Macrocyclic compounds and compositions, and methods of preparing and using the same

Abstract

This invention relates to any macrocyclic compound of formula (I) or a pharmaceutically acceptable form thereof, pharmaceutical compositions comprising such compounds, methods of their preparation, and methods of using such compounds to treat cancers dependent on farnesylated proteins.

Description

technical field

[0001] The present invention relates to macrocyclic compounds useful in the treatment of cancers dependent on farnesylated proteins and pharmaceutical compositions comprising these compounds. The invention also relates to processes for the preparation of such macrocycles and pharmaceutical compositions comprising them. The present invention also relates to the use of such macrocyclic compounds and pharmaceutical compositions comprising them in methods of inhibiting farnesyl transferase and methods of treating cancers dependent on farnesylated proteins. prior art

[0002] The activated Ras oncogene is often found in cancerous tumors, and the transformed Ras protein is involved in the proliferation of cancer cells. Ras protein is the protein product of ras oncogene, which is a small GTPase and is important in signal transduction, cell growth and cell proliferation. Shields, J. M. et al., Trends Cell Biol. 2000, 10, 147-154. Ras proteins must associate (or bind) with the inner surface of the plasma membrane to transduce extracellular signals, which can lead to the proliferation of cancer cells.

[0003] 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 (where C represents cysteine ​​and A represents aliphatic amino acid, and X represents any amino acid). Rowinsky, E.K. et al., J. Clin. Oncol. 1999, 17, 3631-3652. Farnesyltransferase (FTase) recognizes the CAAX motif ("motif") and farnesylates the Ras protein (transfers a 15-carbon farnesyl isoprenoid from farnesyl diphosphate to cysteamine acid residues). Once farnesylated, Ras protein can bind to the cell membrane. Inhibition of farnesyl transferase, thereby blocking Ras protein cell membrane binding, represents a reduction in cancer cell proliferation and may provide potential clinical benefits for cancer patients. Contents of the invention

[0004] In one aspect, provided herein are compounds of formula (I): Formula (I) or a pharmaceutically acceptable form thereof, wherein: Dashed lines indicate single or double bonds between A1 and A2; A 1 is independently N, NR 1a, CR 1b or -C(=O)-; A 2 is independently N, NR 2a, CR 2b or -C(=O)-; A 3 is independently CR 3 or N; A 4 is CR 8 or N; A5 and A6 are each independently CR8 or N, or A5 and A6 together are O, NR9 or S; W is C 6-12 aryl or 5-12 membered heteroaryl, each of which is optionally substituted by 1-4 R substituents; Y is a bond or a linker 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 substituents; R 1a and R 2a are each independently R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10R 11 , -S(O) pR 9 or - S(O) 2NR 10R 11; Each occurrence of R 1b, R 2b, R 3, R 5 and R 8 is independently R 9 , -OR 9 , halo, CN, NO 2 , -C(O)R 9 , -C(O )OR 9, -OC(O)R 9, -OC(O)OR 9, -C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 9, -NR 10C(O)OR 9. -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 9, -S(O) pR 9, -S(O) 2NR 10R 11 or -NR 10S(O) 2NR 10R 11; R independently at each occurrence is 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 14R 15, C 6-12 aryl or 5-12 membered heteroaryl, wherein R 4 is 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 aromatic radical or 5-12 membered heteroaryl as appropriate through one, two, three, four, five or six independently selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkane C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy The substituents of the group and (O) are substituted; 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 10R 11, -NR 10R 11, -NR 10OR 9, -NR 10C(O)R 9, -NR 10C(O)OR 9, -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 9, -NR 10C(NR 10)NR 10R 11, -S(O) pR 9, -S(O) 2NR 10R 11 or -NR 10S(O) 2NR 10R 11; R 7 is a 5-12 membered heteroaryl group, which is independently selected from halo, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O )OR 9, -OC(O)R 9, -OC(O)OR 9, -C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 9, -NR 10C(O)OR 9. Substituents of -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 9, -S(O) pR 9, -S(O) 2NR 10R 11 and -NR 10S(O) 2NR 10R 11 replace; Each occurrence of R 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 each C 1-6 alkane of R 9 Base, 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 independently selected from halogen, hydroxyl, CN through one, two, three, four, five or six , NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (O), -C(O)R 12, -C(O) OR 12, -OC(O)R 12, -OC(O)OR 12, -C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 12, -NR 10C(O)OR 12 , -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 12, -S(O) pR 12, -S(O) 2NR 10R 11 and -NR 10S(O) 2NR 10R 11 ; R 10 and R 11 are each independently hydrogen, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 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 hetero Aryl, or form a 3-6 membered heterocycloalkyl group in combination with the respective connected N, wherein each of R 10 and R 11 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne 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 as the case may be independently selected from one, two, three, four, five or six halo, hydroxyl, CN, NO 2 , C 1 -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkane Base, 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 14R 15, -NR 14R 15, -NR 14C(O)R 13, -NR 14C(O)OR 13, -NR 14C(O)NR 14R 15, -NR 14S (O) 2R 13, -S(O) pR 13, -S(O) 2NR 14R 15 and -NR 14S(O) 2NR 14R 15 are substituted by substituents; Each occurrence of R 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 each C 1-6 of R 12 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 independently selected from halogen, hydroxyl through one, two, three, four, five or six , CN, NO 2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (O), -C(O)R 13, -C( O)OR 13, -OC(O)R 13, -OC(O)OR 13, -C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 13, -NR 10C(O) Substitution of OR 13, -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 13, -S(O) pR 13, -S(O) 2NR 10R 11 and -NR 10S(O) 2NR 10R 11 base substitution; Each occurrence of R 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 are each independently hydrogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 4 hydroxyalkyl group, C 1-4 heteroalkyl group, C 3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, or C 1-6 alkoxy group, or form 3 -6 membered heterocycloalkyl; and Each p is independently an integer of 0, 1 or 2.

