Macrocyclic compound having farnesyltransferase inhibitory activity

Abstract

The present invention relates to macrocyclic compounds of any of Formula (I) or a pharmaceutically acceptable form thereof, pharmaceutical compositions comprising the same, methods of making the same, and methods of using the same to treat farnesylated protein dependent cancers.

Description

[0001] This application is a divisional application of the Chinese national phase application entitled “Macrocyclic compounds with farnesyltransferase inhibitory activity” and application number “202280079660.6” filed on November 29, 2022. Cross-references

[0003] This application claims the benefit of priority to Chinese Application No. 202111442658.4, filed on November 30, 2021, U.S. Provisional Application No. 63 / 285,412, filed on December 2, 2021, Chinese Application No. 202211471486.8, filed on November 23, 2022, and U.S. Provisional Application No. 63 / 385,117, filed on November 28, 2022. Each of the foregoing related applications is incorporated herein by reference in its entirety. Technical Field

[0004] The present invention relates to macrocyclic compounds useful for treating cancers that are dependent on farnesylation proteins and pharmaceutical compositions comprising the macrocyclic compounds. The present invention also relates to methods for preparing such macrocyclic compounds and pharmaceutical compositions comprising the macrocyclic compounds. The present invention also relates to the use of such macrocyclic compounds and pharmaceutical compositions comprising the macrocyclic compounds in methods for inhibiting farnesyltransferase and methods for treating cancers that are dependent on farnesylation proteins. Background Art

[0005] Activated Ras oncogenes are frequently identified in cancerous tumors, and the converted Ras protein is involved in the proliferation of cancer cells. Ras protein is the protein product of the ras oncogene, a small GTPase that is important in signal transduction, cell growth, and cell proliferation. Shields, JM et al., Trends Cell Biol. 2000, 10, 147-154. Ras protein must associate (or bind) with the inner surface of the plasma membrane to transduce extracellular signals, which may lead to the proliferation of cancer cells.

[0006] In order to bind to the plasma membrane of the cell and transduce extracellular signals, the Ras protein must undergo several post-translational modifications, including farnesylation of the C-terminal cysteine ​​in the CAAX box (wherein 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. Farnesyltransferase (FTase) recognizes the CAAX motif and farnesylates the Ras protein (transferring a 15-carbon farnesyl isoprenoid from farnesyl diphosphate to a cysteine ​​residue). Once farnesylated, the Ras protein can bind to the cell membrane. Inhibiting farnesyltransferase, thereby blocking Ras protein cell membrane binding, represents a path to reduce cell proliferation of cancer cells and may provide potential clinical benefits for cancer patients. Summary of the Invention

[0007] In one aspect, provided herein are compounds of formula (I):

[0008]

[0009]

[0010] or a pharmaceutically acceptable form thereof, wherein:

[0011] The dotted line indicates A 1 With A 2 Single or double bonds between

[0012] A 1 Independent as N, NR 1a , CR 1b or -C(=O)-;

[0013] A 2 are independently N, NR 2a , CR 2b or -C(=O)-;

[0014] A 3 Independently for CR 3 or N;

[0015] A 4 CR 8 or N;

[0016] A 5 and A 6 Each independently CR 8 or N, or A 5 With A 6 Together they are O and NR 9 or S;

[0017] W is C 6-12aryl or 5-12 membered heteroaryl, each of which is optionally substituted by 1-4 R 4 Substituent substitution;

[0018] Y is a bond or a linker of up to 6 atoms in length;

[0019] Z is C 6-12 aryl or 5-12 membered heteroaryl, each of which is optionally substituted by 1-4 R 5 Substituent substitution;

[0020] R 1a and R 2a Each independently is 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)2NR 10 R 11 ;

[0021] R 1b 、R 2b 、R 3 、R 5 and R 8 Each occurrence is independently R 9 、-OR 9 、halogen、CN、NO2、-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)2R 9 、-S(O) p R 9 、-S(O)2NR 10 R 11 or -NR 10 S(O)2NR 10 R 11 ;

[0022] 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, 3-6 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, wherein 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 Cycloalkoxy, 3-6 membered heterocycloalkoxy, C 6-12 Aryl or 5-12 membered heteroaryl is optionally independently substituted by one, two, three, four, five or six groups 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 Substitution with a haloalkoxy group and a substituent of (O);

[0023] 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 、-NR10 C(O)R 9 、-NR 10 C(O)OR 9 、-NR 10 C(O)NR 10 R 11 、-NR 10 S(O)2R 9 、-NR 10 C(NR 10 )NR 10 R 11 、-S(O) p R 9 、-S(O)2NR 10 R 11 or -NR 10 S(O)2NR 10 R 11 ;

[0024] R 7 is a 5-12 membered heteroaryl group, which is optionally substituted by 1-4 independently selected from halogen, CN, NO2, 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)2R 9 、-S(O) p R 9 、-S(O)2NR 10 R 11 and -NR 10 S(O)2NR 10 R 11 Substituents substituted;

[0025] R 9 is independently hydrogen, 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, wherein R 9 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 substituted by one, two, three, four, five or six groups selected from halo, hydroxy, CN, NO2, 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)2R 12 、-S(O) p R 12 、-S(O)2NR 10 R 11 and -NR 10 S(O)2NR 10 R 11 Substituents substituted;

[0026] R 10 and R 11 Each occurrence is independently hydrogen, hydroxyl, C 1-6 Alkyl, C2-6 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, or together with the nitrogen to which they are attached, form a 3-6 membered heterocycloalkyl, wherein 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 substituted by one, two, three, four, five or six groups selected from halo, hydroxy, CN, NO2, 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)2R 13 、-S(O) p R 13 、-S(O)2NR 14 R 15 and -NR 14 S(O)2NR 14 R15 Substituents substituted;

[0027] R 12 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, 3-6 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl, wherein 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 are each optionally independently substituted by one, two, three, four, five or six groups selected from halo, hydroxy, CN, NO2, 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)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)2R 13 、-S(O) p R 13 、-S(O)2NR 10 R 11 and -NR10 S(O)2NR 10 R 11 Substituents substituted;

[0028] R 13 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 3-6 membered heterocycloalkyl;

[0029] R 14 and R 15 Each occurrence is independently hydrogen, hydroxyl, 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 together with the nitrogen to which they are attached, form a 3-6 membered heterocycloalkyl; and

[0030] Each p is independently an integer of 0, 1 or 2.

[0031] In certain embodiments, the compound of formula (I) is a compound of formula (II):

[0032]

[0033] in:

[0034] W 1 、W 2 、W 3 and W 4 Each independently is N or CR 4 , or W 1 With W 2 Together they are O and NR 4A or S or W 2 With W 3 Together they are O and NR 4A or S;

[0035] Z 1 、Z 2 、Z 3 and Z 4 Each independently is N or CR 5 , or Z 2 With Z3 Together they are O and NR 5A Or S, or Z 3 With Z 4 Together they are O and NR 5A or S; and

[0036] 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, wherein 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 is optionally independently substituted by one, two, three, four, five or six 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 Substitution with a haloalkoxy group and a substituent of (O);

[0037] or a pharmaceutically acceptable form thereof.

[0038] In certain embodiments, the compound of formula (I) is a compound of formula (III):

[0039]

[0040] in:

[0041] W 1 、W 2 、W 3 and W 4 Each independently is N or CR 4 , or W 1 With W 2 Together they are O and NR 4A or S or W 2 With W 3 Together they are O and NR 4A or S;

[0042] Z 1 , Z 2 , Z 3 and Z 4 Each independently is N or CR 5 , or Z 2 With Z 3 Together they are O and NR 5A Or S, or Z 3 With Z 4 Together they are O and NR 5A or S; and

[0043] 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, wherein 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 is optionally independently substituted by one, two, three, four, five or six groups 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 Substitution with a haloalkoxy group and a substituent of (O);

[0044] or a pharmaceutically acceptable form thereof.

[0045] In certain embodiments, the compound of formula (I) is a compound of formula (IV):

[0046]

[0047] in:

[0048] W 1 、W 2 、W 3 and W 4 Each independently is N or CR4 , or W 1 With W 2 Together they are O and NR 4A or S or W 2 With W 3 Together they are O and NR 4A or S;

[0049] Z 1 , Z 2 , Z 3 and Z 4 Each independently is N or CR 5 , or Z 2 With Z 3 Together they are O and NR 5A Or S, or Z 3 With Z 4 Together they are O and NR 5A or S; and

[0050] 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, wherein 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 is optionally independently substituted by one, two, three, four, five or six groups 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 Substitution with a haloalkoxy group and a substituent of (O);

[0051] or a pharmaceutically acceptable form thereof.

[0052] In certain embodiments, the compound of formula (I) is a compound of formula (V):

[0053]

[0054] in:

[0055] W 1 、W 2 、W 3 and W 4 Each independently is N or CR 4 , or W 1 With W 2 Together they are O and NR 4A or S or W 2 With W 3 Together they are O and NR 4A or S;

[0056] Z 1 、Z 2 、Z 3 and Z 4 Each independently is N or CR 5 , or Z 2 With Z 3 Together they are O and NR 5A Or S, or Z 3 With Z 4 Together they are O and NR 5A or S; and

[0057] 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, wherein 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 is optionally independently substituted by 1-6 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 Substitution with a haloalkoxy group and a substituent of (O);

[0058] or a pharmaceutically acceptable form thereof.

[0059] In certain embodiments, the compound of formula (I) is a compound of formula (VI):

[0060]

[0061] in:

[0062] W 1 、W 2 、W 3 and W 4 Each independently is N or CR 4 , or W 1 With W 2 Together they are O and NR 4A or S or W 2 With W 3 Together they are O and NR 4A or S;

[0063] Z 1 , Z 2 , Z 3 and Z 4 Each independently is N or CR 5 , or Z 2 With Z 3 Together they are O and NR 5A Or S, or Z 3 With Z 4 Together they are O and NR 5A or S; and

[0064] 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, wherein 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 is optionally independently substituted by 1-6 independently selected from halo, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Substitution with a haloalkoxy group and a substituent of (O);

[0065] or a pharmaceutically acceptable form thereof.

[0066] In certain embodiments, provided herein are compounds of Formula (I)-(II)-(III) or (IV)-(V) or (VI)-(V) wherein Y is a bond. In certain embodiments, Y is a linker of up to 5 atoms, up to 4 atoms, up to 3 atoms, or up to 2 atoms in length. In certain embodiments, Y is in the orientation ZYW (wherein Z refers to Z or a ring containing Z, and W refers to W or a ring containing W, all of which apply to Formula (I)-(II)-(III) or (IV)-(V) or (VI) and subformulas thereof). In certain embodiments, Y is C 1-6 Alkylene, wherein one or more -CH2- 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)2N(R 10 )-or-N(R 10 )S(O)2N(R 11 In certain 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 )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)2N(R 10 )(CR 16 R 17 ) n -or-(CR 16 R 17 ) m N(R 10 )S(O)2N(R 11 )(CR 16 R 17 ) n -;

[0067] in:

[0068] R 16 and R 17 Each occurrence is independently hydrogen, halo, hydroxy, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6Heteroalkyl, 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 3-6 membered heterocycloalkoxy, or together with the C to which they are connected, form C(O), C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

[0069] Each m is independently an integer of 0, 1, 2 or 3;

[0070] Each n is independently an integer of 0, 1, 2 or 3;

[0071] Where the sum of m and n is 0, 1, 2, 3, 4, 5 or 6;

[0072] Each p is independently an integer of 0, 1 or 2; and

[0073] Each q is independently an integer of 0, 1, 2, 3, 4, 5 or 6.

[0074] In certain embodiments, provided herein are compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or Formula (V), or Formula (VI), wherein R 7 is imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl or pyrimidinyl, each of which is optionally substituted by 1-4 groups independently selected from halogen, CN, NO2, 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)2R 9 、-S(O) p R 9 、-S(O)2NR 10 R 11 or -NR 10 S(O)2NR 10 R11 substituted by a substituent.

[0075] In certain embodiments, provided herein are compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or Formula (V), or Formula (VI), wherein 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 .

[0076] In certain embodiments, provided herein are compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or Formula (V), or Formula (VI), wherein 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 .

[0077] In certain embodiments, provided herein are compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or Formula (V), or Formula (VI), wherein R 10 and R 11 Together they form a divalent group, such as -(CH2) x -, wherein x = 2-5; -CH2CH2OCH2CH2-; or -CH2CH2NR 18 CH2CH2-, where R 18 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, 3-6 membered heterocycloalkyl or 5-12 membered heteroaryl.

[0078] In certain embodiments, provided herein are compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), or Formula (V), or Formula (VI), wherein R 6 is hydrogen, -CH3, hydroxy, -OCH3, -OCD3, -NH2, -NHCH3 or -NH(OCH3). In some embodiments, R 6 is -NH(CH2CH2)Cl, -NH(CH2CH2)F or an N-linked morpholinyl.

[0079] In certain embodiments, provided herein are compounds of Formula (I), (II), (III), (IV), (V), or (VI), wherein the compound has a MW of no more than 1,000 g / mol. In certain embodiments, the compound has a MW of no more than 900 g / mol, no more than 800 g / mol, no more than 700 g / mol, no more than 600 g / mol, or no more than 500 g / mol. In certain embodiments, the compound has a MW of no more than 600 g / mol. In certain embodiments, the compound has a MW of no more than 500 g / mol.

[0080] In certain embodiments, provided herein are compounds of Formula (I), (II), (III), (IV), (V), or (VI), wherein the compound is a racemate or a mixture of diastereomers or a mixture of stereoisomers.

[0081] 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):

[0082]

[0083] or a pharmaceutically acceptable form thereof.

[0084] 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):

[0085]

[0086] or a pharmaceutically acceptable form thereof.

[0087] In certain embodiments, the compound of formula (II) is a compound of formula (II-1):

[0088]

[0089] or a pharmaceutically acceptable form thereof.

[0090] 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):

[0091]

[0092] or a pharmaceutically acceptable form thereof.

[0093] In certain embodiments, the compound of formula (II) is a compound of formula (II-2):

[0094]

[0095] or a pharmaceutically acceptable form thereof.

[0096] 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):

[0097]

[0098] or a pharmaceutically acceptable form thereof.

[0099] 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):

[0100]

[0101] or a pharmaceutically acceptable form thereof.

[0102] In certain embodiments, the compound of formula (III) is a compound of formula (III-1):

[0103]

[0104] or a pharmaceutically acceptable form thereof.

[0105] 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):

[0106]

[0107] or a pharmaceutically acceptable form thereof.

[0108] In certain embodiments, the compound of formula (III) is a compound of formula (III-2):

[0109]

[0110]

[0111] or a pharmaceutically acceptable form thereof.

[0112] 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):

[0113]

[0114] or a pharmaceutically acceptable form thereof.

[0115] In certain embodiments, the compound of formula (III) is a compound of formula (III-3):

[0116]

[0117] or a pharmaceutically acceptable form thereof.

[0118] In some embodiments, the compound of formula (III-3) is a compound of formula (IIIa-3) or formula (IIIb-3):

[0119]

[0120] or a pharmaceutically acceptable form thereof.

[0121] 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):

[0122]

[0123] or a pharmaceutically acceptable form thereof.

[0124] In certain embodiments, the compound of formula (IV) is a compound of formula (IV-1):

[0125]

[0126] or a pharmaceutically acceptable form thereof.

[0127] 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):

[0128]

[0129] or a pharmaceutically acceptable form thereof.

[0130] In certain embodiments, the compound of formula (IV) is a compound of formula (IV-2):

[0131]

[0132] or a pharmaceutically acceptable form thereof.

[0133] 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):

[0134]

[0135] or a pharmaceutically acceptable form thereof.

[0136] In some embodiments, the compound of Formula (V) is a compound of Formula (Va) or Formula (Vb):

[0137]

[0138] or a pharmaceutically acceptable form thereof.

[0139] In some embodiments, the compound of formula (V) is a compound of formula (V-1):

[0140]

[0141] or a pharmaceutically acceptable form thereof.

[0142] In some embodiments, the compound of formula (V-1) is a compound of formula (Va-1) or formula (Vb-1):

[0143]

[0144] or a pharmaceutically acceptable form thereof.

[0145] In some embodiments, the compound of formula (VI) is a compound of formula (VIa) or formula (VIb):

[0146]

[0147] or a pharmaceutically acceptable form thereof.

[0148] In some embodiments, the compound of formula (VI) is a compound of formula (VI-1):

[0149]

[0150] or a pharmaceutically acceptable form thereof.

[0151] In some embodiments, the compound of formula (VI-1) is a compound of formula (VIa-1) or formula (VIb-1):

[0152]

[0153] or a pharmaceutically acceptable form thereof.

[0154] In certain embodiments, compounds of Formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2) as disclosed herein, such as Formula (Ia), (Ib), (IIa), (IIa-1), (IIa-2), (IIb), (IIb-1), (IIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb), (IIIb-1), A compound of Formula (IIIb-2), (IVa-1), (IVa-2), (IVb-1), (IVb-2), or (III-3), (IIIa-3), (IIIb-3), (IIIb-3), (V), (Va-1), (Vb-1), (VI), (VIa-1), (VIb-1), (VIa-1), or (VIb-1), or a pharmaceutically 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 greater than 10% of the (R)-enantiomer, such as an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more of the (R)-enantiomer. In certain embodiments, the compounds disclosed herein are the (S)-enantiomers. In certain embodiments, the compounds disclosed herein have an enantiomeric excess of the (S)-enantiomer greater than 10%, such as an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more of the (S)-enantiomer.

[0155] In certain embodiments, provided herein are pharmaceutical compositions comprising 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), (IIIa), (IIIa-1), (IIIa-2), (IIIb), (IIIb-1), (IIIb-2), (III Ib-2), a compound of Formula (IVa), Formula (IVa-1), Formula (IVa-2), Formula (IVb), Formula (IVb-1) or Formula (IVb-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), Formula (IIIa-3), Formula (IIIb-3), Formula (V), Formula (Va), Formula (Vb), Formula (V-1), Formula (Va-1), Formula (Vb-1), Formula (VI), Formula (VIa), Formula (VIb), Formula (VI-1), Formula (VIa-1), or Formula (VIb-1), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0156] In certain embodiments, compounds of Formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2) as disclosed herein, such as Formula (Ia), (Ib), (IIa), (IIa-1), (IIa-2), (IIb), (IIb-1), (IIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb), (IIIb-1), (IIIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb), (IIIb-1), (IIIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb), (IIIb-1), (IIIb-2), (IIIa), (IIIa-2), (IIIb-1), (IIIb-2), (IIIa-2), (IIIb-1), (IIIb-2), (IIIb-2)

[0014] A compound of Formula (IVa)-2, (IVa)-1, (IVa-2), (IVb)-1, (IVb-2), or (IVb-1), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), (IIIa-3), (IIIb-3), (IIIb-3), (V), (Va)-2, (Vb)-3, (V-1), (Va-1), (Vb-1), (VI), (VIa)-3, (VIb)-1, (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof, is a farnesyltransferase inhibitor. In certain embodiments, the compounds as disclosed herein, or pharmaceutically acceptable forms thereof, are selective farnesyltransferase inhibitors with respect to inhibition of type 1 geranylgeranyltransferase, such as type 1 geranylgeranyltransferase.

[0157] In certain embodiments, a compound of Formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2) as disclosed herein, for example, 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-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9), (IVa-1), (IVa-2), (IVa-1), (IVa-2), (IVb), (IIIb-1), (IIIb-2), (IVa-1), (IVa-2), (IVa-1), (IVa-2), (IVb-2), (IVa-1), (IVa-2), (IVa-2) -1), a compound of Formula (IVa-2), Formula (IVb), Formula (IVb-1) or Formula (IVb-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), Formula (IIIa-3), Formula (IIIb-3), Formula V), Formula (Va-), Formula (Vb), Formula V-1), Formula (Va-1), Formula (Vb-1), Formula VI), Formula VIa), Formula VIb, Formula VI-1, Formula (VIa-1), or Formula (VIb-1), or a pharmaceutically acceptable form thereof, is metabolically stable, for example, metabolically stable to liver metabolism in a subject, such as to liver metabolism in a human.

[0158] In certain embodiments, provided herein are methods of inhibiting farnesyltransferase, comprising reacting the farnesyltransferase with an 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), (IIIa-2), (IIIb-3), (IIIa-4), (IIIa-5), (IIIa-6), (IIIa-7), (IIIa-8), (IIIa-9), (IIIa-1), (IIIa-1), (IIIa-2), (IIIb-1), (IIIb-1), (IIIb-2), (IIIa-1), (IIIa-2), (III Ib), Formula (IIIb-1), Formula (IIIb-2), Formula (IVa), Formula (IVa-1), Formula (IVa-2), Formula (IVb), Formula (IVb-1) or Formula (IVb-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), Formula (IIIa-3), Formula (IIIb-3), Formula V), Formula Va), Formula Vb, Formula V-1, Formula Va-1, Formula Vb-1, Formula VI), Formula VIa), Formula VIb, Formula VI-1, Formula (VIa-1) or Formula (VIb-1), or a pharmaceutically acceptable form thereof. In certain embodiments, provided herein are methods of inhibiting farnesyltransferase, comprising contacting the farnesyltransferase with an effective amount of a pharmaceutical composition comprising an agent of Formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), e.g., an agent of Formula (Ia), (Ib), (IIa), (IIa-1), (IIa-2), (IIb), (IIb-1), (IIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb-2), (IIIa), (IIIa-1), (IIIa-2), (IIIb-3), (IIIb-4), (IIIb-5), (IIIb-6), (IIIb-7), (IIIb-8), (IIIb-9), (IIIb-1), (IIIb-1), (IIIb-2), (III ), a compound of formula (IIIb-1), formula (IIIb-2), formula (IVa), formula (IVa-1), formula (IVa-2), formula (IVb), formula (IVb-1), or formula (IVb-2), or a pharmaceutically acceptable form thereof, or a compound of formula (III-3), formula (IIIa-3), formula (IIIb-3), formula (V), formula (Va), formula (Vb), formula (V-1), formula (Va-1), formula (Vb-1), formula (VI), formula (VIa), formula (VIb), formula (VI-1), formula (VIa-1), or formula (VIb-1), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. In certain embodiments, the method of inhibiting farnesyltransferase inhibits farnesylation of an H-Ras protein. In certain embodiments, the H-Ras protein has a mutation. In certain embodiments, the method of inhibiting farnesyltransferase inhibits farnesylation of an N-Ras protein.In certain embodiments, the N-Ras protein has a mutation.

[0159] In certain embodiments, provided herein are methods for treating a cancer that is dependent on a farnesylated protein in a subject, the methods comprising administering to a subject having a cancer that is dependent on a farnesylated protein 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), (III-2), (IV), (IV-1), or (IV-2). or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), Formula (IIIa-3), Formula (IIIb-3), Formula (V), Formula (Va), Formula (Vb), Formula (V-1), Formula (Va-1), Formula (Vb-1), Formula (VI), Formula (VIa), Formula (VIb), Formula (VI-1), Formula (VIa-1) or Formula (VIb-1) or a pharmaceutically acceptable form thereof. In certain embodiments, provided herein are methods for treating a cancer that is dependent on a farnesylated protein in a subject, the methods comprising administering to a subject having a cancer that is dependent on a farnesylated protein a therapeutically effective amount of a pharmaceutical composition comprising 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), (III-3), (III-4), (III-5), (III-6), (III-7), (III-8), (III-9), (III-10), (III-11), (III-12), (IV-13), (IV-14), or (IV-2).

[0014] The present invention relates to a compound of formula (Ia-2), formula (IIIb), formula (IIIb-1), formula (IIIb-2), formula (IVa), formula (IVa-1), formula (IVa-2), formula (IVb), formula (IVb-1), or formula (IVb-2), or a pharmaceutically acceptable form thereof, or a compound of formula (III-3), formula (IIIa-3), formula (IIIb-3), formula (V), formula (Va), formula (Vb), formula (V-1), formula (Va-1), formula (Vb-1), formula (VI), formula (VIa), formula (VIb), formula (VI-1), formula (VIa-1), or formula (VIb-1), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. In certain embodiments, the cancer that depends on farnesylation of a protein is a solid tumor.In certain embodiments, the cancer that depends on farnesylated proteins is a cancer that depends on farnesylated H-Ras protein. In certain embodiments, the cancer that depends on farnesylated proteins has an H-Ras protein mutation. In certain embodiments, the cancer that depends on farnesylated proteins is head and neck cancer. In certain embodiments, the cancer that depends on farnesylated proteins is squamous cell carcinoma (SCC). In certain embodiments, head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In certain embodiments, provided herein is a method for treating a subject's cancer that depends on farnesylated proteins, wherein the subject is human.

[0160] In certain embodiments, provided herein are methods for treating a cancer that is dependent on a farnesylated protein in a subject, the methods comprising administering to a subject having a cancer that is dependent on a farnesylated protein 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), (III-2), (IV), (IV-1), or (IV-2). or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), Formula (IIIa-3), Formula (IIIb-3), Formula (V), Formula (Va), Formula (Vb), Formula (V-1), Formula (Va-1), Formula (Vb-1), Formula (VI), Formula (VIa), Formula (VIb), Formula (VI-1), Formula (VIa-1) or Formula (VIb-1) or a pharmaceutically acceptable form thereof. In certain embodiments, provided herein are methods for treating a cancer that is dependent on a farnesylated protein in a subject, the methods comprising administering to a subject having a cancer that is dependent on a farnesylated protein a therapeutically effective amount of a pharmaceutical composition comprising 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), (III-3), (III-4), (III-5), (III-6), (III-7), (III-8), (III-9), (III-10), (III-11), (III-12), (IV-13), (IV-14), or (IV-2).

