NR 10 R 11 In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, R 1a is hydrogen, C 1-3 Alkyl, or C 3-4 Cycloalkyl, C 1-3 Alkyl or C 3-4 Cycloalkyl is optionally independently selected from halo, hydroxy, CN, NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, (O), -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)OR 12 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 12 , -NR 10 C(O)OR 12 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 12 , -S(O) pR 12 , and -S(O) 2 NR 10 R 11 For example, in some embodiments, R 1a is hydrogen, -CH 3 , -CD 3 , -CH 2 CH 3 , -CD 2 CD 3 , isopropyl, 2,3-dihydroxypropyl, or cyclopropyl. 1a -CH 3 , -CD 3 or cyclopropyl. In some embodiments, R 1a -CH 3 OR -CD 3 In some embodiments, R 1a is cyclopropyl. 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 pharma- ceutically acceptable form thereof.

[0120] In some embodiments, the compound is a compound of formula (I) or (III) disclosed herein, e.g., a compound of formula (Ia), (Ib), (IIIa), or (IIIb), or a pharma- ceutically acceptable form thereof, or a compound of formula (V), (Va), (Vb), (VI), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof, wherein R 2b are independently 9 , -OR 9 , Haro, CN, NO 2 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 9 , -S(O)p R 9 , or -S(O) 2 NR 10 R 11 In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, R 2b are independently 9 , -OR 9 , halo, CN, -C(O)NR 10 R 11 , or -NR 10 R 11 In some embodiments, R 2b is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, Hydroxy, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Heterocycloalkoxy, halo, CN, -C(O)NR 10 R 11 , or -NR 10 R 11 where R 10 and R 11 is, at each occurrence, independently, hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, or each of which, together with the N to which it is attached, combines to form a 3-6 membered heterocycloalkyl. In some embodiments, R 2b are independently hydrogen, C 1-3 Alkyl, C 3-4 Cycloalkyl, C 1-3 Alkoxy, C 3-4 Cycloalkoxy, C 3-4 Heterocycloalkoxy, halo, CN, -C(O)NR 10 R 11 , or -NR 10 R 11 where R 10 and R 11 is, at each occurrence, independently, hydrogen, C 1-3alkyl, 3-4 membered heterocycloalkyl, or each of which, together with the N to which it is attached, combines to form a 4-6 membered heterocycloalkyl. 10 is H. In some embodiments, R 11 is C, such as chloroethyl or fluoroethyl. 1-3 For example, in some embodiments, R 2b is hydrogen, -CH 3 , -CD 3 , -CH 2 CH 3 , -CD 2 CD 3 , isopropyl, cyclopropyl, -OCH 3 , -OCD 3 , -OCH 2 CH 3 , -OCD 2 CD 3 , isopropoxy, cyclopropoxy, 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or -C(O)NH 2 In some embodiments, R 2b is -NH 2 In some embodiments, R 2b is independently an electron-withdrawing group. Electron-withdrawing groups can include, for example, halo, cyano, nitro, carbonyl, carboxylic acid, carboxylic acid ester, amide, sulfonyl, sulfonyl ester, or sulfonylamide groups. For example, in some embodiments, R 2b are independently halo, CN, NO 2 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10 R 11 , -S(O) p R 9 , or -S(O) 2 NR 10 R 11 In some embodiments, R 2b is chloro, CN, -C(O)H, -C(O)CH 3, -C(O)OH, -C(O)OCH 3 , -C(O)NH 2 , -C(O)N(H)CH 3 , -C(O)N(CH 3 ) 2 , -S(O)CH 3 , -S(O) 2 CH 3 , -S(O) 2 NH 2 , -S(O) 2 N(H)CH 3 , or -S(O) 2 N(CH 3 ) 2 In some embodiments, the compound is a compound of formula (III-1) or (III-2), such as a compound of formula (IIIa-1), (IIIb-1), (IIIa-2), or (IIIb-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III-3), (IIIa-3), or (IIIb-3), or a pharma- ceutically acceptable form thereof.

[0121] In some embodiments, the compound is a compound of formula (I) disclosed herein, e.g., a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable form thereof, wherein A 1 CR 1b In some embodiments, the compound of formula (I), e.g., a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable form thereof, is disclosed herein, wherein A 2 is N or NR 2a In some embodiments, A 1 and A 2 The bond between is a double bond, and A 1 CR 1b And A 2 is N. In some embodiments, A 1 and A 2 The bond between is a single bond, and A 1 is -C(=O)-, and A 2 is NR 2aIn some embodiments, the compound of formula (I), (Ia), or (Ib), or a pharma- ceutically acceptable form thereof, is a compound of formula (IV), (IVa), or (IVb), or a pharma- ceutically 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (V), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VI), (VIa), (VIb), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof.

[0122] In some embodiments, the compound is a compound of formula (I) or (IV), e.g., a compound of formula (Ia), (Ib), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound of formula (V) or (VI), e.g., a compound of formula (Va), (Vb), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof, as disclosed herein, wherein R 1b are independently 9 , -OR 9 , Haro, CN, NO 2 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 9 , -S(O) p R 9 , or -S(O) 2 NR 10 R 11 For example, in some embodiments, R 1b are independently 9 , -OR 9 , Halo, CN, -C(O)R 9 , or -C(O)OR 9 In some embodiments, R 1b is R9 , -OR 9 , halo, or CN. For example, in some embodiments, R 1b is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkoxy, halo, or CN; C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, or C 3-6 Cycloalkoxy is optionally independently selected from halo, hydroxy, CN, NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, (O), -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)OR 12 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 12 , -NR 10 C(O)OR 12 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 12 , -S(O) p R 12 , and -S(O) 2 NR 10 R 11In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, R 1b is hydrogen, C 1-3 Alkyl, C 3-4 Cycloalkyl, C 1-3 Alkoxy, C 3-4 cycloalkoxy, halo, or CN; C 1-3 Alkyl, C 3-4 Cycloalkyl, C 1-3 Alkoxy, or C 3-4 Cycloalkoxy is optionally and independently selected from halo, hydroxy, CN, NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, (O), -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)OR 12 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 12 , -NR 10 C(O)OR 12 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 12 , -S(O) p R 12 , and -S(O) 2 NR 10 R 11For example, in some embodiments, R 1b is hydrogen, -CH 3 , -CD 3 , -CF 3 , -CH 2 CH 3 , -CD 2 CD 3 , isopropyl, 2,3-dihydroxypropyl, cyclopropyl, -OCH 3 , -OCD 3 , -OCF 3 , -OCH 2 CH 3 , -OCD 2 CD 3 , isopropoxy, 2,3-dihydroxypropoxy, or cyclopropoxy. In some embodiments, the compound is a compound of formula (IV-1) or (IV-2), e.g., a compound of formula (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof.

[0123] In some embodiments, the compound is a compound of formula (I) disclosed herein, e.g., a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable form thereof, wherein R 2a are independently 9 For example, in some embodiments, R 2a is hydrogen, C 1-6 Alkyl, or C 3-6 Cycloalkyl, C 1-6 Alkyl or C 3-6 Cycloalkyl is optionally independently selected from halo, hydroxy, CN, NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, (O), -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)OR 12 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 12 , -NR 10 C(O)OR 12 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 12 , -S(O) p R 12 , and -S(O) 2 NR 10 R 11 For example, in some embodiments, R 2a is hydrogen, C 1-3 Alkyl, or C 3-4 Cycloalkyl, C 1-3 Alkyl or C 3-4 Cycloalkyl is optionally independently selected from halo, hydroxy, CN, NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, (O), -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12, -OC(O)OR 12 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 12 , -NR 10 C(O)OR 12 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 12 , -S(O) p R 12 , and -S(O) 2 NR 10 R 11 In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, R 2a is hydrogen, -CH 3 , -CD 3 , -CH 2 CH 3 , -CD 2 CD 3 , isopropyl, 2,3-dihydroxypropyl, or cyclopropyl.

[0124] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV) disclosed herein, e.g., a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound of formula (VI), (VIa), or (VIb), wherein A 3 CR 3 In some embodiments, R 3 are independently 9 , -OR 9 , halo, or CN. In some embodiments, R 3is hydrogen. In some embodiments, the compound is a compound of formula (I), (II), (III), (IV), or (VI), e.g., a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), (IVb), (VIa), or (VIb), wherein A 3 is N. In some embodiments, the compound is a compound of Formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound of Formula (VIa) or (VIb), or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., (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 pharma- ceutically acceptable form thereof, or a compound of formula (III-3), (IIIa-3), (IIIb-3), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof.

[0125] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV) disclosed herein, e.g., a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound of formula (V), (Va), (Vb), (VI), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof, wherein A 4 CR 8 In some embodiments, A 4 is N. In some embodiments, A 4 is N and A 5 and A 6 In some embodiments, no more than one of A 5 CR8 In some embodiments, A 5 is N. In some embodiments, A 5 is N and A 4 and A 6 In some embodiments, no more than one of A 6 CR 8 In some embodiments, A 6 is N. In some embodiments, A 6 is N and A 4 and A 5 In some embodiments, no more than one of A 4 , A 5 , and A 6 are each independently 8 In some embodiments, R 8 are independently 9 , -OR 9 , halo, or CN. In some embodiments, R 8 is hydrogen. 5 and A 6 Together, O, NR 9 or S. For example, in the compound of formula (I), O, NR 9 , or A replaced with S 5 and A 6 Representative examples of the compounds are shown below as compounds of formula (I-A1), formula (I-A2), and formula (I-A3), respectively: [ka] or a pharma- ceutically acceptable form thereof.

[0126] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV) disclosed herein, e.g., a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound of formula (V) or (VI), e.g., formula (Va), (Vb), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof, wherein Y is a bond or 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. 1-6 Alkylene, with one or more -CH 2 - is optionally, independently, -O-, -C(O)-, -N(R 10 )-, -N(R 10 )C(O)-, -C(O)N(R 10 )-, -N(R 10 )C(O)N(R 11 )-, -S(O) p -, -N(R 10 )S(O) 2 -, -S(O) 2 N(R 10 )-, or -N(R 10 )S(O) 2 N(R 11)-. 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 a ZYW orientation, where Z refers to Z or a Z-containing ring, and W refers to W or a W-containing ring as applicable in formula (I), (II), (III), or (IV), and subformulas thereof. For example, a representative example of Y written in a ZYW orientation in a compound of formula (I) is -N(R 10 )C(O)—, shown below as a compound of formula (I-A4): [ka] On the other hand, Y is -C(O)N(R 10 )--, shown below as a compound of formula (I-A5). [ka] In some embodiments, the compound is a compound of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., (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 pharma- ceutically acceptable form thereof, or a compound of formula (III-3), (V-1), or (VI-1), e.g., formula (IIIa-3), (IIIb-3), (Va-1), (Vb-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, as disclosed herein.

[0127] In some embodiments, Y is -(CR 16 R 17 ) q -, -(CR 16 R 17 ) m O(CR 16 R 17 ) n -, -(CR 16 R17 ) m C(O)(CR 16 R 17 ) n -、-(CR 16 R 17 ) m N(R 10 )(CR 16 R 17 ) n -、-(CR 16 R 17 ) m N(R 10 )C(O)(CR 16 R 17 ) n -、-(CR 16 R 17 ) m C(O)N(R 10 )(CR 16 R 17 ) n -、-(CR 16 R 17 ) m N(R 10 )C(O)N(R 11 )(CR 16 R 17 ) n -、-(CR 16 R 17 ) m ONLY) p (CR 16 R 17 ) n -、-(CR 16 R 17 ) m N(R 10 )ONLY) 2 (CR 16 R 17 ) n -、-(CR 16 R 17 ) m ONLY) 2 N(R 10 )(CR 16 R 17 ) n -、または-(CR 16 R 17 ) m N(R 10 )ONLY) 2 N(R 11 )(CR16 R 17 ) n -, wherein R 16 and R 17 each occurrence independently represents hydrogen, halo, hydroxy, CN, NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkoxy, C 1-6 heteroalkoxy, or 3- to 6-membered heterocycloalkoxy, or each of which is combined with the C to which it is attached to form C(O), C 3-6In 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, n is 0, 1, or 2. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, or 1 ... In some embodiments, each m is independently an integer of 0, and each n is independently an integer of 1, 2, or 3, and 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, and 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, and 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, and 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, and 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.

[0128] In some embodiments, Y is -(CR 16 R 17 ) q -, -(CR 16 R 17 ) m O(CR 16 R 17 ) n -, -(CR 16 R 17 ) m C(O)(CR 16 R 17 ) n -, -(CR 16 R 17 ) m N(R 10 )(CR 16 R 17 ) n -, -(CR 16 R 17 ) m N(R 10 )C(O)(CR 16 R 17 ) n -, -(CR 16 R 17 ) m C(O)N(R 10 )(CR 16 R 17 ) n -, -(CR 16 R 17 ) m N(R 10 )S(O) 2 (CR 16 R 17 ) n - or -(CR 16 R 17 ) m S(O) 2 N(R 10 )(CR 16 R 17 ) n For example, in some embodiments, Y is -(CR 16 R 17 ) q -, -(CR 16 R 17 ) m O(CR 16 R 17 ) n-, -(CR 16 R 17 ) m N(R 10 )C(O)(CR 16 R 17 ) n - or -(CR 16 R 17 ) m C(O)N(R 10 )(CR 16 R 17 ) n For example, in some embodiments, Y is -(CR 16 R 17 ) q For example, in some embodiments, Y is -(CR 16 R 17 ) m O(CR 16 R 17 ) n For example, in some embodiments, Y is -(CR 16 R 17 ) m N(R 10 )C(O)(CR 16 R 17 ) n For example, in some embodiments, Y is -(CR 16 R 17 ) m C(O)N(R 10 )(CR 16 R 17 ) nIn 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 selected from the group consisting of R 16 and R 17 and each occurrence independently represents hydrogen, halo, hydroxy, CN, NO 2 , C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 Cycloalkyl, 3-5 membered heterocycloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkoxy, C 1-3 heteroalkoxy, or 3- to 5-membered heterocycloalkoxy, or each of which is combined with the C to which it is attached to form C(O), C 3-5 cycloalkyl, or 3-5 membered heterocycloalkyl. For example, in some embodiments, R 16 and R 17 each occurrence independently represents hydrogen, chloro, hydroxy, CN, NO 2 , methyl, ethyl, isopropyl, -CF 3 , -CH 2 CF 3 , -CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 )2 OCH 3 , cyclopropyl, 3-oxetanyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF 3 , -OCH 2 CF 3 , -O(CH 2 ) 2 OH, -O(CH 2 ) 2 OCH 3 or 3-oxetanylalkoxy, or each combined with the C to which it is attached to form C(O), cyclopropyl, or a 3- to 5-membered heterocycloalkyl. 16 and R 17 are each hydrogen. In some embodiments, Y is -(CH 2 )O-, -O(CH 2 )-, -(CH 2 ) 2 O-, -O(CH 2 ) 2 - or -(CH 2 ) 2 For example, in some embodiments, Y is -(CH 2 In some embodiments, Y is -O(CH 2 In some embodiments, Y is -(CH 2 ) 2 In some embodiments, Y is -O(CH 2 ) 2 In some embodiments, Y is -(CH 2 ) 2In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV) disclosed herein, such as a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound of formula (V), (Va), (Vb), (VI), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof. 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-1) or (III-2), e.g., a compound of formula (IIIa-1), (IIIb-1), (IIIa-2), or (IIIb-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III-3), (IIIa-3), or (IIIb-3), or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (IV-1) or (IV-2), e.g., a compound of formula (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof.