[0005] In certain embodiments, the compound of formula (I) is a compound of formula (II): Formula (II) in: W 1, W 2, W 3 and W 4 are independently N or CR 4, or W 1 and W 2 together are O, NR 4A or S, or W 2 and W 3 together are O, NR 4A or S; Z 1, Z 2, Z 3 and Z 4 are independently N or CR 5, or Z 2 and Z 3 together are O, NR 5A or S, or Z 3 and Z 4 together are O, NR 5A or S; 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 each of R 4A and R 5A is 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, as the case may be, independently via one , two, three, four, five or six independently selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1- Substituents of 6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and (O); or a pharmaceutically acceptable form thereof.

[0006] In certain embodiments, the compound of formula (I) is a compound of formula (III): Formula (III) in: W 1, W 2, W 3 and W 4 are independently N or CR 4, or W 1 and W 2 together are O, NR 4A or S, or W 2 and W 3 together are O, NR 4A or S; Z 1, Z 2, Z 3 and Z 4 are independently N or CR 5, or Z 2 and Z 3 together are O, NR 5A or S, or Z 3 and Z 4 together are O, NR 5A or S; 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 each of R 4A and R 5A is 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, as the case may be, independently via one , two, three, four, five or six selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 hetero Substituents of alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and (O); or a pharmaceutically acceptable form thereof.

[0007] In certain embodiments, the compound of formula (I) is a compound of formula (IV): Formula (IV) in: W 1, W 2, W 3 and W 4 are independently N or CR 4, or W 1 and W 2 together are O, NR 4A or S, or W 2 and W 3 together are O, NR 4A or S; Z 1, Z 2, Z 3 and Z 4 are independently N or CR 5, or Z 2 and Z 3 together are O, NR 5A or S, or Z 3 and Z 4 together are O, NR 5A or S; 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 each of R 4A and R 5A is 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, as the case may be, independently via one , two, three, four, five or six selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 hetero Substituents of alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and (O); or a pharmaceutically acceptable form thereof.

[0008] In certain embodiments, the compound of formula (I) is a compound of formula (V): Formula (V) in: W 1, W 2, W 3 and W 4 are independently N or CR 4, or W 1 and W 2 together are O, NR 4A or S, or W 2 and W 3 together are O, NR 4A or S; Z 1, Z 2, Z 3 and Z 4 are independently N or CR 5, or Z 2 and Z 3 together are O, NR 5A or S, or Z 3 and Z 4 together are O, NR 5A or S; 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 each of R 4A and R 5A is C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 hydroxyalkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C 6-12 aryl group or 5-12 membered heteroaryl group are independently selected by 1 -6 independently selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl , 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and (O) substituents; or a pharmaceutically acceptable form thereof.

[0009] In certain embodiments, the compound of formula (I) is a compound of formula (VI): Formula (VI) in, W 1, W 2, W 3 and W 4 are independently N or CR 4, or W 1 and W 2 together are O, NR 4A or S, or W 2 and W 3 together are O, NR 4A or S; Z 1, Z 2, Z 3 and Z 4 are independently N or CR 5, or Z 2 and Z 3 together are O, NR 5A or S, or Z 3 and Z 4 together are O, NR 5A or S; 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 each of R 4A and R 5A is C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 hydroxyalkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C 6-12 aryl group or 5-12 membered heteroaryl group are independently selected by 1 -6 independently selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl , 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and (O) substituents; or a pharmaceutically acceptable form thereof.

[0010] In certain embodiments, provided herein are compounds of Formula (I), Formula (II), Formula (III) or Formula (IV), or Formula (V) or Formula (VI), 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 some embodiments, Y is in the direction of Z-Y-W (wherein Z refers to Z or a ring containing Z, W refers to W or a ring containing W, the foregoing can be used in formula (I), formula (II), formula (III) or formula (IV) or formula (V) or formula (VI) and its sub-formula). In certain embodiments, Y is C 1-6 alkylene, wherein one or more -CH 2- are optionally independently modified 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)- substitution. In certain instances, Y is -(CR 16R 17) q-, -(CR 16R 17) mO(CR 16R 17) n-, -(CR 16R 17) mC(O)(CR 16R 17) n-, -(CR 16R 17) mN(R 10)(CR 16R 17) n-, -(CR 16R 17) mN(R 10)C(O)(CR 16R 17) n-, -(CR 16R 17) mC( O)N(R 10)(CR 16R 17) n-, -(CR 16R 17) mN(R 10)C(O)N(R 11)(CR 16R 17) n-,-(CR 16R 17) mS (O) p(CR 16R 17) n-, -(CR 16R 17) mN(R 10)S(O) 2(CR 16R 17) n-, -(CR 16R 17) mS(O) 2N(R 10 )(CR 16R 17) n- or -(CR 16R 17) mN(R 10)S(O) 2N(R 11)(CR 16R 17) n-; in: R 16 and R 17 are each independently hydrogen, halo, hydroxyl, CN, NO 2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 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 combined with the respective connected C to 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; 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.

[0011] 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 is imidazolyl, triazole Base, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl, each of which is 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 10R 11, -NR 10R 11, -NR 10C(O)R 9, -NR 10C(O)OR 9, -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 9, -S(O) pR 9, -S (O) 2NR 10R 11 or -NR 10S(O) 2NR 10R 11 is substituted by a substituent.

[0012] 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 CN, R 9 , -OR 9, -OC(O)R 9, -OC(O)OR 9, -NR 10R 11, -NR 10OR 9, -NR 10C(O)R 9, or -NR 10C(NR 10)NR 10R 11.