[0014] The present invention relates to a compound of formula (Ia-2), formula (IIIb), formula (IIIb-1), formula (IIIb-2), formula (IVa), formula (IVa-1), formula (IVa-2), formula (IVb), formula (IVb-1), or formula (IVb-2), or a pharmaceutically acceptable form thereof, or a compound of formula (III-3), formula (IIIa-3), formula (IIIb-3), formula (V), formula (Va), formula (Vb), formula (V-1), formula (Va-1), formula (Vb-1), formula (VI), formula (VIa), formula (VIb), formula (VI-1), formula (VIa-1), or formula (VIb-1), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. In certain embodiments, the cancer that depends on farnesylation of a protein is a solid tumor.In certain embodiments, the cancer that depends on farnesylated proteins is a cancer that depends on farnesylated N-Ras proteins. In certain embodiments, the cancer that depends on farnesylated proteins has an N-Ras protein mutation. In certain embodiments, the cancer that depends 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 for treating a cancer that depends on farnesylated proteins in a subject, wherein the subject is human. DETAILED DESCRIPTION

[0161] In one embodiment, provided herein are compounds having the structure of any one of Formula (I) (Ia)-C, (IIa)-C, (IIb)-D, (IIIa)-IIIb, (IVa)-IVb), or (IVb) or pharmaceutically acceptable forms thereof. In one embodiment, provided herein are compounds having the structure of any one of Formula (Ia)-C, (Ib)-C, (IIa)-IIIb, (IIIb)-IVa)-IVb, or pharmaceutically acceptable forms thereof. In one embodiment, provided herein are compounds having the structure of any one of Formula (Va)-C, (Vb)-Via)-VIb, or (VIb) or pharmaceutically acceptable forms thereof. In one embodiment, provided herein are compounds having the structure of any one of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof. In one embodiment, provided herein are compounds having the structure of any one of Formula (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof.

[0162] In one embodiment, provided herein are pharmaceutical compositions comprising a compound having the structure of any one of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, provided herein are pharmaceutical compositions comprising a compound having the structure of Formula (V) or Formula (VI), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, provided herein are pharmaceutical compositions comprising a compound having the structure of any one of Formula (Ia), Formula (Ib), Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb), Formula (IVa), or Formula (IVb), or a pharmaceutically acceptable form thereof, or a compound having the structure of any one of Formula (Va), Formula (Vb), Formula (VIa), or Formula (VIb), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, provided herein are pharmaceutical compositions comprising a compound having the structure of any one of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as a compound having the structure 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 pharmaceutically acceptable form thereof, or a compound having the structure of any one of Formula (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0163] In another embodiment, a method for treating a cancer that is 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 Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or administering a pharmaceutical composition comprising the same. In another embodiment, a method for treating a cancer that is 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 Formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or administering a pharmaceutical composition comprising the same. In another embodiment, a method for treating a cancer that is 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 Formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or administering to a subject a pharmaceutical composition comprising the same. In another embodiment, a method for treating cancer is provided, which comprises administering to a subject a therapeutically effective amount of a compound having the structure of any one of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof, or administering a pharmaceutical composition comprising the same. Described herein are examples of cancers that are dependent on farnesylated proteins that can be treated according to the therapeutic methods provided herein.

[0164] While specific embodiments have been discussed, this description is illustrative only and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art after reviewing this description.

[0165] Unless defined otherwise, 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 belongs.

[0166] As used herein, the articles "a", "an" and "the" refer to one or more than one grammatical object of the article. For example, a sample refers to one sample or two or more samples.

[0167] As used herein and unless otherwise indicated, the term "about" or "approximately" means the 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.

[0168] As used herein, the term "administer," "administering," or "administration" refers to the act of delivering or causing a compound or pharmaceutical composition to be delivered to a subject's body by any of the methods described herein or otherwise known in the art. Administering a compound or pharmaceutical composition includes prescribing a compound or pharmaceutical composition to be delivered to a patient. Exemplary administration forms include oral dosage forms such as tablets, capsules, syrups, suspensions; injectable dosage forms such as intravenous (IV), intramuscular (IM), or intraperitoneal (IP); transdermal dosage forms including creams, gels, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and rectal suppositories.

[0169] The term "effective amount" or "therapeutically effective amount" or "dose" refers to an amount of a compound or pharmaceutical composition described herein that is sufficient to achieve the intended application, including but not limited to disease treatment as described below. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo) or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on, for example, the specific compound selected, the dosing regimen to be followed, whether it is administered in combination with other agents, the time of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. In certain embodiments, a therapeutically effective amount is sufficient to provide a therapeutic benefit or to delay or minimize one or more symptoms associated with the disease or condition in the treatment or management of the disease or condition. The term also refers to an amount of a compound that is sufficient to elicit the biological or medical response of a biomolecule (e.g., protein, enzyme, RNA or DNA), cell, tissue, system, animal or human that is sought by a researcher, veterinarian, physician or clinician.

[0170] "Enantiomer" is a pair of stereoisomers that are mirror images that cannot be superimposed on each other. A pair of enantiomers can be referred to as a "racemic" mixture in any ratio. Where appropriate, the terms "(±)" or "(rac)" are used to represent a racemic mixture. "Diastereomer" is a stereoisomer that has at least two asymmetric atoms but is not a mirror image of each other. Absolute stereochemistry can be specified according to the Cahn-Ingold-Prelog RS system. When a compound is an enantiomer, the stereochemistry of each chiral carbon can be specified by R or S. The unknown split compound of absolute configuration can be specified as (+) or (-) according to the direction (right-handed or left-handed) of rotation of the plane polarized light of the sodium D line wavelength. Certain compounds described herein contain one or more asymmetric centers and therefore can produce enantiomers, diastereomers and other stereoisomeric forms, which can be defined as (R)- or (S)- according to the absolute stereochemistry of each asymmetric atom. The chemical entity, pharmaceutical composition and method of the present invention are intended to include all such possible isomers, including racemic mixtures, substantially optically 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.

[0171] The "enantiomeric excess" or "% enantiomeric excess" of a composition (e.g., a composition comprising a mixture of enantiomers of a compound) can be calculated using the equation shown below. In the examples 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 considered to have an enantiomeric excess of 80%.

[0172] ee=(90-10) / 100=80%.

[0173] In some embodiments, the compounds described herein are mixtures of enantiomers of the compounds and contain 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 contain an enantiomeric excess of the S enantiomer relative to the R enantiomer. In other embodiments, the compounds described herein are mixtures of enantiomers of the compounds and contain 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 contain an enantiomeric excess of the R enantiomer relative to the S enantiomer.

[0174] For example, in some embodiments, an isomer / enantiomer may be substantially free of the corresponding enantiomer, and may also be referred to as "optically enriched," "enantiomerically enriched," "enantiomerically pure," and "non-racemic," which are used interchangeably herein. These terms refer to compositions in which the amount of one enantiomer is greater than the amount of the one enantiomer in a control mixture of the racemic composition (e.g., greater than 1:1 by weight). For example, an enantiomerically enriched preparation of the S enantiomer means a preparation of a compound having greater than about 50% by weight of the S enantiomer, such as at least about 55% by weight, at least about 60% by weight, at least about 65% by weight, at least about 70% by weight, at least about 75% by weight, further such as at least about 80% by weight, relative to 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, thereby providing a "substantially enantiomerically enriched," "substantially enantiomerically pure," or "substantially non-racemic" preparation, which refers to a composition preparation having at least about 85% by weight (such as at least about 90% by weight, and further such as at least about 95% by weight) of one enantiomer relative to 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.

[0175] In some embodiments, the compound is a racemic mixture of (S)- and (R)-isomers. In other embodiments, provided herein are mixtures of compounds wherein the individual compounds of the mixture exist predominantly in the (S)- or (R)-isomer configuration. For example, in some embodiments, the compound mixture has 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%, or about 99.5% or more. 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%.

[0176] 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%, or about 99.5% or more. In some embodiments, the compound mixture has an (R)-enantiomeric excess of about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or greater than about 99.5%.

[0177] In other embodiments, the compound mixture contains identical chemical entities except for 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 for each identical chemical entity, -CH(R)- is in the (S)- or (R)- stereochemical orientation (i.e., (S)- or (R)-stereoisomer). 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 primarily (S)-isomers or primarily (R)-isomers. For example, in some embodiments, the (S)-isomer in the mixture of the same 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%, or about 99.5% by weight or more relative to the total weight of the mixture of (S)- and (R)-isomers. In some embodiments, the (S)-enantiomer in the mixture of identical chemical entities (i.e., a mixture of stereoisomers) is present in an (S)-enantiomeric excess of about 10% to about 99.5%, about 20% to about 99.5%, about 30% to about 99.5%, about 40% to about 99.5%, about 50% to about 99.5%, about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or greater than about 99.5%. In other embodiments, the (R)-isomer in the mixture of the same 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%, or about 99.5% by weight or more relative to the total weight of the mixture of (S)- and (R)-isomers.In some embodiments, the (R)-isomer in the mixture of identical chemical entities (i.e., a mixture of stereoisomers) is present at an (R)-enantiomeric excess of about 10% to about 99.5%, about 20% to about 99.5%, about 30% to about 99.5%, about 40% to about 99.5%, about 50% to about 99.5%, about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or greater than about 99.5%. Enantiomers can be separated 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), the formation and crystallization of chiral salts, or 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).

[0178] It should be further understood that, in accordance with the above discussion of enantiomeric enrichment and enantiomeric excess, references to compounds disclosed herein having one or more stereocenters without designation of a specific chirality (e.g., R- or S-enantiomer) should be understood to refer to the compounds as racemic mixtures (or diastereomeric mixtures), while inclusion of the R- or S- designation should be understood to refer to the enantiomeric (or diastereomeric) forms of the compounds, such as enantiomerically (or diastereomeric) enriched forms of the compounds, or enantiomeric excess of a specified enantiomer of the compound. The designation of compounds with R- or S- designations should be 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.

[0179] In certain embodiments, pharmaceutically acceptable forms are isomers. "Isomers" are different compounds with 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 arrangement of their atoms in space. As used herein, the term "isomer" includes any and all geometric isomers and stereoisomers. For example, "isomers" include geometric double bond cis and trans isomers, also known as E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof as fall within the scope of this disclosure.

[0180] Unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except for the replacement or enrichment of one or more hydrogen atoms in a molecule with deuterium or tritium, or the replacement or enrichment of one or more carbon atoms in a molecule with 13 C or 14 C substitution or enrichment, compounds having the structures of the present invention are within the scope of the present disclosure. In one embodiment, provided herein are isotopically labeled compounds, one or more of which are replaced or enriched with deuterium. In one embodiment, provided herein are isotopically labeled compounds, one or more of which are replaced or enriched with tritium. In one embodiment, provided herein are isotopically labeled compounds, one or more of which are replaced or enriched with tritium. 13 In one embodiment, provided herein are isotopically labeled compounds wherein one or more carbon atoms are replaced or enriched by 14 C replacement or enrichment.

[0181] The term "isotopologue" refers to isotopically enriched compounds that are identical to those recited herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 32 P. 33 P. 33 S. 34 S. 35S. 36 S. 18 F. 35 Cl, 36 Cl and 37 Cl, each of which is also within the scope of this specification. For example, compounds having the structures of the present invention are within the scope of this disclosure except that one or more hydrogen atoms in the molecule are replaced or enriched with deuterium or tritium. In one embodiment, provided herein are isotopically labeled compounds wherein one or more hydrogen atoms are replaced or enriched with deuterium. In one embodiment, provided herein are isotopically labeled compounds wherein one or more hydrogen atoms are replaced or enriched with tritium. In addition, compounds labeled with heavier isotopes such as deuterium (i.e., 2 H)) substitution may provide certain therapeutic advantages due to greater metabolic stability (e.g., increased half-life in vivo or reduced dosage requirements). Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for an unlabeled reagent. An isotopically enriched compound of Formula (I), Formula (II), Formula (III) or Formula (IV), or a pharmaceutically acceptable form thereof, or an isotopically enriched compound of Formula (V) or Formula (VI), such as a compound of Formula (Ia), Formula (Ib), Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb), Formula (IVa) or Formula (IVb), such as a compound of Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (IV-1) or Formula (IV-2), such as a compound of Formula (IIa-1), Formula (IIb-1), Formula (IIa-2), Formula (IIb-2), Formula (IIIa-1), Formula (IVa-2), Formula (III ...b-1), Formula (IIIb-2), Formula (IIIb-2), Formula (IIIb-1), Formula (IIIb-2), Formula (IIIb-2), Formula (III A compound of Formula (IIIa-1), Formula (IIIb-2), Formula (IIIb-2), Formula (IVa-1), Formula (IVb-1), Formula (IVa-2) or Formula (IVb-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), Formula (IIIa-3), Formula (IIIb-3), Formula (Va-1), Formula (Va-1), Formula (Vb-1), Formula (VIa-1), Formula (VIb-1), Formula (VIa-1) or Formula (VIb-1), or a pharmaceutically acceptable form thereof, can generally be prepared using procedures known to those of ordinary skill in the art by substituting an appropriately isotopically enriched reagent for a non-isotopically enriched reagent.

[0182] When a compound is deuterium-enriched, the deuterium-to-hydrogen ratio on the deuterated atoms of the molecule substantially exceeds the natural deuterium-to-hydrogen ratio.

[0183] The embodiments described herein may include isotopologues of compounds of Formula (I), (II), (III), or (IV), or pharmaceutically acceptable forms thereof, for example, 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), (IIIb-1), (IIIa-2), (IIIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IIIa-1), (IIIb-2), (IIIa-2), (IIIb-1), (IIIb-2), (IIIa-2), (IIIb-2), (IIIa-1), (IIIb-2), (IIIa-2), (IIIb-3), (IIIb-4), (IIIb-5), (IIIb-6), (IIIb-7), (IIIb-8), (IIIb-9), (IIIb-1), (IIIb-1), (IIIb-1), (IIIb-2), (IIIa-2), (IIIb-1), (IIIb-2), (IIIa-2), (IIIb-3), (IIIb-1), (IIIb-2), (IIIa-3), (IIIb-1), (IIIb-2), (IIIa-3), (IIIb-3), (IIIb-4), (IIIb-5). ), a compound of Formula (IIIb-2), Formula (IVa-1), Formula (IVb-1), Formula (IVa-2) or Formula (IVb-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), Formula (IIIa-3), Formula (IIIb-3), Formula (Va-), Formula (Vb-), Formula (V-1), Formula (Va-1), Formula (Vb-1), Formula (VIa), Formula (VIb), Formula (VI-1), Formula (VIa-1) or Formula (VIb-1), or a pharmaceutically acceptable form thereof, wherein the isotopologue has one or more deuterium atoms substituted on one or more atomic members of the compound or its pharmaceutically acceptable form in place of one or more hydrogen atoms. The embodiments described herein may include compounds of Formula (I), (II), (III), or (IV), or pharmaceutically acceptable forms thereof, for example, 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), (IIb), (IIIb), (IVa-2), (IVb-1), (IIb), (IVa-2), (IVb-2), (IIIa-1), (IIb), (IV-1), or (IV-2). Ib-1), a compound of Formula (IIIa-2), Formula (IIIb-2), Formula (IVa-1), Formula (IVb-1), Formula (IVa-2) or Formula (IVb-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), Formula (IIIa-3), Formula (IIIb-3), Formula (Va), Formula (Vb), Formula (V-1), Formula (Va-1), Formula (Vb-1), Formula (VIa), Formula (VIb), Formula (VI-1), Formula (VIa-1) or Formula (VIb-1), or a pharmaceutically acceptable form thereof, wherein the carbon atom can have 1 to 3 hydrogen atoms optionally replaced by deuterium.

[0184] As used herein, "pharmaceutically acceptable forms" of the compounds disclosed herein include, but are not limited to, pharmaceutically acceptable salts, solvates, isomers, and isotopologues (i.e., isotopically labeled derivatives) of the compounds disclosed herein. In one embodiment, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, solvates, isomers, and isotopologues (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 pharmaceutically acceptable salts, hydrates, stereoisomers, and isotopologues of a compound of Formula (I), (II), (III), or (IV) or a compound of Formula (V) or (VI) as disclosed herein. In one embodiment, pharmaceutically acceptable forms include, but are not limited to, pharmaceutically acceptable salts, solvates, isomers, and isotopologues (i.e., isotopically labeled derivatives) of a compound of Formula (Ia)-(Ib)-(IIa)-(IIb)-(IIId)-(IIId)-(IVa)-(IVb) or a compound of Formula (Va)-(Vb)-(VIa)-(VIb) as disclosed herein, such as pharmaceutically acceptable salts, hydrates, stereoisomers, and isotopologues of a compound of Formula (Ia)-(Ib)-(IIa)-(IIb)-(IIId)-(IIId)-(IVa)-(IVb) or a compound of Formula (Va)-(Vb)-(VIa)-(VIb) disclosed herein. In one embodiment, pharmaceutically acceptable forms include, but are not limited to, pharmaceutically acceptable salts, solvates, isomers, and isotopologues (i.e., isotopically labeled derivatives) of a compound of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2) as disclosed herein, such as Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or Formula (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1).In one embodiment, pharmaceutically acceptable forms include, but are not limited to, pharmaceutically acceptable salts, hydrates, stereoisomers, and isotopologues of compounds of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2) as disclosed herein, such as Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or Formula (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1). One of ordinary skill in the art will recognize that the free form and salt form of the compound may be in the form of a solvate.

[0185] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with the tissue of a subject without excessive toxicity, irritation, allergic reaction, etc. and that are commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from salts of suitable inorganic and organic acids and bases, such as suitable inorganic and organic addition acids and bases.

[0186] In certain embodiments, the pharmaceutically acceptable form is a solvate (e.g., a hydrate). As used herein, the term "solvate" refers to a compound (such as a free form of a compound, an isomer, or an isotopomer, or a pharmaceutically acceptable salt of any of the foregoing substances, such as a solvate in the form of a free form or a pharmaceutically acceptable salt) that also includes a stoichiometric or non-stoichiometric solvent bound by non-covalent intermolecular forces. Solvate can be a solvate of a disclosed compound or a pharmaceutically 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 can, for example, include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. It should be understood that the term "compound" as used herein encompasses solvates of compounds and compounds, and mixtures thereof.

[0187] In certain embodiments, pharmaceutically acceptable form is a tautomer. As used herein, the term "tautomer" is a class of isomers, comprising two or more interconvertible compounds produced by at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond becomes a double bond, a triple bond becomes a double bond, or a triple bond becomes a single bond, or vice versa). "Tautomerization" includes prototropic tautomerization or proton shift tautomerization, which are considered to be a subset of acid-base chemistry. "Prototropic tautomerization" or "proton shift tautomerization" relate to proton migration with bond order changes. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. In the case where tautomerization may occur (e.g., in solution), the chemical equilibrium of tautomers can be reached. Tautomerization (i.e., providing a tautomeric pair reaction) can be catalyzed by acid or base, or can occur in the absence of an external agent or in the presence of an agent. Exemplary tautomerizations include, but are not limited to, keto-enol; amide-imide; lactam-lactim; enamine-imine; and enamine-(different)enamine tautomerizations.

[0188] In certain embodiments, the pharmaceutically acceptable forms of the compounds disclosed herein do not include salt forms (i.e., not salts) of the compounds disclosed herein, sometimes referred to as free base forms. For example, in one embodiment, the pharmaceutically acceptable forms of compounds of Formula (I) (II) (III) (IV) (V) (VI) (VI) as disclosed herein do not include salt forms, and include pharmaceutically acceptable solvates, isomers, and isotopologues (i.e., isotopically labeled derivatives) of compounds of Formula (I) (II) (III) (IV) (V) (VI) (VI) as disclosed herein, such as salt forms and hydrates, stereoisomers, and isotopologues of compounds of Formula (I) (II) (III) (IV) (V) (VI) (VI) (VI) as disclosed herein. In one embodiment, pharmaceutically acceptable forms exclude salt forms and include pharmaceutically acceptable solvates, isomers, and isotopomers of compounds of Formula (Ia)-(Ib)-(IIa)-(IIb)-(IIId)-(IIId)-(IVa)-(IVb) or Formula (Va)-(Vb)-(VIa)-(VIb) as disclosed herein, such as excluding salt forms and hydrates, stereoisomers, and isotopomers of compounds of Formula (Ia)-(Ib)-(IIa)-(IIb)-(IIId)-(IIId)-(IVa)-(IVb) or Formula (Va)-(Vb)-(VIa)-(VIb) as disclosed herein.In one embodiment, the pharmaceutically acceptable form does not include salt forms and includes pharmaceutically acceptable solvates of compounds of Formula (II-1), (II-2), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or Formula (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1) as disclosed herein.

[0015] The present invention also provides 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), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or compounds of formula (III-3), (IIIa-3), (IIIb-3), (V-1), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), including salt forms and hydrates, stereoisomers, and isotopologues (i.e., isotopically labeled derivatives) as disclosed herein.

[0189] As used herein, the term "pharmaceutically acceptable carrier, excipient or diluent" means a carrier, excipient or diluent approved by a regulatory agency of a federal or state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and more particularly in humans. The term "carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient or vehicle administered with a therapeutic agent. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is a specific carrier for pharmaceutical compositions administered intravenously. Saline solutions and aqueous dextrose solutions and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. For example, the term pharmaceutically acceptable carrier, excipient or diluent includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions disclosed herein is contemplated. Supplementary active ingredients may also be incorporated into the pharmaceutical compositions.

[0190] 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, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including but not limited to the manner in which the dosage form is administered to a patient and the specific active ingredient in the dosage form. Further provided herein are anhydrous pharmaceutical compositions and dosage forms comprising one or more compounds of Formula (I)-(C), (II)-(III), or (IV) as described herein, or a pharmaceutically acceptable form thereof, or a compound of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, for example, a compound of Formula (Ia)-(Ib), (IIa)-(IIb), (IIIa)-(IIIb), (IVa)-(IVb), such as a compound of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), 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) as described herein, or a pharmaceutically 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 pharmaceutically acceptable form thereof. Compositions and single unit dosage forms can take the form of solutions or syrups (optionally containing flavorings), suspensions (optionally containing flavorings), emulsions, tablets (e.g., chewable tablets), pills, capsules, granules, powders (optionally for reconstitution), taste-masked or sustained-release formulations, and the like.

[0191] The pharmaceutical compositions suitable for oral administration provided herein can be in discrete dosage forms, such as, but not limited to, tablets, caplets, capsules, granules, powders and liquids. Such dosage forms contain predetermined amounts of active ingredients and can be prepared by pharmaceutical methods well known to those skilled in the art.

[0192] Examples of excipients that can be used in the oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.

[0193] As used herein, the terms "prevention" and "preventing" are used herein to refer to an approach for obtaining beneficial or desired results, including but not limited to prophylactic benefit. For prophylactic benefit, the compounds and pharmaceutical compositions disclosed herein can be administered to a patient at risk for a particular disease, or to a patient reporting one or more physiological symptoms of a disease or condition, even if a diagnosis of such disease or condition has not yet been made.

[0194] As used herein, the term "stereoisomer" is understood to mean isomers that differ only in the way their atoms are arranged in space. As used herein, the term "isomer" includes any and all geometric isomers and stereoisomers. For example, "isomers" include geometric double bond cis and trans isomers, also known as E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof as falling within the scope of the present disclosure.

[0195] In certain embodiments, the symbol represents a bond which may be a single bond or a double bond as described herein.

[0196] In certain embodiments, provided herein are various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or around a carbocyclic ring. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, wherein the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both "E" and "Z" isomers.

[0197] Substituents around a carbon-carbon double bond may be referred to alternatively as "cis" or "trans," where "cis" refers to substituents on the same side of the double bond and "trans" refers to substituents on opposite sides of the double bond. The arrangement of substituents around a carbon ring may also be designated as "cis" or "trans." The term "cis" refers to substituents on the same side of the ring plane, and the term "trans" refers to substituents on opposite sides of the ring plane. A mixture of compounds in which substituents are arranged on both the same and opposite sides of the ring plane is designated "cis / trans."

[0198] As used herein, the term "subject" contemplated for administration includes, but is not limited to, humans (e.g., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young, middle-aged, or elderly)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, dogs, rabbits, and / or rodents; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys. The subject can be a patient, for example, a patient with a cancer that is dependent on a farnesylated protein.

[0199] As used herein, the term "therapeutic effect" encompasses therapeutic benefit and / or prophylactic benefit as described herein. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

[0200] As used herein, the terms "treat," "treating," and "treatment" are used interchangeably herein. These terms refer to an approach for obtaining a beneficial or desired result, including but not limited to a therapeutic benefit. A therapeutic benefit means eradication or amelioration of the underlying condition being treated. In addition, a therapeutic benefit is achieved by eradication or amelioration of one or more physiological symptoms associated with the underlying condition, such that an improvement is observed in the patient, although the patient may still be suffering from the underlying disease or condition. For example, when used to refer to a patient suffering from a cancer that is dependent on a farnesylated protein, refers to an act of reducing the severity of the cancer or delaying or slowing the progression of the cancer, including (a) inhibiting cancer growth, or preventing the development 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.

[0201] The 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 herein. In addition, the 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 edition, 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 edition, Cambridge University Press, Cambridge, 1987.

[0202] When a range of values ​​is listed, it is intended to encompass every value and sub-range within the range. For example, "C 1-6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, 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.