[0129] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV) disclosed herein, e.g., a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound of formula (V), (Va), (Vb), (VI), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof, wherein W 1 , W 2 , W 3 , and W 4are each independently N or CR 4 or W 1 and W 2 But together, O, NR 4A , or S, or W 2 and W 3 But together, O, NR 4A or S. In some embodiments, W 1 , W 2 , W 3 , and W 4 At least one of W is N. 1 , W 2 , and W 3 are each independently 4 and W 4 is N. In some embodiments, W 1 , W 2 , and W 4 are each independently 4 and W 3 is N. In some embodiments, W 1 , W 3 , and W 4 are each independently 4 And W 2 is N. In some embodiments, W 2 , W 3 , and W 4 are each independently 4 And W 1 is N. In some embodiments, W 1 , W 2 , W 3 , and W 4 are each independently 4 In some embodiments, W 2 and W 3 are each independently 4 And W 1 and W 4 are each independently N. In some embodiments, W 1 and W 2 are each independently 4 And W3 and W 4 are each independently N. In some embodiments, W 1 and W 4 are each independently 4 And W 2 and W 3 Together, O, NR 4A or S. In some embodiments, W 3 and W 4 are each independently 4 And W 1 and W 2 Together, O, NR 4A or S. In some embodiments, W 1 CR 4 And W 4 is N and W 2 and W 3 Together, O, NR 4A or S. In some embodiments, W 3 CR 4 And W 4 is N and W 1 and W 2 Together, O, NR 4A , or S.

[0130] In some embodiments, R 4 is, in each occurrence, independently, hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkoxy, C 1-6 Heteroalkoxy, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, or -NR 14 R 15 and R 4 Each C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkoxy, C 1-6 Heteroalkoxy, C 3-6 The cycloalkoxy or 3- to 6-membered heterocycloalkoxy is optionally, independently, selected from halo, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 For example, in some embodiments, R 4 are independently hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, or C 1-6 haloalkoxy, R 4 Each C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, or C 1-6 Haloalkoxy is optionally, independently, halo, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 In some embodiments, R is substituted with 1 to 6 substituents selected from haloalkoxy and (O). 4 are independently hydrogen, halo, C 1-3Alkyl, C 1-3 Haloalkyl, C 3-5 Cycloalkyl, C 1-3 Alkoxy, or C 1-3 In some embodiments, R 4 are independently hydrogen.

[0131] In some embodiments, R 4A are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 aryl, or 5-12 membered heteroaryl; R 4A Each C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 The aryl or 5-12 membered heteroaryl is optionally independently selected from halo, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 substituted with 1, 2, 3, 4, 5, or 6 substituents selected from haloalkoxy, and (O). For example, in some embodiments, R 4A are independently hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; R 4A Each C1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl are optionally, independently, selected from halo, hydroxy, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 Alkoxy, C 1-3 In some embodiments, R is substituted with 1 to 6 substituents independently selected from haloalkoxy, (O), and (O). 4A are independently hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, R 4A are independently hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, or cyclopropyl.

[0132] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV) disclosed herein, e.g., a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound of formula (V), (Va), (Vb), (VI), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof, wherein Z 1 , Z 2 , Z 3 , and Z 4 are each independently N or CR 5or Z 2 and Z 3 But together, O, NR 5A , or S, or Z 3 and Z 4 But together, O, NR 5A or S. In some embodiments, Z 1 , Z 2 , Z 3 , and Z 4 At least one of Z is N. 1 , Z 2 , and Z 3 are each independently 5 and Z 4 is N. In some embodiments, Z 1 , Z 2 , and Z 4 are each independently 5 and Z 3 is N. In some embodiments, Z 1 , Z 3 , and Z 4 are each independently 5 and Z 2 is N. In some embodiments, Z 2 , Z 3 , and Z 4 are each independently 5 and Z 1 is N. In some embodiments, Z 1 , Z 2 , Z 3 , and Z 4 are each independently 5 In some embodiments, Z 2 and Z 3 are each independently 5 and Z 1 and Z 4 are each independently N. In some embodiments, Z 3 and Z 4 are each independently 5 and Z 1 and Z 2are each independently N. In some embodiments, Z 1 and Z 4 are each independently 5 and Z 2 and Z 3 Together, O, NR 5A or S. In some embodiments, Z 1 and Z 2 are each independently 5 and Z 3 and Z 4 Together, O, NR 5A or S. In some embodiments, Z 1 is N and Z 2 and Z 3 Together, O, NR 5A , or S and Z 4 CR 5 In some embodiments, Z 1 is N and Z 2 CR 5 and Z 3 and Z 4 Together, O, NR 5A or S. In some embodiments, R 5 is, in each occurrence, independently, R 9 , -OR 9 , Haro, CN, NO 2 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10 R 11 , -S(O) p R 9 , or -S(O) 2 NR 10 R 11 In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, R 5 represents, independently at each occurrence, hydrogen, halo, CN, NO 2 , -C(O)(C 1-6 alkyl), -C(O)OH, -C(O)O(C1-6 alkyl), -C(O)NR 10 R 11 , -S(O) p (C 1-6 alkyl), or -S(O) 2 NR 10 R 11 In some embodiments, R 5 represents, independently at each occurrence, halo, CN, NO 2 , -C(O)CH 3 , -C(O)OH, -C(O)OCH 3 , -C(O)N(CH 3 ) 2 , -S(O) 2 CH 3 , or -S(O) 2 N(CH 3 ) 2 In some embodiments, R 5 is independently hydrogen, halo, or CN. In some embodiments, R 5 is independently hydrogen. In some embodiments, R 5 is independently an electron withdrawing group. In some embodiments, R 5 is independently chloro. In some embodiments, R 5 is independently CN.

[0133] In some embodiments, R 5A are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12 aryl, or 5-12 membered heteroaryl; R 5A Each C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-12The aryl or 5-12 membered heteroaryl is optionally independently selected from halo, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 substituted with 1 to 6 substituents independently selected from haloalkoxy, (O), and (O). For example, in some embodiments, R 5A are independently hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; R 5A Each C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl are optionally, independently, selected from halo, hydroxy, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 Alkoxy, C 1-3 In some embodiments, R is substituted with 1 to 6 substituents selected from haloalkoxy and (O). 5A are independently hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, R5A are independently hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, or cyclopropyl.

[0134] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV) disclosed herein, e.g., a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound of formula (V), (Va), (Vb), (VI), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof, wherein R 6 CN,R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 OR 9 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 9 , -NR 10 C(NR 10 )NR 10 R 11 , -S(O) p R 9 , -S(O) 2 NR 10 R 11 , or -NR 10 S(O) 2 NR 10 R 11In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, R 6 CN,R 9 , -OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -NR 10 R 11 , -NR 10 OR 9 , -NR 10 C(O)R 9 , or -NR 10 C(NR 10 )NR 10 R 11 In some embodiments, R 6 CN,R 9 , -OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -NR 10 R 11 , -NR 10 OR 9 , or -NR 10 C(O)R 9 In some embodiments, R 6 CN,R 9 , -OR 9 , -NR 10 R 11 , or -NR 10 OR 9 In some embodiments, R 6 CN,R 9 , -OR 9 , or -NR 10 R 11 For example, in some embodiments, R 9 are independently hydrogen or C 1-3 Alkyl, C 1-3 The alkyl is optionally substituted with CN. In some embodiments, R 10 and R 11 are each independently hydrogen, C 1-6 Alkyl, or C 1-6In some embodiments, R 10 and R 11 together form a divalent radical, e.g., -(CH 2 ) x -(in the formula, x=2~5), -CH 2 CH 2 OCH 2 CH 2 -, or -CH 2 CH 2 NR 18 CH 2 CH 2 -, wherein R 18 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 In some embodiments, R is a heteroalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 12-membered heteroaryl. 6 is hydroxy, -OCH 3 , CN, hydrogen, -CH 3 , -CH 2 CN, -NH 2 , -NHCH 3 , or -NH(OCH 3 In some embodiments, R 6 is hydrogen, -CH 3 , Hydroxy, -OCH 3 , -OCD 3 , -NH 2 , -NHCH 3 , or -NH(OCH 3 In some embodiments, R 6 is hydrogen, hydroxyl, -OCH 3 , -OCD 3 , -NH 2 , or -NHCH 3 In some embodiments, R 6 is -NH(CH 2 CH 2 )Cl, -NH(CH 2 CH 2 ) F, or N-linked morpholino. In some embodiments, R 6is hydroxy. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 NH 2 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-1) or (III-2), such as a compound of formula (IIIa-1), (IIIb-1), (IIIa-2), or (IIIb-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III-3), (IIIa-3), or (IIIb-3), or a pharma- ceutically 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof.

[0135] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV) disclosed herein, e.g., a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound of formula (V), (Va), (Vb), (VI), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof, wherein R 7 , Haro, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -C(O)NR 10 R11 , -NR 10 R 11 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 9 , -S(O) p R 9 , -S(O) 2 NR 10 R 11 , or -NR 10 S(O) 2 NR 10 R 11 For example, in some embodiments, R 7 , Haro, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 9 , -S(O) p R 9 , -S(O) 2 NR 10 R 11 , or -NR 10 S(O) 2 NR 10 R 11In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, R 7 , Haro, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 9 , -S(O) p R 9 , or -S(O) 2 NR 10 R 11 In some embodiments, R is an imidazolyl or triazolyl optionally substituted with 1 to 4 substituents independently selected from 7 , Haro, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 9 , -S(O) p R 9 , or -S(O) 2 NR 10 R 11 In some embodiments, R is a C-linked imidazolyl or a C-linked triazolyl, optionally substituted with 1 to 4 substituents independently selected from 7 , Haro, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9, -C(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 9 , -S(O) p R 9 , or -S(O) 2 NR 10 R 11 In some embodiments, R is an N-linked imidazolyl or an N-linked triazolyl, optionally substituted with 1 to 4 substituents independently selected from 7 is methyl-substituted imidazolyl or methyl-substituted triazolyl. In some embodiments, R 7 is C-methyl substituted imidazolyl or C-methyl substituted triazolyl. 7 is N-methyl substituted imidazolyl or N-methyl substituted triazolyl. In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-1) or (III-2), such as a compound of formula (IIIa-1), (IIIb-1), (IIIa-2), or (IIIb-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III-3), (IIIa-3), or (IIIb-3), or a pharma- ceutically 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof.

[0136] In some embodiments, the compounds disclosed herein are compounds of formula (I), e.g., compounds of formula (Ia) or (Ib), or pharma- ceutically acceptable forms thereof. In some embodiments, the pharma- ceutically acceptable forms of the compounds of formula (I), e.g., compounds of formula (Ia) or (Ib), do not include salt forms (i.e., are not salts), but include pharma- ceutically acceptable solvates, isomers, and isotopic substitutes (i.e., isotopically labeled derivatives) of the compounds of formula (I), e.g., compounds of formula (Ia) or (Ib), respectively.

[0137] In some embodiments, the compound of formula (I), (Ia), or (Ib), or a pharma- ceutically acceptable form thereof, is a compound of formula (II), (IIa), or (IIb), or a pharma- ceutically acceptable form thereof, respectively. In some embodiments, the compound is a compound of formula (II-1) or (II-2), or a pharma- ceutically acceptable form thereof, for example, a compound of formula (IIa-1), (IIb-1), (IIa-2), or (IIb-2), or a pharma- ceutically acceptable form thereof, respectively. In some embodiments, a pharma- ceutically acceptable form of a compound of Formula (II), (IIa), or (IIb), e.g., a compound of Formula (II-1) or (II-2), e.g., a compound of Formula (IIa-1), (IIb-1), (IIa-2), or (IIb-2), does not include salt forms (i.e., not salts), but includes pharma- ceutically acceptable solvates, isomers, and isotopic substitutes (i.e., isotopically labeled derivatives) of a compound of Formula (II), (IIa), or (IIb), e.g., a compound of Formula (II-1) or (II-2), e.g., a compound of Formula (IIa-1), (IIb-1), (IIa-2), or (IIb-2), respectively.

[0138] In some embodiments, the compound of formula (I), (Ia), or (Ib), or a pharma- ceutically acceptable form thereof, is a compound of formula (III), (IIIa), or (IIIb), or a pharma- ceutically acceptable form thereof, respectively. In some embodiments, the compound is a compound of formula (III-1) or (III-2), or a pharma- ceutically acceptable form thereof, for example, a compound of formula (IIIa-1), (IIIb-1), (IIIa-2), or (IIIb-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III-3), (IIIa-3), or (IIIb-3), or a pharma- ceutically acceptable form thereof, respectively. In some embodiments, a pharma- ceutically acceptable form of a compound of Formula (III), (IIIa), or (IIIb), e.g., a compound of Formula (III-1) or (III-2), e.g., a compound of Formula (IIIa-1), (IIIb-1), (IIIa-2), or (IIIb-2), or a compound of Formula (III-3), (IIIa-3), or (IIIb-3), does not include salt forms (i.e., is not a salt), but includes pharma- ceutically acceptable solvates, isomers, and isotopic substitutes (i.e., isotopically labeled derivatives) of a compound of Formula (III), (IIIa), or (IIIb), e.g., a compound of Formula (III-1) or (III-2), e.g., a compound of Formula (IIIa-1), (IIIb-1), (IIIa-2), or (IIIb-2), or a compound of Formula (III-3), (IIIa-3), or (IIIb-3), respectively.

[0139] In some embodiments, the compound of formula (I), (Ia), or (Ib), or a pharma- ceutically acceptable form thereof, is a compound of formula (IV), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, respectively. In some embodiments, the compound is a compound of formula (IV-1) or (IV-2), or a pharma- ceutically acceptable form thereof, for example, a compound of formula (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharma- ceutically acceptable form thereof, respectively. In some embodiments, a pharma- ceutically acceptable form of a compound of formula (IV), (IVa), or (IVb), e.g., a compound of formula (IV-1) or (IV-2), e.g., a compound of formula (IVa-1), (IVb-1), (IVa-2), or (IVb-2), does not include salt forms (i.e., not salts), but includes pharma- ceutically acceptable solvates, isomers, and isotopic substitutes (i.e., isotopically labeled derivatives) of a compound of formula (IV), (IVa), or (IVb), e.g., a compound of formula (IV-1) or (IV-2), e.g., a compound of formula (IVa-1), (IVb-1), (IVa-2), or (IVb-2), respectively.

[0140] In some embodiments, the compound of formula (I), (Ia), or (Ib), or a pharma- ceutically acceptable form thereof, is a compound of formula (V), (Va), or (Vb), or a pharma- ceutically acceptable form thereof, respectively. In some embodiments, the compound is a compound of formula (V-1), or a pharma- ceutically acceptable form thereof, such as a compound of formula (Va-1) or (Vb-1), or a pharma- ceutically acceptable form thereof, respectively. In some embodiments, a pharma- ceutically acceptable form of a compound of Formula (V), (Va), or (Vb), e.g., a compound of Formula (V-1), e.g., a compound of Formula (Va-1) or (Vb-1), does not include salt forms (i.e., not salts), but includes pharma- ceutically acceptable solvates, isomers, and isotopic substitutes (i.e., isotopically labeled derivatives) of a compound of Formula (V), (Va), or (Vb), e.g., a compound of Formula (V-1), e.g., a compound of Formula (Va-1) or (Vb-1).

[0141] In some embodiments, the compound of formula (I), (Ia), or (Ib), or a pharma- ceutically acceptable form thereof, is a compound of formula (VI), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof, respectively. In some embodiments, the compound is a compound of formula (VI-1), or a pharma- ceutically acceptable form thereof, such as a compound of formula (VIa-1) or (VIb-1), or a pharma- ceutically acceptable form thereof, respectively. In some embodiments, a pharma- ceutically acceptable form of a compound of Formula (VI), (VIa), or (VIb), e.g., a compound of Formula (VI-1), e.g., a compound of Formula (VIa-1) or (VIb-1), does not include salt forms (i.e., not salts), but includes pharma- ceutically acceptable solvates, isomers, and isotopic substitutes (i.e., isotopically labeled derivatives) of a compound of Formula (VI), (VIa), or (VIb), e.g., a compound of Formula (VI-1), e.g., a compound of Formula (VIa-1) or (VIb-1).