[0013] 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 CN, R 9 , -OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -NR 10R 11 , -NR 10OR 9 or -NR 10C(O)R 9 .

[0014] 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 form two Valence groups, such as -(CH 2 ) x-, where x = 2-5; -CH 2CH 2OCH 2CH 2-; or -CH 2CH 2NR 18CH 2CH 2-, 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.

[0015] 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, —CH 3 , hydroxyl, -OCH 3 , -OCD 3 , -NH 2 , -NHCH 3 , or -NH(OCH 3 ). In some embodiments, R 6 is -NH(CH 2 CH 2 )Cl, -NH(CH 2CH 2 )F, or N-linked morpholinyl.

[0016] In certain embodiments, provided herein are compounds of formula (I), formula (II), formula (III) or formula (IV), or formula (V) or formula (VI), wherein the compound has no more than 1,000 g / mol of MW. In certain embodiments, the compound has a MW of no greater than 900 g / mol, no greater than 800 g / mol, no greater than 700 g / mol, no greater than 600 g / mol, or no greater than 500 g / mol. In certain embodiments, the compound has a MW no greater than 600 g / mol. In certain embodiments, the compound has a MW no greater than 500 g / mol.

[0017] In certain embodiments, provided herein are compounds of formula (I), formula (II), formula (III) or formula (IV), or formula (V) or formula (VI), wherein the compound is a racemate or Mixtures of diastereomers or mixtures of stereoisomers.

[0018] 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): Formula (Ia) Formula (Ib) or a pharmaceutically acceptable form thereof.

[0019] 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): Formula (IIa) Formula (IIb) or a pharmaceutically acceptable form thereof.

[0020] In certain embodiments, the compound of formula (II) is a compound of formula (II-1): Formula (II-1) or a pharmaceutically acceptable form thereof.

[0021] 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): Formula (IIa-1) Formula (IIb-1) or a pharmaceutically acceptable form thereof.

[0022] In certain embodiments, the compound of formula (II) is a compound of formula (II-2): Formula (II-2) or a pharmaceutically acceptable form thereof.

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

[0024] 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): Formula (IIIa) Formula (IIIb) or a pharmaceutically acceptable form thereof.

[0025] In certain embodiments, the compound of formula (III) is a compound of formula (III-1): Formula (III-1) or a pharmaceutically acceptable form thereof.

[0026] 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): Formula (IIIa-1) Formula (IIIb-1) or a pharmaceutically acceptable form thereof.

[0027] In certain embodiments, the compound of formula (III) is a compound of formula (III-2): Formula (III-2) or a pharmaceutically acceptable form thereof.

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

[0029] In certain embodiments, the compound of formula (III) is a compound of formula (III-3): Formula (III-3) or a pharmaceutically acceptable form thereof.

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

[0031] 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): Formula (IVa) Formula (IVb) or a pharmaceutically acceptable form thereof.

[0032] In certain embodiments, the compound of formula (IV) is a compound of formula (IV-1): Formula (IV-1) or a pharmaceutically acceptable form thereof.

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

[0034] In certain embodiments, the compound of formula (IV) is a compound of formula (IV-2): Formula (IV-2) or a pharmaceutically acceptable form thereof.

[0035] 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): Formula (IVa-2) Formula (IVb-2) or a pharmaceutically acceptable form thereof.

[0036] In certain embodiments, the compound of formula (V) is a compound of formula (Va) or formula (Vb): Formula (Va) Formula (Vb) or a pharmaceutically acceptable form thereof.

[0037] In certain embodiments, the compound of formula (V) is a compound of formula (V-1): Formula (V-1) or a pharmaceutically acceptable form thereof.

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

[0039] In certain embodiments, the compound of formula (VI) is a compound of formula (VIa) or formula (VIb): Formula (VIa) Formula (VIb) or a pharmaceutically acceptable form thereof.

[0040] In certain embodiments, the compound of formula (VI) is a compound of formula (VI-1): Formula (VI-1) or a pharmaceutically acceptable form thereof.

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

[0042] In certain embodiments, formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1 ), formula ( III-2), formula (IV), formula (IV-1) or formula (IV-2) compound, for example formula (Ia), formula (Ib), formula (IIa), formula (IIa-1), formula ( IIa-2), formula (IIb), formula (IIb-1), formula (IIb-2), formula (IIIa), formula (IIIa-1), formula (IIIa-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 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) compound or its pharmaceutical Acceptable forms are the single enantiomer or the single diastereomer. In certain embodiments, the compounds disclosed herein are a single enantiomer. In certain embodiments, the compounds disclosed herein are (R)-enantiomers. In certain embodiments, the compounds disclosed herein have a (R)-enantiomer in excess of greater than 10%, such as in 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 The (R)-enantiomer. In certain embodiments, the compounds disclosed herein are (S)-enantiomers. In certain embodiments, the compounds disclosed herein have a (S)-enantiomer in excess of greater than 10%, such as in 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 The (S)-enantiomer.

[0043] In certain embodiments, provided herein are pharmaceutical compositions comprising Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1) , formula (III-2), formula (IV), formula (IV-1) or formula (IV-2) compound, for example formula (Ia), formula (Ib), formula (IIa), formula (IIa-1) , formula (IIa-2), formula (IIb), formula (IIb-1), formula (IIb-2), formula (IIIa), formula (IIIa-1), formula (IIIa-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) The compound, or its pharmaceutically acceptable form, or 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 a compound of formula (VIb-1), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0044] In certain embodiments, formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1 ), formula ( III-2), formula (IV), formula (IV-1) or formula (IV-2) compound, for example formula (Ia), formula (Ib), formula (IIa), formula (IIa-1), formula ( IIa-2), formula (IIb), formula (IIb-1), formula (IIb-2), formula (IIIa), formula (IIIa-1), formula (IIIa-2), formula (IIIb), formula ( Compounds 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 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 The compound of (VIb-1) or a pharmaceutically acceptable form thereof is a farnesyl transferase inhibitor. In certain embodiments, relative to inhibition of geranylgeranyltransferase type 1 (such as geranylgeranyltransferase type 1), a compound as disclosed herein, or a pharmaceutically acceptable equivalent thereof, The form is a selective farnesyltransferase inhibitor.