[0203] "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 from one to ten carbon atoms (e.g., C1-C 10Alkyl). A linear or straight alkyl group refers to an alkyl group without branches, for example, methyl, ethyl, n-propyl. Whenever a numerical range such as "1 to 10" appears herein, it refers to each integer in the given range; for example, "1 to 10 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 10 carbon atoms, but this definition also covers the occurrence of the term "alkyl" without specifying a numerical range. In some embodiments, the alkyl group is a C1-C6 alkyl group. In some embodiments, the alkyl group has 1 to 10, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Representative saturated straight chain alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl, while saturated branched chain alkyl groups 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, etc. The alkyl group is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted with one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, thiol, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamido, sulfinyl, 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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), S(O) t N(R a )2 (wherein t is 1 or 2) or -OP(=O)(OR a )2, where each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

[0204] "Alkenyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, and in some embodiments, having from two to ten carbon atoms (i.e., C2-C 10 Alkenyl). Whenever it appears in this article, a numerical range such as "2 to 10" refers to each integer in the given range; for example, "2 to 10 carbon atoms" means that the alkenyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, the alkenyl group contains two to eight carbon atoms. In other embodiments, the alkenyl group contains two to five carbon atoms (for example, C2-C5 alkenyl). The alkenyl group is connected to the parent molecular structure by a single bond, such as ethenyl (i.e., vinyl (vinyl)), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, etc. One or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4Examples of alkenyl groups include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified in the specification, an alkenyl group is optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, sulfhydryl, sulfhydryl, alkylthio, arylthio, sulfanylcarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamido, sulfinyl, 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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), S(O) t N(R a )2 (wherein t is 1 or 2) or -OP(=O)(OR a )2, where each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

[0205] "Alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, and in some embodiments, having from two to ten carbon atoms (i.e., C2-C10 Alkynyl). Whenever it occurs in this article, a numerical range such as "2 to 10" refers to each integer in a given range; for example, "2 to 10 carbon atoms" means that the alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, the alkynyl group comprises two to eight carbon atoms. In other embodiments, the alkynyl group has two to five carbon atoms (e.g., C2-C5 alkynyl). The alkynyl group is connected to the parent molecular structure by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless stated otherwise in the specification, an alkynyl group is optionally substituted with one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, thiol, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamido, sulfinyl, 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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2) or -OP(=O)(OR a )2, where each R ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

[0206] The term "alkoxy" refers to a radical -O-alkyl (in some embodiments, comprising 1 to 10 carbon atoms) in a straight chain, branched chain, cyclic configuration, and combinations thereof, attached to the parent molecular structure via an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. "Lower alkoxy" refers to an alkoxy group containing one to six carbon atoms. In some embodiments, C1-C4 alkoxy is an alkoxy group encompassing straight and branched chain alkyl groups of 1 to 4 carbon atoms. Unless stated otherwise in the specification, an alkoxy group is optionally substituted with one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, thiol, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamido, sulfinyl, 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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2) or -OP(=O)(ORa )2, where each R a and alkyl. The term "alkeneoxy" and "alkynyloxy" are independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of these moieties may be optionally substituted as defined herein. The terms "alkenyloxy" and "alkynyloxy" reflect the above description of "alkoxy," with the prefix "alk" replaced by "alkenyl" or "alkynyl," respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein.

[0207] "Aryl" refers to a group having six to fourteen ring atoms (e.g., C6-C 14 or C6-C 10 In one embodiment, a divalent group formed by a substituted benzene derivative and having a free valence at a ring atom is named a substituted phenylene group. In other embodiments, a divalent group derived from a monovalent monocyclic or polycyclic hydrocarbon group whose name ends with "base" by removing a hydrogen atom from a carbon atom with a free valence is named by adding "idene" to the name of the corresponding monovalent group, for example, a naphthyl group with two connection points is called a naphthylene group. Whenever it appears in this article, a numerical range such as "6 to 10 aryl groups" refers to each integer in a given range; for example, "6 to 10 ring atoms" means that the aryl group can be composed of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent ring atom pairs) groups. Unless stated otherwise in the specification, aryl moieties can be optionally substituted with one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, thiol, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamido, sulfinyl, 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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2) or -OP(=O)(OR a )2, where each R a and heteroarylalkyl, and each of these moieties may be optionally substituted as defined herein. In one embodiment, unless otherwise indicated, "aryl" also includes ring systems in which an aromatic ring as defined above is fused to one or more cycloalkyl or heterocyclyl groups, wherein the point of attachment to the parent molecular structure is on the aromatic ring.

[0208] "Cycloalkyl" or alternatively "carbocyclyl" refers to a monocyclic or polycyclic group containing only carbon and hydrogen and may be saturated or partially unsaturated. If the carbocyclic ring contains at least one double bond, a partially unsaturated cycloalkyl may be referred to as a "cycloalkenyl" group, and if the carbocyclic ring contains at least one triple bond, it may be referred to as a "cycloalkynyl" group. Cycloalkyl groups include groups having 3 to 10 ring atoms (e.g., C3-C 10 Cycloalkyl). Whenever it appears in this article, a numerical range such as "3 to 10" refers to each integer in the given range; for example, "3 to 10 carbon atoms" means that the cycloalkyl group can be composed 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 is a C3-C8 cycloalkyl group. In some embodiments, it is a C3-C5 cycloalkyl group. Illustrative examples of cycloalkyl groups include, but are not limited to, the following: C 3-6Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-8 Examples of the carbocyclic group include the above-mentioned C 3-6 Carbocyclic groups and cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, etc. 3-10 Examples of the carbocyclic group include the above-mentioned C 3-8 Unless otherwise stated in the specification, cycloalkyl is optionally substituted with one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, sulfhydryl, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamido, sulfinyl, 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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2) or -OP(=O)(OR a )2, where each Ra In one embodiment, unless otherwise indicated, "cycloalkyl" or "carbocyclyl" also includes ring systems in which a cycloalkyl or carbocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment to the parent molecular structure is on the cycloalkyl or carbocyclyl ring.

[0209] The term "halo," "halide," or alternatively "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0210] 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 substituted with halogen atoms. In certain embodiments, an alkyl group is substituted with 1, 2, 3, 4, 5, or 6 halogen atoms. In certain embodiments, an alkyl group is substituted with 1, 2, or 3 halogen atoms. In certain other examples, an alkyl group is substituted with 2 halogen atoms. In certain embodiments, an alkyl group is substituted with 1 halogen atom. In certain embodiments, a haloalkyl group includes trifluoromethyl, fluoromethyl, perfluoroethyl, or chloromethyl. Certain other embodiments of haloalkyl groups include chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, or 1,1,1-trifluoroethoxy. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, where the halo group is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Each of alkyl, alkenyl, alkynyl and alkoxy is as defined herein, and may be optionally further substituted as defined herein.

[0211] "Heteroalkyl", "heteroalkenyl" and "heteroalkynyl" include alkyl, alkenyl and alkynyl groups, respectively, which have one or more backbone chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur and phosphorus, or combinations thereof. A numerical range can be given, for example, C1-C4 heteroalkyl, which refers to the total chain length, which in this example can be up to 4 atoms. For example, a -CH2OCH2CH3 group is referred to as a "C4" heteroalkyl, which includes the heteroatom center in the description of the atomic chain length. Attachment to the parent molecular structure can be via a heteroatom or a carbon in the heteroalkyl chain. For example, an N-containing heteroalkyl moiety refers to a group in which at least one backbone atom is a nitrogen atom. One or more heteroatoms in the heteroalkyl group can be optionally oxidized. If present, one or more nitrogen atoms 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 methoxyethoxy (-CH2CH2OCH3), ethoxymethoxy (-CH2OCH2CH3), (methoxymethoxy)ethoxy (-CH2CH2-OCH2OCH3), (methoxymethoxy)methoxy (-CH2OCH2OCH3), and (methoxyethoxy)methoxy-CH2OCH2CH2OCH3), and the like; amines such as -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2NHCH2CH3, -CH2N(CH2CH3)(CH3), and the like. The heteroalkyl, heteroalkenyl, and heteroalkynyl groups can each be optionally substituted with one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, thiol, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamido, sulfinyl, sulfonate, urea, -Si(R)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(Ra )2、-N(R a )C(NR a )N(R a )2、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2) or -OP(=O)(OR a )2, where each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

[0212] "Heteroaryl" or alternatively "heteroaromatic" refers to a radical of a 5- to 18-membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in the cyclic array) having ring carbon atoms and 1 to 6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 18-membered heteroaryl"). A heteroaryl polycyclic ring system may include one or more heteroatoms in one or more rings. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range; for example, "5 to 18 ring atoms" means that the heteroaryl group may 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, a divalent radical derived from a monovalent heteroaryl whose name ends in "radical" by removing one hydrogen atom from the atom with the free valence is named by adding "idene" to the name of the corresponding monovalent radical, for example, a pyridyl radical having two points of attachment is a pyridylene radical.

[0213] For example, an N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the backbone atoms of the ring is a nitrogen atom. One or more heteroatoms in a heteroaryl group may be optionally oxidized. If present, one or more nitrogen atoms may also be optionally quaternized. Heteroaryl groups also include ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as pyridyl N-oxide. A heteroaryl group is attached to the parent molecular structure via any atom of the ring.

[0214] "Heteroaryl" also includes a ring system in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment to the parent molecular structure is on the aryl or heteroaryl ring, or wherein a heteroaryl ring as defined above is fused to one or more cycloalkyl or heterocyclyl groups, wherein the point of attachment to the parent molecular structure is on the heteroaryl ring. For polycyclic heteroaryls in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment to the parent molecular structure can be on any ring with a heteroatom (e.g., 2-indolyl) or on a ring without a heteroatom (e.g., 5-indolyl). In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur (“5- to 6-membered heteroaryl”). In some embodiments, the 5- to 6-membered heteroaryl group has 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl group has 1 to 2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0215] Examples of heteroaryl groups include, but are not limited to, azacycloheptatrienyl, 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, benzopyrone, benzofuranyl, benzofuranone, benzofurazanyl, 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]cycloheptatrienol[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazolidinyl, furanone, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraenol[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraenol[d]pyrimidinyl, [d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraenol[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepine, oxazolyl, oxirane, 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 pyridyl, pyridyl, 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-cycloheptatrienol[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiopyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c] pyridyl and thiophenyl (i.e., thienyl).

[0216] Unless stated otherwise in the specification, heteroaryl moieties are optionally substituted with one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, thiol, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamido, sulfinyl, 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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), S(O) t N(R a )2 (wherein t is 1 or 2) or -OP(=O)(OR a )2, where each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

[0217] "Heterocyclyl," "heterocycloalkyl," or "heterocarbocyclyl" each refers to any 3- to 18-membered non-aromatic monocyclic or polycyclic moiety containing at least one ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur. A heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein a polycyclic ring system may be a fused, bridged, or spirocyclic ring system. A heterocyclyl polycyclic ring system may include one or more heteroatoms in one or more rings. A heterocyclyl group may be saturated or partially unsaturated. If the heterocyclyl group contains at least one double bond, a partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl group," and if the heterocyclyl group contains at least one triple bond, it may be referred to as a "heterocycloalkynyl group." Whenever a numerical range such as "5 to 18" appears herein, it refers to each integer in the given range; for example, "5 to 18 ring atoms" means that the heterocyclyl group may 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, a divalent radical derived from a monovalent heterocyclic radical whose name ends in "radical" by removing one hydrogen atom from the atom with the free valence is named by adding "idene" to the name of the corresponding monovalent radical, for example, a piperidinyl radical having two points of attachment is a piperidinylene radical.

[0218] The N-containing heterocyclic moiety refers to a non-aromatic group in which at least one ring atom is a nitrogen atom. The heteroatoms in the heterocyclic group may optionally be oxidized. One or more nitrogen atoms (if present) may optionally be quaternized. The heterocyclic group also includes a ring system substituted with one or more nitrogen oxide (-O-) substituents, such as piperidinyl N-oxide. The heterocyclic group is connected to the parent molecular structure via any atom of any one or more rings.

[0219] "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl rings, wherein the point of attachment is on the carbocyclyl or heterocyclyl rings, or a ring system in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment to the parent molecular structure is on the heterocyclyl ring. In some embodiments, a heterocyclyl is a 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("3 to 10 membered heterocyclyl"). In some embodiments, a heterocyclyl is a 5 to 8 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5 to 8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl group has 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl group has 1 to 2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl group has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0220] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiirane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thiirane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl, and triazinyl. Exemplary 7-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azocanyl, oxepanyl, and thiepanyl. Exemplary bicyclic heterocyclyls include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthylimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinetrienyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5-[[1,4]-benzo[e][1,4]diazepinetrienyl] ... ,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, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, etc.

[0221] Unless otherwise indicated, the heterocyclyl moiety is optionally substituted with one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, thiol, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamido, sulfinyl, 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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), S(O) t N(R a )2 (wherein t is 1 or 2) or -OP(=O)(OR a )2, where each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

[0222] "Hydroxyalkyl" means a group of the formula -R-(OH) z wherein R is an alkyl group as defined herein, and z is 1 or 2. In one embodiment, the hydroxyalkyl group is -ROH. In one embodiment, the hydroxyalkyl group includes -CH2OH. In one embodiment, the hydroxyalkyl group is -R(OH)2.

[0223] A "leaving group or atom" is any group or atom that will cleave from the starting material under the reaction conditions, thereby promoting the reaction at the specified site. Unless otherwise specified, suitable non-limiting examples of such groups include halogen atoms, methanesulfonyloxy, o-nitrobenzenesulfonyloxy, p-nitrobenzenesulfonyloxy, trifluoromethoxy, and toluenesulfonyloxy.

[0224] "Protecting group" has the meaning conventionally associated therewith in organic synthesis, such as 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 another unprotected reactive site and the group can be easily removed after the selective reaction is complete. Various protecting groups are disclosed in, for example, TH Greene and PGM Wuts, 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 hydroxyl-protected form is a form in which at least one hydroxyl group present in a compound is protected by a hydroxyl-protecting group. Similarly, amines and other reactive groups can also be similarly protected.

[0225] As used herein, the term "substituted" or "substitution" means that at least one hydrogen present on an atom of a group (e.g., a carbon or nitrogen atom) is replaced with a permitted substituent, for example, a substituent that, when substituted for the hydrogen, results in a stable compound (e.g., a compound that does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, or other reactions). 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 substituent may be the same or different at each position. Unless otherwise indicated, substituents may include one or more groups individually and independently selected from the group consisting of acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, azide, carbonate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, thiol, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamido, sulfinylsulfonate, 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(Ra )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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2) or -OP(=O)(OR a )2, where each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties may be optionally substituted as defined herein. For example, cycloalkyl substituents may be substituted with halides or the like at one or more ring carbons. Protective groups that can form protective derivatives of the above-mentioned substituents are known to those skilled in the art and can be found in references such as the aforementioned Greene and Wuts.

[0226] 5.1 Compounds

[0227] In some embodiments, the compound is a compound of Formula (I), Formula (Ia), or Formula (Ib) as disclosed herein, wherein A 1 N or NR 1a In some embodiments, a compound of Formula (I), Formula (Ia), or Formula (Ib) as disclosed herein, wherein A 2 CR 2b Or -C(=O)-. In some embodiments, A 1 With A 2 The bond between is a single bond, A 1 NR 1a , and A 2 is -C(=O)-. In some embodiments, A 1 With A 2 The bond between is a double bond, A 1 is N, and A 2 CR 2b .

[0228] In some embodiments, the compound is a compound of Formula (I), Formula (Ia), or Formula (Ib) as disclosed herein, wherein for

[0229] In some embodiments, the compound is a compound of Formula (I), Formula (Ia), or Formula (Ib) as disclosed herein, wherein for For example, in some instances, for In some embodiments, for In some embodiments, for

[0230] In some embodiments, the compound is a compound of Formula (I), Formula (Ia), or Formula (Ib) as disclosed herein, wherein for In some embodiments, for

[0231] In some embodiments, the compound is a compound of Formula (I), Formula (Ia), or Formula (Ib) as disclosed herein, wherein Y and A 1 、A 2 and A 3 The fused ring system of is connected to W in a 1,2-relationship. In some embodiments, Y and the ring containing A 1 、A 2 and A 3 The fused ring system of is connected to W in a 1,3-relationship. In some embodiments, W is C 6-12 In some embodiments, W is phenyl. In some embodiments, W is a 5-12 membered heteroaryl. In some embodiments, W is pyridyl. In some embodiments, W is substituted with one, two, three or four R 4 In some embodiments, W is substituted with two R 4 In some embodiments, W is substituted with a R 4 In some embodiments, R 4 are independently hydrogen, halogen, 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 1-6Haloalkoxy, C 1-6 Hydroxyalkoxy, C 1-6 Heteroalkoxy, C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy or -NR 14 R 15 , where each R 4 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 or 3-6 membered heterocycloalkoxy is optionally independently substituted by one, two, three, four, five or six groups selected from halogen, 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, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, where each R 4 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy is optionally independently substituted with one, two, three, four, five or six radicals 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 In some embodiments, R 4 are independently hydrogen.

[0232] In some embodiments, the compound is a compound of Formula (I), Formula (Ia), or Formula (Ib) as disclosed herein, wherein -(C(R 6 )(R 7 )(Contains A 4 、A 5 and A 6 In some embodiments, -(C(R 6 )(R 7 )(Contains A 4 、A 5 and A 6 In some embodiments, Z is C 6-12 In some embodiments, Z is phenyl. In some embodiments, Z is a 5-12 membered heteroaryl. In some embodiments, Z is pyridyl. In some embodiments, Z is substituted by one, two, three or four R 5 In some embodiments, Z is substituted with two R 5 In some embodiments, Z is substituted with one R 5 In some embodiments, R 5 are independently hydrogen, halo or CN. In some embodiments, R 5 are independently hydrogen. In some embodiments, R 5 are independently electron withdrawing groups. 5 In some embodiments, R 5 are independently CN.

[0233] In some embodiments, the compound is a compound of formula (I) or formula (II) as disclosed herein, such as a compound of formula (Ia), formula (Ib), formula (IIa), or formula (IIb), or a pharmaceutically acceptable form thereof, wherein R 1a Independently R 9 For example, in some embodiments, R 1a For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl or the C 3-6 Cycloalkyl is optionally independently substituted with 1-6 independently selected from halo, hydroxy, CN, NO2, 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 3-6Cycloalkyl, 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)2R 12 、-S(O) p R 12 and -S(O)2NR 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 For hydrogen, C 1-3 Alkyl or C 3-4 Cycloalkyl, wherein the C 1-3 Alkyl or the C 3-4 The cycloalkyl group is optionally independently substituted by one, two or three independently selected from halo, hydroxy, CN, NO2, 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)OR12 、-NR 10 C(O)NR 10 R 11 、-NR 10 S(O)2R 12 、-S(O) p R 12 and -S(O)2NR 10 R 11 For example, in some embodiments, R 1a is hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, 2,3-dihydroxypropyl or cyclopropyl. In some embodiments, R 1a In some embodiments, R 1a In some embodiments, R 1a In some embodiments, the compound is a compound of formula (II-1) or formula (II-2), such as a compound of formula (IIa-1), formula (IIb-1), formula (IIa-2), or formula (IIb-2), or a pharmaceutically acceptable form thereof.

[0234] In some embodiments, the compound is a compound of Formula (I) or (III) as disclosed herein, such as a compound of Formula (Ia) (Ib) (IIIa) (IIIb) or a pharmaceutically acceptable form thereof, or a compound of Formula (V) (Va) (Vb) (VI) (VIa) (VIb) or a pharmaceutically acceptable form thereof, wherein R 2b Independently R 9 、-OR 9 、halogen、CN、NO2、-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)2NR 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 Independently R 9 、-OR 9 , halogen, CN, -C(O)NR 10 R 11or -NR 10 R 11 In some embodiments, R 2b For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, hydroxyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Heterocycloalkoxy, halogen, CN, -C(O)NR 10 R 11 or -NR 10 R 11 ; where R 10 and R 11 Each occurrence is independently hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, or together with the N to which they are attached, 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, halogen, CN, -C(O)NR 10 R 11 or -NR 10 R 11 ; where R 10 and R 11 Each occurrence is independently hydrogen, C 1-3 alkyl, 3-4 membered heterocycloalkyl, or together with the N to which they are attached, form a 4-6 membered heterocycloalkyl. In some embodiments, R 10 is H. In some embodiments, R 11 C 1-3 haloalkyl, such as chloroethyl or fluoroethyl. For example, in some embodiments, R 2b is hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, cyclopropyl, -OCH3, -OCD3, -OCH2CH3, -OCD2CD3, isopropyloxy, cyclopropyloxy, 3-oxetanylalkoxy, chloro, CN, morpholinyl, piperazinyl, 3-oxetanylamino, or -C(O)NH2. In some embodiments, R 2b In some embodiments, R 2b is independently an electron withdrawing group. The electron withdrawing group may include, for example, a halide, a cyano, a nitro, a carbonyl, a carboxylic acid, a carboxylate, an amide, a sulfonyl, a sulfonyl ester, or a sulfonylamide group. For example, in some embodiments, R 2b are independently selected from halogen, CN, NO2, -C(O)R9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-S(O) p R 9 or -S(O)2NR 10 R 11 In some embodiments, R 2b is chloro, CN, -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)N(H)CH3, -C(O)N(CH3)2, -S(O)CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2N(H)CH3, or -S(O)2N(CH3)2. In some embodiments, the compound is a compound of Formula (III-1) or Formula (III-2), such as a compound of Formula (IIIa-1), Formula (IIIb-1), Formula (IIIa-2), or Formula (IIIb-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), Formula (IIIa-3), or Formula (IIIb-3), or a pharmaceutically acceptable form thereof.

[0235] In some embodiments, the compound is a compound of formula (I) as disclosed herein, such as a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable form thereof, wherein A 1 CR 1b In some embodiments, a compound of formula (I), such as a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein A 2 N or NR 2a In some embodiments, A 1 With A 2 The bond between is a double bond, A 1 CR 1b , and A 2 is N. In some embodiments, A 1 With A 2 The bond between is a single bond, A 1 is -C(=O)-, and A 2 NR 2a. In some embodiments, the compound of formula (I), formula (la) or formula (lb) or a pharmaceutically acceptable form thereof is a compound of formula (IV), formula (IVa) or formula (IVb), respectively, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (IV-1), formula (IVa-1), formula (IVb-1), formula (IV-2), formula (Iva-2) or formula (IVb-2) or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (V), formula (Va), formula (Vb), formula (V-1), formula (Va-1), formula (Vb-1), formula (VI), formula (VIa), formula (VIb), formula (VIa-1) or formula (VIb-1) or a pharmaceutically acceptable form thereof.

[0236] In some embodiments, the compound is a compound of formula (I) or (IV), such as a compound of formula (Ia), (Ib), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or a compound of formula (V) or (VI), such as a compound of formula (Va), (Vb), (VIa), or (VIb), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein R 1b Independently R 9 、-OR 9 、halogen、CN、NO2、-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)2NR 10 R 11 For example, in some embodiments, R 1b R 9 、-OR 9 , halogen, CN, -C(O)R 9 or-C(O)OR 9 In some embodiments, R 1b R 9 、-OR 9 , halo or CN. For example, in some embodiments, R 1b For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, halo or CN, wherein the C 1-6 Alkyl, the C3-6 Cycloalkyl, the C 1-6 Alkoxy or the C 3-6 Cycloalkoxy is optionally independently substituted by one, two, three, four, five or six independently selected from halo, hydroxy, CN, NO2, 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)2R 12 、-S(O) p R 12 and -S(O)2NR 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 1b For hydrogen, C 1-3 Alkyl, C 3-4 Cycloalkyl, C 1-3 Alkoxy, C 3-4 Cycloalkoxy, halo or CN, wherein the C 1-3 Alkyl, the C 3-4 Cycloalkyl, the C 1-3 Alkoxy or the C 3-4 Cycloalkoxy is optionally independently substituted by one, two or three groups selected from halo, hydroxy, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C1-6 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)2R 12 、-S(O) p R 12 and -S(O)2NR 10 R 11 For example, in some embodiments, R 1b is hydrogen, -CH3, -CD3, -CF3, -CH2CH3, -CD2CD3, isopropyl, 2,3-dihydroxypropyl, cyclopropyl, -OCH3, -OCD3, -OCF3, -OCH2CH3, -OCD2CD3, isopropyl, 2,3-dihydroxypropyloxy or cyclopropyloxy. In some embodiments, the compound is a compound of formula (IV-1) or formula (IV-2), such as a compound of formula (IVa-1), formula (IVb-1), formula (IVa-2) or formula (IVb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (V-1), formula (Va-1), formula (Vb-1), formula (VI-1), formula (VIa-1) or formula (VIb-1), or a pharmaceutically acceptable form thereof.

[0237] In some embodiments, the compound is a compound of formula (I) as disclosed herein, such as a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable form thereof, wherein R 2a Independently R 9 For example, in some embodiments, R 2a For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl or the C 3-6Cycloalkyl is optionally independently substituted by one, two, three, four, five or six independently selected from halo, hydroxy, CN, NO2, 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)2R 12 、-S(O) p R 12 and -S(O)2NR 10 R 11 For example, in some embodiments, R 2a For hydrogen, C 1-3 Alkyl or C 3-4 Cycloalkyl, wherein the C 1-3 Alkyl or the C 3-4 Cycloalkyl is optionally independently substituted with one, two or three alkyl radicals selected from halo, hydroxy, CN, NO2, 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)NR10 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)2R 12 、-S(O) p R 12 and -S(O)2NR 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 It is hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, 2,3-dihydroxypropyl or cyclopropyl.