[0142] In some embodiments, the compound is a compound of formula (II-1), (II-2), (III-1), or (III-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III-3), or a pharma- ceutically acceptable form thereof, wherein: Y is -(CR 16 R 17 ) q -or- (CR 16 R 17 ) m O(CR 16 R 17 ) n - and R 1a But independently, R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10 R 11 , -S(O) p R 9 , or -S(O) 2 NR 10 R11 and R 2b and R 5 each occurrence independently represents R 9 , -OR 9 , Haro, CN, NO 2 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 9 , -S(O) p R 9 , -S(O) 2 NR 10 R 11 , or -NR 10 S(O) 2 NR 10 R 11 and R 6 But, CN,R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 OR 9 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R9 , -NR 10 C(NR 10 )NR 10 R 11 , -S(O) p R 9 , -S(O) 2 NR 10 R 11 , or -NR 10 S(O) 2 NR 10 R 11 and R 7 But, Hello, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 9 , -S(O) p R 9 , -S(O) 2 NR 10 R 11 , or -NR 10 S(O) 2 NR 10 R 11 is a 5-12 membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 9 may, in each occurrence, independently represent hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C3-5 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 9-membered heteroaryl, each C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-9 membered heteroaryl are optionally independently selected from halo, hydroxy, CN, NO 2 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, (O), -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)OR 12 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 12 , -NR 10 C(O)OR 12 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 12 , -S(O) p R 12 , -S(O) 2 NR 10 R 11 , and -NR 10 S(O) 2 NR 10 R 11 and is substituted with 1 to 6 substituents independently selected from R10 and R 11 is, in each occurrence, independently, hydrogen, hydroxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-4 alkoxy, phenyl, or 5- to 9-membered heteroaryl, or each of which, together with the N to which it is attached, combines to form a 3- to 6-membered heterocycloalkyl; R 10 and R 11 Each C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-4 alkoxy, phenyl, or 5-9 membered heteroaryl are each optionally independently selected from halo, hydroxy, CN, NO 2 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, (O), -C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -OC(O)OR 13 , -C(O)NR 14 R 15 , -NR 14 R 15 , -NR 14 C(O)R 13 , -NR 14 C(O)OR 13 , -NR14 C(O)NR 14 R 15 , -NR 14 S(O) 2 R 13 , -S(O) p R 13 , -S(O) 2 NR 14 R 15 , and -NR 14 S(O) 2 NR 14 R 15 and is substituted with 1 to 6 substituents independently selected from R 12 may, in each occurrence, independently represent hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-5 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-9 membered heteroaryl; R 12 Each C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-9 membered heteroaryl are optionally independently selected from halo, hydroxy, CN, NO 2 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, (O), -C(O)R 13 , -C(O)OR 13 , -OC(O)R13 , -OC(O)OR 13 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 13 , -NR 10 C(O)OR 13 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 13 , -S(O) p R 13 , -S(O) 2 NR 10 R 11 , and -NR 10 S(O) 2 NR 10 R 11 and is substituted with 1 to 6 substituents independently selected from R 13 may, in each occurrence, independently represent hydrogen, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 cycloalkyl, or 3- to 6-membered heterocycloalkyl; R 14 and R 15 is, in each occurrence, independently, hydrogen, hydroxy, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, or C 1-4 alkoxy, or each taken together with the N to which it is attached forms a 3- to 6-membered heterocycloalkyl; R 16 and R 17each occurrence independently represents hydrogen, halo, hydroxy, CN, NO 2 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, C 1-4 heteroalkoxy, or 3- to 6-membered heterocycloalkoxy, or each of which is combined with the C to which it is attached to form C(O), C 3-5 forming a cycloalkyl or a 3- to 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; 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; Each q is independently an integer of 0, 1, 2, 3, 4, 5, or 6.

[0143] In some embodiments, the compound is a compound of formula (II-1), (II-2), (III-1), or (III-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III), or a pharma- ceutically acceptable form thereof, wherein: Y is -(CH 2 ) q -or-(CH 2 ) m O(CH 2 ) n - and R 1a But independently, R 9 and R 2b But independently, R 9 , -OR 9, halo, CN, -C(O)NR 10 R 11 , or -NR 10 R 11 and R 5 But independently, R 9 , -OR 9 , Haro, CN, NO 2 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10 R 11 , -S(O) p R 9 , or -S(O) 2 NR 10 R 11 and R 6 But, CN,R 9 , -OR 9 , -NR 10 R 11 , or -NR 10 OR 9 and R 7 But, Hello, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 9 , -S(O) p R 9 , -S(O) 2 NR 10 R 11 , or -NR 10 S(O) 2 NR 10 R 11is a 5-12 membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 9 may, in each occurrence, independently represent hydrogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-5 cycloalkyl, or 3- to 6-membered heterocycloalkyl, each C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-5 Cycloalkyl or 3-6 membered heterocycloalkyl are optionally independently selected from halo, hydroxy, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, (O), and -NR 10 R 11 and is substituted with 1 to 5 substituents independently selected from R 10 and R 11 is, in each occurrence, independently, hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, or C 1-3 alkoxy, or each of which, together with the N to which it is attached, combines to form a 3- to 6-membered heterocycloalkyl; R 10 and R 11 Each C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, or C 1-3Alkoxy is each optionally independently selected from halo, hydroxy, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, (O), and -NR 14 R 15 is substituted with 1 to 5 substituents selected from R 14 and R 15 is, in each occurrence, independently, hydrogen, hydroxy, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, or C 1-3 alkoxy, or each taken together with the N to which it is attached forms a 3- to 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; 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; Each q is independently an integer of 0, 1, 2, 3, 4, or 5.

[0144] In some embodiments, the compound is a compound of formula (II-1), (II-2), (III-1), or (III-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III-3), or a pharma- ceutically acceptable form thereof, wherein: Y is -(CH 2 ) q -or-(CH 2 ) m O(CH 2 ) n - and R 1a But independently, R9 and R 2b But independently, R 9 , -OR 9 , halo, CN, -C(O)NR 10 R 11 , or -NR 10 R 11 and R 5 But independently, R 9 , -OR 9 , Haro, CN, NO 2 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10 R 11 , -S(O) p R 9 , or -S(O) 2 NR 10 R 11 and R 6 But R 9 , -OR 9 , -NR 10 R 11 , or -NR 10 OR 9 and R 7 But, Hello, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 9 , -NR 10 S(O) 2 R 9 , -S(O) p R 9 , or -S(O) 2 NR 10 R 11 is a 5-12 membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 9 may, in each occurrence, independently represent hydrogen, C 1-4Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-5 cycloalkyl, or 3- to 6-membered heterocycloalkyl, each C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-5 Cycloalkyl or 3-6 membered heterocycloalkyl are optionally independently selected from halo, hydroxy, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, (O), and -NR 10 R 11 and is substituted with 1 to 5 substituents independently selected from R 10 and R 11 is, in each occurrence, independently, hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, or C 1-3 alkoxy, or each of which, together with the N to which it is attached, combines to form a 3- to 6-membered heterocycloalkyl; R 10 and R 11 Each C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, or C 1-3 Alkoxy is each optionally independently selected from halo, hydroxy, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Heteroalkyl, C 3-5Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, (O), and -NR 14 R 15 and is substituted with 1 to 5 substituents independently selected from R 14 and R 15 is, in each occurrence, independently, hydrogen, hydroxy, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, or C 1-3 alkoxy, or each taken together with the N to which it is attached forms a 3- to 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; 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; Each q is independently an integer of 0, 1, 2, 3, 4, or 5.

[0145] In some embodiments, the compound is a compound of formula (II-1), (II-2), (III-1), or (III-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III-3), or a pharma- ceutically acceptable form thereof, wherein: Y is -(CH 2 ) q -or-(CH 2 ) m O(CH 2 ) n - and R 1a But independently, R 9 and R 2b But independently, R 9 , -OR 9 , halo, CN, -C(O)NR 10 R11 , or -NR 10 R 11 and R 5 But independently, R 9 , Haro, CN, NO 2 , -C(O)R 9 , -S(O) p R 9 , or -S(O) 2 NR 10 R 11 and R 6 But R 9 , -OR 9 , or -NR 10 R 11 and R 7 But, Hello, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 9 , -NR 10 S(O) 2 R 9 , -S(O) p R 9 , or -S(O) 2 NR 10 R 11 is a 5-9 membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 9 may, in each occurrence, independently represent hydrogen, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 cycloalkyl, or 3- to 6-membered heterocycloalkyl, each C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 Cycloalkyl or 3-6 membered heterocycloalkyl are optionally independently selected from halo, hydroxy, CN, C1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, or C 1-3 substituted with 1, 2, or 3 substituents independently selected from alkoxy; R 10 and R 11 is, in each occurrence, independently, hydrogen, C 1-3 Alkyl, C 1-3 heteroalkyl, or 3- to 6-membered heterocycloalkyl, or each of which, together with the N to which it is attached, combines to form a 3- to 6-membered heterocycloalkyl; R 10 and R 11 Each C 1-3 Alkyl, C 1-3 Heteroalkyl or 3- to 6-membered heterocycloalkyl are each optionally independently selected from halo, hydroxy, CN, C 1-3 Alkyl, C 1-3 substituted with 1, 2, or 3 substituents independently selected from heteroalkyl, or 3- to 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; 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; Each q is independently an integer of 0, 1, 2, 3, 4, or 5.

[0146] In some embodiments, the compound is a compound of formula (II-1), (II-2), (III-1), or (III-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III-3), or a pharma- ceutically acceptable form thereof, wherein: Y is -(CH 2 ) q -or-(CH 2 ) m O(CH 2 ) n - and R 1ais hydrogen, -CH 3 , -CD 3 , -CH 2 CH 3 , -CD 2 CD 3 , isopropyl, 2,3-dihydroxypropyl, or cyclopropyl; R 2b (a) Hydrogen, -CH 3 , -CD 3 , -CH 2 CH 3 , -CD 2 CD 3 , isopropyl, cyclopropyl, -OCH 3 , -OCD 3 , -OCH 2 CH 3 , -OCD 2 CD 3 , isopropoxy, cyclopropoxy, 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or -C(O)NH 2 or R 2b However, (b)-NH 2 and R 5 But hydrogen, halo, CN, NO 2 , -C(O)CH 3 , -S(O)CH 3 , -S(O) 2 CH 3 , -S(O) 2 NH 2 , -S(O) 2 NHCH 3 , or -S(O) 2 N(CH 3 ) 2 and R 6 is hydrogen, -CH 3 , Hydroxy, -OCH 3 , -OCD 3 , -NH 2 , -NHCH 3 , or -NH(OCH 3 ) or R 6 But -NH(CH 2 CH 2 )Cl, -NH(CH2 CH 2 ) F, or N-linked morpholino. R 7 But -CH 3 , -CD 3 , -CH 2 CH 3 , -CD 2 CD 3 , isopropyl, cyclopropyl, -OCH 3 , -OCD 3 , -OCH 2 CH 3 , -OCD 2 CD 3 imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, or pyrimidinyl optionally substituted with 1 to 4 substituents independently selected from , 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; the sum of m and n is 0, 1, 2, 3, or 4; Each q is independently an integer of 0, 1, 2, 3, 4, or 5.

[0147] In some embodiments, the compound is a compound of formula (II-1), (II-2), (III-1), or (III-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III-3), or a pharma- ceutically acceptable form thereof, wherein: Y is -(CH 2 ) 2 -, -O(CH 2 )-, -O(CH 2 ) 2 -, -(CH 2 )O-, or -(CH 2 ) 2 O-, R 1a is hydrogen, -CH 3 , -CD 3 , 2,3-dihydroxypropyl, or cyclopropyl; R 2b But (a)-OCH 3 , -OCD 3 , 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or -C(O)NH 2 or R 2b However, (b)-NH 2 and R 5 is hydrogen, chloro, bromo, or CN; R 6 Hydrogen, hydroxyl, -OCH 3 , -OCD 3 , -NH 2 , or -NHCH 3 and R 7 But -CH 3 , -CD 3 , -CH 2 CH 3 , -CD 2 CD 3 , isopropyl, cyclopropyl, -OCH 3 , -OCD 3 , -OCH 2 CH 3 , -OCD 2 CD 3 , isopropoxy, cyclopropoxy, chloro, and CN, and optionally substituted with 1 to 4 substituents independently selected from CN, ...

[0148] In some embodiments, the compound is a compound of formula (II-1), (II-2), (III-1), or (III-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III-3), or a pharma- ceutically acceptable form thereof, wherein: Y is -(CH 2 ) 2 -, -O(CH 2 )-, -O(CH 2 ) 2 -, -(CH 2 )O-, or -(CH2 ) 2 O-, R 1a is hydrogen, -CH 3 , -CD 3 , 2,3-dihydroxypropyl, or cyclopropyl; R 2b But (a)-OCH 3 , -OCD 3 , 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or -C(O)NH 2 or R 2b However, (b)-NH 2 and R 5 is hydrogen, chloro, bromo, or CN; R 6 Hydrogen, hydroxyl, -OCH 3 , -OCD 3 , -NH 2 , or -NHCH 3 and R 7 is a methyl-substituted imidazolyl or a methyl-substituted triazolyl.

[0149] In some embodiments, the compound is a compound of formula (II-1), (II-2), (III-1), or (III-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III-3), or a pharma- ceutically acceptable form thereof, wherein: Y is -(CH 2 ) 2 -, -O(CH 2 )-, -O(CH 2 ) 2 -, -(CH 2 )O-, or -(CH 2 ) 2 O-, R 1a is hydrogen, -CH 3 , -CD 3 , 2,3-dihydroxypropyl, or cyclopropyl; R 2b But (a)-OCH3 , -OCD 3 , 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or -C(O)NH 2 or R 2b However, (b)-NH 2 and R 5 is hydrogen, chloro, bromo, or CN; R 6 Hydrogen, hydroxyl, -OCH 3 , -OCD 3 , -NH 2 , or -NHCH 3 and R 7 but, [ka] It is.

[0150] In some embodiments, the compound is a compound of formula (II-1), (II-2), (III-1), or (III-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III-3), or a pharma- ceutically acceptable form thereof, wherein: Y is -(CH 2 ) 2 -, -O(CH 2 )-, -O(CH 2 ) 2 -, -(CH 2 )O-, or -(CH 2 ) 2 O-, R 1a is hydrogen, -CH 3 , -CD 3 , 2,3-dihydroxypropyl, or cyclopropyl; R 2b But (a)-OCH 3 , -OCD 3 , 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or -C(O)NH 2 or R 2bHowever, (b)-NH 2 and R 5 is hydrogen, chloro, bromo, or CN; R 6 Hydrogen, hydroxyl, -OCH 3 , -OCD 3 , -NH 2 , or -NHCH 3 and R 7 but, [ka] It is.

[0151] In some embodiments, the compound is a compound of formula (II-1), e.g., a compound of formula (II-1a) or formula (II-1b), or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (II-2), e.g., a compound of formula (II-2a) or formula (II-2b), or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-1), e.g., a compound of formula (III-1a) or formula (III-1b), or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-2), e.g., a compound of formula (III-2a) or formula (III-2b), or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-3), e.g., a compound of formula (III-3a) or formula (III-3b), or a pharma- ceutically acceptable form thereof. In some embodiments, a pharma- ceutically acceptable form of a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), e.g., a compound of Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), or a compound of Formula (III-3), (IIIa-3), or (IIIb-3), does not include a salt form (i.e., is not a salt), respectively. This includes pharma- ceutically acceptable solvates, isomers, and isotopically substituted (i.e., isotopically labeled) derivatives of a compound of formula (II-1), (II-2), (III-1), or (III-2), e.g., a compound of formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), or a compound of formula (III-3), (IIIa-3), or (IIIb-3).

[0152] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV) disclosed herein, such as a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound of formula (V), (Va), (Vb), (VI), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof, and the compound has a MW of 1,000 g / mol or less. In some embodiments, the compound has a MW of 900 g / mol or less, 800 g / mol or less, 700 g / mol or less, 600 g / mol or less, or 500 g / mol or less. In some embodiments, the compound has a MW of 600 g / mol or less. In some embodiments, the compound has a MW of 500 g / mol or less. In some embodiments, the compound is a compound of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., 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 pharma- ceutically acceptable form thereof, or a compound of formula (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, as disclosed herein.