[0045] In certain embodiments, formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1 ), formula ( III-2), formula (IV), formula (IV-1) or formula (IV-2) compound, for example formula (Ia), formula (Ib), formula (IIa), formula (IIa-1), formula ( IIa-2), formula (IIb), formula (IIb-1), formula (IIb-2), formula (IIIa), formula (IIIa-1), formula (IIIa-2), formula (IIIb), formula ( Compounds 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 its pharmaceutically acceptable form, or 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 ( The VIb-1) compound, or a pharmaceutically acceptable form thereof, is metabolically stable, eg, metabolically stable to the liver metabolism of an individual, such as metabolically stable to the liver metabolism of a human.

[0046] In certain embodiments, this paper provides a method for inhibiting farnesyl transferase, which comprises making the farnesyl transferase and an effective amount of formula (I), formula (II), formula (II-1), formula ( II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1) or formula (IV-2) compound, for example formula (Ia), Formula (Ib), formula (IIa), formula (IIa-1), formula (IIa-2), formula (IIb), formula (IIb-1), formula (IIb-2), formula (IIIa), formula ( IIIa-1), formula (IIIa-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) compound, or its pharmaceutically acceptable form, or 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) compound, or its pharmaceutically acceptable form. In certain embodiments, provided herein is a method for inhibiting farnesyl transferase, which comprises contacting the farnesyl transferase with an effective amount of a pharmaceutical composition comprising formula (I), formula (II) , formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1) or formula (IV- 2), such as formula (Ia), formula (Ib), formula (IIa), formula (IIa-1), formula (IIa-2), formula (IIb), formula (IIb-1), formula (IIb-2 ), formula (IIIa), formula (IIIa-1), formula (IIIa-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) compound, or its pharmaceutically acceptable form, or 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) compound or its pharmaceutically acceptable form, and pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, the method of inhibiting farnesyltransferase inhibits farnesylation of H-Ras protein. In certain embodiments, the H-Ras protein has mutations. In certain embodiments, the method of inhibiting farnesyltransferase inhibits farnesylation of N-Ras protein. In certain embodiments, the N-Ras protein has mutations.

[0047] In certain embodiments, provided herein are methods of treating a farnesylated protein-dependent cancer in an individual comprising administering to an individual having a farnesylated protein-dependent cancer a therapeutically effective amount of formula (I), Formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1) or Compounds of formula (IV-2), such as formula (Ia), formula (Ib), formula (IIa), formula (IIa-1), formula (IIa-2), formula (IIb), formula (IIb-1), Formula (IIb-2), formula (IIIa), formula (IIIa-1), formula (IIIa-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) compound, or its pharmaceutically acceptable form, or 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) compound, or a pharmaceutically acceptable form thereof. In certain embodiments, provided herein are methods of treating a farnesylated protein-dependent cancer in an individual comprising administering to an individual having a farnesylated protein-dependent cancer a therapeutically effective amount of a pharmaceutical composition, the The pharmaceutical composition comprises formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV ), formula (IV-1) or formula (IV-2) compound, such as formula (Ia), formula (Ib), formula (IIa), formula (IIa-1), formula (IIa-2), formula (IIb ), formula (IIb-1), formula (IIb-2), formula (IIIa), formula (IIIa-1), formula (IIIa-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) compound or its pharmaceutically acceptable The form, or 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) compound, or A pharmaceutically acceptable form, and a pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, the farnesylated protein-dependent cancer is a solid tumor. In certain embodiments, the farnesylated protein dependent cancer is a farnesylated H-Ras protein dependent cancer. In certain embodiments, the farnesylated protein dependent cancer has a mutation in the H-Ras protein. In certain embodiments, the farnesylated protein dependent cancer is head and neck cancer. In certain embodiments, the farnesylated protein dependent cancer is squamous cell carcinoma (SCC). In certain embodiments, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In certain embodiments, provided herein are methods of treating a farnesylated protein-dependent cancer in an individual, wherein the individual is a human.

[0048] In certain embodiments, provided herein are methods of treating a farnesylated protein-dependent cancer in an individual comprising administering to an individual having a farnesylated protein-dependent cancer a therapeutically effective amount of formula (I), Formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1) or Compounds of formula (IV-2), such as formula (Ia), formula (Ib), formula (IIa), formula (IIa-1), formula (IIa-2), formula (IIb), formula (IIb-1), Formula (IIb-2), formula (IIIa), formula (IIIa-1), formula (IIIa-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) compound, or its pharmaceutically acceptable form, or 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) compound, or a pharmaceutically acceptable form thereof. In certain embodiments, provided herein are methods of treating a farnesylated protein-dependent cancer in an individual comprising administering to an individual having a farnesylated protein-dependent cancer a therapeutically effective amount of a pharmaceutical composition, the The pharmaceutical composition comprises formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV ), formula (IV-1) or formula (IV-2) compound, such as formula (Ia), formula (Ib), formula (IIa), formula (IIa-1), formula (IIa-2), formula (IIb ), formula (IIb-1), formula (IIb-2), formula (IIIa), formula (IIIa-1), formula (IIIa-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) compound or its pharmaceutically acceptable Form, or 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) compound, or its medicine Pharmaceutically acceptable form, and pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, the farnesylated protein-dependent cancer is a solid tumor. In certain embodiments, the farnesylated protein dependent cancer is a farnesylated N-Ras protein dependent cancer. In certain embodiments, the farnesylated protein-dependent cancer has a mutation in the N-Ras protein. In certain embodiments, the farnesylated protein-dependent cancer is melanoma, acute myeloid leukemia (AML), thyroid cancer, lung adenocarcinoma, rectal cancer, endometrial cancer, or colorectal cancer. In certain embodiments, provided herein are methods of treating a farnesylated protein-dependent cancer in an individual, wherein the individual is a human. Implementation