[0238] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV) as disclosed herein, such as a compound of Formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (VI), (VIa), or (VIb), wherein A 3 CR 3 In some embodiments, R 3 Independently R 9 、-OR 9 , halo or CN. In some embodiments, R 3 is hydrogen. In some embodiments, the compound is a compound of Formula (I), (II), (III), (IV), or (VI), such as a compound of Formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), (IVb), (VIa), or (VIb), wherein A 3is N. In some embodiments, the compound is a compound of Formula (Ia)-(Ib)-(IIa)-(IIb)-(IIIa)-(IIIb)-(IVa)-(IVb) or a pharmaceutically acceptable form thereof, or a compound of Formula (VIa)-(VIb)-(VIb) or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (IV-1), or Formula (IV-2), such as Formula (IIa-1), Formula (IIb-1), Formula (IIa-2), Formula (IIb-2), Formula (IIIa-1), Formula (IIIb-1), Formula (IIIa-2), Formula (IIIb-2), Formula (IVa-1), Formula (IVb-1), Formula (IVa-2), or Formula (IVb-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), Formula (IIIa-3), Formula (IIIb-3), Formula (VIa-1), or Formula (VIb-1), or a pharmaceutically acceptable form thereof.

[0239] In some embodiments, the compound is a compound of Formula (I)-(II), (III)-(III), or (IV) as disclosed herein, such as a compound of Formula (Ia)-(Ib), (IIa)-(IIb), (IIIa)-(IIIb), (IVa)-(IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V), (Va)-(Vb), (VI), (VIa)-(VIb), or (VIb)-(VIb), or a pharmaceutically 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 No more than one of A is N. In some embodiments, A 5 CR 8 In some embodiments, A 5 is N. In some embodiments, A 5 is N, and A 4 and A 6 No more than one of A is N. In some embodiments, A 6 CR 8 In some embodiments, A 6 is N. In some embodiments, A 6 is N, and A 4 and A 5 No more than one of A is N. In some embodiments, A 4 、A 5 and A6 Each independently CR 8 In some embodiments, R 8 Independently R 9 、-OR 9 , halo or CN. In some embodiments, R 8 In some embodiments, A 5 With A 6 Together they are O and NR 9 Or S. For example, as in the compound of formula (I) A 5 With A 6 Combined with O, NR 9 Representative examples of or S substitution are shown below as compounds of formula (I-A1), formula (I-A2) and formula (I-A3), respectively:

[0240]

[0241] or a pharmaceutically acceptable form thereof.

[0242] In some embodiments, the compound is a compound of Formula (I)-(II), (III)-(IIId), or (IV) as disclosed herein, for example, a compound of Formula (Ia)-(Ib), (IIa)-(IIb), (IIIa)-(IIIb), (IVa)-(IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V)-(Vl), such as a compound of Formula (Va)-(Vb), (Via)-(Vlla)-(Vlla), or (VIb)-(VIb), or a pharmaceutically acceptable form thereof, wherein Y is a bond or a linker of up to 5 atoms, up to 4 atoms, up to 3 atoms, or up to 2 atoms in length. In some embodiments, Y is a bond. In some embodiments, Y is a linker of 5 atoms in length. In some embodiments, Y is a linker of 4 atoms in length. In some embodiments, Y is a linker of 3 atoms in length. In some embodiments, Y is a linker of 2 atoms in length. In some embodiments, Y is a linker of 1 atom in length. In some embodiments, Y is C 1-6 Alkylene, wherein one or more -CH2- 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)2N(R 10 )-or-N(R 10)S(O)2N(R 11 )-substituted. In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. In some embodiments, Y is in the direction of ZYW (wherein Z refers to Z or a ring containing Z, and W refers to W or a ring containing W, all of which apply to Formula (I), Formula (II), Formula (III) or Formula (IV) and subformulas thereof). For example, as a representative example of Y in the compound of Formula (I) written along the direction of ZYW, wherein Y is -N(R 10 )C(O)-, which is a compound of formula (I-A4) as shown below:

[0243]

[0244] and Y is -C(O)N(R 10 )-, which is a compound of formula (I-A5) as shown below:

[0245]

[0246]

[0247] In some embodiments, the compound is a compound of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2) as disclosed herein, such as Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof, or is a compound of Formula (III-3), (V-1), or (VI-1), such as Formula (IIIa-3), (IIIb-3), (Va-1), (Vb-1), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof.

[0248] 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 -、-(CR16 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)2N(R 10 )(CR 16 R 17 ) n -or-(CR 16 R 17 ) m N(R 10 )S(O)2N(R 11 )(CR 16 R 17 ) n -; Among them: R 16 and R 17 Each occurrence is independently hydrogen, halo, hydroxy, CN, NO2, C 1-6 Alkyl, C2-6 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 3-6 membered heterocycloalkoxy, or together with the C to which they are connected, form C(O), C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; each m is independently an integer of 0, 1, 2, or 3; each n is independently an integer of 0, 1, 2, or 3; wherein the sum of m and n is 0, 1, 2, 3, 4, 5, or 6; each p is independently an integer of 0, 1, or 2; and each q is independently an integer of 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, n is 0, 1, or 2. In some embodiments, each m is independently an integer of 0 or 1; and each n is independently an integer of 1, 2, or 3; wherein the sum of m and n is 1, 2, 3, or 4. In some embodiments, each m is independently an integer of 0; and each n is independently an integer of 1, 2, or 3; wherein the sum of m and n is 1, 2, or 3. In some embodiments, each m is independently an integer of 0; and each n is independently an integer of 1 or 2; wherein the sum of m and n is 1 or 2. In some embodiments, each m is independently an integer of 1, 2, or 3; and each n is independently an integer of 0 or 1; wherein the sum of m and n is 1, 2, 3, or 4. In some embodiments, each m is independently an integer of 1, 2, or 3; and each n is independently an integer of 0; wherein the sum of m and n is 1, 2, or 3. In some embodiments, each m is independently an integer of 1 or 2; and each n is independently an integer of 0; wherein the sum of m and n is 1 or 2. In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. In some embodiments, q is independently an integer of 1, 2, 3, 4, or 5. In some embodiments, q is independently an integer of 1, 2, 3, or 4. In some embodiments, q is independently an integer of 1, 2, or 3. In some embodiments, q is independently an integer of 2 or 3. In some embodiments, q is independently an integer of 1 or 2.

[0249] In some embodiments, Y is -(CR 16 R 17 ) q -、-(CR 16 R 17 ) m O(CR16 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)2N(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 ) n -. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, q is independently an integer of 1, 2, 3, 4, or 5. In some embodiments, q is independently an integer of 1, 2, 3, or 4. In some embodiments, q is independently an integer of 1, 2, or 3. In some embodiments, q is independently an integer of 2 or 3. In some embodiments, q is independently an integer of 1 or 2. In some embodiments, Y is R 16 and R 17 , each independently at each occurrence is hydrogen, halogen, hydroxyl, CN, NO2, 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 3-5 membered heterocycloalkoxy, or together with the C to which they are connected, form C(O), C3-5 Cycloalkyl or 3-5 membered heterocycloalkyl. For example, in some embodiments, R 16 and R 17 Each occurrence is independently hydrogen, chloro, hydroxy, CN, NO2, methyl, ethyl, isopropyl, -CF3, -CH2CF3, -CH2OH, -(CH2)2OH, -(CH2)2OCH3, cyclopropyl, 3-oxetanyl, methoxy, ethoxy, isopropyloxy, cyclopropyloxy, -OCF3, -OCH2CF3, -O(CH2)2OH, -O(CH2)2OCH3 or 3-oxetanylalkoxy, or is combined with each attached C to form C(O), cyclopropyl or 3-5 membered heterocycloalkyl. In some embodiments, R 16 and R 17Each is hydrogen. In some embodiments, Y is -(CH2)O-, -O(CH2)-, -(CH2)2O-, -O(CH2)2-, or -(CH2)2-. For example, in some embodiments, Y is -(CH2)O-. In some embodiments, Y is -O(CH2)-. In some embodiments, Y is -(CH2)2O-. In some embodiments, Y is -O(CH2)2-. In some embodiments, Y is -(CH2)2-. In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV) as disclosed herein, for example, a compound of Formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V), (Va), (Vb), (VI), (VIa), or (VIb), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (II-1) or formula (II-2), such as a compound of formula (IIa-1), formula (IIb-1), formula (IIa-2), or formula (IIb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-1) or formula (III-2), such as a compound of formula (IIIa-1), formula (IIIb-1), formula (IIIa-2), or formula (IIIb-2), or a pharmaceutically acceptable form thereof, or a compound of formula (III-3), formula (IIIa-3), or formula (IIIb-3), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (IV-1) or formula (IV-2), such as a compound of formula (IVa-1), formula (IVb-1), formula (IVa-2), or formula (IVb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (V-1), Formula (Va-1), Formula (Vb-1), Formula (VI-1), Formula (VIa-1), or Formula (VIb-1), or a pharmaceutically acceptable form thereof.

[0250] In some embodiments, the compound is a compound of Formula (I)-(II), (III)-(IIId), or (IV) as disclosed herein, such as a compound of Formula (Ia)-(Ib), (IIa)-(IIb), (IIIa)-(IIId), (IVa)-(IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V), (Va)-(Vb), (VI), (VIa)-(VIb), or (VIb)-(VId), or a pharmaceutically acceptable form thereof, wherein W 1 、W 2 、W 3 and W 4 Each independently is N or CR 4, or W 1 With W 2 Together they are O and NR 4A or S or W 2 With W 3 Together they are O and NR 4A Or S. In some embodiments, W 1 、W 2 、W 3 and W 4 At least one of is N. In some embodiments, W 1 、W 2 and W 3 Each independently CR 4 , and W 4 is N. In some embodiments, W 1 、W 2 and W 4 Each independently CR 4 , and W 3 is N. In some embodiments, W 1 、W 3 and W 4 Each independently CR 4 , and W 2 is N. In some embodiments, W 2 、W 3 and W 4 Each independently CR 4 , and W 1 is N. In some embodiments, W 1 、W 2 、W 3 and W 4 Each independently CR 4 In some embodiments, W 2 and W 3 Each independently CR 4 , and W 1 and W 4 are each independently N. In some embodiments, W 1 and W 2 Each independently CR 4 , and W 3 and W 4 are each independently N. In some embodiments, W 1 and W 4 Each independently CR 4 , and W 2 With W 3 Together they are O and NR 4A Or S. In some embodiments, W 3 and W4 Each independently CR 4 , and W 1 With W 2 Together they are O and NR 4A Or S. In some embodiments, W 1 CR 4 , W 4 is N, and W 2 With W 3 Together they are O and NR 4A Or S. In some embodiments, W 3 CR 4 , W 4 is N, and W 1 With W 2 Together they are O and NR 4A or S.

[0251] In some embodiments, 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, 3-6 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 , where 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 Cycloalkoxy or 3-6 membered heterocycloalkoxy is optionally independently substituted by 1-6 groups independently selected from halogen, 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 1-6For example, in some embodiments, R 4 are independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cycloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, where R 4 Each C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally independently substituted by 1-6 groups 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 In some embodiments, R 4 are independently hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-5 Cycloalkyl, C 1-3 Alkoxy or C 1-3 In some embodiments, R 4 are independently hydrogen.

[0252] 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, wherein 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 Aryl or 5-12 membered heteroaryl is optionally independently substituted by one, two, three, four, five or six groups selected from halo, hydroxy, 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 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, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein R 4A Each C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1-6 groups 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 4A are independently hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-6 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.

[0253] In some embodiments, the compound is a compound of Formula (I)-(II), (III)-(IIId), or (IV) as disclosed herein, such as a compound of Formula (Ia)-(Ib), (IIa)-(IIb), (IIIa)-(IIId), (IVa)-(IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V), (Va)-(Vb), (VI), (VIa)-(VIb), or (VIb)-(VId), or a pharmaceutically acceptable form thereof, wherein Z 1 , Z 2 , Z 3 and Z 4Each independently is N or CR 5 , or Z 2 With Z 3 Together they are O and NR 5A Or S, or Z 3 With Z 4 Together they are O and NR 5A or S. In some embodiments, Z 1 , Z 2 , Z 3 and Z 4 At least one of is N. In some embodiments, Z 1 , Z 2 and Z 3 Each independently CR 5 , and Z 4 is N. In some embodiments, Z 1 , Z 2 and Z 4 Each independently CR 5 , and Z 3 is N. In some embodiments, Z 1 , Z 3 and Z 4 Each independently CR 5 , and Z 2 is N. In some embodiments, Z 2 , Z 3 and Z 4 Each independently CR 5 , and Z 1 is N. In some embodiments, Z 1 , Z 2 , Z 3 and Z 4 Each independently CR 5 In some embodiments, Z 2 and Z 3 Each independently CR 5 , and Z 1 and Z 4 are each independently N. In some embodiments, Z 3 and Z 4 Each independently CR 5 , and Z 1 and Z 2 are each independently N. In some embodiments, Z 1 and Z 4 Each independently CR 5 , and Z 2 With Z 3 Together they are O and NR 5A or S. In some embodiments, Z1 and Z 2 Each independently CR 5 , and Z 3 With Z 4 Together they are O and NR 5A or S. In some embodiments, Z 1 N, Z 2 With Z 3 Together they are O and NR 5A or S, and Z 4 CR 5 In some embodiments, Z 1 N, Z 2 CR 5 , and Z 3 With Z 4 Together they are O and NR 5A Or S. In some embodiments, R 5 R independently at each occurrence 9 、-OR 9 、halogen、CN、NO2、-C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-S(O) p R 9 or -S(O)2NR 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 Each occurrence is independently hydrogen, halo, CN, NO2, -C(O)(C 1-6 alkyl), -C(O)OH, -C(O)O(C 1-6 Alkyl), -C(O)NR 10 R 11 、-S(O) p (C 1-6 Alkyl) or -S(O)2NR 10 R 11 In some embodiments, R 5 is independently at each occurrence halo, CN, NO2, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)N(CH3)2, -S(O)2CH3, or -S(O)2N(CH3)2. In some embodiments, R 5 are independently hydrogen, halo or CN. In some embodiments, R 5 are independently hydrogen. In some embodiments, R 5are independently electron withdrawing groups. 5 In some embodiments, R 5 are independently CN.

[0254] 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, wherein 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 is optionally independently substituted by 1-6 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 5A are independently hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein R 5A Each C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted with 1-6 groups selected from halogen, 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, R5A are independently hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-6 In some embodiments, R 5A are independently hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 heteroalkyl or cyclopropyl.

[0255] In some embodiments, the compound is a compound of Formula (I)-(II), (III)-(III), or (IV) as disclosed herein, such as a compound of Formula (Ia)-(Ib), (IIa)-(IIb), (IIIa)-(IIIb), (IVa)-(IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V), (Va)-(Vb), (VI), (VIa)-(VIb), or (VIb), or a pharmaceutically 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)2R 9 、-NR 10 C(NR 10 )NR 10 R 11 、-S(O) p R 9 、-S(O)2NR 10 R 11 or -NR 10 S(O)2NR 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, wherein the C 1-3 Alkyl is optionally substituted with CN. In some embodiments, R 10 and R 11 are independently hydrogen, C 1-6 Alkyl or C 1-6 In some embodiments, R 10 With R 11 Together they form a divalent group, such as -(CH2) x -(wherein x=2-5), -CH2CH2OCH2CH2- or -CH2CH2NR 18CH2CH2-, where R 18 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 In some embodiments, R 6 In some embodiments, R is hydroxy, -OCH3, CN, hydrogen, -CH3, -CH2CN, -NH2, -NHCH3, or -NH(OCH3). In some embodiments, R6 is hydrogen, -CH3, hydroxy, -OCH3, -OCD3, -NH2, -NHCH3, or -NH(OCH3). 6 is hydrogen, hydroxy, -OCH3, -OCD3, -NH2 or -NHCH3. In some embodiments, R 6 is -NH(CH2CH2)Cl, -NH(CH2CH2)F or N-attached morpholinyl. In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 is NH2. In some embodiments, the compound is a compound of formula (II-1) or formula (II-2), such as a compound of formula (IIa-1), formula (IIb-1), formula (IIa-2) or formula (IIb-2) or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-1) or formula (III-2), such as a compound of formula (IIIa-1), formula (IIIb-1), formula (IIIa-2) or formula (IIIb-2) or a pharmaceutically acceptable form thereof, or a compound of formula (III-3), formula (IIIa-3) or formula (IIIb-3) or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (IV-1) or formula (IV-2), such as a compound of formula (IVa-1), formula (IVb-1), formula (IVa-2) or formula (IVb-2) or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (V-1), Formula (Va-1), Formula (Vb-1), Formula (VI-1), Formula (VIa-1), or Formula (VIb-1), or a pharmaceutically acceptable form thereof.

[0256] In some embodiments, the compound is a compound of Formula (I)-(II), (III)-(III), or (IV) as disclosed herein, such as a compound of Formula (Ia)-(Ib), (IIa)-(IIb), (IIIa)-(IIIb), (IVa)-(IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V), (Va)-(Vb), (VI), (VIa)-(VIb), or (VIb), or a pharmaceutically acceptable form thereof, wherein R 7 is a 5-12 membered heteroaryl group, which is optionally substituted by 1-4 independently selected from halogen, CN, NO2, 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)2R 9 、-S(O) p R 9 、-S(O)2NR 10 R 11 or -NR 10 S(O)2NR 10 R 11 For example, in some embodiments, R 7 is imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl or pyrimidinyl, which is optionally substituted by 1-4 independently selected from halo, CN, NO2, 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 、-NR10 C(O)OR 9 、-NR 10 C(O)NR 10 R 11 、-NR 10 S(O)2R 9 、-S(O) p R 9 、-S(O)2NR 10 R 11 or -NR 10 S(O)2NR 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 7 is imidazolyl or triazolyl, which is optionally substituted by 1-4 independently selected from halogen, CN, NO2, 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)2NR 10 R 11 In some embodiments, R 7 is a C-attached imidazolyl or C-attached triazolyl, which is optionally substituted by 1-4 groups independently selected from halo, CN, NO2, 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)2NR 10 R 11 In some embodiments, R 7 is an N-linked imidazolyl or N-linked triazolyl, which is optionally substituted by 1-4 groups independently selected from halogen, CN, NO2, 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)2NR 10 R 11 In some embodiments, R 7 is methyl substituted imidazolyl or methyl substituted triazolyl. In some embodiments, R 7 is C-methyl substituted imidazolyl or C-methyl substituted triazolyl. In some embodiments, R 7 is N-methyl substituted imidazolyl or N-methyl substituted triazolyl. 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, the compound is a compound of formula (II-1) or formula (II-2), such as a compound of formula (IIa-1), formula (IIb-1), formula (IIa-2), or formula (IIb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-1) or formula (III-2), such as a compound of formula (IIIa-1), formula (IIIb-1), formula (IIIa-2), or formula (IIIb-2), or a pharmaceutically acceptable form thereof, or a compound of formula (III-3), formula (IIIa-3), or formula (IIIb-3), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (IV-1) or formula (IV-2), such as a compound of formula (IVa-1), formula (IVb-1), formula (IVa-2), or formula (IVb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (V-1), Formula (Va-1), Formula (Vb-1), Formula (VI-1), Formula (VIa-1), or Formula (VIb-1), or a pharmaceutically acceptable form thereof.

[0257] In some embodiments, the compounds disclosed herein are compounds of formula (I), such as compounds of formula (Ia) or (Ib), or pharmaceutically acceptable forms thereof. In some embodiments, pharmaceutically acceptable forms of compounds of formula (I), such as compounds of formula (Ia) or (Ib), do not include salt forms (i.e., are not salts), and include pharmaceutically acceptable solvates, isomers, and isotopologues (i.e., isotopically labeled derivatives) of compounds of formula (I), such as compounds of formula (Ia) or (Ib).

[0258] In some embodiments, the compound of formula (I), formula (Ia) or formula (Ib) or a pharmaceutically acceptable form thereof is a compound of formula (II), formula (IIa) or formula (IIb) or a pharmaceutically acceptable form thereof, respectively. In some embodiments, the compound is a compound of formula (II-1) or formula (II-2) or a pharmaceutically acceptable form thereof, such as a compound of formula (IIa-1), formula (IIb-1), formula (IIa-2) or formula (IIb-2) or a pharmaceutically acceptable form thereof, respectively. In some embodiments, pharmaceutically acceptable forms of compounds of Formula (II), (IIa), or (IIb) (e.g., compounds of Formula (II-1) or (II-2), such as compounds of Formula (IIa-1), (IIb-1), (IIa-2), or (IIb-2)) do not include salt forms (i.e., are not salts), and include pharmaceutically acceptable solvates, isomers, and isotopologues (i.e., isotopically labeled derivatives) of compounds of Formula (II), (IIa), or (IIb) (e.g., compounds of Formula (II-1) or (II-2), such as compounds of Formula (IIa-1), (IIb-1), (IIa-2), or (IIb-2), respectively.

[0259] In some embodiments, the compound of formula (I), formula (Ia) or formula (Ib) or a pharmaceutically acceptable form thereof is a compound of formula (III), formula (IIIa) or formula (IIIb) or a pharmaceutically acceptable form thereof, respectively. In some embodiments, the compound is a compound of formula (III-1) or formula (III-2) or a pharmaceutically acceptable form thereof, such as a compound of formula (IIIa-1), formula (IIIb-1), formula (IIIa-2) or formula (IIIb-2) or a pharmaceutically acceptable form thereof, or a compound of formula (III-3), formula (IIIa-3) or formula (IIIb-3) or a pharmaceutically acceptable form thereof, respectively. In some embodiments, pharmaceutically acceptable forms of a compound of Formula (III), (IIIa) or (IIIb) (e.g., 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 compound of Formula (III-3), (IIIa-3) or (IIIb-3)) do not include salt forms (i.e., are not salts), and include pharmaceutically acceptable solvates, isomers, and isotopologues (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), such as 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.

[0260] In some embodiments, the compound of Formula (I), Formula (Ia), or Formula (Ib), or a pharmaceutically acceptable form thereof, is a compound of Formula (IV), Formula (IVa), or Formula (IVb), respectively, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (IV-1) or Formula (IV-2), or a pharmaceutically acceptable form thereof, such as a compound of Formula (IVa-1), Formula (IVb-1), Formula (IVa-2), or Formula (IVb-2), respectively, or a pharmaceutically acceptable form thereof. In some embodiments, pharmaceutically acceptable forms of a compound of Formula (IV) (IVa) (IVb) (IVb) (IVa-1) or (IV-2) (IVa-2), such as a compound of Formula (IVa-1), (IVb-1), (IVa-2), or (IVb-2)) do not include salt forms (i.e., are not salts), and include pharmaceutically acceptable solvates, isomers, and isotopologues (i.e., isotopically labeled derivatives) of a compound of Formula (IV) (IVa) (IVb) (IVb) (IVa-1) or (IV-2) (IVa-2), such as a compound of Formula (IVa-1), (IVb-1), (IVa-2), or (IVb-2)), respectively.

[0261] In some embodiments, the compound of Formula (I), Formula (Ia), or Formula (Ib), or a pharmaceutically acceptable form thereof, is a compound of Formula (V), Formula (Va), or Formula (Vb), respectively, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (V-1), or a pharmaceutically acceptable form thereof, such as a compound of Formula (Va-1), or Formula (Vb-1), respectively, or a pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutically acceptable form of a compound of Formula (V), Formula (Va), or Formula (Vb) (e.g., a compound of Formula (V-1), such as a compound of Formula (Va-1), or Formula (Vb-1)) does not include a salt form (i.e., is not a salt), and includes pharmaceutically acceptable solvates, isomers, and isotopologues (i.e., isotopically labeled derivatives) of a compound of Formula (V), Formula (Va), or Formula (Vb) (e.g., a compound of Formula (V-1), such as a compound of Formula (Va-1), or Formula (Vb-1)).

[0262] In some embodiments, the compound of formula (I), formula (Ia) or formula (Ib) or its pharmaceutically acceptable form is respectively a compound of formula (VI), formula (VIa) or formula (VIb) or its pharmaceutically acceptable form. In some embodiments, the compound is a compound of formula (VI-1) or its pharmaceutically acceptable form, such as respectively a compound of formula (VIa-1) or formula (VIb-1) or its pharmaceutically acceptable form. In some embodiments, the pharmaceutically acceptable form of the compound of formula (VI), formula (VIa) or formula (VIb) (e.g., a compound of formula (VI-1), such as a compound of formula (VIa-1) or formula (VIb-1)) does not include a salt form (i.e., not a salt), and includes pharmaceutically acceptable solvates, isomers, and isotopologues (i.e., isotopically labeled derivatives) of the compound of formula (VI), formula (VIa) or formula (VIb) (e.g., a compound of formula (VI-1), such as a compound of formula (VIa-1) or formula (VIb-1)).