[0153] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV) disclosed herein, such as a compound of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), or a pharma- ceutically acceptable form thereof, or a compound of formula (III-3), (V), (V-1), (VI), or (VI-1), or a pharma- ceutically acceptable form thereof, and the compound is a racemic or diastereomeric mixture, or a mixture of stereoisomers. In some embodiments, the compound is a single enantiomer or a single diastereomeric mixture. In some embodiments, the compound is a single enantiomer. For example, in some embodiments, the compound is a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb) disclosed herein, such as a compound of 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 pharma- ceutically acceptable form thereof, or a compound of formula (IIIa-1), (IIIb-1), (Va-1), (Vb-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer. In some embodiments, the compound has an enantiomeric excess of the (R)-enantiomer of more than 10%. In some embodiments, the compound has an enantiomeric excess of the (R)-enantiomer 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. In some embodiments, the compound has an enantiomeric excess of the (R)-enantiomer of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, the compound is the (S)-enantiomer.In some embodiments, the compound has an enantiomeric excess of the (S)-enantiomer of more than 10%. In some embodiments, the compound has an enantiomeric excess of the (S)-enantiomer 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. In some embodiments, the compound has an enantiomeric excess of the (S)-enantiomer of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%.

[0154] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV), or a compound of formula (V) or (VI), as disclosed herein, wherein the compound is racemic, and is selected from the group consisting of 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, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112 , 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or a compound of Formula (V) or (VI), as disclosed herein, and the compound is a single enantiomer.In some embodiments, the compound is 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, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 199 For example, in some embodiments, the compound comprises the (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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is 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 (S)-enantiomer, or a pharma- ceutically acceptable form thereof.For example, in some embodiments, the compound comprises the (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 pharma- ceutically acceptable form thereof.

[0155] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV), or a compound of formula (V) or (VI), as disclosed herein, and the compound is a racemate or a single enantiomer thereof, e.g., an (R)-enantiomer or an (S)-enantiomer thereof, and is selected from the group consisting of 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, 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, 109, 108, 1 , 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 6, 7, 8, 76, 77, 79, or 80, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (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 pharma- ceutically acceptable form thereof.

[0156] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV), or formula (V) or (VI), as disclosed herein, and 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compounds 9, 78, 89, 90, 91, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (S)-enantiomer of compound 21, 48, 58, 66, 70, 78, 89, 90, 91, or a pharma- ceutically acceptable form thereof.

[0157] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or a compound of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, e.g., an (R)-enantiomer or an (S)-enantiomer thereof, and is selected from the group consisting 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, 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, 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, 109, 104, 105, 106, 108, 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (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 pharma- ceutically acceptable form thereof.

[0158] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV), or formula (V) or (VI), as disclosed herein, and the compound is a racemate or a single enantiomer thereof, such as its (R)-enantiomer or (S)-enantiomer, selected from compounds 31, 32, 33, 34, 35, 38, 39, 49, 50, and 51, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 34, 35, 39, or 51, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (S)-enantiomer of compound 34, 35, 39, or 51, or a pharma- ceutically acceptable form thereof.

[0159] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV), or a compound of formula (V) or (VI), as disclosed herein, and the compound is a racemate or a single enantiomer thereof, e.g., an (R)-enantiomer or an (S)-enantiomer thereof, and is selected from the group consisting of Compounds 1, 2, 3, 5, 6, 10, 11, 12, 13, 14, 16, 17, 18, 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, 11 , 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer, or compound 6, 14, 18, 25, 28, 29, 36, 55, or 78, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (S)-enantiomer of compound 3, 6, 14, 18, 25, 28, 29, 36, 55, or 78, or a pharma- ceutically acceptable form thereof.

[0160] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or a compound of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, e.g., an (R)-enantiomer or an (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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (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 pharma- ceutically acceptable form thereof.

[0161] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or a compound of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as an (R)-enantiomer or an (S)-enantiomer thereof, and is selected from the group consisting of 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, 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, 109, 109, 102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 12 , 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 4, 14, 15, 25, 27, 28, 29, 30, 34, 35, 46, 47, 48, 51, 76, 77, or 80, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (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 pharma- ceutically acceptable form thereof.

[0162] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or a compound of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, e.g., an (R)-enantiomer or an (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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (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 pharma- ceutically acceptable form thereof.

[0163] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV), or a compound of formula (V) or (VI), as disclosed herein, and the compound is a racemate or a single enantiomer thereof, such as its (R)-enantiomer or its (S)-enantiomer, 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 4, 6, 7, 8, or 9, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (S)-enantiomer of compound 3, 4, 6, 7, 8, or 9, or a pharma- ceutically acceptable form thereof.

[0164] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV), or a compound of formula (V) or (VI), as disclosed herein, and the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 14, 15, 18, 19, 20, or 21, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (S)-enantiomer of compound 14, 15, 18, 19, 20, or 21, or a pharma- ceutically acceptable form thereof.

[0165] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV), or a compound of formula (V) or (VI), as disclosed herein, and 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 25, 27, 28, 29, 30, 34, 35, 36, 37, or 39, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (S)-enantiomer of compound 25, 27, 28, 29, 30, 34, 35, 36, 37, or 39, or a pharma- ceutically acceptable form thereof.

[0166] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV), or a compound of formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as an (R)-enantiomer or an (S)-enantiomer thereof, and is selected from the group consisting of compounds 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, 109, 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, In some embodiments, the compound is selected from 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (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 pharma- ceutically acceptable form thereof.

[0167] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or a compound of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, e.g., an (R)-enantiomer or an (S)-enantiomer thereof, and is selected from compounds 63, 64, 65, 94, 99, 104, 109, 114, 119, 124, 129, and 134, or a pharma- ceutically acceptable form thereof.

[0168] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV), or a compound of formula (V) or (VI), or a pharma- ceutically acceptable form thereof, disclosed herein, and is a farnesyltransferase inhibitor. For example, in some embodiments, the compounds disclosed herein have an IC for inhibition of farnesyltransferase of 300 nM or less, e.g., 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. 50 In some embodiments, the compounds disclosed herein are selective farnesyltransferase inhibitors. In some embodiments, the compounds disclosed herein have a higher potency (lower IC) relative to the inhibition level of geranylgeranyltransferase type 1. 50 For example, in some embodiments, the compounds disclosed herein have an IC value for inhibition of geranylgeranyltransferase type 1 of 100 nM or more, e.g., 300 nM or more, 500 nM or more, 750 nM or more, or 1,000 nM or more. 50 For example, in some embodiments, the compounds disclosed herein selectively inhibit farnesyltransferase relative to geranylgeranyltransferase type 1, and have an IC of at least 1:5. 50 (Farnesyltransferase) vs. IC 50 (Geranylgeranyltransferase type 1) IC 50 Ratios, e.g., 1:10, 1:25:1:50, 1:100, 1:300, 1:500, 1:750, or 1:1000, or higher IC 50 The ratio is:

[0169] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV), or a compound of formula (V) or (VI), as disclosed herein, and the compound is a racemate or a single enantiomer thereof, e.g., an (R)-enantiomer or an (S)-enantiomer thereof, and is selected from the group consisting of compounds 3, 4, 5, 6, 7, 8, 9, 11, 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 In some embodiments, the compound is selected from the group consisting of 5, 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 6, 7, 8, 9, 66, or 91, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (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 pharma- ceutically acceptable form thereof.

[0170] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV), or a compound of formula (V) or (VI), as disclosed herein, and the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 6, 7, 8, or 9, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (S)-enantiomer of compound 4, 18, 19, 20, 21, 27, 28, 36, 37, 39, 46, 55, 56, 57, or 58, or a pharma- ceutically acceptable form thereof.

[0171] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV), or formula (V) or (VI), as disclosed herein, and the compound is a racemate or a single enantiomer thereof, such as an (R)-enantiomer or an (S)-enantiomer thereof, selected from compounds 4, 6, 7, 8, 18, 27, 34, 37, 46, 47, 48, 55, 57, and 58, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 6, 7, or 8, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (S)-enantiomer of compound 4, 18, 27, 34, 37, 46, 47, 48, 55, 57, or 58, or a pharma- ceutically acceptable form thereof.

[0172] In some embodiments, the compound is a compound of formula (I), (II), (III), or (IV), or formula (V) or (VI), as disclosed herein, and the compound is a racemate or a single enantiomer thereof, such as its (R)-enantiomer or its (S)-enantiomer, selected from compounds 4, 6, 7, 8, 18, 27, 37, 46, 55, 57, and 58, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 6, 7, or 8, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is the (S)-enantiomer of compound 4, 18, 27, 37, 46, 55, 57, or 58, or a pharma- ceutically acceptable form thereof.

[0173] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or a compound 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 the following: 3-Hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1,2 2 -Dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (001), 3-Hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (002), 4 4 -Chloro-3-hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (003), 3-Amino-4 4 -Chloro-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (004), 3-Hydroxy-2 2 -Methoxy-3-(1-methyl-1H-imidazol-5-yl)-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile (005), 3-Hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile (006), 3-Amino-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1,2 2 -Dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile (007), 3-Amino-2 1 -(methyl-d 3 )-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-2 1 ,2 2 -Dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile (008), 3-Amino-3-(1-methyl-1H-imidazol-5-yl)-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile (009), 2 2 -Methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol (010), 3-Hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (011), 4 4 -Chloro-2 2 -Methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol (012), 4 4 -Chloro-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (013), 4 4-Chloro-3-hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (014), 3-Amino-4 4 -Chloro-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (015), 3-Hydroxy-2 2 -Methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile (016), 3-Hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile (017), 3-Hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile (018), 3-Amino-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44 -carbonitrile (019), 3-Amino-2 1 -(methyl-d 3 )-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -Carbonitrile (020), 3-Amino-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile (021), 3-Hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On (022), 3-Hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On (023), 4 4 -Chloro-2 2 -Methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-3-ol (024), 4 4 -Chloro-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On (025), 4 4-Chloro-3-hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On (026), 3-Amino-4 4 -Chloro-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On (027), 4 4 -Chloro-3-hydroxy-2 1 -(methyl-d 3 )-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On (028), 4 4 -Chloro-2 1 -Cyclopropyl-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On (029), 3-Amino-4 4 -Chloro-2 1 -Cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On (030), 4 4 -Chloro-3-hydroxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 1 ,22 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On (031), 4 4 -Chloro-3-hydroxy-2 1 -(methyl-d 3 )-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On (032), 4 4 -Chloro-3-(methoxy-d 3 )-21-(methyl-d 3 )-3-(4-methyl-4H-1,2,4-triazol-3-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On (033), 3-Amino-4 4 -Chloro-2 1 -(methyl-d 3 )-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On (034), 3-Amino-4 4 -Chloro-2 1 -Cyclopropyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On (035), 3-Hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2-Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-4 4 -Carbonitrile (036), 3-Amino-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-4 4 -Carbonitrile (037), 3-Hydroxy-2 1 -Methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-4 4 -Carbonitrile (038), 3-Amino-21-methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-4 4 -Carbonitrile (039), 2 2 -Methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol (040), 3-Hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (041), 3-Hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2-Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (042), 4 4 -Chloro-2 2 -Methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol (043), 4 4 -Chloro-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (044), 4 4 -Chloro-3-hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (045), 3-Amino-4 4 -Chloro-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (046), 3-Amino-4 4 -Chloro-2 1 -(methyl-d 3 )-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (047), 3-Amino-4 4-Chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -Carbonitrile (048), 4 4 -Chloro-2 2 -Methoxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol (049), 4 4 -Chloro-2 1 -Methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-3-(methylamino)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (051), 3-Amino-4 4 -Chloro-2 1 -Methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (051), 4 4 -Bromo-2 2 -Methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol (052), 3-Hydroxy-2 2 -Methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -Carbonitrile (053), 3-Hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2-Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -Carbonitrile (054), 3-Hydroxy-21-(methyl-d 3 )-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -Carbonitrile (055), 3-Amino-2 1 -(methyl-d 3 )-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -Carbonitrile (056), 3-Amino-21-cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -Carbonitrile (057), 3-Amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile (058), 4 6 -Chloro-2 2 -Methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-4(3,5)-pyridin-1(1,3)-benzenacyclohexaphan-3-ol (059), 3-Hydroxy-2 2-Methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-4(3,5)-pyridina-1(1,3)-benzenacyclohexaphane-4 6 -Carbonitrile (060), 3-Hydroxy-2 1 -(methyl-d 3 )-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-4(3,5)-pyridina-1(1,3)-benzenacyclohexaphane-4 6 -Carbonitrile (061), 3-Amino-2 1 -(methyl-d 3 )-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-4(3,5)-pyridina-1(1,3)-benzenacyclohexaphane-4 6 -Carbonitrile (062), 3-Hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-7-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On (063), 4 4 -Chloro-2 2 -Methoxy-3-(1-methyl-1H-imidazol-5-yl)-7-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-3-ol (064), 4 4 -Chloro-3-hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-7-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2-On (065), 3-Amino-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Morpholino-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -Carbonitrile (066), 3-Amino-3-(1-methyl-1H-imidazol-5-yl)-2 2 -(Piperazin-1-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -Carbonitrile (067), 3-Amino-3-(1-methyl-1H-imidazol-5-yl)-2 2 -(Oxetan-3-ylamino)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -Carbonitrile (068), 3-Amino-2 1 -(2,3-dihydroxypropyl)-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -Carbonitrile (069), 3-Amino-3-(1-(methyl-d 3 )-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile (070), 4 4 -Bromo-2 2 -Chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol (071), 3-Hydroxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22 ,4 4 -dicarbonitrile (072), 4 4 -Cyano-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -Carboxamide (073), 4 4 -Bromo-2 2 -Chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-amine (074), 4 4 -Bromo-3-(1-methyl-1H-imidazol-5-yl)-2 2 -(oxetan-3-yloxy)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-amine (075), 4 4 -Chloro-2 1 -(methyl-d 3 )-3-(5-methyl-1H-imidazol-1-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (076), and 4 4 -Chloro-2 1 -(methyl-d 3 )-3-(4-methyl-1H-imidazol-1-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On (077), or a pharma- ceutically acceptable form thereof.

[0174] In some embodiments, the compound is selected from: (R)-3-Hydroxy-2 1-Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile ((R)-006), (R)-3-amino-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile ((R)-007), (R)-3-amino-2 1 -(methyl-d 3 )-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-2 1 ,2 2 -Dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile ((R)-008), (R)-3-Amino-3-(1-methyl-1H-imidazol-5-yl)-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile ((R)-009), and (R)-4 4 -Chloro-2 1 -(methyl-d 3 )-3-(4-methyl-1H-imidazol-1-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On ((R)-077), or a pharma- ceutically acceptable form thereof.

[0175] In some embodiments, the compound is selected from: (S)-4 4-Chloro-3-hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On ((S)-003), (S)-3-amino-4 4 -Chloro-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On ((S)-004), (S)-4 4 -Chloro-3-hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On ((S)-014), (S)-3-amino-4 4 -Chloro-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On ((S)-015), (S)-3-Hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile ((S)-018), (S)-3-amino-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2-Oxo-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile ((S)-019), (S)-3-amino-2 1 -(methyl-d 3 )-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile ((S)-020), (S)-3-Amino-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile ((S)-021), (S)-4 4 -Chloro-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On ((S)-025), (S)-3-amino-4 4 -Chloro-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On ((S)-027), (S)-4 4 -Chloro-3-hydroxy-2 1 -(methyl-d 3 )-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2-Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On ((S)-028), (S)-4 4 -Chloro-2 1 -Cyclopropyl-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On ((S)-029), (S)-3-amino-4 4 -Chloro-2 1 -Cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On ((S)-030), (S)-3-amino-4 4 -Chloro-2 1 -(methyl-d 3 )-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On ((S)-034), (S)-3-amino-4 4 -Chloro-2 1 -Cyclopropyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-2 2 -On ((S)-035), (S)-3-Hydroxy-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2-Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-4 4 -carbonitrile ((S)-036), (S)-3-amino-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-4 4 -carbonitrile ((S)-037), (S)-3-amino-21-methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-4 4 -carbonitrile ((S)-039), (S)-3-amino-4 4 -Chloro-2 1 -Methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On ((S)-046), (S)-3-amino-4 4 -Chloro-2 1 -(methyl-d 3 )-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On ((S)-047), (S)-3-amino-4 4 -Chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2-carbonitrile ((S)-048), (S)-3-amino-4 4 -Chloro-2 1 -Methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On ((S)-051), (S)-3-Hydroxy-21-(methyl-d 3 )-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile ((S)-051), (S)-3-amino-2 1 -(methyl-d 3 )-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile ((S)-056), (S)-3-amino-21-cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile ((S)-057), (S)-3-Amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile ((S)-058), (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Morpholino-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile ((S)-066), (S)-3-amino-2 1 -(2,3-dihydroxypropyl)-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile ((S)-069), and (S)-3-amino-3-(1-methyl-d 3 )-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile ((S)-070), or a pharma- ceutically acceptable form thereof.