[0049] cross reference

[0050] This application claims Chinese application No. 202111442658.4 filed on November 30, 2021, U.S. Provisional Application No. 63 / 285,412 filed on December 2, 2021, and Chinese application filed on November 23, 2022 202211471486.8 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.

[0051] In one embodiment, provided herein is a compound having the structure of any of Formula (I), Formula (II), Formula (III) or Formula (IV), or a pharmaceutically acceptable form thereof. In one embodiment, provided herein is a compound having the structure of Formula (V) or Formula (VI), or a pharmaceutically acceptable form thereof. In one embodiment, provided herein are compounds having formula (Ia), formula (Ib), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) A compound of either structure or a pharmaceutically acceptable form thereof. In one embodiment, provided herein is a compound having the structure of any of Formula (Va), Formula (Vb), Formula (VIa), or Formula (VIb), or a pharmaceutically acceptable form thereof. In one embodiment, provided herein have 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 a compound of any one of formula (IVb-2), or its pharmaceutical acceptable form. In one embodiment, provided herein have formula (III-3), formula (IIIa-3), formula (IIIb-3), formula (V-1), formula (Va-1), formula (Vb-1) , a compound of any one of formula (VI-1), formula (VIa-1) or formula (VIb-1), or a pharmaceutically acceptable form thereof.

[0052] In one embodiment, provided herein are pharmaceutical compositions comprising a compound having a structure of any one of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable form, and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, provided herein is a pharmaceutical composition comprising a compound 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 formula (Ia), formula (Ib), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or A compound of any one of formula (IVb) or a pharmaceutically acceptable form thereof, or comprising any one of formula (Va), formula (Vb), formula (VIa) or formula (VIb) The compound of the structure or its pharmaceutically acceptable form, and the pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, provided herein is a pharmaceutical composition comprising formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1) or Compounds of any one of 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) The compound of the structure, or its pharmaceutically acceptable form, or contains formula (III-3), formula (IIIa-3), formula (IIIb-3), formula (V-1), formula (Va- 1), a compound of any one of formula (Vb-1), formula (VI-1), formula (VIa-1) or formula (VIb-1), or a pharmaceutically acceptable form thereof, And a pharmaceutically acceptable carrier, diluent or excipient.

[0053] In another embodiment, there is provided a method of treating a cancer dependent on a farnesylated protein comprising administering to an individual a therapeutically effective amount of a compound having formula (I), formula (II), formula (III) or formula (IV) A compound of any one of the structures, or a pharmaceutically acceptable form thereof, or administered to a pharmaceutical composition comprising it. In another embodiment, a method for treating cancers dependent on farnesylated proteins is provided, comprising administering to an individual a therapeutically effective amount of a compound having the structure of formula (V) or formula (VI), or a pharmaceutically acceptable amount thereof received form, or administered a pharmaceutical composition comprising it. In another embodiment, there is provided a method of treating cancers dependent on farnesylated proteins, comprising administering to an individual a therapeutically effective amount of a compound having formula (Ia), formula (Ib), formula (IIa), formula (IIb) , a compound of any one of formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb), or a pharmaceutically acceptable form thereof, or a compound of formula (Va), formula (Vb ), a compound of any one of formula (VIa) or formula (VIb), or a pharmaceutically acceptable form thereof, or administered to a pharmaceutical composition comprising the same. In another embodiment, a method for treating cancer is provided, which includes administering to an individual a therapeutically effective dose of , 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) A compound of any one of the structures or a pharmaceutically acceptable form thereof, or having formula (III-3), formula (IIIa-3), formula (IIIb-3), formula (V-1), formula ( A compound of any one of Va-1), formula (Vb-1), formula (VI-1), formula (VIa-1) or formula (VIb-1), or a pharmaceutically acceptable form thereof , or administer a pharmaceutical composition comprising it. Set forth herein are examples of cancers that depend on farnesylated proteins that are treated according to the methods of treatment provided herein.

[0054] While specific embodiments have been discussed, the description is illustrative only and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art after reading this specification.

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this specification belongs.

[0056] As used herein, the articles "a, an" and "the" refer to one or more grammatical objects of the article. By way of example, a sample refers to one sample or two or more samples.

[0057] As used herein, and unless otherwise indicated, the terms "about" or "approximately" mean an acceptable error for a particular value as determined by one skilled in the art, depending in part on how the value was 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% of a given value or range , 4%, 3%, 2%, 1%, 0.5% or 0.05%.

[0058] As used herein, the term "administer, administering or administration" refers to the act of delivering or causing delivery of a compound or pharmaceutical composition to the body of an individual by methods described herein or otherwise known in the art. Administering a compound or pharmaceutical composition includes prescribing the compound or pharmaceutical composition to be delivered into a patient. Exemplary administration forms include oral dosage forms, such as lozenges, 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 formulations; inhalation powders, sprays, suspensions, and rectal suppositories.