[0263] In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), or a pharmaceutically acceptable form thereof, wherein:

[0264] Y is -(CR 16 R 17 ) q -or-(CR 16 R 17 ) m O(CR 16 R 17 ) n -;

[0265] R 1a 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)2NR 10 R 11 ;

[0266] R 2b and R 5 Each occurrence is independently R 9 、-OR 9 、halogen、CN、NO2、-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)2R 9 、-S(O) p R 9 、-S(O)2NR 10 R 11 or -NR 10 S(O)2NR 10 R 11 ;

[0267] 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)2R 9 、-NR 10 C(NR 10 )NR 10 R 11 、-S(O) p R 9 、-S(O)2NR 10 R 11 or -NR 10 S(O)2NR 10 R 11 ;

[0268] R 7 is a 5-12 membered heteroaryl group, which is optionally substituted by 1-4 independently selected from halogen, CN, NO2, 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)2R 9 、-S(O) p R 9 、-S(O)2NR 10 R 11 or -NR 10 S(O)2NR 10 R 11 Substituents substituted;

[0269] R 9 is independently hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-9 membered heteroaryl, wherein 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 substituted by 1-6 groups independently selected from halo, hydroxy, CN, NO2, 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)2R 12 、-S(O) p R 12 、-S(O)2NR 10 R 11 and -NR 10 S(O)2NR 10 R 11 Substituents substituted;

[0270] R 10 and R 11 Each occurrence is independently hydrogen, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-4 Alkoxy, phenyl or 5-9 membered heteroaryl, or together with the nitrogen to which they are attached, form a 3-6 membered heterocycloalkyl, wherein 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 substituted by 1-6 groups independently selected from halogen, hydroxy, CN, NO2, 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 、-NR 14 C(O)NR 14 R 15 、-NR 14 S(O)2R 13 、-S(O) p R 13 、-S(O)2NR 14 R 15 and -NR 14 S(O)2NR 14 R 15 Substituents substituted;

[0271] R 12 is independently hydrogen, C 1-4 Alkyl, C2-4 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, wherein 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 substituted by 1-6 groups independently selected from halo, hydroxy, CN, NO2, 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)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)2R 13 、-S(O) p R 13 、-S(O)2NR 10 R 11 and -NR 10 S(O)2NR 10 R 11 Substituents substituted;

[0272] R 13 is independently hydrogen, C 1-3 Alkyl, C 2-3Alkenyl, C 2-3 Alkynyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 Cycloalkyl or 3-6 membered heterocycloalkyl;

[0273] R 14 and R 15 Each occurrence is independently hydrogen, hydroxyl, 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 together with the nitrogen to which they are attached, form a 3-6 membered heterocycloalkyl;

[0274] R 16 and R 17 Each occurrence is independently hydrogen, halo, hydroxy, CN, NO2, 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 3-6 membered heterocycloalkoxy, or together with the C to which they are connected, form C(O), C 3-5 Cycloalkyl or 3-6 membered heterocycloalkyl;

[0275] Each m is independently an integer of 0, 1, 2 or 3;

[0276] Each n is independently an integer of 0, 1, 2 or 3;

[0277] Where the sum of m and n is 0, 1, 2, 3, 4, 5 or 6;

[0278] Each p is independently an integer of 0, 1 or 2; and

[0279] Each q is independently an integer of 0, 1, 2, 3, 4, 5 or 6.

[0280] In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III), or a pharmaceutically acceptable form thereof, wherein:

[0281] Y is -(CH2) q -or-(CH2) m O(CH2) n -;

[0282] R 1a Independently R 9 ;

[0283] R 2b Independently R 9 、-OR 9 , halogen, CN, -C(O)NR 10 R 11 or -NR 10 R 11 ;

[0284] R 5 Independently R 9 、-OR 9 、halogen、CN、NO2、-C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-S(O) p R 9 or -S(O)2NR 10 R 11 ;

[0285] R 6 CN, R 9 、-OR 9 、-NR 10 R 11 or -NR 10 OR 9 ;

[0286] R 7 is a 5-12 membered heteroaryl group, which is optionally substituted by 1-4 independently selected from halogen, CN, NO2, 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)2R 9 、-S(O) p R 9 、-S(O)2NR 10 R 11 or -NR 10 S(O)2NR 10 R 11 Substituents substituted;

[0287] R 9 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 independently substituted by 1-5 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 Substituents substituted;

[0288] R 10 and R 11 Each occurrence is 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 together with the nitrogen to which they are attached, form a 3-6 membered heterocycloalkyl group, wherein R 10 and R 11 Each C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5Cycloalkyl, 3-6 membered heterocycloalkyl or C 1-3 Each alkoxy group is optionally independently substituted with 1-5 groups 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 Substituents substituted;

[0289] R 14 and R 15 Each occurrence is independently hydrogen, hydroxyl, 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 together with the nitrogen to which they are attached, form a 3-6 membered heterocycloalkyl;

[0290] Each m is independently an integer of 0, 1, 2 or 3;

[0291] Each n is independently an integer of 0, 1, 2 or 3;

[0292] The sum of m and n is 0, 1, 2, 3, 4 or 5;

[0293] Each p is independently an integer of 0, 1 or 2; and

[0294] Each q is independently an integer of 0, 1, 2, 3, 4 or 5.

[0295] In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), or a pharmaceutically acceptable form thereof, wherein:

[0296] Y is -(CH2) q -or-(CH2) m O(CH2) n -;

[0297] R 1a Independently R 9 ;

[0298] R 2b Independently R 9 、-OR 9 , halogen, CN, -C(O)NR 10 R11 or -NR 10 R 11 ;

[0299] R 5 Independent for R 9 、-OR 9 、halogen、CN、NO2、-C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-S(O) p R 9 or -S(O)2NR 10 R 11 ;

[0300] R 6 R 9 、-OR 9 、-NR 10 R 11 or -NR 10 OR 9 ;

[0301] R 7 is a 5-12 membered heteroaryl group, which is optionally substituted by 1-4 independently selected from halogen, CN, NO2, 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)2R 9 、-S(O) p R 9 or -S(O)2NR 10 R 11 Substituents substituted;

[0302] R 9 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 3-5Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by 1-5 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 Substituents substituted;

[0303] R 10 and R 11 Each occurrence is 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 together with the nitrogen to which they are attached, form a 3-6 membered heterocycloalkyl group, wherein 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 Each alkoxy group is optionally independently substituted with 1-5 groups 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 Substituents substituted;

[0304] R 14 and R 15 Each occurrence is independently hydrogen, hydroxyl, 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 together with the nitrogen to which they are attached, form a 3-6 membered heterocycloalkyl;

[0305] Each m is independently an integer of 0, 1, 2 or 3;

[0306] Each n is independently an integer of 0, 1, 2 or 3;

[0307] The sum of m and n is 0, 1, 2, 3, 4 or 5;

[0308] Each p is independently an integer of 0, 1 or 2; and

[0309] Each q is independently an integer of 0, 1, 2, 3, 4 or 5.

[0310] In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), or a pharmaceutically acceptable form thereof, wherein:

[0311] Y is -(CH2) q -or-(CH2) m O(CH2) n -;

[0312] R 1a Independently R 9 ;

[0313] R 2b Independently R 9 、-OR 9 , halogen, CN, -C(O)NR 10 R 11 or -NR 10 R 11 ;

[0314] R 5 Independent for R 9 、halogen、CN、NO2、-C(O)R 9 、-S(O) p R 9 or -S(O)2NR 10 R 11 ;

[0315] R 6 R 9 、-OR 9 or -NR 10 OR 11 ;

[0316] R 7 is a 5-9 membered heteroaryl group, which is optionally substituted by 1-4 independently selected from halogen, CN, NO2, R 9 、-OR 9 、-C(O)R 9 、-C(O)NR 10 R11 、-NR 10 R 11 、-NR 10 C(O)R 9 、-NR 10 S(O)2R 9 、-S(O) p R 9 or -S(O)2NR 10 R 11 Substituents substituted;

[0317] R 9 is independently hydrogen, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein each C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 3-5 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by one, two or three independently selected from halo, hydroxy, CN, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl or C 1-3 Substitution of alkoxy groups;

[0318] R 10 and R 11 Each occurrence is independently hydrogen, C 1-3 Alkyl, C 1-3 heteroalkyl or 3-6 membered heterocycloalkyl, or together with the N to which they are attached, form a 3-6 membered heterocycloalkyl, wherein R 10 and R 11 Each C 1-3 Alkyl, C 1-3 Heteroalkyl or 3-6 membered heterocycloalkyl are each optionally independently substituted by one, two or three independently selected from halo, hydroxy, CN, C 1-3 Alkyl, C 1-3 Substitution by a heteroalkyl group or a 3-6 membered heterocycloalkyl group;

[0319] Each m is independently an integer of 0, 1, 2 or 3;

[0320] Each n is independently an integer of 0, 1, 2 or 3;

[0321] The sum of m and n is 0, 1, 2, 3, 4 or 5;

[0322] Each p is independently an integer of 0, 1 or 2; and

[0323] Each q is independently an integer of 0, 1, 2, 3, 4 or 5.

[0324] In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), or a pharmaceutically acceptable form thereof, wherein:

[0325] Y is -(CH2) q -or-(CH2) m O(CH2) n -;

[0326] R 1a is hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, 2,3-dihydroxypropyl or cyclopropyl;

[0327] R 2b is (a) hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, cyclopropyl, -OCH3, -OCD3, -OCH2CH3, -OCD2CD3, isopropyloxy, cyclopropyloxy, 3-oxetanylalkoxy, chloro, CN, morpholinyl, piperazinyl, 3-oxetanylamino, or -C(O)NH2; or R 2b is (b)-NH2;

[0328] R 5 is hydrogen, halogen, CN, NO2, -C(O)CH3, -S(O)CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2NHCH3 or -S(O)2N(CH3)2;

[0329] R 6 is hydrogen, -CH3, hydroxy, -OCH3, -OCD3, -NH2, -NHCH3 or -NH(OCH3); or R 6 is -NH(CH2CH2)Cl, -NH(CH2CH2)F or N-linked morpholinyl.

[0330] R 7 is imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl, which is optionally substituted with 1-4 substituents independently selected from -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, cyclopropyl, -OCH3, -OCD3, -OCH2CH3, -OCD2CD3, isopropyloxy, cyclopropyloxy, chloro and CN;

[0331] Each m is independently an integer of 0, 1 or 2;

[0332] Each n is independently an integer of 0, 1 or 2;

[0333] wherein the sum of m and n is 0, 1, 2, 3, or 4; and

[0334] Each q is independently an integer of 0, 1, 2, 3, 4 or 5.

[0335] In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), or a pharmaceutically acceptable form thereof, wherein:

[0336] Y is -(CH2)2-, -O(CH2)-, -O(CH2)2-, -(CH2)O- or -(CH2)2O-;

[0337] R 1a is hydrogen, -CH3, -CD3, 2,3-dihydroxypropyl or cyclopropyl;

[0338] R 2b (a) -OCH3, -OCD3, 3-oxetanylalkoxy, chloro, CN, morpholinyl, piperazinyl, 3-oxetanylamino or -C(O)NH2; or R 2b is (b)-NH2;

[0339] R 5 is hydrogen, chlorine, bromine or CN;

[0340] R 6 is hydrogen, hydroxy, -OCH3, -OCD3, -NH2 or -NHCH3; and

[0341] R 7 is imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl, which is optionally substituted with 1-4 substituents independently selected from -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, cyclopropyl, -OCH3, -OCD3, -OCH2CH3, -OCD2CD3, isopropyloxy, cyclopropyloxy, chloro and CN.

[0342] In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), or a pharmaceutically acceptable form thereof, wherein:

[0343] Y is -(CH2)2-, -O(CH2)-, -O(CH2)2-, -(CH2)O- or -(CH2)2O-;

[0344] R 1a is hydrogen, -CH3, -CD3, 2,3-dihydroxypropyl or cyclopropyl;

[0345] R 2b (a) -OCH3, -OCD3, 3-oxetanylalkoxy, chloro, CN, morpholinyl, piperazinyl, 3-oxetanylamino or -C(O)NH2; or R 2b is (b)-NH2;

[0346] R 5 is hydrogen, chlorine, bromine or CN;

[0347] R 6 is hydrogen, hydroxy, -OCH3, -OCD3, -NH2 or -NHCH3; and

[0348] R 7 is a methyl-substituted imidazolyl group or a methyl-substituted triazolyl group.

[0349] In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), or a pharmaceutically acceptable form thereof, wherein:

[0350] Y is -(CH2)2-, -O(CH2)-, -O(CH2)2-, -(CH2)O- or -(CH2)2O-;

[0351] R 1a is hydrogen, -CH3, -CD3, 2,3-dihydroxypropyl or cyclopropyl;

[0352] R 2b (a) -OCH3, -OCD3, 3-oxetanylalkoxy, chloro, CN, morpholinyl, piperazinyl, 3-oxetanylamino or -C(O)NH2; or R 2b is (b)-NH2;

[0353] R 5 is hydrogen, chlorine, bromine or CN;

[0354] R 6 is hydrogen, hydroxy, -OCH3, -OCD3, -NH2 or -NHCH3; and

[0355] R 7 for

[0356] In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), or a pharmaceutically acceptable form thereof, wherein:

[0357] Y is -(CH2)2-, -O(CH2)-, -O(CH2)2-, -(CH2)O- or -(CH2)2O-;

[0358] R 1a is hydrogen, -CH3, -CD3, 2,3-dihydroxypropyl or cyclopropyl;

[0359] R 2b (a) -OCH3, -OCD3, 3-oxetanylalkoxy, chloro, CN, morpholinyl, piperazinyl, 3-oxetanylamino or -C(O)NH2; or R 2b is (b)-NH2;

[0360] R 5 is hydrogen, chlorine, bromine or CN;

[0361] R 6 is hydrogen, hydroxy, -OCH3, -OCD3, -NH2 or -NHCH3; and

[0362] R 7 for

[0363] In some embodiments, the compound is a compound of formula (II-1), such as a compound of formula (II-1a) or formula (II-1b), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (II-2), such as a compound of formula (II-2a) or formula (II-2b), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-1), such as a compound of formula (III-1a) or formula (III-1b), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-2), such as a compound of formula (III-2a) or formula (III-2b), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-3), such as a compound of formula (III-3a) or formula (III-3b), or a pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutically acceptable form of 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) does not include a salt form (i.e., is not a salt) and includes Pharmaceutically acceptable solvates, isomers and isotopologues (i.e., isotopically labeled derivatives) of a compound of formula (II-1), formula (II-2), formula (III-1) or formula (III-2) (e.g., compounds of formula (IIa-1), formula (IIb-1), formula (IIa-2), formula (IIb-2), formula (IIIa-1), formula (IIIb-1), formula (IIIa-2), formula (IIIb-2) respectively) or a compound of formula (III-3), formula (IIIa-3) or formula (IIIb-3).

[0364] In some embodiments, the compound is a compound of Formula (I)-(II), (III)-(IIId), or (IV) as disclosed herein, such as a compound of Formula (Ia)-(Ib), (IIa)-(IIb), (IIId)-(IIId), (IVa)-(IVb), or (IVb) or a pharmaceutically acceptable form thereof, or a compound of Formula (V)-(Va)-(Vb), (VI)-(VIa)-(VIb), or (VIb) or a pharmaceutically acceptable form thereof, wherein the compound has a MW of no more than 1,000 g / mol. In some embodiments, the compound has a MW of no more than 900 g / mol, no more than 800 g / mol, no more than 700 g / mol, no more than 600 g / mol, or no more than 500 g / mol. In some embodiments, the compound has a MW of no more than 600 g / mol. In some embodiments, the compound has a MW of no more than 500 g / mol. In some embodiments, the compound is a compound of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2) as 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 pharmaceutically 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 pharmaceutically acceptable form thereof.

[0365] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV) as disclosed herein, for example, a compound of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), (V), (V-1), (VI), or (VI-1), or a pharmaceutically acceptable form thereof, wherein the compound is a racemate or a mixture of diastereomers, or a mixture of stereoisomers. In some embodiments, the compound is a single enantiomer or a single diastereomer. In some embodiments, the compound is a single enantiomer. For example, in some embodiments, the compound is a compound of Formula (Ia)-2, (IIb)-3, (IIIa)-4, (IIIb)-5, (IIIb)-6, (IIIa)-7, (IIIb)-8, (IIIb)-9, (IIIa)-10, (IIIb)-11, (IIIb)-12, (IIIb)-13, (IIIa)-14, (IIIb)-15, (IVa)-16, (IVb)-17, (IVa)-18, (IVb)-19, (IVb)-20, (IVa)-19, (IVb)-21, (IVa)-11, (IVb)-12, (IVa)-13, (IVb)-14, (IVb)-15, (IVa)-16, (IVb)-17, (IVb)-19, (IVa)-21, (IVb)-22, (IVb)-23, (IVa)-11, (IVb)-11, (IVa)-2, (IVb)-23, (IVb)-24, (IVb)-25, (IVb)-26, (IVa)-11, (IVb)-11, (IVa)-2, (IVb)-25, (IVb)-26, (IVb)-27, (IVb)-28, (IVb)-29, (IVb)-29, (IVb)-29, (IVb)-29, (IVb)-29, (IVb)-29, (IVb)-29, (IVa)-11, (IVb)-11, (IVa)-11, (IVb)-12 In some embodiments, the compound has an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more of the (R)-enantiomer. In some embodiments, the compound has an enantiomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% of the (R)-enantiomer. In some embodiments, the compound is an (S)-enantiomer. In some embodiments, the compound has an enantiomeric excess of greater than 10% of the (S)-enantiomer.In some embodiments, the compound has an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more of the (S)-enantiomer. In some embodiments, the compound has an enantiomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% of the (S)-enantiomer.

[0366] 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 and is selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 4, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, and 135, or a pharmaceutically acceptable form thereof. 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 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, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, and 135, or a pharmaceutically acceptable form thereof. For example, in some embodiments, the compound is 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 pharmaceutically 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, or a pharmaceutically acceptable form thereof.For example, 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, or 70, or a pharmaceutically acceptable form thereof.

[0367] In some embodiments, the compound is a compound of formula (I), formula (II), formula (III), or formula (IV), or a compound of formula (V) or formula (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as its (R)-enantiomer or (S)-enantiomer, and is selected from compounds 1, 2, 3, 4, 6, 7, 8, 11, 13, 14, 15, 17, 18, 19, 20, 22, 23, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 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, 105 102, 103, 104, 105, 106, 107, 108, 109 and 110, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 6, 7, 8, 76, 77, 79 or 80, or a pharmaceutically 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 pharmaceutically acceptable form thereof.

[0368] 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 (S)-enantiomer thereof, and is selected from compounds 5, 9, 10, 12, 16, 21, 24, 40, 43, 48, 49, 52, 53, 58, 59, 60, 64, 66, 67, 68, 70, 71, 72, 73, 74, 75, 78, 89, 90, and 91, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compounds 9, 78, 89, 90, 91, or a pharmaceutically 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 pharmaceutically acceptable form thereof.

[0369] 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 compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 36, 37, 40, 41, 42, 43, 44, 45, 46, 47, 48, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93 1, 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 7, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, and 135, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is 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 pharmaceutically 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 pharmaceutically acceptable form thereof.

[0370] 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 its (R)-enantiomer or (S)-enantiomer, and is selected from compounds 31, 32, 33, 34, 35, 38, 39, 49, 50, and 51, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 34, 35, 39, or 51, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is the (S)-enantiomer of compound 34, 35, 39, or 51, or a pharmaceutically acceptable form thereof.

[0371] In some embodiments, the compound is a compound of formula (I), formula (II), formula (III), or formula (IV), or a compound of formula (V) or formula (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as its (R)-enantiomer or (S)-enantiomer, and is selected from compounds 1, 2, 3, 5, 6, 10, 11, 12, 13, 14, 16, 17, 18, 22, 23, 24, 25, 18, 25, 28, 29, 36, 55, or 78, or a pharmaceutically 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 pharmaceutically acceptable form thereof.

[0372] 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 (S)-enantiomer thereof, and is selected from compounds 4, 7, 8, 9, 16, 19, 20, 21, 27, 30, 34, 35, 37, 39, 46, 47, 48, 51, 56, 57, 58, 62, 66, 67, 68, 69, 70, 74, 75, 82, 86, 89, and 92, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is 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 pharmaceutically 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 pharmaceutically acceptable form thereof.

[0373] 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 its (R)-enantiomer or (S)-enantiomer, and is selected from compounds 3, 4, 12, 13, 14, 15, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 43, 44, 45, 46, 47, 48, 49, 50, 51, 59, 64, , 65, 76, 77, 80, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134 and 135, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is 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 pharmaceutically 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 pharmaceutically acceptable form thereof.

[0374] In some embodiments, the compound is a compound of formula (I)-(II), (III)-(IV), or (V)-(VI) as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or (S)-enantiomer thereof, and is selected from compounds 5, 6, 7, 8, 9, 16, 17, 18, 19, 20, 21, 36, 37, 38, 39, 53, 54, 55, 56, 57, 58, 60, 61, 62, 66, 67, 68, 69, 70, 72, 73, 78, 85, 86, 88, 89, 90, and 91, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is 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 pharmaceutically 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 pharmaceutically acceptable form thereof.

[0375] 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 (S)-enantiomer thereof, and is selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 93, 98, 103, 108, 113, 118, 123, 128, and 133, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 4, 6, 7, 8, or 9, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is the (S)-enantiomer of compound 3, 4, 6, 7, 8, or 9, or a pharmaceutically acceptable form thereof.

[0376] 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 (S)-enantiomer thereof, and is selected from compounds 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 92, 96, 101, 106, 111, 116, 121, 126, and 131, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 14, 15, 18, 19, 20, or 21, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is the (S)-enantiomer of compound 14, 15, 18, 19, 20, or 21, or a pharmaceutically acceptable form thereof.

[0377] 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 (S)-enantiomer thereof, and is selected from compounds 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 97, 102, 107, 112, 117, 122, 127, and 132, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compounds 25, 27, 28, 29, 30, 34, 35, 36, 37, or 39, or a pharmaceutically 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 pharmaceutically acceptable form thereof.

[0378] In some embodiments, the compound is a compound of formula (I), formula (II), formula (III), or formula (IV), or a compound of formula (V) or formula (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as its (R)-enantiomer or (S)-enantiomer, and is selected from compounds 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 70, 76, 77, 78, 79, 80, 86, 89, 90, 91, 95, 100, 105, 110, 115, 120, 125, 130, and 135, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is 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 pharmaceutically 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 pharmaceutically acceptable form thereof.

[0379] 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 its (R)-enantiomer or (S)-enantiomer, and is selected from compounds 63, 64, 65, 94, 99, 104, 109, 114, 119, 124, 129, and 134, or a pharmaceutically acceptable form thereof.

[0380] In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a compound of Formula (V) or Formula (VI), as disclosed herein, or a pharmaceutically acceptable form thereof, that is a farnesyltransferase inhibitor. For example, in some embodiments, the compounds disclosed herein inhibit the IC 50In some embodiments, the compounds disclosed herein are selective farnesyltransferase inhibitors. In some embodiments, the compounds disclosed herein inhibit geranylgeranyltransferase type 1 with greater potency (lower IC) relative to the level of inhibition of geranylgeranyltransferase type 1. 50 For example, in some embodiments, the compounds disclosed herein inhibit type 1 geranylgeranyltransferase with an IC of 1. 50 is 100 nM or higher, such as 300 nM or higher, 500 nM or higher, 750 nM or higher, or 1,000 nM or higher. For example, in some embodiments, the compounds disclosed herein selectively inhibit farnesyltransferase relative to type 1 geranylgeranyltransferase, wherein the IC 50 (Farnesyltransferase) to IC 50 IC of (geranylgeranyltransferase type 1) 50 The ratio is at least 1:5, such as IC 50 The ratio is 1:10, 1:25, 1:50, 1:100, 1:300, 1:500, 1:750 or 1:1000 or higher.

[0381] In some embodiments, the compound is a compound of formula (I)-(II), (III)-(IV), or (V)-(VI) as disclosed herein, or a compound of formula (V)-(VI), wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or (S)-enantiomer thereof, and is selected from compounds 3, 4, 5, 6, 7, 8, 9, 11, 14, 15, 17, 18, 19, 20, 21, 23, 25, 27, 28, 29, 30, 34, 35, 36, 37, 38, 39, 42, 44, 45, 46, 47, 48, 50, 51, 53, 54, 55, 56, 57, 58, 61, 62, 65, 66, 69, 70, 72, 78, 82, 83, 86, 88, 89, and 91, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 6, 7, 8, 9, 66, or 91, or a pharmaceutically 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 pharmaceutically acceptable form thereof.

[0382] 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 (S)-enantiomer thereof, and is selected from compounds 4, 6, 7, 8, 9, 18, 19, 20, 21, 23, 26, 27, 28, 36, 37, 39, 46, 55, 56, 57, and 58, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 6, 7, 8, or 9, or a pharmaceutically 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 pharmaceutically acceptable form thereof.

[0383] 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 (S)-enantiomer thereof, and is selected from compounds 4, 6, 7, 8, 18, 27, 34, 37, 46, 47, 48, 55, 57, and 58, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 6, 7, or 8, or a pharmaceutically 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 pharmaceutically acceptable form thereof.

[0384] 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 (S)-enantiomer thereof, and is selected from compounds 4, 6, 7, 8, 18, 27, 37, 46, 55, 57, and 58, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 6, 7, or 8, or a pharmaceutically 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 pharmaceutically acceptable form thereof.