[0176] In some embodiments, the compound is selected from: (R)-3-Hydroxy-3-(1-methyl-d 3 )-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile ((R)-078), (S)-3-Hydroxy-3-(1-(methyl-d 3 )-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile ((S)-078), (R)-4 4 -Chloro-21-(methyl-d 3)-3-(5-methyl-1H-1,2,4-triazol-1-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On ((R)-079), (S)-4 4 -Chloro-2 1 -(methyl-d 3 )-3-(5-methyl-1H-1,2,4-triazol-1-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On ((S)-079), (R)-4 4 -Chloro-2 1 -(methyl-d 3 )-3-(3-methyl-1H-1,2,4-triazol-1-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On ((R)-080), (S)-4 4 -Chloro-2 1 -(methyl-d 3 )-3-(3-methyl-1H-1,2,4-triazol-1-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 -On ((S)-080), 4 4 -Bromo-2 2 -Chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinazolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol (081), 4 4 -Bromo-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinazolina-1,4(1,3)-dibenzenacyclohexaphane-2 2,3-diamine (082), 4 4 -Bromo-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol (083), 4 4 -Bromo-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol (084), 3-Hydroxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile (085), 3-Amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -Carbonitrile (086), (R)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile ((R)-086), (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile ((S)-086), 4 4 -Bromo-2 7 -Methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(5,3)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol (087), 3-Hydroxy-2 7 -Methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(5,3)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -Carbonitrile (088), (R)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-22 -(Oxetan-3-yloxy)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -Carbonitrile ((R)-089), (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-2 2 -(Oxetan-3-yloxy)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -Carbonitrile ((S)-089), (S)-3-(4-methyl-1H-imidazol-1-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile ((S)-090), (R)-3-(4-methyl-1H-imidazol-1-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile ((R)-090), (S)-3-(5-methyl-1H-imidazol-1-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile ((S)-091), (R)-3-(5-methyl-1H-imidazol-1-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile ((R)-091), [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable form thereof.

[0177] In some embodiments, the compound is selected from: [ka] [ka] [ka] [ka] and stereoisomers thereof, and pharma- ceutically acceptable forms thereof.

[0178] 5.2 Pharmaceutical Compositions In some embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure of any one of Formulas (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof (e.g., a pharma- ceutically acceptable salt, solvate, isomer, or isotopic substitution thereof), or a compound having the structure of any one of Formulas (V) or (VI), or a pharma- ceutically acceptable form thereof, and a pharma- ceutically acceptable carrier, diluent, or excipient. For example, in some embodiments, the pharmaceutical compositions provided herein comprise a therapeutically effective amount of a compound having the structure of any one of Formulas (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound having the structure of any one of Formulas (Va), (Vb), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof, and a pharma- ceutically acceptable carrier, diluent, or excipient. For example, in some embodiments, the pharmaceutical compositions provided herein comprise a therapeutically effective amount of a compound of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as a compound of formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or or (IVb-2), or a pharma- ceutically acceptable form thereof, or a compound having the structure of any one of formulas (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, together with a pharma- ceutically acceptable carrier, diluent, or excipient.

[0179] The compound of any one of formula (I), (II), (III) or (IV), or its pharmaceutically acceptable form, or the compound of any one of formula (V) or (VI), or its pharmaceutically acceptable form, 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 sterile solutions or suspensions for ophthalmic or parenteral administration, as well as transdermal patch preparations and dry powder inhalers.Typically, the compounds disclosed herein are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, for example, Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).

[0180] The composition can be formulated for single dose administration.To formulate the composition, the weight fraction of the compound disclosed herein is dissolved, suspended, dispersed or otherwise mixed in the selected vehicle at effective concentration so as to alleviate or improve the treated condition.The pharmaceutical carrier or vehicle suitable for administration of the compound disclosed herein provided herein includes any such carrier known to those skilled in the art to be suitable for specific administration mode.

[0181] In addition, a compound of any one of formula (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, or a compound of any one of formula (V) or (VI), or a pharma- ceutically acceptable form thereof, may be formulated as the sole pharma- ceutically active ingredient in the composition or may be combined with other therapeutically active ingredients.

[0182] The compound of any one of formula (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, or the compound of any one of formula (V) or (VI), or a pharma- ceutically acceptable form thereof, is included in a pharma- ceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects in the treated patient. Therapeutically effective concentrations can be empirically determined by testing the compounds in the in vitro and in vivo systems described herein, and then extrapolated therefrom for human doses.

[0183] The compound of any one of formula (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, or the compound of any one of formula (V) or (VI), or a pharma-ceutically acceptable form thereof, can be administered once or divided into several smaller doses administered at time intervals. It is understood that the exact dosage and duration of treatment is a function of the disease being treated and can be empirically determined using known testing protocols or by extrapolation from in vivo or in vitro test data. It is noted that concentration and dosage values ​​can also vary with the severity of the condition being alleviated. It is further understood that for any particular subject, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges described herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[0184] Thus, effective concentration or amount of one or more compounds described herein or their pharma- ceutically acceptable salts are mixed with suitable pharmaceutical carriers or vehicles for systemic, local, or local administration to form pharmaceutical compositions.The compound is included in an amount effective to alleviate or treat, slow down, or prevent one or more symptoms.The concentration of active compound in the composition depends on the absorption, tissue distribution, metabolism, excretion rate, administration schedule, amount administered, specific formulation, and other factors known to those skilled in the art.

[0185] The compositions are intended to be administered by a suitable route, including, but not limited to, oral, parenteral, rectal, topical, and local. For oral administration, capsules and tablets may be formulated. The compositions may be in liquid, semi-liquid, or solid form, and are formulated in a manner suitable for each administration route.

[0186] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may contain any of the following components: sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, dimethylacetamide, or other synthetic solvents, antimicrobial agents such as benzyl alcohol and methylparabens, 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 adjusting isotonicity such as sodium chloride or dextrose. Parenteral preparations may be enclosed in ampoules, pens, disposable syringes, or single or multiple dose vials made of glass, plastic, or other suitable material.

[0187] 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 oil-water emulsions containing a suitable amount of the compound or its pharma- ceutically acceptable salts. Pharmaceutically therapeutically active compounds and their salts are formulated and administered in unit dosage forms or multiple dosage forms. Unit dosage forms as used herein refer to physically separate units suitable for human and animal subjects and individually packaged, as known in the art. Each unit dose contains a predetermined amount of therapeutically active compound sufficient to produce a desired therapeutic effect, in association with the necessary pharmaceutical carrier, vehicle, or diluent. Examples of unit dosage forms include ampoules and syringes, as well as individually packaged tablets or capsules. Unit dosage forms may be administered in fractions or multiples thereof. Multiple dosage forms are a plurality of identical unit dosage forms packaged in a single container to be administered in divided unit dosage form. Examples of multiple dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit doses that are not segregated in packaging.

[0188] Sustained release preparations can also be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds provided herein, which matrices are in the form of shaped articles, for example, films or microcapsules. Examples of sustained release matrices include iontophoretic patches, polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as 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 allow the release of molecules for over 100 days, certain hydrogels release proteins for shorter periods of time. If encapsulated compounds 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 loss of biological activity and possible changes in their structure. Depending on the mechanism of action involved, rational strategies for stabilization can be taken. For example, if the aggregation mechanism is found to be intermolecular S--S bond formation via thio-disulfide interchange, stabilization can be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling the moisture content, using appropriate additives, and developing specific polymer matrix compositions.

[0189] Dosage forms or compositions may be prepared that contain active ingredients in the range of 0.001% to 100%, with the remainder consisting of non-toxic carriers. For oral administration, pharma- ceutically acceptable non-toxic compositions are formed by incorporating any of the commonly used excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, croscarmellose sodium, 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, as well as biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, and the like. Methods for preparing these compositions are known to those skilled in the art. Contemplated compositions may contain from about 0.001% to 100% active ingredient, and in certain embodiments, from about 0.1 to 85%, from about 75 to 95%, or from about 80 to 98%.

[0190] The compound of any one of formula (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, or the compound of any one of formula (V) or (VI), or a pharma- ceutically acceptable form thereof, may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.

[0191] The composition can contain other active compounds to obtain the desired combination of properties.The compound provided herein, or its pharmaceutically acceptable salt as described herein, can also be administered with another pharmacological agent known in the general art to be of value in treating one or more of the above-mentioned diseases or medical conditions, such as diseases associated with oxidative stress.

[0192] Oral pharmaceutical dosage forms are either solid, gel, or liquid. Solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets that 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 combinations of other ingredients known to those skilled in the art.

[0193] In certain embodiments, the formulation is a solid dosage form such as a capsule or tablet. The tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients, or compounds of a similar nature: binders, diluents, disintegrants, lubricants, glidants, sweeteners, and flavoring agents.

[0194] Examples of binders include microcrystalline cellulose, tragacanth gum, glucose solution, acacia mucilage, gelatin solution, sucrose, and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopersicon gracilis, 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. Disintegrants include, for example, croscarmellose 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 any of the water-insoluble FD and C dyes suspended on alumina hydrate. Sweeteners include sucrose, lactose, mannitol, and artificial sweeteners 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 that 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 phthalate. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate.

[0195] When dosage unit form is capsule, it can contain liquid carrier such as fatty oil in addition to the above-mentioned type of material.In addition, dosage unit form can contain various other materials that modify the physical form of dosage unit, such as coating of sugar and other enteric agents.Compound can also be administered as a component of elixir, suspension, syrup, wafer, sprinkle, chewing gum etc.Syrup can contain sucrose as sweetener, and certain preservatives, dyes, and colorings and flavors in addition to active compound.

[0196] The pharma- ceutically acceptable carriers contained in the tablet are binders, lubricants, diluents, disintegrants, colorants, flavoring agents, and wetting agents. Enteric-coated tablets resist the action of stomach acid and dissolve or disintegrate in neutral or alkaline intestines due to the enteric coating. Sugar-coated tablets are compressed tablets with different layers of pharma- ceutical acceptable materials. Film-coated tablets are compressed tablets coated with polymer or other suitable coatings. Multiple compressed tablets are compressed tablets made by two or more compression cycles using the aforementioned pharma- ceutical acceptable materials. Coloring agents may also be used in the above dosage forms. Flavoring agents and sweeteners are used in compressed tablets, sugar-coated, multiple compressed, and chewable tablets. Flavoring agents and sweeteners are particularly useful in the formation of chewable tablets and lozenges.

[0197] 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.

[0198] Elixirs are clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, such as sucrose, and may contain preservatives. Emulsions are two-phase systems 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 pharma-ceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non-effervescent granules to be reconstituted into liquid oral dosage forms include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable substances used in effervescent granules to be reconstituted into liquid oral dosage forms include organic acids and a carbon dioxide source. Coloring and flavoring agents are used in all of the above dosage forms.

[0199] Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of preservatives include glycerin, methyl and propyl parabens, benzoic acid, 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, syrup, glycerin, and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic additives include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate.Coloring agents include any of the approved, certified water-soluble FD and C dyes, and mixtures thereof.Flavors include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds that produce a pleasant sensation.

[0200] For solid dosage forms, the solution or suspension, for example in propylene carbonate, vegetable oils, or triglycerides, is encapsulated in a gelatin capsule. Such solutions, and their preparation and encapsulation, are disclosed in U.S. Patents 4,328,245, 4,409,239, and 4,410,545. For liquid dosage forms, the solution, for example in polyethylene glycol, may be diluted with a sufficient quantity of a pharma- ceutically acceptable liquid carrier, for example water, to be easily measured for administration.

[0201] Alternatively, liquid or semisolid 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 (350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol)), and one or more antioxidants (e.g., butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates).

[0202] Other formulations include, but are not limited to, aqueous alcoholic solutions containing acetals that are pharma- ceutically acceptable.The alcohols used in these formulations are any pharma-ceutically acceptable water-miscible solvents that have 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.

[0203] In all embodiments, tablet and capsule formulations may be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with conventional enteric coatings such as phenylsalicylate, waxes, and cellulose acetate phthalate.

[0204] 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, in 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 administered pharmaceutical composition can also contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffers, stabilizers, solubility enhancers, and other such agents, such as sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins. Implantation of a sustained-release or sustained-release system is also contemplated herein, such that a constant level of dosage is maintained. Briefly, the compounds provided herein are dispersed in a solid internal matrix (e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate), which are capable of being absorbed by body fluids. The compound is surrounded by an insoluble outer polymeric membrane (e.g., polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / acrylic acid ethylene copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers). 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.

[0205] Parenteral administration of the composition includes intravenous, subcutaneous, and intramuscular administration. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products that can be combined with a solvent immediately before use, such as freeze-dried powders, subcutaneous tablets, sterile suspensions ready for injection, sterile dry insoluble products that can be combined with a vehicle immediately before use, and sterile emulsions. The solutions can be either aqueous or non-aqueous.

[0206] If administered intravenously, suitable carriers include saline or phosphate buffered saline (PBS), as well as solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0207] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetic agents, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other pharma- ceutically acceptable substances.

[0208] Examples of aqueous vehicles include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose, and lactated Ringer's injection. Non-aqueous 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 multi-dose containers, including phenol or cresol, 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 phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN® 80). Sequestering or chelating agents 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.

[0209] Injectables are designed for local and systemic administration. Typically, therapeutically effective amounts are formulated to contain at least about 0.1% w / w to a maximum of about 90% w / w or more of the active compound, for example, greater than 1% w / w to the treated tissue(s). The active ingredient may be administered once or divided into several smaller doses to be administered at time intervals. It is understood that the exact 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 noted that concentration and dosage values ​​may also vary with the age of the individual being treated. It is further understood that for any particular subject, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the formulation, 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.

[0210] The compound of any one of formula (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, or the compound of any one of formula (V) or (VI), or a pharma-ceutically acceptable form thereof, may be suspended in micronized or other suitable form to produce a more soluble active product. The form of the resulting mixture depends on several factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to alleviate the symptoms of the condition and may be empirically determined.

[0211] Topical mixtures are prepared as described for local and systemic administration. The resulting mixture may be a solution, suspension, emulsion, etc., and is formulated as a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, irrigate, spray, suppository, bandage, skin patch, or any other formulation suitable for topical administration.

[0212] The compound of any one of formula (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, or the compound of any one of formula (V) or (VI), or a pharma- ceutically acceptable form thereof, or a pharmaceutical composition comprising them, may be formulated for local or topical application, e.g., in the eye, for example, for topical application to the skin and mucous membranes, in the form of gels, creams, and lotions, as well as for application to the eye, or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery, administration to the eye or mucous membranes, or for inhalation therapy. Nasal solutions of the active compound alone or in combination with other pharma- ceutically acceptable excipients may also be administered. These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01% to 10% isotonic solutions with appropriate salts and a pH of about 5 to 7.