[0059] The term "effective amount" or "therapeutically effective amount" or "dose or dosage" refers to an amount of a compound or pharmaceutical composition described herein sufficient to achieve its intended use, including but not limited to the diseases described below treat. A therapeutically effective amount may vary depending on the intended use (in vitro or in vivo) or on the subject and the disease condition being treated, such as the weight and age of the subject, severity of the disease condition, mode of administration, and the like, which can be determined by those skilled in the art. are easily determined. The specific dosage will vary depending, for example, on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other agents, the time of administration, the tissue to which it is administered, and the physical delivery system on which it is carried. In certain embodiments, a therapeutically effective amount is sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder or to delay or minimize one or more symptoms associated with the disease or disorder. The term also refers to an amount of a compound sufficient to elicit the biological or medical response of a biomolecule (eg, protein, enzyme, RNA or DNA), cell, tissue, system, animal or human being sought by the researcher, veterinarian, physician or clinician.

[0060] "Mirror-image isomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any ratio may be referred to as a "racemic" mixture. The term "(±)" or "(rac)" is used to denote a racemic mixture, where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry can be assigned according to the Cahn-Ingold-Prelog R-S system. When the compound is a mirror image isomer, the stereochemistry of each chiral carbon can be designated by R or S. Resolved compounds of unknown absolute configuration can be assigned (+) or (-) according to the direction (dextrorotatory or levorotatory) of plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms which can be determined according to the absolute stereogenicity of each asymmetric atom. Chemically defined as (R)- or (S)-. The chemical entities, pharmaceutical compositions and methods of the invention are intended to include all such possible isomers, including racemic mixtures, optically substantially pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0061] The "enantiomer excess" or "enantiomer excess %" of a composition (eg, 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 (eg, the S enantiomer) and 10% of the other enantiomer (eg, the R enantiomer) is considered to have an 80 % enantiomer excess. ee = (90-10) / 100 = 80%.

[0062] In some embodiments, a compound described herein is a mixture of enantiomers of the compound and contains an enantiomer 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 S mirror image isomers. In other words, in some embodiments, a compound described herein is a mixture of enantiomers of the compound, and contains an excess of the S enantiomer relative to the R enantiomer enantiomer. In other embodiments, the compounds described herein are mixtures of enantiomers of the compound and contain an enantiomer 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 R mirror image isomers. In other words, in some embodiments, a compound described herein is a mixture of enantiomers of the compound and contains an excess of the R enantiomer relative to the S enantiomer.

[0063] 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", "enantiomer-enriched", ", "enantiomerically pure" and "non-racemic" are used interchangeably herein. These terms refer to a composition in which the amount of one enantiomer is greater than the amount of that one enantiomer in a control mixture of a racemic composition (eg, greater than 1:1 by weight). For example, an enantiomer-enriched preparation of the S enantiomer means having greater than about 50% by weight of the S enantiomer relative to the total weight of the preparation (e.g., the total weight of the S and R isomers). A compound formulation of a substance, such as at least about 55% by weight, at least about 60% by weight, at least about 65% by weight, at least about 70% by weight, at least about 75% by weight, further such as at least about 80% by weight. In some embodiments, the enrichment can be much greater than about 80% by weight, which provides "substantially enantiomerically enriched", "substantially enantiomerically pure", or "substantially nonracemic" A formulation, which refers to a formulation of a composition 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. In certain embodiments, the compounds provided herein consist of at least about 90% by weight of one enantiomer. In other embodiments, the compound consists of at least about 95%, about 98%, or about 99% by weight of one enantiomer.

[0064] In some embodiments, the compound is a racemic mixture of (S)- and (R)-isomers. In other embodiments, provided herein are mixtures of compounds, wherein individual compounds of the mixture exist primarily in the (S)- or (R)- isomeric form. For example, in some embodiments, the compound mixture has 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% of (S)-enantiomer excess. In some embodiments, the compound mixture has 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 of the (S)-enantiomer excess. In some embodiments, the compound mixture has 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% excess of (S)-enantiomer.

[0065] In other embodiments, the compound mixture has 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% ( R) - enantiomer in excess. In some embodiments, the compound mixture has 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 of the (R)-enantiomer in excess. In some embodiments, the compound mixture has 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% excess of (R)-enantiomer.

[0066] In other embodiments, compound mixtures contain identical chemical entities except for stereochemical orientation, ie (S)- or (R)-isomers. For example, if a compound disclosed herein has a -CH(R)- unit, and R is other than hydrogen, then for each identical chemical entity, -CH(R)- is either (S)- or (R) - stereochemical orientation (ie (S)- or (R)-stereoisomer). In some embodiments, the mixture of the same chemical entity (ie, mixture of stereoisomers) is a racemic mixture of (S)- and (R)-isomers. In another embodiment, a mixture of identical chemical entities (ie, a mixture of stereoisomers) contains predominantly the (S)-isomer or predominantly contains the (R)-isomer. For example, in some embodiments, the (S)-isomer in a mixture of the same chemical entity (i.e., a mixture of stereoisomers) is relative to a mixture of (S)- and (R)-isomers The total weight is about 55% by weight, about 60% by weight, about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, about 85% by weight, about 90% by weight, about 95% by weight, About 96%, about 97%, about 98%, about 99%, or about 99.5% by weight or more is present. In some embodiments, the (S)-enantiomer is present in a mixture of the same chemical entity (i.e., a mixture of stereoisomers) at 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% about 99.5% , from about 97% to about 99.5%, from about 98% to about 99.5%, or from about 99% to about 99.5%, or greater than about 99.5%, of the (S)-enantiomer is present in excess. In other embodiments, the (R)-isomer in a mixture of the same chemical entity (i.e., a mixture of stereoisomers) relative to the total weight of the mixture of (S)- and (R)-isomers is At about 55% by weight, about 60% by weight, about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, about 85% by weight, about 90% by weight, about 95% by weight, about 96% by weight , about 97% by weight, about 98% by weight, about 99% by weight, or about 99.5% by weight or more present. In some embodiments, the (R)-isomer in a mixture of the same chemical entity (i.e., a mixture of stereoisomers) is present in an amount 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%, of the (R)-enantiomer is present in excess. Enantiomers can be separated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and supercritical fluid chromatography (SFC), formation of chiral salts and crystallized, 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, McGraw-Hill, NY, 1962); and Tables of Resolving Agents and Optical Resolutions, p. 268 (ed. E.L. Eliel, Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0067] It should be further understood that, in light of the discussion above regarding enantiomer enrichment and enantiomer excess, the absence of specific chirality (e.g., R- or S- References to compounds that are enantiomers) should be understood to refer to the compounds as racemic mixtures (or diastereomeric mixtures), while inclusion of R- or S-designations should be understood to refer to the enantiomers of the compounds Enantiomer (or diastereomeric) form, such as an enantiomerically (or diastereomerically) enriched form of a compound, or a given enantiomerically excess form of a compound. Designations of compounds with R- or S-designations are understood to include enantiomerically enriched or enantiomerically excess compounds of the designated enantiomer, and are not limited to only 100% of the compound's single designated enantiomer.