[0385] 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 its (R)-enantiomer or (S)-enantiomer, and is selected from the following compounds:

[0386] 3-Hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (001);

[0387] 3-Hydroxy-2 1 -methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (002);

[0388] 4 4-Chloro-3-hydroxy-2 1 -methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (003);

[0389] 3-amino-4 4 -Chloro-2 1 -methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (004);

[0390] 3-Hydroxy-2 2 -Methoxy-3-(1-methyl-1H-imidazol-5-yl)-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-yl 4 -formonitrile (005);

[0391] 3-Hydroxy-2 1 -methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -formonitrile (006);

[0392] 3-amino-2 1 -methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile (007);

[0393] 3-amino-2 1 -(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile (008);

[0394] 3-Amino-3-(1-methyl-1H-imidazol-5-yl)-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-2 2,4 4 -dicarbonitrile (009);

[0395] 2 2 -methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-3-ol (010);

[0396] 3-Hydroxy-2 1 -methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (011);

[0397] 4 4 -Chloro-2 2 -methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexyl-3-ol (012);

[0398] 4 4 -chloro-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (013);

[0399] 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)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (014);

[0400] 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)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (015);

[0401] 3-Hydroxy-2 2 -methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-yl)4 -carbonitrile (016);

[0402] 3-Hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile (017);

[0403] 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)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile (018);

[0404] 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)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile (019);

[0405] 3-amino-2 1 -(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -formonitrile (020);

[0406] 3-Amino-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-2 2 ,4 4 -dicarbonitrile (021);

[0407] 3-Hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone (022);

[0408] 3-Hydroxy-2 1-methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone (023);

[0409] 4 4 -Chloro-2 2 -methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcycloheptan-3-ol (024);

[0410] 4 4 -chloro-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone (025);

[0411] 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)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone (026);

[0412] 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)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone (027);

[0413] 4 4 -Chloro-3-hydroxy-2 1 -(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone (028);

[0414] 4 4 -Chloro-2 1 -cyclopropyl-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,22 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone (029);

[0415] 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)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone (030);

[0416] 4 4 -chloro-3-hydroxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone (031);

[0417] 4 4 -Chloro-3-hydroxy-2 1 -(methyl-d3)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone (032);

[0418] 4 4 -chloro-3-(methoxy-d3)-2 1 -(methyl-d3)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone (033);

[0419] 3-amino-4 4 -Chloro-2 1 -(methyl-d3)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone (034);

[0420] 3-amino-4 4 -Chloro-21 -cyclopropyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone (035);

[0421] 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)-quinoline-1,4(1,3)-diphenylcyclohepta-4 4 -carbonitrile (036);

[0422] 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)-quinoline-1,4(1,3)-diphenylcyclohepta-4 4 -carbonitrile (037);

[0423] 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)-quinoline-1,4(1,3)-diphenylcyclohepta-4 4 -carbonitrile (038);

[0424] 3-amino-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)-quinoline-1,4(1,3)-diphenylcyclohepta-4 4 -carbonitrile (039);

[0425] 2 2 -methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexan-3-ol (040);

[0426] 3-Hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,22 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (041);

[0427] 3-Hydroxy-2 1 -methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (042);

[0428] 4 4 -Chloro-2 2 -methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexan-3-ol (043);

[0429] 4 4 -chloro-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (044);

[0430] 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)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (045);

[0431] 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)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (046);

[0432] 3-amino-4 4 -Chloro-2 1 -(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2-ketone (047);

[0433] 3-amino-4 4 -chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -carbonitrile (048);

[0434] 4 4 -Chloro-2 2 -Methoxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexan-3-ol (049);

[0435] 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)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (050);

[0436] 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)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (051);

[0437] 4 4 -Br-2 2 -methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexan-3-ol (052);

[0438] 3-Hydroxy-2 2 -methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-yl) 4 -carbonitrile (053);

[0439] 3-Hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4-carbonitrile (054);

[0440] 3-Hydroxy-2 1 -(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile (055);

[0441] 3-amino-2 1 -(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile (056);

[0442] 3-amino-2 1 -cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile (057);

[0443] 3-Amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-2 2 ,4 4 -dicarbonitrile (058);

[0444] 4 6 -Chloro-2 2 -methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolin-4(3,5)-pyridine-1(1,3)-phenylcyclohexaphenyl-3-ol (059);

[0445] 3-Hydroxy-2 2 -methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolin-4(3,5)-pyridine-1(1,3)-phenylcyclohexane-4-nitropropene 6 -formonitrile (060);

[0446] 3-Hydroxy-2 1 -(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-2 2-Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-4(3,5)-pyridine-1(1,3)-phenylcyclohexaphenyl-4-nitropropene 6 -carbonitrile (061);

[0447] 3-amino-2 1 -(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-4(3,5)-pyridine-1(1,3)-phenylcyclohexaphenyl-4-nitropropene 6 -formonitrile (062);

[0448] 3-Hydroxy-2 1 -methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-7-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone (063);

[0449] 4 4 -Chloro-2 2 -methoxy-3-(1-methyl-1H-imidazol-5-yl)-7-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcycloheptan-3-ol (064);

[0450] 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)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone (065);

[0451] 3-amino-3-(1-methyl-1H-imidazol-5-yl)-2 2 -morpholino-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4- 4 -carbonitrile (066);

[0452] 3-amino-3-(1-methyl-1H-imidazol-5-yl)-2 2 -(Hexahydropyrazin-1-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile (067);

[0453] 3-amino-3-(1-methyl-1H-imidazol-5-yl)-2 2 -(Oxetan-3-ylamino)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile (068);

[0454] 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)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile (069);

[0455] 3-amino-3-(1-(methyl-d3)-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-2 2 ,4 4 -dicarbonitrile (070);

[0456] 4 4 -Br-2 2 -Chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexyl-3-ol (071);

[0457] 3-Hydroxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-2 2 ,4 4 -dicarbonitrile (072);

[0458] 4 4 -cyano-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -Formamide (073);

[0459] 4 4 -Br-2 2 -Chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-3-amine (074);

[0460] 4 4 -Bromo-3-(1-methyl-1H-imidazol-5-yl)-2 2-(Oxetane-3-oxy)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-3-amine (075);

[0461] 4 4 -Chloro-2 1 -(methyl-d3)-3-(5-methyl-1H-imidazol-1-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (076); and

[0462] 4 4 -Chloro-2 1 -(methyl-d3)-3-(4-methyl-1H-imidazol-1-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone (077);

[0463] or a pharmaceutically acceptable form thereof.

[0464] In some embodiments, the compound is selected from:

[0465] (R)-3-Hydroxy-2 1 -methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile ((R)-006);

[0466] (R)-3-amino-2 1 -methyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile ((R)-007);

[0467] (R)-3-amino-2 1 -(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4-carbonitrile ((R)-008);

[0468] (R)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-2-yl) 2 ,4 4 -dicarbonitrile ((R)-009); and

[0469] (R)-4 4 -Chloro-2 1 -(methyl-d3)-3-(4-methyl-1H-imidazol-1-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone ((R)-077);

[0470] or a pharmaceutically acceptable form thereof.

[0471] In some embodiments, the compound is selected from:

[0472] (S)-4 4 -Chloro-3-hydroxy-2 1 -methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone ((S)-003);

[0473] (S)-3-amino-4 4 -Chloro-2 1 -methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone ((S)-004);

[0474] (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)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone ((S)-014);

[0475] (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)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone ((S)-015);

[0476] (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)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -Carbonitrile ((S)-018);

[0477] (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)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -Carbonitrile ((S)-019);

[0478] (S)-3-amino-2 1 -(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -Carbonitrile ((S)-020);

[0479] (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-2 2 ,4 4 -dicarbonitrile ((S)-021);

[0480] (S)-4 4 -chloro-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone ((S)-025);

[0481] (S)-3-amino-4 4 -Chloro-21 -methyl-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone ((S)-027);

[0482] (S)-4 4 -Chloro-3-hydroxy-2 1 -(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone ((S)-028);

[0483] (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)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone ((S)-029);

[0484] (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)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone ((S)-030);

[0485] (S)-3-amino-4 4 -chloro-21-(methyl-d3)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2 1 ,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2 -ketone ((S)-034);

[0486] (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)-quinoline-1,4(1,3)-diphenylcycloheptan-22 -ketone ((S)-035);

[0487] (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)-quinoline-1,4(1,3)-diphenylcyclohepta-4 4 -Carbonitrile ((S)-036);

[0488] (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)-quinoline-1,4(1,3)-diphenylcyclohepta-4 4 -Carbonitrile ((S)-037);

[0489] (S)-3-amino-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)-quinoline-1,4(1,3)-diphenylcyclohepta-4 4 -Carbonitrile ((S)-039);

[0490] (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)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone ((S)-046);

[0491] (S)-3-amino-4 4 -Chloro-2 1 -(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone ((S)-047);

[0492] (S)-3-amino-4 4-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -Carbonitrile ((S)-048);

[0493] (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)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone ((S)-051);

[0494] (S)-3-Hydroxy-2 1 -(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -Carbonitrile ((S)-055);

[0495] (S)-3-amino-2 1 -(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -Carbonitrile ((S)-056);

[0496] (S)-3-amino-2 1 -cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-2 2 -Oxo-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -Carbonitrile ((S)-057);

[0497] (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-2-yl) 2 ,4 4 -dicarbonitrile ((S)-058);

[0498] (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-22 -morpholino-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4- 4 -Carbonitrile ((S)-066);

[0499] (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)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile ((S)-069); and

[0500] (S)-3-amino-3-(1-(methyl-d3)-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-2 2 ,4 4 -dicarbonitrile ((S)-070);

[0501] or a pharmaceutically acceptable form thereof.

[0502] In some embodiments, the compound is selected from:

[0503] (R)-3-Hydroxy-3-(1-(methyl-d3)-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-2 2 ,4 4 -dicarbonitrile ((R)-078);

[0504] (S)-3-Hydroxy-3-(1-(methyl-d3)-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-2 2 ,4 4 -dicarbonitrile ((S)-078);

[0505] (R)-4 4 -Chloro-2 1 -(methyl-d3)-3-(5-methyl-1H-1,2,4-triazol-1-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone ((R)-079);

[0506] (S)-4 4 -Chloro-2 1-(methyl-d3)-3-(5-methyl-1H-1,2,4-triazol-1-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone ((S)-079);

[0507] (R)-4 4 -Chloro-2 1 -(methyl-d3)-3-(3-methyl-1H-1,2,4-triazol-1-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone ((R)-080);

[0508] (S)-4 4 -Chloro-2 1 -(methyl-d3)-3-(3-methyl-1H-1,2,4-triazol-1-yl)-2 1 ,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 -ketone ((S)-080);

[0509] 4 4 -Br-2 2 -Chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexan-3-ol (081);

[0510] 4 4 -Bromo-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 ,3-diamine (082);

[0511] 4 4 -Bromo-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-isoquinolin-1,4(1,3)-diphenylcyclohexan-3-ol (083);

[0512] 4 4 -Bromo-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinolin-1,4(1,3)-diphenylcyclohexan-3-ol (084);

[0513] 3-Hydroxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile (085);

[0514] 3-Amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile (086);

[0515] (R)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile ((R)-086);

[0516] (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -Carbonitrile ((S)-086);

[0517] 4 4 -Br-2 7 -methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(5,3)-quinolin-1,4(1,3)-diphenylcyclohexan-3-ol (087);

[0518] 3-Hydroxy-2 7 -methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(5,3)-quinolin-1,4(1,3)-diphenylcyclohexane-4-yl)- 4 -carbonitrile (088);

[0519] (R)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-2 2 -(Oxetane-3-oxy)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -carbonitrile ((R)-089);

[0520] (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-2 2 -(Oxetane-3-oxy)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4-nitropropane 4 -Carbonitrile ((S)-089);

[0521] (S)-3-(4-methyl-1H-imidazol-1-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-2-yl) 2 ,4 4 -dicarbonitrile ((S)-090);

[0522] (R)-3-(4-methyl-1H-imidazol-1-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-2-yl) 2 ,4 4 -dicarbonitrile ((R)-090);

[0523] (S)-3-(5-methyl-1H-imidazol-1-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-2-yl) 2 ,4 4 -dicarbonitrile ((S)-091);

[0524] (R)-3-(5-methyl-1H-imidazol-1-yl)-6-oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexane-2-yl) 2 ,4 4 -dicarbonitrile ((R)-091);

[0525]

[0526]

[0527]

[0528] or a pharmaceutically acceptable form thereof.

[0529] In some embodiments, the compound is selected from:

[0530]

[0531]

[0532]

[0533] and their stereoisomers, and pharmaceutically acceptable forms.

[0534] 5.2 Pharmaceutical Compositions

[0535] In some embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, solvate, isomer, or isotopologue thereof), or a compound of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. For example, in some embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure of any one of Formula (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (Va), (Vb), (VIa), or (VIb), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. For example, in some embodiments, the pharmaceutical compositions provided herein contain a therapeutically effective amount of a compound having the structure of any of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof, or 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 pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0536] The compound of any one of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable form thereof, or a compound of formula (V) or formula (VI), or a pharmaceutically acceptable form thereof, can be formulated into a suitable pharmaceutical preparation, such as a solution, suspension, tablet, dispersible tablet, pill, capsule, powder, sustained release formulation or elixir for oral administration or for ocular or parenteral administration in a sterile solution or suspension, as well as transdermal patch formulations 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).

[0537] The composition can be formulated for single-dose administration. To prepare the composition, the weight fraction of the compound disclosed herein is dissolved, suspended, dispersed, or otherwise mixed in a selected vehicle at an effective concentration such that the condition being treated is alleviated or improved. Pharmaceutical carriers or vehicles suitable for administering the compounds disclosed herein provided herein include any such carriers known to those skilled in the art to be suitable for a particular mode of administration.

[0538] In addition, a compound of any of Formula (I), Formula (II), Formula (III) or Formula (IV), or a pharmaceutically acceptable form thereof, or a compound of Formula (V) or Formula (VI), or a pharmaceutically acceptable form thereof, may be formulated in a composition as the sole pharmaceutically active ingredient or may be combined with other therapeutically active ingredients.

[0539] The compound of any one of formula (I), formula (II), formula (III) or formula (IV) or a pharmaceutically acceptable form thereof, or the compound of formula (V) or formula (VI) or a pharmaceutically acceptable form thereof, is contained in a pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect and without producing undesirable side effects on the treated patient. The therapeutically effective concentration can be determined empirically by testing the compound in the in vitro and in vivo systems described herein and then extrapolating the dosage for use in humans.

[0540] The compound of any one of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable form thereof, or a compound of formula (V) or formula (VI), or a pharmaceutically acceptable form thereof, can be administered at once, or can be divided into a plurality of smaller doses for administration at intervals. It should be understood that the precise dosage and duration of treatment vary with the disease being treated, and can be determined empirically using known test protocols or by extrapolation from in vivo or in vitro test data. It should be noted that concentrations and dosage values ​​may also vary with the severity of the disease to be alleviated. It should be further understood that for any particular subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the desired composition.

[0541] Thus, an effective concentration or amount of one or more compounds described herein, or a pharmaceutically acceptable salt thereof, is mixed with a suitable pharmaceutical carrier or vehicle for systemic, topical, or local administration to form a pharmaceutical composition. The compound is incorporated in an amount effective to improve one or more symptoms, or for treatment, delaying progression, or prevention. The concentration of the active compound in the composition will depend on the absorption, tissue distribution, metabolism, excretion rate, dosage schedule, dosage amount, specific formulation, and other factors known to those skilled in the art of the active compound.

[0542] The composition is 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 can be formulated. The composition is in liquid, semi-liquid or solid form and is formulated in a manner suitable for each route of administration.

[0543] Solutions or suspensions for parenteral, intradermal, subcutaneous or topical application may include any of the following components: a sterile diluent such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerol, propylene glycol, dimethylacetamide or other synthetic solvents; antimicrobial agents such as benzyl alcohol and methyl paraben; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates and phosphates; and tonicity adjusting agents such as sodium chloride or dextrose. Parenteral formulations may be packaged in ampoules, pens, disposable syringes, or single-dose or multi-dose vials made of glass, plastic or other suitable materials.

[0544] Pharmaceutical compositions for administration to humans and animals in unit dosage forms are provided, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, as well as oil-water emulsions containing a suitable amount of a compound or a pharmaceutically acceptable salt thereof. Pharmaceutical therapeutically active compounds and their salts are formulated and administered in unit dosage forms or multiple dosage forms. As used herein, unit dosage forms refer to physically discrete units suitable for human and animal subjects and individually packaged as known in the art. Each unit dose contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect, as well as the required 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 can be administered in portions or multiple times. Multiple dosage forms are multiple identical unit dosage forms packaged in a single container for administration in separate unit dosage forms. Examples of multiple dosage forms include vials, bottles of tablets or capsules, or pint or gallon bottles. Thus, multiple dosage forms are multiple unit doses that are not separated in the packaging.

[0545] Sustained release preparation can also be prepared.The applicable example of sustained release preparation comprises the semipermeable matrix of the solid hydrophobic polymer containing the compound provided herein, and described matrix is ​​the form of molded articles, for example film or microcapsule.The example of sustained release matrix comprises iontophoresis patch, polyester, hydrogel (for example, poly-(2-hydroxyethyl-methacrylate) or poly-(vinyl alcohol)), polylactic acid, the copolymer of L-glutamic acid and L-glutamic acid ethyl ester, nondegradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymer, such as LUPRON DEPOT TM(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 are able to release molecules for more than 100 days, certain hydrogels release proteins over shorter time periods. When the encapsulated compound remains in the body for a long time, it may denature or aggregate due to exposure to moisture at 37°C, resulting in loss of biological activity and possible changes in its structure. Rational stabilization strategies can be designed depending on the mechanism of action involved. For example, if the aggregation mechanism is found to be through the formation of intermolecular SS bonds via sulfhydryl-disulfide exchange, stabilization can be achieved by modifying the sulfhydryl residues, lyophilizing from acidic solutions, controlling the moisture content, using appropriate additives, and developing specific polymer matrix compositions.

[0546] Dosage forms or compositions can be prepared containing an active ingredient in an amount ranging from 0.001% to 100%, with the remainder being made up of a non-toxic carrier. For oral administration, pharmaceutically acceptable non-toxic compositions are formed by incorporating any commonly used excipients, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, cross-linked sodium carboxymethyl cellulose, 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% active ingredient.

[0547] A compound of any of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable form thereof, or a compound of Formula (V) or Formula (VI), or a pharmaceutically acceptable form thereof, can be prepared with carriers that protect the compound against rapid elimination from the body, such as a time-release formulation or coating.

[0548] The compositions may include other active compounds to obtain the desired combination of properties. The compounds provided herein or pharmaceutically acceptable salts thereof as described herein may also be administered with another pharmacological agent known in the general art to be valuable in treating one or more of the diseases or medical conditions mentioned above, such as diseases associated with oxidative stress.

[0549] Oral pharmaceutical dosage forms are solid, gel, or liquid. Solid dosage forms include 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 a non-effervescent or effervescent form in combination with other ingredients known to those skilled in the art.

[0550] In certain embodiments, the formulation is a solid dosage form, such as a capsule or tablet. Tablets, pills, capsules, sugar tablets, etc. may contain any of the following ingredients or compounds of similar nature: binders; diluents; disintegrants; lubricants; glidants; sweeteners; and flavorings.

[0551] Examples of binders include microcrystalline cellulose, tragacanth gum, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste. Lubricants include talc, starch, magnesium stearate or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrants include cross-linked sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Colorants include, for example, any approved and certified water-soluble FD and C dyes, mixtures thereof, and water-insoluble FD and C dyes suspended on alumina hydrate. Sweeteners include sucrose, lactose, mannitol and artificial sweeteners (such as saccharin), as well as a variety of spray-dried flavorings. Flavorings include natural flavorings extracted from plants (such as fruits) and synthetic blends of compounds that produce pleasant sensations, such as, but not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene laurate. Enteric coatings include fatty acids, fats, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Film coatings include hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate.

[0552] When the dosage unit form is a capsule, it can also contain a liquid carrier, such as a fatty oil, in addition to the materials of the above types. In addition, the dosage unit form can contain various other materials that change the physical form of the dosage unit, such as coatings of sugar and other enteric solvents. The compound can also be used as a component of an elixir, suspension, syrup, sheet, spray, chewing gum, etc. In addition to the active compound, the syrup can also contain sucrose as a sweetener and some preservatives, dyes and coloring agents and flavorings.

[0553] The pharmaceutically acceptable carriers included in the tablets are binders, lubricants, diluents, disintegrants, colorants, flavorings, and wetting agents. Enteric-coated tablets resist the effects of gastric acid due to the enteric coating and dissolve or disintegrate in neutral or alkaline intestines. Sugar-coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances are applied. Film-coated tablets are compressed tablets coated with polymers or other suitable coatings. Multiple compressed tablets are compressed tablets made by using the previously mentioned pharmaceutically acceptable substances in more than one compression cycle. Colorants can also be used in the above dosage forms. Flavorings and sweeteners are used in compressed tablets, sugar-coated tablets, multiple compressed tablets, and chewable tablets. Flavorings and sweeteners are particularly useful in forming chewable tablets and diamond-shaped tablets.

[0554] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent particles, and effervescent formulations reconstituted from effervescent particles. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

[0555] Elixirs are clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable carriers for elixirs include solvents. Syrups are concentrated aqueous solutions of sugars (e.g., sucrose) and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed in another liquid in the form of globules. Pharmaceutically acceptable carriers for emulsions are non-aqueous liquids, emulsifiers, and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non-foaming granules to be reconstituted into a liquid oral dosage form include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable substances used in foaming granules to be reconstituted into a liquid oral dosage form include organic acids and a source of carbon dioxide. Colorants and flavorings are used in all of the above dosage forms.

[0556] Solvents include glycerin, sorbitol, ethanol, and syrup. Examples of preservatives include glycerin, methyl and propyl parabens, benzoic acid, sodium benzoate, and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifiers include gelatin, gum arabic, gum tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, gum tragacanth, magnesium aluminum silicate (Veegum), and gum arabic. Diluents include lactose and sucrose. Sweeteners include sucrose, syrup, glycerin, and artificial sweeteners (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 approved certified water-soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavorings extracted from plants (such as fruits), as well as synthetic blends of compounds that produce a pleasant taste.

[0557] For solid dosage forms, solutions or suspensions in, for example, propylene carbonate, vegetable oils, or triglycerides are encapsulated in gelatin capsules. Such solutions and their preparation and encapsulation are disclosed in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. For liquid dosage forms, solutions in, for example, polyethylene glycol can be diluted with sufficient pharmaceutically acceptable liquid carrier (e.g., water) to be easily measured for administration.

[0558] Alternatively, liquid or semisolid oral preparations can 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 as provided herein, a dialkylated mono- or poly-alkylene glycol (including, but not limited to, 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol)), and one or more antioxidants (such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates).

[0559] Other formulations include, but are not limited to, aqueous alcohol solutions comprising pharmaceutically acceptable acetals. The alcohol used in these formulations is any pharmaceutically acceptable water-miscible solvent having one or more hydroxyl groups, including but not limited to propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal.

[0560] In all embodiments, tablet and capsule formulations may be coated as known to those skilled in the art to regulate or maintain dissolution of the active ingredient. Thus, for example, they may be coated with conventional enteric digestible coatings such as phenyl salicylate, wax and cellulose acetate phthalate.

[0561] Parenteral administration is also provided herein, which is characterized in that it is generally injected subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional form as liquid solutions or suspensions, solid forms suitable for solutions or suspensions in liquids before injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical composition to be used can also contain a small amount of nontoxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, stabilizers, solubilizers and other such agents, such as sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. It is also contemplated herein that the implantation of a sustained-release or sustained-release system allows the dosage to be maintained at a constant level. Briefly, the compounds provided herein are dispersed in a solid internal matrix, e.g., polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, polysiloxane carbonate copolymers, hydrophilic polymers (e.g., hydrogels of esters of acrylic acid and methacrylic acid), collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate, wherein the solid internal matrix The parenteral composition is surrounded by an outer polymeric membrane, for example, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers and ethylene / vinyloxyethanol copolymers, which is insoluble in body fluids. In the release rate controlling step, the compound diffuses through the outer polymeric membrane. The percentage of active compound contained in these parenteral compositions is highly dependent on its specific properties and the activity of the compound and the needs of the experimenter.

[0562] The parenteral administration of the composition includes intravenous, subcutaneous and intramuscular administration. The preparations for parenteral administration include sterile solutions prepared for injection, sterile dry soluble products (such as lyophilized powders, including subcutaneous tablets) prepared for combination with solvents just before use, sterile suspensions prepared for injection, sterile dry insoluble products and sterile emulsions prepared for combination with vehicles just before use. The solution can be aqueous or non-aqueous.

[0563] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0564] Pharmaceutically acceptable carriers used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifiers, binders or chelating agents and other pharmaceutically acceptable substances.

[0565] 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, cottonseed oil, corn oil, sesame oil and peanut oil of plant origin. Antimicrobial agents that inhibit bacterial or fungal concentrations must be added to parenteral preparations packaged in multidose containers, including phenol or cresol, mercurial preparations, benzyl alcohol, chlorobutanol, methyl and propyl parabens, 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 agents and dispersants include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinyl pyrrolidone. Emulsifiers include polysorbate 80 ( 80). Metal ion clamping or chelating agents include EDTA. Pharmaceutical carriers also include ethanol, polyethylene glycol, and propylene glycol for water-miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0566] Injectables are designed for local and systemic administration. Typically, therapeutically effective agents are formulated to contain a concentration of at least about 0.1% w / w to about 90% w / w or higher, such as more than 1% w / w of active compound for one or more tissues being treated. The active ingredient can be administered at once, or can be divided into multiple smaller doses for administration at intervals. It should be understood that the precise dosage and duration of treatment vary with the tissue being treated and can be determined empirically using known testing protocols or by extrapolating from in vivo or in vitro test data. It should be noted that concentrations and dosage values ​​may also vary with the age of the individual being treated. It should be further understood that for any particular subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the formulation, and the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the desired formulation.

[0567] The compound of any one of formula (I), formula (II), formula (III) or formula (IV) or its pharmaceutically acceptable form, or the compound of formula (V) or formula (VI) or its pharmaceutically acceptable form can be suspended in micronized form or other suitable form to produce a more soluble active product. The form of the resulting mixture depends on many 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 improve the symptoms of the disease and can be determined empirically.

[0568] The topical mixtures are prepared as described for topical and systemic administration. The resulting mixtures can be solutions, suspensions, emulsions, etc., and formulated into creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, rinses, sprays, suppositories, bandages, skin patches, or any other formulation suitable for topical administration.

[0569] A compound of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or a compound of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising the same, can be formulated for topical or external application (such as topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions), and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery, and also for administration to the eye or mucous membranes, or for inhalation therapy. Nasal solutions of the active compounds may also be administered, alone or in combination with other pharmaceutically acceptable excipients. These solutions, particularly those for ophthalmic use, can be formulated as 0.01%-10% isotonic solutions containing appropriate salts, with a pH of approximately 5-7.