[0213] 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, as used herein, refer to solid bodies for insertion into the rectum that melt or soften at body temperature to release 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 suitable mixtures of mono-, di-, and triglycerides of fatty acids. Combinations of various bases may be used. Agents to raise the melting point of the suppository include spermaceti and wax. Rectal suppositories can be prepared by either 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 pharma- ceutically acceptable substance and by the same methods as for formulations for oral administration.

[0214] A compound of any one of formula (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, or a compound of any one of formula (V) or (VI), or a pharma- ceutically acceptable form thereof, or a pharmaceutical composition comprising same, may be administered by controlled release means or by delivery devices well known to those skilled in the art. Examples include U.S. Pat. Nos. 3,845,770, 3,916,899, 3,536,809, and 3,598,123, as well as U.S. Pat. Nos. 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, and 5,972,891, Nos. 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 sustained or controlled release of the compounds disclosed herein, for example, using hydropropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, microspheres, or combinations thereof in various proportions to provide the desired release profile. Suitable controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

[0215] In certain embodiments, a compound of any one of formula (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, or a compound of any one of formula (V) or (VI), or a pharma- ceutically acceptable form thereof, may 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, a polymeric material may be used. In yet another embodiment, a controlled release system may be placed in close proximity to the therapeutic target, and thus require only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)).

[0216] A compound of any one of Formula (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, or a compound of any one of Formula (V) or (VI), or a pharma- ceutically acceptable form thereof, or a pharmaceutical composition comprising same, can be packaged as an article of manufacture containing packaging material, a compound provided herein, or a pharma- ceutically acceptable form thereof, for use in the treatment, prevention, or amelioration of one or more symptoms or progression of cancer dependent on a farnesylated protein, and labeling indicating that the compound, or a pharma- ceutically acceptable form thereof, is used for the treatment, prevention, or amelioration of one or more symptoms or progression of cancer dependent on a farnesylated protein.

[0217] The products provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those skilled in the art. For example, see 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 the selected formulation and intended mode of administration and treatment. A wide variety of formulations of the compounds and compositions provided herein are contemplated.

[0218] In some embodiments, the article of manufacture is a kit. The kit can include the compounds or pharmaceutical compositions described herein in suitable packaging and written materials that can include instructions for use, clinical study discussions, side effect listings, and the like. Such kits can also include information such as scientific literature references, package inserts, clinical trial results, and / or summaries thereof, which indicate or establish the activity and / or benefits of the pharmaceutical composition, and / or describe dosage, administration, side effects, drug interactions, or other information useful to health care providers. Such information can be based on the results of various studies, for example, studies using laboratory animals, including in vivo models, and studies based on human clinical trials.

[0219] In some embodiments, the memory aid is provided in the kit, for example in the form of numbers next to the tablets or capsules, whereby the numbers correspond to the days of the regimen on which the tablets or capsules so designated should be taken. A "daily dose" can be a single tablet or capsule or multiple tablets or capsules to be taken on a given day.

[0220] Suitable packaging and additional items for use (e.g., measuring cups for liquid preparations, foil packaging to minimize exposure to air, etc.) are known in the art and may be included in the kit. In other embodiments, the kit may further include a device used to administer the active agent. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers. The kits described herein may be provided, marketed, and / or promoted to health care providers, including physicians, nurses, pharmacists, dispensing personnel, and the like. The kits may also be marketed directly to consumers in some embodiments.

[0221] An example of such a kit is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). A blister pack generally consists 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. The tablets or capsules are then placed in the recesses and the sheet of relatively stiff material is sealed to the plastic foil on the face of the foil opposite to 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 applying manual pressure to the recesses, which forms an opening in the sheet at the location of the recesses. The tablets or capsules can then be removed through said openings.

[0222] The kit can further include a pharma- ceutically acceptable vehicle that can be used to administer the active agent. For example, if the active agent is provided in a solid form that must be reconstituted for parenteral administration, the kit can include a sealed container of a suitable vehicle in which the active agent can be dissolved to form a particulate-free sterile solution suitable for parenteral administration. Examples of pharma-ceutically 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.

[0223] 5.3 Use and Method 5.3.1 Therapeutic Uses and Methods 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 to activate is the farnesylation of a cysteine ​​in the C-terminal CAAX box (C stands for cysteine, A stands for an aliphatic amino acid, and X stands for any amino acid). Rowinsky, EK, et al., J. Clin. Oncol. 1999, 17, 3631-3652. The enzyme farnesyltransferase (FTase) recognizes the CAAX motif and transfers the 15-carbon farnesyl isoprenoid from farnesyl diphosphate to a cysteine ​​residue. The AAX amino acid is then cleaved by Ras convertase I, and the farnesylated cysteine ​​is carboxymethylated by isoprenylcysteine ​​carboxylmethyltransferase. Prior, IA, 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, JF, et al., Cell 1990, 63, 133-139. Observations suggest that prenylation is required for the function of all RAS isoforms, including mutant forms. However, some farnesylated proteins, including KRAS and NRAS, can be rescued from membrane displacement in the presence of farnesyltransferase inhibitors (FTIs) by alternative prenylation with the enzyme geranylgeranyltransferase (GGTase). Zhang, FL, et al., J. Biol. Chem. 1997, 272, 10232-10239; Whyte, DB, et al. al., J. Biol. Chem. 1997, 272, 14459-14464. Conversely, the third family member, HRAS, is not a GGTase substrate and its membrane localization and cellular function are impaired by FTIs.Whyte, DB, et al. Thus, the use of FTIs to target enriched patient populations of tumors, e.g., tumors that are dependent on farnesylated proteins such as HRAS, e.g., tumors with HRAS mutations, should provide clinical benefit.

[0224] One particular FTI in clinical development is tipifarnib. The efficacy of tipifarnib has been investigated 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, 1784-1796. Genomic analyses have revealed that HRAS mutations occur in 6% of HNSCC at initial diagnosis (Hoadley, KA, et al., Cell 2018, 173, 291-304) and in 15% of patients during acquired cetuximab resistance (Braig, F., et al., Oncotarget 2016, 7, 42988-42995), and have demonstrated that HRAS mutations correlate with a reduced response of HNSCC patients to cetuximab treatment. “Rampias, T., et al., Clin. Cancer Res. 2014, 20, 2933-2946.

[0225] HRAS is also recurrently mutated in other cancer types, including urothelial cell carcinoma and salivary gland tumors, with 24% of patients with HRAS mutated metastatic urothelial carcinoma treated with tipifarnib experiencing 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 their best response. Ho, AL, et al., J. Clin. Oncol. 2020, 38, 6504. Other tumor types that show recurrent HRAS driver mutations include lung squamous cell carcinoma, thyroid carcinoma, pheochromocytoma, and paraganglioma. Hoadley, KA, et al.

[0226] In certain embodiments, the compounds disclosed herein, such as compounds of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), e.g., compounds of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., compounds of 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 pharma- ceutically acceptable form thereof, are farnesyltransferase inhibitors. In some embodiments, the compounds disclosed herein are of formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VIa), (VIb), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, and are farnesyltransferase inhibitors. In certain embodiments, the compounds disclosed herein, or a pharma- ceutically acceptable form thereof, are selective farnesyltransferase inhibitors, as compared to inhibition of geranylgeranyltransferase type 1, e.g., geranylgeranyltransferase type 1.

[0227] In some embodiments, provided herein are methods of inhibiting farnesyltransferase, comprising contacting the farnesyltransferase with an effective amount of a compound of formula (I), (II), (III), or (IV) disclosed herein, or a pharma- ceutically acceptable form thereof. In some embodiments, provided herein are methods of inhibiting farnesyltransferase, comprising contacting the farnesyltransferase with an effective amount of a compound of formula (V) or (VI) disclosed herein, or a pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), e.g., a compound of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., a compound of 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is of formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VIa), (VIb), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof. In some embodiments, the method of inhibiting farnesyltransferase comprises contacting farnesyltransferase with a pharmaceutical composition containing an effective amount of a compound of formula (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, as disclosed herein, and a pharma- ceutically acceptable carrier, diluent, or excipient. In some embodiments, the method of inhibiting farnesyltransferase comprises contacting the farnesyltransferase with a pharmaceutical composition containing an effective amount of a compound of Formula (V) or (VI), or a pharma- ceutically acceptable form thereof, as disclosed herein, and a pharma- ceutically acceptable carrier, diluent, or excipient.In some embodiments, the pharmaceutical composition contains a compound of Formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), e.g., a compound of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., a compound of 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 pharma- ceutically acceptable form thereof. In some embodiments, the pharmaceutical composition comprises a compound of Formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VIa), (VIb), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof. In some embodiments, the contacting of the farnesyltransferase occurs intracellularly. In some embodiments, the farnesyltransferase is present intracellularly. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the subject is afflicted with a cancer dependent on a farnesylated protein. In some embodiments, the subject is human.

[0228] In some embodiments, the method inhibits farnesylation of an H-Ras protein. In some embodiments, the H-Ras protein has a mutation. In some embodiments, the H-Ras protein mutation is or includes a modification in a codon that codes for 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. In some embodiments, the inhibition of farnesylation of an H-Ras protein, such as an H-Ras protein having a mutation, is performed 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 is a human cell. In some embodiments, the inhibition of farnesyltransferase present in the cell is performed in a subject suffering from a 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 farnesylated protein dependent cancer is dependent on the farnesylated protein(s) for progression and / or survival of the cancer. In some embodiments, the farnesylated protein dependent cancer is a farnesylated H-Ras protein dependent cancer. In some embodiments, the farnesylated protein dependent cancer has an H-Ras protein mutation. In some embodiments, the H-Ras protein mutation is or includes 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. In some embodiments, the farnesylated protein dependent cancer 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, e.g., HNSCC, is dependent on one or more farnesylated proteins, e.g., dependent on farnesylated H-Ras protein. In some embodiments, the head and neck cancer, e.g., HNSCC, has an H-Ras protein mutation. In some embodiments, the cancer dependent on farnesylated proteins is carcinoma, melanoma, sarcoma, or chronic granulomatous disease. For example, in some embodiments, the cancer dependent on farnesylated proteins is thyroid cancer, head and neck cancer, urothelial cancer, salivary gland cancer, upper gastrointestinal tract cancer, 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), esophageal 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 tracheal HNSCC, maxillary HNSCC, oral HNSCC. In some embodiments, the SCC, e.g., HNSCC, lung SCC, thyroid SCC, esophageal SCC, bladder SCC, or urothelial carcinoma, depends on one or more farnesylated proteins, e.g., depends on farnesylated H-Ras protein. In some embodiments, the HNSCC, e.g., HNSCC, lung SCC, thyroid SCC, esophageal SCC, bladder SCC, or urothelial carcinoma, has H-Ras protein mutation. In some embodiments, the HNSCC has H-Ras protein mutation. In some embodiments, the subject is a human.

[0229] In some embodiments, the method inhibits farnesylation of an N-Ras protein. In some embodiments, the N-Ras protein has a mutation. In some embodiments, the N-Ras protein mutation is or includes a modification in a codon that codes for 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. In some embodiments, the inhibition of farnesylation of an N-Ras protein, such as an N-Ras protein having a mutation, is performed 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 is a human cell. In some embodiments, the inhibition of farnesyltransferase present in the cell is performed in a subject suffering from a 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 farnesylated protein dependent cancer is dependent on the farnesylated protein(s) for the progression and / or survival of the cancer. In some embodiments, the farnesylated protein dependent cancer is a farnesylated N-Ras protein dependent cancer. In some embodiments, the farnesylated protein dependent cancer has an N-Ras protein mutation. In some embodiments, the N-Ras protein mutation is or includes a modification in a codon that codes for 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. In some embodiments, the farnesylated protein dependent cancer is melanoma, acute myeloid leukemia (AML), thyroid cancer, lung adenocarcinoma, rectal cancer, endometrial cancer, or colorectal cancer.In some embodiments, melanoma, acute myeloid leukemia (AML), thyroid cancer, lung adenocarcinoma, rectal cancer, endometrial cancer, or colorectal cancer depends on one or more farnesylated proteins, for example, depends on farnesylated N-Ras protein. In some embodiments, melanoma, acute myeloid leukemia (AML), thyroid cancer, lung adenocarcinoma, rectal cancer, endometrial cancer, or colorectal cancer has N-Ras protein mutation. In some embodiments, the subject is a human.

[0230] In some embodiments, provided herein is a method of treating a cancer dependent on a farnesylated protein in a subject, comprising administering a therapeutically effective amount of a compound of formula (I), (II), (III), or (IV) disclosed herein, or a pharmaceutically acceptable form thereof, to a subject having a cancer dependent on a farnesylated protein. In some embodiments, provided herein is a method of treating a cancer dependent on a farnesylated protein in a subject, comprising administering a therapeutically effective amount of a compound of formula (V) or (VI) disclosed herein, or a pharmaceutically acceptable form thereof, to a subject having a cancer dependent on a farnesylated protein. In some embodiments, the compound is a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), e.g., a compound of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., a compound of 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VIa), (VIb), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof. In some embodiments, a method of treating a cancer dependent on a farnesylated protein in a subject comprises administering to a subject having a cancer dependent on a farnesylated protein a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, or a compound of formula (V) or (VI), or a pharma- ceutically acceptable form thereof, as disclosed herein, and a pharma- ceutically acceptable carrier, diluent, or excipient.In some embodiments, the pharmaceutical composition contains a compound of Formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), e.g., a compound of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., a compound of 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 pharma- ceutically acceptable form thereof. In some embodiments, the pharmaceutical composition comprises a compound of formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VIa), (VIb), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof. In some embodiments, the farnesylated protein dependent cancer is a solid tumor. In some embodiments, the farnesylated protein dependent cancer is a cancer dependent on one or more farnesylated proteins. In some embodiments, the farnesylated protein dependent cancer is dependent on a farnesylated protein(s) for progression and / or survival of the cancer. In some embodiments, the farnesylated protein dependent cancer is a cancer dependent on a farnesylated H-Ras protein. In some embodiments, the farnesylated protein dependent cancer has an H-Ras protein mutation. In some embodiments, the H Ras protein mutation is or includes a modification in a codon encoding 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. In some embodiments, the cancer dependent on farnesylated proteins 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, e.g., HNSCC, is dependent on one or more farnesylated proteins, e.g., dependent on farnesylated H-Ras protein.In some embodiments, the head and neck cancer, for example, HNSCC, has H-Ras protein mutation. In some embodiments, the cancer dependent on farnesylated protein is carcinoma, melanoma, sarcoma, or chronic granulomatous disease. For example, in some embodiments, the cancer dependent on farnesylated protein is thyroid cancer, head and neck cancer, urothelial cancer, salivary gland cancer, upper gastrointestinal cancer, 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 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), esophageal SCC (ESCC), bladder SCC (BSCC), or urothelial carcinoma (UC). In some embodiments, the SCC is HNSCC. In some embodiments, the SCC is a human papillomavirus (HPV) negative SCC. In some embodiments, the HNSCC is a HPV negative HNSCC. For example, in some embodiments, the HNSCC is a tracheal HNSCC, a maxillary HNSCC, or an oral HNSCC. In some embodiments, the SCC, e.g., HNSCC, lung SCC, thyroid SCC, esophageal SCC, bladder SCC, or urothelial carcinoma, depends on one or more farnesylated proteins, e.g., depends on farnesylated H-Ras protein. In some embodiments, the HNSCC, e.g., HNSCC, lung SCC, thyroid SCC, esophageal 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.