[0068] In certain embodiments, the pharmaceutically acceptable form is an isomer. "Isomers" are different compounds having the same molecular formula. In some embodiments, isomers may be stereoisomers. In some embodiments, isomers may be tautomers. In some embodiments, isomers may be geometric isomers. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. As used herein, the term "isomer" includes any and all geometric isomers and stereoisomers. "Isomers" include, for example, geometric double bond cis and trans isomers, also known as E- and Z-isomers; R- and S-mirror isomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof if within the scope of the present disclosure.

[0069] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except that the hydrogen on one or more atoms in the molecule is replaced or enriched by deuterium or tritium, or the carbon on one or more atoms in the molecule is replaced or enriched by 13C or 14C, the compound having the structure of the present invention All are within the scope of this disclosure. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced or enriched with deuterium. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced or enriched with tritium. In one embodiment, provided herein are isotopically labeled compounds having one or more carbon atoms replaced or enriched with C. In one embodiment, provided herein are isotopically labeled compounds having one or more carbon atoms replaced or enriched with C.

[0070] The term "isotopologue" refers to an isotopically enriched compound that is identical to those enumerated herein except that one or more atoms differ by atomic mass or mass number from that normally found in nature. atomic replacement. 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, respectively, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 32P, 33P, 33S , 34S, 35S, 36S, 18F, 35Cl, 36Cl and 37Cl, each of which is also within the scope of this specification. For example, compounds having structures of the present invention are within the scope of the disclosure, except that hydrogen on one or more atoms in the molecule has been replaced or enriched with deuterium or tritium. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced or enriched with deuterium. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced or enriched with tritium. In addition, substitution with heavier isotopes such as deuterium (ie, 2H) may afford certain therapeutic advantages due to greater metabolic stability (eg, increased in vivo half-life or reduced dosage requirements). Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. 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) or a pharmaceutically acceptable form thereof, such as formula (Ia), formula (Ib), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) Compounds, such as compounds 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) compound, or its pharmaceutically acceptable form, or formula (III- 3), formula (IIIa-3), formula (IIIb-3), formula (Va), formula (Vb), formula (V-1), formula (Va-1), formula (Vb-1), formula ( A compound of formula VIa), formula (VIb), formula (VI-1), formula (VIa-1) or formula (VIb-1), or a pharmaceutically acceptable form thereof, can generally be obtained using procedures known to those skilled in the art Prepared by substituting an appropriately isotopically enriched reagent for a non-isotopically enriched reagent.

[0071] When a compound is enriched in deuterium, the deuterium-to-hydrogen ratio on the deuterated atoms of the molecule substantially exceeds the natural deuterium-to-hydrogen ratio.

[0072] The embodiments described herein may include isotopologues of compounds of Formula (I), Formula (II), Formula (III) or Formula (IV) or pharmaceutically acceptable forms thereof, such as Formula (Ia), Formula ( Ib), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) compound, such as 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) compound, or its pharmaceutically acceptable form, or 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 A compound of formula (VIb-1), or a pharmaceutically acceptable form thereof, wherein the isotopologue is substituted by one or more deuterium atoms on one or more atomic members of the compound or a pharmaceutically acceptable form thereof, to replace one or more hydrogen atoms. Embodiments described herein may include compounds of formula (I), formula (II), formula (III) or formula (IV) or pharmaceutically acceptable forms thereof, such as formula (Ia), formula (Ib), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) compound, such as formula (II-1), formula (II-2), formula (III-1 ), formula (III-2), formula (IV-1) or formula (IV-2) compound, 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 a compound of formula (IVb-2) or a pharmaceutically acceptable form thereof, or 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) A compound, or a pharmaceutically acceptable form thereof, wherein the carbon atom may have 1 to 3 hydrogen atoms optionally replaced by deuterium.