[0570] Other routes of administration are also contemplated herein, such as transdermal patches and rectal administration. For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules, and tablets for systemic effects. Rectal suppositories as used herein refer to solids that melt or soften at body temperature for insertion into the rectum to release one or more pharmacologically or therapeutically active ingredients. The pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents that raise the melting point. Examples of bases include cocoa butter (cocoa butter), glycerinated gelatin, carbowax (polyoxyethylene glycol), and an appropriate mixture of monoglycerides, diglycerides, and triglycerides of fatty acids. A combination of various bases can be used. Agents that raise the melting point of suppositories include spermaceti and wax. Rectal suppositories can be prepared by compression or by molding. The exemplary weight of a rectal suppository is about 2 to 3 grams. Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substances as those for oral administration and by the same method.

[0571] The compound of any one of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable form thereof, or a compound of formula (V) or formula (VI), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising the same, can be administered by controlled release means or by delivery devices well known to those skilled in the art. Examples include, but are not limited to, those described in the following patents: U.S. Patent Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123 and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, ,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358, 6,699,500 and 6,740,634, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled release of the compounds disclosed herein using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

[0572] In certain embodiments, the compound of any one of formula (I), formula (II), formula (III) or formula (IV) or its pharmaceutically acceptable form, or formula (V) or formula (VI) compound or its pharmaceutically acceptable form can be administered using intravenous infusion, implantable osmotic pump, transdermal patch, liposome or other modes of administration. In one embodiment, a pump can 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 can be used. In yet another embodiment, a controlled release system can be placed near the therapeutic target, that is, so that only a portion of the systemic dose is required (see, for example, Goodson, Medical Applications of Controlled Release, Vol. 2, pp. 115-138 (1984)).

[0573] A compound of any one of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable form thereof, or a compound of Formula (V) or Formula (VI), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising the same, can be packaged into an article of manufacture containing packaging materials, a compound or a pharmaceutically acceptable form thereof provided herein for treating, preventing, or ameliorating one or more symptoms or progression of a cancer that depends on a farnesylated protein, and a label indicating that the compound or a pharmaceutically acceptable form thereof is used to treat, prevent, or ameliorate one or more symptoms or progression of a cancer that depends on a farnesylated protein.

[0574] The articles provided herein contain packaging materials. Packaging materials for packaging pharmaceutical products are well known to those skilled in the art. See, for example, 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 materials suitable for selected formulations and intended administration and treatment modes. Numerous formulations of the compounds and compositions provided herein are contemplated.

[0575] In some embodiments, the article is a kit. The kit may include a compound or pharmaceutical composition as described herein in suitable packaging, and may include written materials such as instructions for use, clinical study discussions, side effect lists, etc. Such kits may also include information such as scientific literature references, package inserts, clinical trial results, and / or summaries of these items, which indicate or determine the activity and / or advantages of the pharmaceutical composition, and / or describe dosing, application, side effects, drug interactions, or other information useful to health care providers. Such information can be based on the results of various studies, such as studies using experimental animals involving in vivo models and studies based on human clinical trials.

[0576] In some embodiments, the kit provides a memory aid, for example in the form of numbers next to the tablets or capsules, whereby these numbers correspond to the days of the regimen on which the specified tablets or capsules should be taken. A "daily dose" can be a single tablet or capsule or several tablets or capsules to be taken on a given day.

[0577] Suitable packaging and additional products used (e.g., measuring cups for liquid preparations, foil packages for minimizing exposure to air, etc.) are known in the art and can be included in the kit. In other embodiments, the kit can also include a device for administering the active agent. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers. The kits described herein can be provided, sold, and / or promoted to health providers, including physicians, nurses, pharmacists, prescription management personnel, etc. In some embodiments, the kit can also be sold directly to consumers.

[0578] The example of such test kit is so-called blister pack. Blister pack is well-known in the packaging industry and is widely used in the packaging of pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister pack is generally composed of a relatively hard material sheet covered with a foil of a preferably transparent plastic material. During the packaging process, a groove is formed in the plastic foil. The groove has the size and shape of the tablet or capsule to be packaged. Then, the tablet or capsule is placed in the groove, and the relatively hard material sheet is sealed on the plastic foil at the foil surface opposite to the direction in which the groove is formed. As a result, the tablet or capsule is sealed in the groove between the plastic foil and the sheet. The strength of the sheet makes it possible for the tablet or capsule to be taken out from the blister pack by manually applying pressure on the groove, thereby forming an opening in the sheet at the groove. The tablet or capsule can then be taken out via the opening.

[0579] The kit may also include a pharmaceutically 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 may include a sealed container of a suitable vehicle in which the active agent can be dissolved to form a sterile, particulate-free solution suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to, Water for Injection, USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethanol, 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.

[0580] 5.3 Purpose and Method

[0581] 5.3.1 Therapeutic uses and methods

[0582] RAS isoforms associate with the inner surface of the plasma membrane to transduce extracellular signals. In order to become active, RAS undergoes several post-translational modifications. The first step in activation is the farnesylation of the cysteine ​​at the C-terminus in the CAAX box (where 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. Farnesyltransferase (FTase) recognizes the CAAX motif and transfers a 15-carbon farnesyl isoprene 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 prenylcysteine ​​carboxymethyltransferase. Prior, IA et al., J. Cell Sci. 2001, 114, 1603-1608. Further palmitoylation (the presence of KRAS4A, NRAS and HRAS or a polybasic domain (KRAS4B)) results in protein anchoring in the plasma membrane. Hancock, JF et al., Cell 1990, 63, 133-139. Observations indicate that prenylation is required for the function of all RAS isoforms, including their mutant forms. However, some farnesylated proteins (including KRAS and NRAS) can be protected from membrane displacement by alternative prenylation by geranylgeranyltransferase (GGTase) in the presence of farnesyltransferase inhibitors (FTIs). Zhang, FL et al., J. Biol. Chem. 1997, 272, 10232-10239; Whyte, DB et al., J. Biol. Chem. 1997, 272, 14459-14464. In contrast, the third family member, HRAS, is not a GGTase substrate, and therefore FTIs impair its membrane localization and cellular function. Whyte, DB et al. Therefore, using FTIs to target enriched patient populations of tumors (eg, tumors that are dependent on farnesylated proteins such as HRAS, eg, tumors carrying HRAS mutations) should provide clinical benefit.

[0583] A specific FTI in clinical development is tipifarnib. The efficacy of tipifarnib is examined in a series of cell-derived and patient-derived head and neck squamous cell carcinoma (HNSCC) xenograft models. Gilardi, M. et al., Mol. Cancer Ther. 2020, 19, 1784-1796. Genomic analysis revealed that 6% of HNSCC had HRAS mutations at initial diagnosis (Hoadley, KA et al., Cell 2018, 173, 291-304), and 15% of patients had HRAS mutations during the acquisition of resistance to cetuximab (Braig, F. et al., Oncotarget 2016, 7, 42988-42995), and HRAS mutations have been shown to be associated with a reduced response to cetuximab treatment in HNSCC patients. Rampias, T. et al., Clin. Cancer Res. 2014, 20, 2933-2946.

[0584] HRAS is also repeatedly mutated in other cancer types, including urothelial carcinoma and salivary gland tumors, and 24% of patients with HRAS-mutated metastatic urothelial carcinoma treated with tipifarnib experienced an objective response. In addition, of 13 patients with recurrent / metastatic salivary gland tumors (SGT) treated with tipifarnib, 1 patient experienced an objective response, and the other 7 patients had stable disease as the best response. Ho, AL et al., J. Clin. Oncol. 2020, 38, 6504. Other tumor types that exhibit recurrent HRAS driver mutations include squamous cell carcinoma of the lung, thyroid cancer, pheochromocytoma, and paraganglioma. Hoadley, KA et al.

[0585] In certain embodiments, the compounds disclosed herein are compounds of Formula (Ia)-(Ib)-(IIa), (IIb)-(IIIa), (IIIb)-(IIIlb), (IVa)-(IVb), for example, compounds of Formula (II-1)-(IIb), (III-1)-(IIIl-2), (IV-1)-(IV-2), such as 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 pharmaceutically acceptable forms thereof, are farnesyltransferase inhibitors. In some embodiments, the compounds disclosed herein are compounds of Formula (III-3), (IIIa-3), (IIIb-3), (Va-1), (Vb-1), (Via-2), (Vlla-3), (IIIb-3), (IIId-4), (IIId-5), (IIId-6), (IIId-7), (IIId-8), (IIId-9), (IIId-10), (IIId-11), (IIId-12), (IIId-13), (IIId-14), (IIId-15), (IIId-16), (IIId-17), (IIId-18), (IIId-19), (IVa-20), (IVb-21), (IVa-22), (IVb-23), (IVd-24), (IVd-25), (IVd-26), (IVd-27), (IVd-28), (IVd-29), (IVd-30), (IVd-31), (IVd-32), (IVd-33), (IVd-34), (IVd-35)

[0586] In some embodiments, provided herein are methods of inhibiting farnesyltransferase comprising contacting farnesyltransferase with an effective amount of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV) as disclosed herein, or a pharmaceutically acceptable form thereof. In some embodiments, provided herein are methods of inhibiting farnesyltransferase comprising contacting farnesyltransferase with an effective amount of a compound of Formula (V) or Formula (VI) as disclosed herein, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (Ia)-(Ib)-(IIa), (IIb)-(IIIa), (IIIb)-(IIIlb), (IVa)-(IVb), or (IVb)-(IVb), for example, 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 (IVb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (III-3), (IIIa-3), (IIIb-3), (Va-7), (Vb-8), (V-1), (Va-1), (Vb-1), (Via-1), (VIb-1), (VIa-1), (VIb-1), or (VIb-1), or a pharmaceutically acceptable form thereof. In some embodiments, the method of inhibiting farnesyltransferase comprises contacting farnesyltransferase with an effective amount of a pharmaceutical composition as disclosed herein, comprising a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the method of inhibiting farnesyltransferase comprises contacting farnesyltransferase with an effective amount of a pharmaceutical composition as disclosed herein, comprising a compound of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.In some embodiments, the pharmaceutical composition contains a compound of Formula (Ia)-(Ib)-(IIa), (IIb)-(IIIa), (IIIb)-(IIIlb), (IVa)-(IVb), or (IVb)-(IVb), for example, 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 (IVb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutical composition comprises a compound of Formula (III-3), (IIIa-3), (IIIb-3), (Va-7), (Vb-8), (V-1), (Va-1), (Vb-1), (Via-1), (VIb-1), (VIa-1), (VIb-1), or (VIb-1), or a pharmaceutically acceptable form thereof. In some embodiments, the contacting of the farnesyltransferase occurs in a cell. In some embodiments, the farnesyltransferase is present in a cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the subject suffers from a cancer that is dependent on a farnesylated protein. In some embodiments, the subject is human.

[0587] 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 a modification in a codon or comprises 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 inhibition of farnesylation of an H-Ras protein (such as an H-Ras protein with a mutation) occurs 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 a farnesyl transferase present in a cell occurs in a subject suffering from a cancer that is dependent on a farnesylated protein. In some embodiments, the cancer that is dependent on a farnesylated protein is a solid tumor. In some embodiments, the cancer that is dependent on a farnesylated protein is a cancer that is dependent on one or more farnesylated proteins. In some embodiments, the cancer that depends on farnesylated proteins depends on farnesylated proteins for the progression and / or survival of the cancer. In some embodiments, the cancer that depends on farnesylated proteins is a cancer that depends on farnesylated H-Ras protein. In some embodiments, the cancer that depends on farnesylated proteins has an H-Ras protein mutation. In some embodiments, the H Ras protein mutation is a modification in a codon or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from G12, G13, Q61, Q22, K117, A146, and any combination thereof in the corresponding mutant H-Ras protein. In some embodiments, the cancer that depends on farnesylated proteins is head and neck cancer. In some embodiments, head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, head and neck cancer (e.g., HNSCC) depends on one or more farnesylated proteins, such as depends on farnesylated H-Ras protein. In some embodiments, head and neck cancer (e.g., HNSCC) has an H-Ras protein mutation. In some embodiments, the cancer that depends on farnesylated proteins is a carcinoma, melanoma, sarcoma, or chronic granulomatous disease. For example, in some embodiments, the cancer that depends on farnesylated proteins is thyroid cancer, head and neck cancer, urothelial cancer, salivary cancer, upper gastrointestinal cancer, bladder cancer, breast cancer, ovarian cancer, brain cancer, stomach 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, 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, SCC is HNSCC.In some embodiments, the SCC is a human papillomavirus (HPV) negative SCC. In some embodiments, the HNSCC is an 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) is dependent on one or more farnesylated proteins, such as farnesylated H-Ras protein. In some embodiments, the HNSCC is dependent on one or more farnesylated proteins, such as farnesylated H-Ras protein. In some embodiments, the SCC (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 human.

[0588] In some embodiments, the method inhibits farnesylation of N-Ras protein. In some embodiments, N-Ras protein has a mutation. In some embodiments, the N Ras protein mutation is a modification in a codon or comprises 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 N-Ras protein. In some embodiments, the inhibition of farnesylation of N-Ras protein (such as an N-Ras protein with a mutation) occurs 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 farnesyl transferase present in the cell occurs in a subject suffering from a cancer that depends on a farnesylated protein. In some embodiments, the cancer that depends on a farnesylated protein is a solid tumor. In some embodiments, the cancer that depends on a farnesylated protein is a cancer that depends on one or more farnesylated proteins. In some embodiments, the cancer that depends on farnesylated proteins depends on farnesylated proteins for the progression and / or survival of the cancer. In some embodiments, the cancer that depends on farnesylated proteins is a cancer that depends on farnesylated N-Ras proteins. In some embodiments, the cancer that depends on farnesylated proteins has an N-Ras protein mutation. In some embodiments, the N-Ras protein mutation is a modification in a codon or comprises 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 N-Ras protein. In some embodiments, the cancer that depends on farnesylated proteins 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 is dependent on one or more farnesylated proteins, such as a farnesylated N-Ras protein. In some embodiments, 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 human.

[0589] In some embodiments, provided herein are methods for treating a subject's cancer that is dependent on a farnesylated protein, comprising administering to a subject suffering from a cancer that is dependent on a farnesylated protein a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) as disclosed herein, or a pharmaceutically acceptable form thereof. In some embodiments, provided herein are methods for treating a subject's cancer that is dependent on a farnesylated protein, comprising administering to a subject suffering from a cancer that is dependent on a farnesylated protein a therapeutically effective amount of a compound of Formula (V) or Formula (VI) as disclosed herein, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (Ia)-(Ib)-(IIa), (IIb)-(IIIa), (IIIb)-(IIIlb), (IVa)-(IVb), or (IVb)-(IVb), for example, 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 (IVb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (III-3), (IIIa-3), (IIIb-3), (Va-1), (Vb-1), (Via-2), (Vlla-3), (IIIb-3), (Vlla-1), (Vlla-1), (Vb-1), (Via-2), (Vlla-1), (Vlla-2), (Vlla-1), (Vlb-1), (Via-2), (Vlla-2), (Vlb-2), (Via-3), (Vlla-1), (Vlb-1), (Via-2), (Vlla-2), (Vlb-2), (Via-3), (Vlla-1), or (Vlb-1), or a pharmaceutically acceptable form thereof. In some embodiments, a method of treating a cancer that is dependent on a farnesylated protein in a subject comprises administering to a subject suffering from a cancer that is dependent on a farnesylated protein a therapeutically effective amount of a pharmaceutical composition as disclosed herein, the pharmaceutical composition comprising a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or a compound of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.In some embodiments, the pharmaceutical composition contains a compound of Formula (Ia)-(Ib)-(IIa), (IIb)-(IIIa), (IIIb)-(IIIlb), (IVa)-(IVb), or (IVb)-(IVb), for example, 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 (IVb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutical composition contains a compound of Formula (III-3), (IIIa-3), (IIIb-3), (Va-1), (Vb-1), (Via-1), (Vlb-1), (Via-2), (Vlla-3), (IIIb-3), (IIIb-3), (Vlla-3), (IIIb-4), (Vlla-5), (Vlla-6), (Vlla-7), (Vlla-8), (Vlla-9), (Vlla-10), (Vlla-11), (Vlla-12), (Vlla-13), (Vlla-14), (Vlla-15), (Vlla-16), (Vlla-17), (Vlla-18), (Vlla-19), (Vlla-20), (Vlla-21), (Vlla-22), (Vlla-23), (Vlla-24), (Vlla-25), (Vlla-26), (Vlla-27), (Vlla-28), (Vlla-29), (Vlla-30), (Vlla-31), (Vlla-32), (Vlla-33), (Vlla-34), (Vlla-35), (Vlla-36), (Vlla-37), (Vlla-38), (Vlla-40), (Vlla-41), (Vlla-42), (Vlla-43), (Vlla-44), (Vlla-45), (Vlla-46), (Vlla-47) In some embodiments, the H Ras protein mutation is a modification in a codon or comprises 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 that depends on farnesylated proteins is head and neck cancer. In some embodiments, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, head and neck cancer (e.g., HNSCC) depends on one or more farnesylated proteins, such as depends on farnesylated H-Ras proteins. In some embodiments, head and neck cancer (e.g., HNSCC) has an H-Ras protein mutation. In some embodiments, the cancer that depends on farnesylated proteins is a carcinoma, melanoma, sarcoma, or chronic granulomatous disease. For example, in some embodiments, the cancer that depends on farnesylation protein is thyroid cancer, head and neck cancer, urothelial cancer, salivary cancer, upper gastrointestinal cancer, bladder cancer, breast cancer, ovarian cancer, brain cancer, stomach cancer, prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer or pancreatic cancer. In some embodiments, the cancer that depends on farnesylation 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 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) is dependent on one or more farnesylated proteins, such as dependent on farnesylated H-Ras protein. In some embodiments, the HNSCC is dependent on one or more farnesylated proteins, such as dependent on farnesylated H-Ras protein. In some embodiments, the SCC (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 human.

[0590] In some embodiments, provided herein are methods for treating a subject's cancer that is dependent on a farnesylated protein, comprising administering to a subject suffering from a cancer that is dependent on a farnesylated protein a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) as disclosed herein, or a pharmaceutically acceptable form thereof. In some embodiments, provided herein are methods for treating a subject's cancer that is dependent on a farnesylated protein, comprising administering to a subject suffering from a cancer that is dependent on a farnesylated protein a therapeutically effective amount of a compound of Formula (V) or Formula (VI) as disclosed herein, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (Ia)-(Ib)-(IIa), (IIb)-(IIIa), (IIIb)-(IIIlb), (IVa)-(IVb), or (IVb)-(IVb), for example, 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 (IVb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (III-3), (IIIa-3), (IIIb-3), (Va-1), (Vb-1), (Via-2), (Vlla-3), (IIIb-3), (IIIb-4), (Vlla-5), (Vlla-6), (Vlla-7), (Vlla-8), (Vlla-9), (Vlla-1), (Vlla-1), (Vlla-1), (Vlla-1), (Vlla-1), (Vlla-1), (Vlla-1), or (Vlb-1), or a pharmaceutically acceptable form thereof. In some embodiments, a method of treating a farnesylated protein-dependent cancer in a subject comprises administering to a subject suffering from a farnesylated protein-dependent cancer a therapeutically effective amount of a pharmaceutical composition as disclosed herein, the pharmaceutical composition comprising a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, a method of treating a farnesylation-dependent cancer in a subject comprises administering to a subject suffering from a farnesylation-dependent cancer a therapeutically effective amount of a pharmaceutical composition as disclosed herein, comprising a compound of Formula (V) or Formula (VI), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.In some embodiments, the pharmaceutical composition contains a compound of Formula (Ia)-(Ib)-(IIa), (IIb)-(IIIa), (IIIb)-(IIIlb), (IVa)-(IVb), or (IVb)-(IVb), for example, 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 (IVb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutical composition contains a compound of Formula (III-3), (IIIa-3), (IIIb-3), (Va-1), (Vb-1), (Via-1), (Vlb-1), (Via-2), (Vlla-3), (IIIb-3), (Vlla-3), (IIIb-3), (Va-1), (Vb-1), (Via-2), (Vlla-1), (Vlb ...lb-2), (Vlla-1), (Vlb-2), (Vlla-1), (Vlb-1), (Vlla-2), (Vlb-2), (Vlla-3), (IIIb-3), (Va-1), (Vb-1), (Via-2), (Vlb-2), (Vlla-1), (Vlb-2), (Vlla-1), (Vlb-2), (Vlla-2), (Vlb-2) or (Vlb-1) or a pharmaceutically acceptable form thereof. In some embodiments, the cancer that is dependent on a farnesylated protein is a solid tumor. In some embodiments, the cancer that is dependent on a farnesylated protein is dependent on one or more farnesylated proteins. In some embodiments, the cancer that is dependent on a farnesylated protein is dependent on a farnesylated protein for the progression and / or survival of the cancer. In some embodiments, the cancer that is dependent on a farnesylated protein is a cancer that is dependent on a farnesylated N-Ras protein. In some embodiments, the cancer that is dependent on a farnesylated protein has an N-Ras protein mutation. In some embodiments, the N Ras protein mutation is a modification in a codon or comprises 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 N-Ras protein. In some embodiments, the cancer that depends on farnesylated proteins 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, such as farnesylated N-Ras protein. In some embodiments, 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 human.

[0591] In some embodiments, the method for treating a cancer that depends on a farnesylated protein as disclosed herein, wherein the method further comprises determining the presence or absence of an H-Ras mutation. In some embodiments, the method for treating a cancer that depends on a farnesylated protein as disclosed herein, wherein the method 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 acids obtained from a sample of a subject. In some embodiments, determining the presence or absence of an N-Ras mutation comprises analyzing nucleic acids obtained from a sample of a 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 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.

[0592] In some embodiments, the compound as disclosed herein is a compound of Formula (Ia) (Ib) (IIa) (IIb) (IIIa) (IIIb) (IIIb) (IVa) (IVb), for example, a compound of Formula (II-1) (II-2) (III-1) (III-2) (IV-1) (IV-2), such as a compound of Formula (IIa-1) (IIb-1) (IIa-2) (IIb-2) (IIIa-1) (IIIb-1) (IIIa-2) (IIIb-2) (IIIa-1) (IIIb-1) (IIIa-2) (IIIb-2) (IIIa-1) (IIIb-2) (IIIa-2) (IIIb-2) (IIIa-1) (IIIb-1) (IIIb-2) (IIIa-2) (IIIb-2) (III b-2), Formula (IVa-1), Formula (IVb-1), Formula (IVa-2) or Formula (IVb-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), Formula (IIIa-3), Formula (IIIb-3), Formula (Va-), Formula (Vb-), Formula (V-1), Formula (Va-1), Formula (Vb-1), Formula (VIa-1) or Formula (VIb-1), or a pharmaceutically acceptable form thereof, and is metabolically stable, for example, to the liver metabolism of a subject, such as to the liver metabolism of a human.

[0593] 5.3.2 Dosage and regimen

[0594] The compounds described herein can be delivered in the form of a pharmaceutical composition comprising a therapeutically effective amount of a compound of any of Formula (I) (I), (II) (III), or (IV), such as a compound of Formula (Ia)-(Ib), (IIa)-(IIb), (IIIa)-(IIIb), (IVa)-(IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V) or (VI), such as a compound of Formula (Va)-(Vb), (VIa)-(VIb), or (VIb), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (II-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 (IVb-2), or a pharmaceutically 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 pharmaceutically 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 topical. In some embodiments, the selected dosage level will depend upon a variety of factors including, for example, the activity of the particular compound employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0595] A suitable daily dose of a compound described herein administered to a subject will be the lowest dose of the compound effective to produce a therapeutic effect in some embodiments. Such an effective dose will generally depend on the factors described herein. In some embodiments, a therapeutically effective amount of a compound of any of Formula (I)-(II), (III)-(IIId), or (IV)-(IVb), such as a compound of Formula (Ia)-(Ib), (IIa)-(IIb), (IIId), (IVa)-(IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V)-(Via)-(Via), (Vlla)-(Vlla), or (VIb), or a pharmaceutically accepta...

Claims

1. A compound of formula (I), in: The dotted line indicates A 1 With A 2 Single or double bonds between A 1 N, NR independently 1a , CR 1b or -C(=O)-; A 2 N, NR independently 2a , CR 2b or -C(=O)-; A 3 Independently for CR 3 or N; A 4 CR 8 or N; A 5 and A 6 Each independently is CR 8 or N, or A 5 With A 6 Together they are O and NR 9 or S; W is C 6-12 aryl or 5-12 membered heteroaryl, each of which is optionally substituted by 1-4 R 4 Substituent substitution; Y is a bond or a linker of up to 6 atoms in length; Z is C 6-12 aryl or 5-12 membered heteroaryl, each of which is optionally substituted by 1-4 R 5 Substituent substitution; R 1a and R 2a Each independently is 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)2NR 10 R 11 ; R 1b , R 2b , R 3 , R 5 and R 8 Each time it occurs, it is independently R 9 、-OR 9 、halogen、CN、NO2、-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)2R 9 、-S(O) p R 9 、-S(O)2NR 10 R 11 or -NR 10 S(O)2NR 10 R 11 ; 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, 3-6 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, wherein 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 Cycloalkoxy, 3-6 membered heterocycloalkoxy, C 6-12 Aryl or 5-12 membered heteroaryl is optionally independently substituted with one, two, three, four, five or six 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 Substitution by haloalkoxy and (O) substituents; 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)2R 9 , -NR 10 C(NR 10 )NR 10 R 11 , -S(O) p R 9 , -S(O)2NR 10 R 11 or -NR 10 S(O)2NR 10 R 11 ; R 7 is a 5-12 membered heteroaryl group, which is optionally substituted by 1-4 independently selected from halo, CN, NO2, 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)2R 9 、-S(O) p R 9 、-S(O)2NR 10 R 11 and-NR 10 S(O)2NR 10 R 11 Substituents are substituted; R 9 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, 3-6 membered heterocycloalkyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein R 9 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 substituted by one, two, three, four, five or six selected from halo, hydroxy, CN, NO2, 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)2R 12 、-S(O) p R 12 、-S(O)2NR 10 R 11 and-NR 10 S(O)2NR 10 R 11 Substituents are substituted; R 10 and R 11 Each occurrence is independently hydrogen, hydroxyl, 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, or together with the N to which they are attached, form a 3-6 membered heterocycloalkyl, wherein the R 10 and the 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 substituted by one, two, three, four, five or six selected from halo, hydroxy, CN, NO2, 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)2R 13 、-S(O) p R 13 、-S(O)2NR 14 R 15 and-NR 14 S(O)2NR 14 R 15 Substituents are substituted; R 12 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, 3-6 membered heterocycloalkyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein 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 substituted by one, two, three, four, five or six selected from halo, hydroxy, CN, NO2, 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)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)2R 13 、-S(O) p R 13 、-S(O)2NR 10 R 11 and-NR 10 S(O)2NR 10 R 11 Substituents are substituted; R 13 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 3-6 membered heterocycloalkyl; R 14 and R 15 Each occurrence is independently hydrogen, hydroxyl, 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 together with the nitrogen to which they are attached, form a 3-6 membered heterocycloalkyl; and Each p is independently an integer of 0, 1 or 2, or a pharmaceutically acceptable form thereof.