[0231] In some embodiments, provided herein is a method of treating a cancer dependent on a farnesylated protein in a subject, comprising administering a therapeutically effective amount of a compound of formula (I), (II), (III), or (IV) disclosed herein, or a pharmaceutically acceptable form thereof, to a subject having a cancer dependent on a farnesylated protein. In some embodiments, provided herein is a method of treating a cancer dependent on a farnesylated protein in a subject, comprising administering a therapeutically effective amount of a compound of formula (V) or (VI) disclosed herein, or a pharmaceutically acceptable form thereof, to a subject having a cancer dependent on a farnesylated protein. In some embodiments, the compound is a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), e.g., a compound of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., a compound of 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VIa), (VIb), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof. In some embodiments, a method of treating a cancer dependent on a farnesylated protein in a subject comprises administering to a subject having a cancer dependent on a farnesylated protein a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I), (II), (III), or (IV), or a pharma- ceutically acceptable form thereof, as disclosed herein, and a pharma- ceutically acceptable carrier, diluent, or excipient.In some embodiments, a method for treating a cancer dependent on a farnesylated protein in a subject comprises administering to a subject having a cancer dependent on a farnesylated protein a pharmaceutical composition containing a therapeutically effective amount of a compound of Formula (V) or (VI), or a pharma- ceutically acceptable form thereof, as disclosed herein, and a pharma- ceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition contains a compound of Formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), e.g., a compound of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., a compound of 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 pharma- ceutically acceptable form thereof. In some embodiments, the pharmaceutical composition comprises a compound of formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VIa), (VIb), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof. In some embodiments, the farnesylated protein dependent cancer is a solid tumor. In some embodiments, the farnesylated protein dependent cancer is dependent on one or more farnesylated proteins. In some embodiments, the farnesylated protein dependent cancer is dependent on a farnesylated protein(s) for the progression and / or survival of the cancer. In some embodiments, the farnesylated protein dependent cancer is a cancer dependent on a farnesylated N-Ras protein. In some embodiments, the farnesylated protein dependent cancer has an N-Ras protein mutation.In some embodiments, the N-Ras protein mutation is or includes a modification in a codon that codes for 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. In some embodiments, the cancer dependent on farnesylated protein is melanoma, acute myeloid leukemia (AML), thyroid cancer, lung adenocarcinoma, rectal cancer, endometrial cancer, or colorectal cancer. In some embodiments, the melanoma, acute myeloid leukemia (AML), thyroid cancer, lung adenocarcinoma, rectal cancer, endometrial cancer, or colorectal cancer is dependent on one or more farnesylated proteins, e.g., dependent on farnesylated N-Ras protein. In some embodiments, the melanoma, acute myeloid leukemia (AML), thyroid cancer, lung adenocarcinoma, rectal cancer, endometrial cancer, or colorectal cancer has an N-Ras protein mutation. In some embodiments, the subject is a human.

[0232] In some embodiments, the method of treating a cancer dependent on a farnesylated protein disclosed herein further comprises determining the presence or absence of an H-Ras mutation. In some embodiments, the method of treating a cancer dependent on a farnesylated protein disclosed herein further comprises determining the presence or absence of an N-Ras mutation. In some embodiments, determining the presence or absence of an H-Ras mutation comprises analyzing nucleic acid obtained from a sample from the subject. In some embodiments, determining the presence or absence of an N-Ras mutation comprises analyzing nucleic acid obtained from a sample from the subject. In some embodiments, the sample is a tissue biopsy. In some embodiments, the 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.

[0233] In some embodiments, the compounds disclosed herein are compounds of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), e.g., compounds of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., compounds of formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), or a compound of formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-1), (Va-1), (Vb-1), (VIa), (VIb), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof, which is metabolically stable, e.g., metabolically stable to hepatic metabolism in a subject, e.g., metabolically stable to hepatic metabolism in a human.

[0234] 5.3.2 Dosage and regimen The compounds described herein may be delivered in the form of a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of formula (I), (II), (III), or (IV), e.g., a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound of formula (V) or (VI), e.g., a compound of formula (Va), (Vb), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof, and a pharma- ceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition is a therapeutically effective amount of a compound of formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), e.g., (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 pharma- ceutically acceptable form thereof, or a compound of formula (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VIa-1), or (VIb-1), or a pharma- ceutically acceptable form thereof. The pharmaceutical compositions disclosed herein are intended to be administered by a suitable route, including, but not limited to, oral, parenteral, rectal, topical, and local. In some embodiments, the selected dose level will depend on a variety of factors, including, for example, the activity of the particular compound used, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound used, the rate and extent of absorption, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound used, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[0235] A suitable daily dose of the compounds described herein administered to a subject is, in some embodiments, the amount of the compound that may be the minimum effective dose to produce a therapeutic effect. Such an effective dose generally depends on the factors described herein. In some embodiments, a therapeutically effective amount of a compound of any one of formulas (I), (II), (III), or (IV), such as a compound of formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharma- ceutically acceptable form thereof, or a compound of formula (V) or (VI), such as a compound of formula (Va), (Vb), (VIa), or (VIb), or a pharma- ceutically acceptable form thereof, is administered to a subject. Acceptable forms are in an amount of about 0.01 to about 500 mg / kg per day of active ingredient, either as a single dose or subdivided into two or more doses, or, more specifically, in an amount of about 0.01 to about 400 mg / kg per day, e.g., about 0.01 to about 300 mg / kg per day, about 0.01 to about 200 mg / kg per day, about 0.01 to about 100 mg / kg per day, about 0.01 to about 5 ... In an amount of 1 to about 25 mg / kg, or about 0.01 to about 10 mg / kg per day, for example, about 0.01 mg / kg per day, about 0.025 mg / kg per day, about 0.05 mg / kg per day, about 0.075 mg / kg per day, about 0.1 mg / kg per day, about 0.25 mg / kg per day, about 0.5 mg / kg per day, about 0.75 mg / kg per day, about 1 mg / kg per day, about 2.5 ... about 5 mg / kg, about 7.5 mg / kg per day, about 10 mg / kg per day, about 15 mg / kg per day, about 20 mg / kg per day, about 25 mg / kg per day, about 50 mg / kg per day, about 75 mg / kg per day, about 100 mg / kg per day, about 100 mg / kg per day, about 200 mg / kg per day, about 300 mg / kg per day, about 400 mg / kg per day, or about 500 mg / kg per day.For example, in some embodiments, the dosage or therapeutically effective amount of a compound disclosed herein or a pharma- ceutically acceptable form thereof is in an amount of abou...

Claims

1. A compound of formula (III): 【Chemistry 221】 During the ceremony, A 3 is CR 3 or N; A 4 is CR 8 or N; A 5 and A 6 are each independently CR 8 or N, or A 5 and A 6 together are O, NR 9 , or S; W 1 , W 2 , W 3 , and W 4 are each independently N or CR 4 , or W 1 and W 2 together are O, NR 4A , or S, or W 2 and W 3 together are O, NR 4A , or S; Y is a bond or a linker having a length of up to 6 atoms; Z 1 , Z 2 , Z 3 , and Z 4 are each independently N or CR 5 , or Z 2 and Z 3 together are O, NR 5A , or S, or Z 3 and Z 4 together are O, NR 5A , or S; R 2b , R 3 , R 5 , and R 8 , in each occurrence, are each independently R 9 , —OR 9 , halo, CN, NO 2 , —C(O)R 9 , —C(O)OR 9 , —OC(O)R 9 , —OC(O)OR 9 , —C(O)NR 10 R 11 , —NR 10 R 11 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , —NR 10 C(O)NR 10 R 11 , —NR 10 S(O) 2 R 9 , —S(O) p R 9 , —S(O) 2 NR 10 R 11 , or —NR 10 S(O) 2 NR 10 R 11 , R 4 in each occurrence is independently hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 1-6 heteroalkoxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, —NR 14 R 15 , C 6-12 aryl, or 5- to 12-membered heteroaryl, and each C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C wherein the 1-6 heteroalkoxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 6-12 aryl, or 5- to 12-membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and (O); R 4A and R 5A are each independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6-12 aryl, or 5- to 12-membered heteroaryl, and each C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6-12 aryl, or 5- to 12-membered heteroaryl of said R 4A and said R 5A is optionally independently halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C substituted with 1, 2, 3, 4, 5, or 6 substituents selected from C 1-6 alkoxy, C 1-6 haloalkoxy, and (O); R 6 is CN, R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 OR 9 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , -NR 10 C(O)NR 10 R 11 , -NR 10 S(O) 2 R 9 , -NR 10 C(NR 10 )NR 10 R 11 , -S(O) p R 9 , -S(O) 2 NR 10 R 11 or -NR 10 S(O) 2 NR 10 R 11 ; R 7 is halo, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -C(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(O)R 9, -NR10C(O)OR9, -NR10C(O)NR10R11, -NR10S(O)2R9, -S(O)pR9, -S(O)2NR10R11, and -NR10S(O)2NR10R 11 is a 5- to 12-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 9 in each occurrence is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-12 aryl, or 5 to 12 membered heteroaryl, and each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-12 aryl, or 5 to 12 membered heteroaryl of said R 9 is optionally independently halo, hydroxy, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (O), —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —OC(O)OR 12 , —C(O)NR 10 R 11 , —NR 10 R 11 , —NR 10 C(O)R 12 , —NR 10 C(O)OR 12 , —NR 10 C(O)NR 10 R 11 , —NR 10 S(O) 2 R 12 , —S(O) p R 12 , —S(O) 2 substituted with 1, 2, 3, 4, 5, or 6 substituents selected from -NR 10 R 11 and -NR 10 S(O) 2 NR 10 R 11 ; R 10 and R 11 , in each occurrence, are each independently hydrogen, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 6-12 aryl, or 5- to 12-membered heteroaryl, or each combines with the N to which it is attached to form a 3- to 6-membered heterocycloalkyl, and each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 6-12 aryl, or 5- to 12-membered heteroaryl. Aryl, or 5-12 membered heteroaryl is optionally independently selected from halo, hydroxy, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (O), —C(O)R 13 , —C(O)OR 13 , —OC(O)R 13 , —OC(O)OR 13 , —C(O)NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)R 13 , —NR 14 C(O)OR 13 , —NR 14 C(O)NR 14 substituted with 1, 2, 3, 4, 5, or 6 substituents selected from -R 15 , -NR 14 S(O) 2 R 13 , -S(O) p R 13 , -S(O) 2 NR 14 R 15 , and -NR 14 S(O) 2 NR 14 R 15 ; R 12 in each occurrence is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-12 aryl, or 5 to 12 membered heteroaryl, and each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-12 aryl, or 5 to 12 membered heteroaryl of said R 12 is optionally independently halo, hydroxy, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (O), —C(O)R 13 , —C(O)OR 13 , —OC(O)R 13 , —OC(O)OR 13 , —C(O)NR 10 R 11 , —NR 10 R 11 , —NR 10 C(O)R 13 , —NR 10 C(O)OR 13 , —NR 10 C(O)NR 10 R 11 , —NR 10 S(O) 2 R 13 , —S(O) p R 13 , —S(O) 2 NR 10 R 11 , and —NR 10 S(O) 2 NR 10 R 11 ; R 13 in each occurrence is independently hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; R 14 and R 15 , in each occurrence, are each independently hydrogen, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, or C 1-6 alkoxy, or each, together with the N to which they are attached, combine to form a 3- to 6-membered heterocycloalkyl; The compound, or a pharmaceutically acceptable form thereof, wherein each p is independently an integer of 0, 1, or 2.

2. The compound is a compound of formula (IIIa) or a compound of formula (IIIb), 【Chemistry 222】 or a pharmaceutically acceptable form thereof.

3. The compound of claim 1, wherein A 3 is CR 3 , and optionally R 3 is (a) R 9 , —OR 9 , halo, or CN, or (b) hydrogen.

4. The compound of claim 1, wherein A 4 is CR 8 .

5. The compound of claim 1, wherein A 5 is CR 8 .

6. The compound of claim 1, wherein A 6 is CR 8 .

7. (a) A 4 is N, and at most one of A 5 and A 6 is N, or (b) A 5 is N and not more than one of A 4 and A 6 is N; or (c) A 6 is N and not more than one of A 4 and A 5 is N; or (d) The compound of claim 1, wherein A 4 , A 5 , and A 6 are each independently CR 8 .

8. The compound of claim 1, wherein each R 8 is independently R 9 , —OR 9 , halo, or CN, and optionally each R 8 is hydrogen.

9. At least one of W 1 , W 2 , W 3 , and W 4 is N, and optionally, W 1 , W 2 and W 3 are each independently CR 4 , and W 4 is N; or W 1 , W 2 and W 4 are each independently CR 4 and W 3 is N; or W 1 , W 3 , and W 4 are each independently CR 4 and W 2 is N; or The compound of claim 1 , wherein W 2 , W 3 , and W 4 are each independently CR 4 ; and W 1 is N.

10. The compound of claim 1, wherein W 1 , W 2 , W 3 , and W 4 are each independently CR 4 .

11. (a) each R 4 is independently hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 1-6 heteroalkoxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, or -NR 14 R 15 , and each C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 1-6 heteroalkoxy, C 3-6 the cycloalkoxy or 3- to 6-membered heterocycloalkoxy is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and (O); (b) each R 4 is independently hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, and each C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy of said R 4 is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and (O); (c) each R 4 is independently hydrogen, halo, C 1-3 alkyl, C 1-3 haloalkyl, C 3-5 cycloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy; or (d) The compound of claim 1, wherein each R 4 is hydrogen.

12. At least one of Z 1 , Z 2 , Z 3 , and Z 4 is N, and optionally, Z 1 , Z 2 and Z 3 are each independently CR 5 , and Z 4 is N; or Z 1 , Z 2 and Z 4 are each independently CR 5 , and Z 3 is N; or Z 1 , Z 3 , and Z 4 are each independently CR 5 and Z 2 is N; or The compound of claim 1 , wherein Z 2 , Z 3 , and Z 4 are each independently CR 5 ; and Z 1 is N.

13. The compound of claim 1, wherein Z 1 , Z 2 , Z 3 , and Z 4 are each independently CR 5 .

14. R 5 , in each occurrence, is independently R 9 , —OR 9 , halo, CN, NO 2 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 10 R 11 , —S(O) p R 9 , or —S(O) 2 NR 10 R 11 ; or R 5 in each occurrence is independently hydrogen, halo, CN, NO 2 , —C(O)CH 3 , —C(O)OH, —C(O)OCH 3 , —C(O)N(CH 3 ) 2 , —S(O) 2 CH 3 , or —S(O) 2 N(CH 3 ) 2 ; or each R 5 is independently hydrogen, halo, or CN; or 10. The compound of claim 1, wherein each R<5> is hydrogen.

15. The compound of claim 1, 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). 【Chemistry 223-1】 【Chemistry 223-2】 or a pharmaceutically acceptable form thereof.

16. The compound of claim 15, wherein R 2b is R 9 , —OR 9 , halo, CN, NO 2 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 10 R 11 , —NR 10 R 11 , —NR 10 C(O)R 9 , —S(O) p R 9 , or —S(O) 2 NR 10 R 11 .

17. R 2b is (a) R 9 , —OR 9 , halo, CN, —C(O)NR 10 R 11 , or —NR 10 R 11 ; or (b) hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, hydroxy, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 heterocycloalkoxy, halo, CN, —C(O)NR 10 R 11 , or —NR 10 R 11 ; wherein R 10 and R 11 in each occurrence are each independently hydrogen, C 1-6 alkyl, 3- to 6-membered heterocycloalkyl, or each combine with the N to which it is attached to form a 3- to 6-membered heterocycloalkyl; or (c) hydrogen, C 1-3 alkyl, C 3-4 cycloalkyl, C 1-3 alkoxy, C 3-4 cycloalkoxy, C 3-4 heterocycloalkoxy, halo, CN, —C(O)NR 10 R 11 , or —NR 10 R 11 ; wherein R 10 and R 11 in each occurrence are each independently hydrogen, C 1-3 alkyl, 3- to 4-membered heterocycloalkyl, or each taken together with the N to which they are attached combine to form a 4- to 6-membered heterocycloalkyl; (d) hydrogen, —CH 3 , —CD 3 , —CH 2 CH 3 , —CD 2 CD 3 , isopropyl, cyclopropyl, —OCH 3 , —OCD 3 , —OCH 2 CH 3 , —OCD 2 CD 3 , isopropoxy, cyclopropoxy, 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or —C(O)NH 2 ; or (e) The compound of claim 15, which is -NH 2 .