2. The compound according to claim 1, wherein the compound is a compound of formula (Ia): or a pharmaceutically acceptable form thereof.

3. The compound according to claim 1, wherein the compound is a compound of formula (Ib): or a pharmaceutically acceptable form thereof.

4. The compound according to any one of claims 1 to 3, wherein: (a)A 1 N or NR 1a and / or A 2 CR 2b or -C(=O)-; or (b)A 1 With A 2 The bond between is a single bond; 1 NR 1a ; and A 2 is -C(=O)-; or (c)A 1 With A 2 The bond between is a double bond; 1 is N; and A 2 CR 2b ;or (d)A 1 CR 1b or -C(=O)- and / or A 2 N or NR 2a ;or (e)A 1 With A 2 The bond between is a double bond; 1 CR 1b ; and A 2 is N; or (f)A 1 With A 2 The bond between is a single bond; 1 is -C(=O)-; and A 2 NR 2a .

5. The compound according to any one of claims 1 to 4, wherein: For (a) or (b) 6. The compound according to any one of claims 1 to 5, wherein Y and A 1 , A 2 and A 3 The fused ring system of is connected to W in a 1,3-relationship.

7. The compound according to any one of claims 1 to 6, wherein W is C 6-12 aryl, or W is phenyl, or W is 5-12 membered heteroaryl, or W is pyridyl, optionally wherein W is substituted by one, two, three or four R 4 Substituents, optionally wherein W is substituted by one R 4 Substituent substitution.

8. A compound as described in any one of claims 1 to 7, wherein -(C(R 6 )(R 7 )(Contains A 4 , A 5 and A 6 The fused ring system)) group is connected to Z in a 1,3-relationship with Y.

9. The compound of any one of claims 1 to 8, wherein Z is C 6-12 aryl, or Z is phenyl, or Z is 5-12 membered heteroaryl, or Z is pyridyl, optionally wherein Z is substituted by one, two, three or four R 5 Substituents, optionally wherein Z is substituted by one R 5 Substituent substitution.

10. The compound according to any one of claims 1 to 9, wherein the compound is a compound of formula (II): in: W 1 , W 2 , W 3 and W 4 Each independently is N or CR 4 , or W 1 With W 2 Together they are O and NR 4A or S, or W 2 With W 3 Together they are O and NR 4A or S; Z 1 , Z 2 , Z 3 and Z 4 Each independently is N or CR 5 , or Z 2 With Z 3 Together they are O and NR 5A or S or Z 3 With Z 4 Together they are O and NR 5A or S; and 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, wherein R 4A and the 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 is optionally independently substituted with one, two, three, four, five or six 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 Substitution by haloalkoxy and (O) substituents; or a pharmaceutically acceptable form thereof.

11. The compound according to claim 10, wherein the compound is a compound of formula (IIa) or a compound of formula (IIb): or a pharmaceutically acceptable form thereof.

12. The compound of claim 10, wherein the compound is a compound of formula (II-1), formula (IIa-1), formula (IIb-1), formula (II-2), formula (IIa-2) or formula (IIb-2): or a pharmaceutically acceptable form thereof.

13. The compound according to any one of claims 1 to 10, wherein the compound is a compound of formula (III): in: W 1 , W 2 , W 3 and W 4 Each independently is N or CR 4 , or W 1 With W 2 Together they are O and NR 4A or S, or W 2 With W 3 Together they are O and NR 4A or S; Z 1 , Z 2 , Z 3 and Z 4 Each independently is N or CR 5 , or Z 2 With Z 3 Together they are O and NR 5A or S or Z 3 With Z 4 Together they are O and NR 5A or S; and 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, wherein R 4A and the 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 is optionally independently substituted with one, two, three, four, five or six 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 Substitution by haloalkoxy and (O) substituents; or a pharmaceutically acceptable form thereof.

14. The compound of claim 13, wherein the compound is a compound of formula (IIIa) or a compound of formula (IIIb): or a pharmaceutically acceptable form thereof.

15. The compound of claim 13, wherein the compound is a compound of formula (III-1), formula (IIIa-1), formula (IIIb-1), formula (III-2), formula (IIIa-2), formula (IIIb-2), formula (III-3), formula (IIIa-3) or formula (IIIb-3): or a pharmaceutically acceptable form thereof.

16. The compound of any one of claims 1 to 10, wherein the compound is a compound of formula (IV): in: W 1 , W 2 , W 3 and W 4 Each independently is N or CR 4 , or W 1 With W 2 Together they are O and NR 4A or S, or W 2 With W 3 Together they are O and NR 4A or S; Z 1 , Z 2 , Z 3 and Z 4 Each independently is N or CR 5 , or Z 2 With Z 3 Together they are O and NR 5A or S or Z 3 With Z 4 Together they are O and NR 5A or S; and 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, wherein R 4A and the 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 is optionally independently substituted with one, two, three, four, five or six 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 Substitution by haloalkoxy and (O) substituents; or a pharmaceutically acceptable form thereof.

17. The compound of claim 16, wherein the compound is a compound of formula (IVa) or a compound of formula (IVb): or a pharmaceutically acceptable form thereof.

18. The compound of claim 16, wherein the compound is a compound of formula (IV-1), formula (IVa-1), formula (IVb-1), formula (IV-2), formula (IVa-2) or formula (IVb-2): or a pharmaceutically acceptable form thereof.

19. The compound of any one of claims 1 to 10, wherein the compound is a compound of formula (V): in: W 1 , W 2 , W 3 and W 4 Each independently is N or CR 4 , or W 1 With W 2 Together they are O and NR 4A or S, or W 2 With W 3 Together they are O and NR 4A or S; Z 1 , Z 2 , Z 3 and Z 4 Each independently is N or CR 5 , or Z 2 With Z 3 Together they are O and NR 5A or S or Z 3 With Z 4 Together they are O and NR 5A or S; and 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, wherein R 4A and the 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 is optionally independently substituted by 1-6 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 Substitution by haloalkoxy and (O) substituents; or a pharmaceutically acceptable form thereof.

20. The compound of claim 19, wherein the compound is a compound of formula (Va) or formula (Vb): or a pharmaceutically acceptable form thereof.

21. The compound of claim 19, wherein the compound is a compound of formula (V-1), formula (Va-1) or formula (Vb-1): or a pharmaceutically acceptable form thereof.

22. The compound of any one of claims 1 to 10, wherein the compound is a compound of formula (VI): in: W 1 , W 2 , W 3 and W 4 Each independently is N or CR 4 , or W 1 With W 2 Together they are O and NR 4A or S, or W 2 With W 3 Together they are O and NR 4A or S; Z 1 , Z 2 , Z 3 and Z 4 Each independently is N or CR 5 , or Z 2 With Z 3 Together they are O and NR 5A or S or Z 3 With Z 4 Together they are O and NR 5A or S; and 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, wherein R 4A and the 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 is optionally independently substituted by 1-6 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 Substitution by haloalkoxy and (O) substituents; or a pharmaceutically acceptable form thereof.

23. The compound of claim 22, wherein the compound is a compound of formula (VIa) or formula (VIb): or a pharmaceutically acceptable form thereof.

24. The compound of claim 22, wherein the compound is a compound of formula (VI-1), formula (VIa-1) or formula (VIb-1): or a pharmaceutically acceptable form thereof.

25. A compound as described in any one of claims 1 to 12, wherein R 1a Independently for R 9 .

26. A compound as described in any one of claims 1 to 12, wherein R 1a For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl or the C 3-6 Cycloalkyl is optionally independently substituted with one, two, three, four, five or six radicals selected from halo, hydroxy, CN, NO2, 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)2R 12 、-S(O) p R 12 and -S(O)2NR 10 R 11 substituted by a substituent.

27. The compound of claim 26, wherein R 1a For hydrogen, C 1-3 Alkyl or C 3-4 Cycloalkyl; wherein the C 1-3 Alkyl or the C 3-4 Cycloalkyl is optionally independently substituted with one, two or three cycloalkyl groups selected from halo, hydroxy, CN, NO2, 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)2R 12 、-S(O) p R 12 and -S(O)2NR 10 R 11 substituted by a substituent.

28. The compound of claim 26, wherein R 1a for: (a) hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, 2,3-dihydroxypropyl or cyclopropyl; or (b) -CH3, -CD3 or cyclopropyl; or (c) -CH3 or -CD3; or (d) R 1a It is cyclopropyl.

29. A compound as described in any one of claims 1-9, 13-15, 19-20 or 22-23, wherein R 2b For R 9 、-OR 9 、halogen、CN、NO2、-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)2NR 10 R 11 .

30. A compound as described in any one of claims 1-9, 13-15, 19-20 or 22-23, wherein R 2b for: (a)R 9 、-OR 9 , halogen, CN, -C(O)NR 10 R 11 or -NR 10 R 11 ;or (b) Hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, hydroxyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Heterocycloalkoxy, halogen, CN, -C(O)NR 10 R 11 or -NR 10 R 11 ; Where R 10 and R 11 Each occurrence is independently hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, or together with the N to which they are attached, form a 3-6 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, halogen, CN, -C(O)NR 10 R 11 or -NR 10 R 11 ; Where R 10 and R 11 Each occurrence is independently hydrogen, C 1-3 alkyl, 3-4 membered heterocycloalkyl, or together with the N to which they are attached, form a 4-6 membered heterocycloalkyl; or (d) hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, cyclopropyl, -OCH3, -OCD3, -OCH2CH3, -OCD2CD3, isopropoxy, cyclopropyloxy, 3-oxetanylalkoxy, chloro, CN, morpholinyl, piperazinyl, 3-oxetanylamino, or -C(O)NH2; or (e)R 2b is -NH2.

31. A compound as described in any one of claims 1-9, 13-15, 19-20 or 22-23, wherein R 2b is an electron withdrawing group, optionally wherein R 2b for: (a) Halogen, CN, NO2, -C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-S(O) p R 9 or -S(O)2NR 10 R 11 ;or (b) Chlorine, CN, -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)N(H)CH3, -C( O)N(CH3)2, -S(O)CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2N(H)CH3 or -S(O)2N(CH3)2.

32. A compound as described in any one of claims 1-11, 13-14, 16-17 or 22-23, wherein A 3 CR 3 , optionally wherein R 3 (a) independently R 9 、-OR 9 , halogen or CN; or (b) is hydrogen.

33. A compound as described in any one of claims 1-11, 13-14, 16-17, 19-20 or 22-23, wherein A 4 CR 8 .

34. A compound as described in any one of claims 1-11, 13-14, 16-17, 19-20 or 22-23, wherein A 4 is N.

35. A compound as described in any one of claims 1-11, 13-14, 16-17, 19-20 or 22-23, wherein A 5 CR 8 .

36. A compound as described in any one of claims 1-11, 13-14, 16-17, 19-20 or 22-23, wherein A 5 is N.

37. A compound as described in any one of claims 1-11, 13-14, 16-17, 19-20 or 22-23, wherein A 6 CR 8 .

38. A compound as described in any one of claims 1-11, 13-14, 16-17, 19-20 or 22-23, wherein A 6 is N.

39. The compound of any one of claims 1 to 34, wherein: (a)A 4 is N, and A 5 and A 6 not more than one of them is N; or (b)A 5 is N, and A 4 and A 6 not more than one of them is N; or (c)A 6 is N, and A 4 and A 5 not more than one of them is N; or (d)A 4 , A 5 and A 6 Each independently is CR 8 .

40. A compound as described in any one of claims 1-39, wherein R 8 Independently for R 9 、-OR 9 , halogen or CN, optionally wherein R 8 For hydrogen.

41. The compound of any one of claims 1-40, wherein Y is a bond.

42. The compound of any one of claims 1-40, wherein Y is a linker of up to 5 atoms, up to 4 atoms, up to 3 atoms, or up to 2 atoms in length.

43. The compound of any one of claims 1-40 or 42, wherein Y is in the orientation of ZYW.

44. A compound as described in any one of claims 1-40, 42 or 43, wherein Y is C 1-6 Alkylene, wherein one or more -CH2- 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)2N(R 10 )-or-N(R 10 )S(O)2N(R 11 )-Permutation.

45. The compound of any one of claims 1-40 or 42-44, wherein: 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)2N(R 10 )(CR 16 R 17 ) n -or-(CR 16 R 17 ) m N(R 10 )S(O)2N(R 11 )(CR 16 R 17 ) n -; and in which: R 16 and R 17 Each occurrence is independently hydrogen, halo, hydroxyl, CN, NO2, 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 3-6 membered heterocycloalkoxy, or together with the C to which they are connected, form C(O), C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; Each m is independently an integer of 0, 1, 2 or 3; Each n is independently an integer of 0, 1, 2 or 3; Where the sum of m and n is 0, 1, 2, 3, 4, 5 or 6; Each p is independently an integer of 0, 1 or 2; and Each q is independently an integer of 0, 1, 2, 3, 4, 5 or 6; Optionally wherein m is 0, 1 or 2; and Optionally wherein n is 0, 1 or 2.

46. ​​The compound of claim 45, wherein Y is: (a)-(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)2N(R 10 )(CR 16 R 17 ) n -; or (b)-(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 -; or (c)-(CR 16 R 17 ) q -; or (d)-(CR 16 R 17 ) m O(CR 16 R 17 ) n -; or (e)-(CR 16 R 17 ) m N(R 10 )C(O)(CR 16 R 17 ) n -; or (f)-(CR 16 R 17 ) m C(O)N(R 10 )(CR 16 R 17 ) n -。 47. A compound according to claim 45 or claim 46, wherein: (a)R 16 and R 17 Each occurrence is independently hydrogen, halo, hydroxyl, CN, NO2, 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 3-5 membered heterocycloalkoxy, or together with the C to which they are connected, form C(O), C 3-5 Cycloalkyl or 3-5 membered heterocycloalkyl; or (b)R 16 and R 17 is independently hydrogen, chloro, hydroxy, CN, NO2, methyl, ethyl, isopropyl, -CF3, -CH2CF3, -CH2OH, -(CH2)2OH, -(CH2)2OCH3, cyclopropyl, 3-oxetanyl, methoxy, ethoxy, isopropoxy, cyclopropyloxy, -OCF3, -OCH2CF3, -O(CH2)2OH, -O(CH2)2OCH3 or 3-oxetanylalkoxy at each occurrence, or is combined with the C to which it is attached to form C(O), cyclopropyl or 3-5 membered heterocycloalkyl; or (c)R 16 and R 17 Each is hydrogen.

48. A compound as described in any one of claims 45-47, wherein Y is -(CH2)O-, or Y is -O(CH2)-, or Y is -(CH2)2O-, or Y is -O(CH2)2-, or Y is -(CH2)2-.

49. A compound as described in any one of claims 10-11, 13-14, 16-17, 19-20, 22-23 or 25-48, wherein W 1 , W 2 , W 3 and W 4 At least one of is N, optionally wherein: W 1 , W 2 and W 3 Each independently is CR 4 , and W 4 is N; W 1 , W 2 and W 4 Each independently is CR 4 , and W 3 is N; W 1 , W 3 and W 4 Each independently is CR 4 , and W 2 is N; or W 2 , W 3 and W 4 Each independently is CR 4 , and W 1 is N.

50. A compound as described in any one of claims 10-11, 13-14, 16-17, 19-20, 22-23 or 25-48, wherein W 1 , W 2 , W 3 and W 4 Each independently is CR 4 .

51. A compound as described in any one of claims 49-50, wherein: (a)R 4 are independently hydrogen, halogen, 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 , wherein 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 Cycloalkoxy or 3-6 membered heterocycloalkoxy is optionally independently substituted by one, two, three, four, five or six groups 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 A haloalkoxy group and a substituent of (O); or (b)R 4 are independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy group, wherein R 4 Each C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally independently substituted with one, two, three, four, five or six groups 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 A haloalkoxy group and a substituent of (O); or (c)R 4 are independently hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-5 Cycloalkyl, C 1-3 Alkoxy or C 1-3 haloalkoxy; or (d) Each R 4 are independently hydrogen.

52. A compound as described in any one of claims 10-11, 13-14, 16-17, 19-20, 22-23 or 25-51, wherein Z 1 , Z 2 , Z 3 and Z 4 At least one of is N, optionally wherein: Z 1 , Z 2 and Z 3 Each independently is CR 5 , and Z 4 is N; Z 1 , Z 2 and Z 4 Each independently is CR 5 , and Z 3 is N; Z 1 , Z 3 and Z 4 Each independently is CR 5 , and Z 2 is N; or Z 2 , Z 3 and Z 4 Each independently is CR 5 , and Z 1 is N.

53. A compound as described in any one of claims 10-11, 13-14, 16-17, 19-20, 22-23 or 25-51, wherein Z 1 , Z 2 , Z 3 and Z 4 Each independently is CR 5 .

54. A compound as described in any one of claims 52-53, wherein R 5 R independently at each occurrence 9 、-OR 9 、halogen、CN、NO2、-C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-S(O) p R 9 or -S(O)2NR 10 R 11 ; or R 5 is independently at each occurrence hydrogen, halo, CN, NO2, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)N(CH3)2, -S(O)2CH3, or -S(O)2N(CH3)2; or each R 5 is independently hydrogen, halo or CN; or each R 5 are independently hydrogen.

55. A compound as described in any one of claims 52-53, wherein R 5 are independently electron-withdrawing groups, optionally wherein R 5 are independently chlorine or R 5 Independently CN.

56. A compound as described in any one of claims 1-55, wherein R 7 is imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl or pyrimidinyl, which is optionally substituted by 1-4 independently selected from halo, CN, NO2, 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)2R 9 、-S(O) p R 9 、-S(O)2NR 10 R 11 or -NR 10 S(O)2NR 10 R 11 Substituents are substituted; Optionally R 7 is imidazolyl or triazolyl, which is optionally substituted by 1-4 independently selected from halogen, CN, NO2, 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)2NR 10 R 11 Substituents are substituted; Optionally R 7 is a C-attached imidazolyl or C-attached triazolyl, which is optionally substituted by 1-4 groups independently selected from halo, CN, NO2, 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)2NR 10 R 11 substituted by a substituent.

57. A compound as described in any one of claims 1-55, wherein R 7 is an N-linked imidazolyl or N-linked triazolyl, which is optionally substituted by 1-4 independently selected from halo, CN, NO2, 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)2NR 10 R 11 substituted by a substituent; optionally wherein R 7 is methyl-substituted imidazolyl or methyl-substituted triazolyl; or R 7 is C-methyl substituted imidazolyl or C-methyl substituted triazolyl, optionally wherein R 7 for or R 7 is N-methyl substituted imidazolyl or N-methyl substituted triazolyl; optionally wherein R 7 for: or R 7 for 58. A compound as described in any one of claims 1-57, wherein 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 , or where R 6 CN, R 9 、-OR 9 、-NR 10 R 11 or -NR 10 OR 9 , or where R 6 CN, R 9 、-OR 9 or -NR 10 R 11 , optionally wherein R 9 are independently hydrogen or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with CN, and optionally wherein R 10 and R 11 are independently hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy.

59. The compound of claim 58, wherein R 6 is hydrogen, -CH3, hydroxy, -OCH3, -OCD3, -NH2, -NHCH3 or -NH(OCH3), or R 6 is hydroxyl, or R 6 is hydrogen, or R 6 is NH2, or R 6 is -NH(CH2CH2)Cl, -NH(CH2CH2)F or an N-linked morpholinyl.

60. The compound of any one of claims 1-59, wherein: The MW of the compound does not exceed 1,000 g / mol; or The MW of the compound is no more than 900 g / mol, no more than 800 g / mol, no more than 700 g / mol, no more than 600 g / mol or no more than 500 g / mol; or The MW of the compound does not exceed 600 g / mol; or The MW of the compound does not exceed 500 g / mol.

61. The compound of claim 1, wherein the compound is selected from 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, and 77, or a pharmaceutically acceptable form thereof.

62. The compound of claim 1, wherein the compound is selected from Compounds 78 to 91, Compounds 92 to 135, including their (R)- or (S)-stereoisomers and racemates, and pharmaceutically acceptable forms thereof.

63. The compound of any one of claims 1-62, wherein the pharmaceutically acceptable form of the compound does not include a salt form.

64. The compound of any one of claims 1-63, wherein the compound is a racemate or a mixture of diastereomers or stereoisomers.

65. The compound of any one of claims 1-63, wherein the compound is a single enantiomer or a single diastereomer.

66. The compound of any one of claims 1-63 or 65, wherein the compound is the (R)-enantiomer.

67. The compound of any one of claims 1-63 or 65, wherein the compound is the (S)-enantiomer.

68. A pharmaceutical composition comprising a compound according to any one of claims 1 to 67 or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

69. A method of inhibiting farnesyl transferase, the method comprising contacting the farnesyl transferase with an effective amount of a compound of any one of claims 1-67 or a pharmaceutically acceptable form thereof, or with a pharmaceutical composition of claim 68, optionally wherein the farnesyl transferase is present in a cell, Optionally wherein said contacting of said farnesyl transferase occurs in a cell, optionally wherein said cell is in a subject, optionally wherein said cell is a mammalian cell, optionally wherein said cell is a human cell, and Optionally wherein the subject suffers from a cancer that is dependent on a farnesylated protein.

70. A method of treating a cancer that depends on a farnesylated protein in a subject, the method comprising administering to the subject suffering from a cancer that depends on a farnesylated protein a therapeutically effective amount of a compound of any one of claims 1-67 or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of claim 68, optionally wherein the subject is a human.

71. The method of claim 69 or claim 70, wherein the cancer that is dependent on farnesylated proteins is a cancer that is dependent on farnesylated H-Ras proteins, optionally wherein the cancer that is dependent on farnesylated proteins has an H-Ras protein mutation, optionally wherein the H-Ras protein mutation is or comprises a modification in a codon encoding an amino acid substitution at a specific position in the corresponding mutant H-Ras protein selected from the group consisting of G12, G13, Q61, Q22, K117, A146, and any combination thereof; Optionally wherein the presence or absence of the H-Ras mutation is determined by analyzing nucleic acid obtained from a sample from the subject, optionally wherein the sample is a tissue biopsy or a tumor biopsy, optionally wherein the H-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.

72. The method of any one of claims 69-71, wherein the cancer that is dependent on a farnesylated protein is a cancer that is dependent on a farnesylated N-Ras protein, optionally wherein the cancer that is dependent on a farnesylated protein has an N-Ras protein mutation, optionally wherein the N-Ras mutation is or comprises a modification in a codon encoding an amino acid substitution at a specific position in the corresponding mutant N-Ras protein selected from the group consisting of G12, G13, Q61, Q22, K117, A146, and any combination thereof; Optionally, determining the presence or absence of the N-Ras mutation comprises analyzing nucleic acid obtained from a sample from the subject, optionally wherein 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, optionally wherein the sample is a tissue biopsy or a tumor biopsy.

73. The method of any one of claims 69-72, wherein the cancer that is dependent on farnesylation proteins is melanoma, acute myeloid leukemia (AML), thyroid cancer, lung adenocarcinoma, rectal cancer, endometrial cancer, or colorectal cancer.

74. The method of any one of claims 69-72, wherein the cancer dependent on farnesylation of a protein is a carcinoma, a melanoma, a sarcoma, or a chronic granulomatous disease.

75. The method of any one of claims 69-72, wherein the cancer that is dependent on farnesylation of a protein is thyroid cancer, head and neck cancer, urothelial cancer, salivary gland cancer, upper gastrointestinal cancer, bladder cancer, breast cancer, ovarian cancer, brain cancer, stomach cancer, prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer, or pancreatic cancer.

76. The method of any one of claims 69-72, wherein the cancer that depends on farnesylation proteins is head and neck cancer, optionally wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC); or wherein the cancer dependent on farnesylation protein is squamous cell carcinoma (SCC), optionally wherein the SCC is head and neck SCC (HNSCC), lung SCC (LSCC), thyroid SCC (TSCC), esophageal SCC (ESCC), bladder SCC (BSCC) or urothelial carcinoma (UC), optionally wherein the SCC is HNSCC, optionally wherein the HNSCC is tracheal HNSCC, maxillary HNSCC, oral HNSCC.

77. The method of any one of claims 69-78, wherein the cancer dependent on farnesylation proteins is a solid tumor.

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