18. R 2b is an electron withdrawing group, and optionally, R 2b is (a) halo, CN, NO 2 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 10 R 11 , —S(O) p R 9 , or —S(O) 2 NR 10 R 11 , or (b) The compound of claim 15, which is chloro, CN, —C(O)H, —C(O)CH 3 , —C(O)OH, —C(O)OCH 3 , —C(O)NH 2 , —C(O)N(H)CH 3 , —C(O)N(CH 3 ) 2 , —S(O)CH 3 , —S(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 N(H)CH 3 , or —S(O) 2 N(CH 3 ) 2 .

19. The compound of claim 15, wherein Y is in the Z-Y-W orientation, Y is C 1-6 alkylene, one or more -CH 2 - are optionally independently replaced by -O-, -C(O)-, -N(R 10 )-, -N(R 10 )C(O)-, -C(O)N(R 10 )-, -N(R 10 )C(O)N(R 11 )-, -S(O) p -, -N(R 10 )S(O) 2 -, -S(O) 2 N(R 10 )-, or -N(R 10 )S(O) 2 N(R 11 )-, and Y has a length of up to 6 atoms.

20. Y is -(CR 16 R 17 ) q -, -(CR 16 R 17 ) m O(CR 16 R 17 ) n -, -(CR 16 R 17 ) m C(O)(CR 16 R 17 ) n -, -(CR 16 R 17) m N(R 10 )(CR 16 R 17 ) n -, -(CR 16 R 17 ) m N(R 10 )C(O)(CR 16 R 17 ) n -, -(CR 16 R 17 ) m C(O)N(R 10 )(CR 16 R 17) n -, -(CR 16 R 17 ) m N(R 10 )C(O)N(R 11 )(CR 16 R 17 ) n −, −(CR 16 R 17 ) m S(O) p (CR 16 R 17 ) n −, −(CR 16 R 17 ) m N(R 10 )S(O) 2 (CR 16 R 17 ) n -, -(CR 16 R 17 ) m S(O) 2 N(R 10 )(CR 16 R 17 ) n -, or -(CR 16 R 17 ) m N(R 10 )S(O) 2 N(R 11 )(CR 16 R 17 ) n -, and Y has a length of up to 6 atoms; During the ceremony, R 16 and R 17 in each occurrence are each independently hydrogen, halo, hydroxy, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 1-6 heteroalkoxy, or 3- to 6-membered heterocycloalkoxy, or each combined with the C to which they are attached form C(O), C 3-6 cycloalkyl, or 3- to 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; the sum of m and n is 0, 1, 2, 3, 4, or 5; q is an integer of 0, 1, 2, 3, 4, 5, or 6; Optionally, each m is independently 0, 1, or 2; 20. The compound of claim 19, wherein optionally each n is independently 0, 1, or 2.

21. The compound of claim 19, wherein Y is —(CH 2 )O—, or Y is —O(CH 2 )—, or Y is —(CH 2 ) 2 O—, or Y is —O(CH 2 ) 2 —, or Y is —(CH 2 ) 2 —.

22. R 7 is imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, or pyrimidinyl, each of which is halo, CN, NO 2 , R 9 , —OR 9 , —C(O)R 9 , —C(O)OR 9 , —OC(O)R 9 , —OC(O)OR 9 , —C(O)NR 10 R 11 , —NR 10 R 11 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , —NR 10 C(O)NR 10 R 11 , —NR 10 S(O) 2 R 9 , —S(O) p R 9 , —S(O) 2 NR 10 R 11 , and —NR 10 S(O) 2 NR 10 R 11 ; optionally, R 7 is imidazolyl or triazolyl, each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, CN, NO 2 , R 9 , —OR 9 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 10 R 11 , —NR 10 R 11 , —NR 10 C(O)R 9 , —S(O) p R 9 , and —S(O) 2 NR 10 R 11 ; Optionally, the compound of claim 15 wherein R 7 is C-linked imidazolyl or C-linked triazolyl, each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, CN, NO 2 , R 9 , —OR 9 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 10 R 11 , —NR 10 R 11 , —NR 10 C(O)R 9 , —S(O) p R 9 , and —S(O) 2 NR 10 R 11 .

23. R 7 is an N-linked imidazolyl or an N-linked triazolyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, CN, NO 2 , R 9 , —OR 9 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 10 R 11 , —NR 10 R 11 , —NR 10 C(O)R 9 , —S(O) p R 9 , or —S(O) 2 NR 10 R 11 , and optionally R 7 is a methyl-substituted imidazolyl or a methyl-substituted triazolyl; R 7 is C-methyl substituted imidazolyl or C-methyl substituted triazolyl, optionally R 7 is 【Chemical 233】 Or Alternatively, R 7 is N-methyl substituted imidazolyl or N-methyl substituted triazolyl, optionally wherein R 7 is: 【Chemistry 234】 or R 7 is 【Chemical 235】 16. The compound of claim 15, wherein:

24. The compound of claim 24, wherein R 6 is CN, R 9 , —OR 9 , —OC(O)R 9 , —OC(O)OR 9 , —NR 10 R 11 , —NR 10 OR 9 , —NR 10 C(O)R 9 , or —NR 10 C(NR 10 )NR 10 R 11 , or R 6 is CN, R 9 , —OR 9 , —NR 10 R 11 , or —NR 10 OR 9 , or R 6 is CN, R 9 , —OR 9 , or —NR 10 R 11 , optionally wherein each R 9 is independently hydrogen or C 1-3 alkyl, and said C 1-3 16. The compound of claim 15, wherein alkyl is optionally substituted with CN, and optionally R 10 and R 11 are each independently hydrogen, C 1-6 alkyl, or C 1-6 alkoxy.

25. The compound of claim 15, wherein R 6 is hydrogen, -CH 3 , hydroxy, -OCH 3 , -OCD 3 , -NH 2 , -NHCH 3 , or -NH(OCH 3 ), or R 6 is hydroxy, or R 6 is hydrogen, or R 6 is NH 2 , or R 6 is -NH(CH 2 CH 2 )Cl, -NH(CH 2 CH 2 )F, or N-linked morpholino.

26. The compound according to claim 26, wherein Y is —(CH 2 ) q — or —(CH 2 ) m O(CH 2 ) n —; R 2b is R 9 , —OR 9 , halo, CN, —C(O)NR 10 R 11 , or —NR 10 R 11 ; R 5 is R 9 , —OR 9 , halo, CN, NO 2 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 10 R 11 , —S(O) p R 9 , or —S(O) 2 NR 10 R 11 ; R 6 is CN, R 9 , —OR 9 , —NR 10 R 11 , or —NR 10 OR 9 ; R 7 is optionally independently halo, CN, NO 2 , R 9 , —OR 9 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 10 R 11 , —NR 10 R 11 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , —NR 10 C(O)NR 10 R 11 , —NR 10 S(O) 2 R 9 , —S(O) p R 9 , —S(O) 2 NR 10 R 11 , or —NR 10 S(O) 2 NR 10 R 11 is a 5- to 12-membered heteroaryl substituted with 1, 2, 3, or 4 substituents selected from R 9 in each occurrence is independently hydrogen, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, C 3-5 cycloalkyl, or 3-6 membered heterocycloalkyl, wherein each C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, C 3-5 cycloalkyl, or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, hydroxy, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 3-5 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, (O), and —NR 10 R 11 ; R 10 and R 11 , in each occurrence, are each independently hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 3-5 cycloalkyl, 3- to 6-membered heterocycloalkyl, or C 1-3 alkoxy, or each combine with the N to which it is attached to form a 3- to 6-membered heterocycloalkyl, and each C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 3-5 cycloalkyl, 3- to 6-membered heterocycloalkyl, or C 1-3 alkoxy of said R 10 and said R 11 is each optionally independently halo, hydroxy, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 3-5 substituted with 1, 2, 3, 4, or 5 substituents selected from cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, (O), and —NR 14 R 15 ; R 14 and R 15 , in each occurrence, are each independently hydrogen, hydroxy, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 3-5 cycloalkyl, 3- to 6-membered heterocycloalkyl, or C 1-3 alkoxy, or each, together with the N to which it is attached, combine to form a 3- to 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; the sum of m and n is 0, 1, 2, 3, 4, or 5; 16. The compound of claim 15, wherein q is an integer of 0, 1, 2, 3, 4, or 5.

27. The compound according to claim 27, wherein Y is —(CH 2 ) q — or —(CH 2 ) m O(CH 2 ) n —; R 2b is (a) hydrogen, —CH 3 , —CD 3 , —CH 2 CH 3 , —CD 2 CD 3 , isopropyl, cyclopropyl, —OCH 3 , —OCD 3 , —OCH 2 CH 3 , —OCD 2 CD 3 , isopropoxy, cyclopropoxy, 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or —C(O)NH 2 , or R 2b is (b) —NH 2 ; R 5 is hydrogen, halo, CN, NO 2 , —C(O)CH 3 , —S(O)CH 3 , —S(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 NHCH 3 or —S(O) 2 N(CH 3 ) 2 ; R 6 is hydrogen, —CH 3 , hydroxy, —OCH 3 , —OCD 3 , —NH 2 , —NHCH 3 , or —NH(OCH 3 ), or R 6 is —NH(CH 2 CH 2 )Cl, —NH(CH 2 CH 2 )F, or N-linked morpholino; R 7 is imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, or pyrimidinyl, each optionally substituted with 1, 2, 3, or 4 substituents independently selected from —CH 3 , —CD 3 , —CH 2 CH 3 , —CD 2 CD 3 , isopropyl, cyclopropyl, —OCH 3 , —OCD 3 , —OCH 2 CH 3 , —OCD 2 CD 3 , 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; the sum of m and n is 0, 1, 2, 3, or 4; 16. The compound of claim 15, wherein q is an integer of 0, 1, 2, 3, 4, or 5.

28. Y is -(CH 2 ) 2 -, -O(CH 2 )-, -O(CH 2 ) 2 -, -(CH 2 )O-, or -(CH 2 ) 2 O-; R 2b is (a) —OCH 3 , —OCD 3 , 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or —C(O)NH 2 , or R 2b is (b) —NH 2 ; R 5 is hydrogen, chloro, bromo, or CN; R 6 is hydrogen, hydroxy, —OCH 3 , —OCD 3 , —NH 2 , or —NHCH 3 ; 16. The compound of claim 15, wherein R 7 is imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, or pyrimidinyl, each optionally substituted with 1, 2, 3, or 4 substituents independently selected from -CH 3 , -CD 3 , -CH 2 CH 3 , -CD 2 CD 3 , isopropyl, cyclopropyl, -OCH 3 , -OCD 3 , -OCH 2 CH 3 , -OCD 2 CD 3 , isopropoxy, cyclopropoxy, chloro, and CN.

29. Y is —(CH 2 ) 2 —, —O(CH 2 )—, —O(CH 2 ) 2 —, —(CH 2 )O—, or —(CH 2 ) 2 O—; R 2b is (a) —OCH 3 , —OCD 3 , 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or —C(O)NH 2 , or R 2b is (b) —NH 2 ; R 5 is hydrogen, chloro, bromo, or CN; R 6 is hydrogen, hydroxy, —OCH 3 , —OCD 3 , —NH 2 , or —NHCH 3 ; 16. The compound of claim 15, wherein R7 is methyl-substituted imidazolyl or methyl-substituted triazolyl.

30. Y is —(CH 2 ) 2 —, —O(CH 2 )—, —O(CH 2 ) 2 —, —(CH 2 )O—, or —(CH 2 ) 2 O—; R 2b is (a) —OCH 3 , —OCD 3 , 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or —C(O)NH 2 , or R 2b is (b) —NH 2 ; R 5 is hydrogen, chloro, bromo, or CN; R 6 is hydrogen, hydroxy, —OCH 3 , —OCD 3 , —NH 2 , or —NHCH 3 ; R 7 is 【Chemistry 236】 16. The compound of claim 15, wherein:

31. Y is -(CH 2 ) 2 -, -O(CH 2 )-, -O(CH 2 ) 2 -, -(CH 2 )O-, or -(CH 2 ) 2 O-; R 2b is (a) —OCH 3 , —OCD 3 , 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or —C(O)NH 2 , or R 2b is (b) —NH 2 ; R 5 is hydrogen, chloro, bromo, or CN; R 6 is hydrogen, hydroxy, —OCH 3 , —OCD 3 , —NH 2 , or —NHCH 3 ; R 7 is 【Chemistry 237】 16. The compound of claim 15, wherein:

32. The compound of claim 15, wherein the compound is of formula (III-1), (IIIa-1), or (IIIb-1), or a pharmaceutically acceptable form thereof.

33. The compound of claim 1, wherein the pharmaceutically acceptable form of the compound does not include a salt form.

34. The compound of claim 1, wherein the compound is a racemate, a mixture of diastereomers, or a mixture of stereoisomers, or a pharmaceutically acceptable form thereof.

35. The compound of claim 1, wherein the compound is a single enantiomer or a single diastereomer, or a pharmaceutically acceptable form thereof.

36. The compound of claim 1, wherein the compound is a single enantiomer having the (R) configuration at the R 6 / R 7 substituted carbon, or a pharmaceutically acceptable form thereof.

37. The compound of claim 1, wherein the compound is a single enantiomer having the (S) configuration at the R 6 / R 7 substituted carbon, or a pharmaceutically acceptable form thereof.

38. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

39. A compound selected from the group consisting of: 3-hydroxy-2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4,4-carbonitrile, 3-amino-3-(1-methyl-1H-imidazol-5-yl)-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile, 22-Methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol, 4,4-chloro-2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol, 3-hydroxy-2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4,4-carbonitrile, 3-amino-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile, 4,4-chloro-2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-3-ol, 22-Methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol, 4,4-chloro-2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol, 3-amino-4,4-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2,2-carbonitrile, 4,4-chloro-2,2-methoxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol, 4,4-bromo-2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol, 3-hydroxy-2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4,4-carbonitrile, 3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile, 4,6-chloro-2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-4(3,5)-pyridin-1(1,3)-benzenacyclohexaphan-3-ol, 3-hydroxy-2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-4(3,5)-pyridina-1(1,3)-benzenacyclohexaphane-4,6-carbonitrile, 4,4-chloro-2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-7-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-3-ol, 3-amino-3-(1-methyl-1H-imidazol-5-yl)-2 2 -morpholino-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile, 3-amino-3-(1-methyl-1H-imidazol-5-yl)-2,2-(piperazin-1-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4,4-carbonitrile, 3-amino-3-(1-methyl-1H-imidazol-5-yl)-2 2 -(oxetan-3-ylamino)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile, 3-amino-3-(1-(methyl-d 3 )-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile, 4,4-bromo-2,2-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)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile, 4,4-cyano-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2,2-carboxamide, 4,4-bromo-2,2-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-amine, 4,4-bromo-3-(1-methyl-1H-imidazol-5-yl)-2,2-(oxetan-3-yloxy)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-amine, 3-hydroxy-3-(1-(methyl-d 3 )-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile, 4,4-bromo-2,2-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinazolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol, 4,4-bromo-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinazolina-1,4(1,3)-dibenzenacyclohexaphane-2,3-diamine, 3-amino-3-(1-methyl-1H-imidazol-5-yl)-2 2 -(oxetan-3-yloxy)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-4 4 -carbonitrile, 3-(4-methyl-1H-imidazol-1-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile, 3-(5-methyl-1H-imidazol-1-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile, 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)-dibenzenacycloheptaphan-3-ol, 4,4-chloro-3-(1-methyl-1H-imidazol-5-yl)-7-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-3-ol, and 4,4-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol The compound, including its (R)- or (S)-enantiomer or racemate, or a pharmaceutically acceptable form thereof.

40. A pharmaceutical composition comprising the compound of claim 39 or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

41. The compound of claim 1, 3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile, or its (R)- or (S)-enantiomer, or a pharmaceutically acceptable form thereof.

42. A pharmaceutical composition comprising the compound of claim 41 or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

43. The compound of claim 1, 【Chemical 238】 or a pharmaceutically acceptable form thereof.

44. A pharmaceutical composition comprising the compound of claim 43 or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

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