[0073] 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 forms) of the compounds disclosed herein. derivatives). In one embodiment, "pharmaceutically acceptable form" includes, but is not limited to, a compound of formula (I), formula (II), formula (III) or formula (IV) or formula (V) or Pharmaceutically acceptable salts, solvates, isomers and isotopologues (i.e. isotopically labeled derivatives) of compounds of formula (VI), such as formula (I), formula (II), Pharmaceutically acceptable salts, hydrates, stereoisomers and isotopologues of compounds of formula (III) or formula (IV) or compounds of formula (V) or formula (VI). In one embodiment, pharmaceutically acceptable forms include, but are not limited to, formula (Ia), formula (Ib), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb) as disclosed herein ), formula (IVa) or formula (IVb) compound or the pharmaceutically acceptable salt, solvate, isomer of formula (Va), formula (Vb), formula (VIa) or formula (VIb) compound and Isotopologues (i.e. isotopically labeled derivatives), such as Formula (Ia), Formula (Ib), Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb), Formula ( Pharmaceutically acceptable salts, hydrates, stereoisomers and isotopologues of compounds of IVa) or formula (IVb) or formula (Va), formula (Vb), formula (VIa) or formula (VIb). In one embodiment, pharmaceutically acceptable forms include, but are not limited to, formula (II-1), formula (II-2), formula (III-1), formula (III-2), as disclosed herein. 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 Formula (III-3), Formula (IIIa-3), Formula (IIIb-3), Formula (V-1), Formula (Va-1), Formula (Vb-1), Formula (VI-1), Formula (VIa-1) or the pharmaceutically acceptable salts, solvates, isomers and isotopologues (ie isotopically labeled derivatives) of the compound of formula (VIb-1). In one embodiment, pharmaceutically acceptable forms include, but are not limited to, formula (II-1), formula (II-2), formula (III-1), formula (III-2), as disclosed herein. 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 Formula (III-3), Formula (IIIa-3), Formula (IIIb-3), Formula (V-1), Formula (Va-1), Formula (Vb-1), Formula (VI-1), Formula Pharmaceutically acceptable salts, hydrates, stereoisomers and isotopologues of compounds of (VIa-1) or formula (VIb-1). Those skilled in the art will recognize that the free and salt forms of the compounds may be in the form of solvates.

[0074] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" means, within the scope of sound medical judgment, suitable for use in contact with the tissues of an individual without undue toxicity, irritation, allergic reaction and the like and with a reasonable benefit / risk ratio. worthy of those salts. 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 suitable inorganic and organic acids and bases, such as suitable inorganic and organic addition acids and bases.

[0075] In certain embodiments, the pharmaceutically acceptable form is a solvate (eg, hydrate). As used herein, the term "solvate" refers to a compound (such as the free form of a compound, isomer or isotopologue, or any A pharmaceutically acceptable salt of the aforementioned substances, such as a solvate in free form or a pharmaceutically acceptable salt form). A solvate may 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, which may include, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4 solvent or water molecules. It should be understood that the term "compound" as used herein encompasses compounds and solvates of compounds, as well as mixtures thereof.

[0076] In certain embodiments, the pharmaceutically acceptable forms are tautomers. As used herein, the term "tautomer" refers to a class of isomers that includes at least one formal shift of two or more hydrogen atoms and at least one change in valency (e.g., a single bond to a double bond). , a triple bond to a double bond, or a triple bond to a single bond, or vice versa) resulting in interconvertible compounds. "Tautomerization" includes prototropic tautomerization or prototropic tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "prototropic tautomerization" involves the migration of protons with a concomitant change in bond order. The exact ratio of tautomers depends on several factors including temperature, solvent and pH. Where tautomerization is possible (eg, in solution), chemical equilibrium of the tautomers can be achieved. Tautomerization (ie, a reaction that affords a tautomeric pair) can be acid- or base-catalyzed, or can occur without the action or presence of external agents. Exemplary tautomerisms include, but are not limited to, keto-enol; amido-imine; lactam-lactimine; enamine-imine; and enamine-(different)enamine tautomerisms structure.

[0077] In certain embodiments, pharmaceutically acceptable forms of the compounds disclosed herein do not include salt forms of the compounds disclosed herein (ie, are not salts), sometimes referred to as free base forms. For example, in one embodiment, the pharmaceutical compound of formula (I), formula (II), formula (III) or formula (IV) or formula (V) or formula (VI) compound as disclosed herein Acceptable forms do not include salt forms and include pharmaceutically acceptable forms of compounds of formula (I), formula (II), formula (III) or formula (IV) or formula (V) or formula (VI) as disclosed herein. Acceptable solvates, isomers and isotopologues (i.e. isotopically labeled derivatives), such as those excluding formula (I), formula (II), formula (III) or formula (IV) as disclosed herein Or salt forms and hydrates, stereoisomers and isotopologues of compounds of formula (V) or formula (VI). In one embodiment, pharmaceutically acceptable forms exclude salt forms and include formula (Ia), formula (Ib), formula (IIa), formula (IIb), formula (IIIa), Pharmaceutically acceptable solvates, isomers and Isotopologues, such as excluding formula (Ia), formula (Ib), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) as disclosed herein Or salt forms and hydrates, stereoisomers and isotopologues of compounds of formula (Va), formula (Vb), formula (VIa) or formula (VIb). In one embodiment, pharmaceutically acceptable forms exclude salt forms and include formula (II-1), formula (II-2), 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 formula (III-3), formula (IIIa-3), formula (IIIb-3), formula (V-1), formula (Va-1), formula (Vb-1 ), pharmaceutically acceptable solvates, isomers and isotopologues (i.e. isotopically labeled derivatives) of compounds of formula (VI-1), formula (VIa-1) or formula (VIb-1), Such as not including formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1 ) or formula (IV-2) as disclosed herein, 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 formula (III-3), formula (IIIa-3), Formula (IIIb-3), formula (V-1), formula (Va-1), formula (Vb-1), formula (VI-1), formula (VIa-1) or formula (VIb-1) compound Salt forms and hydrates, stereoisomers and isotopologues.

[0078] As used herein, the term "pharmaceutically acceptable carrier, excipient, or diluent" means a pharmaceutically acceptable carrier, excipient, or diluent that is approved by a regulatory agency of the federal or state government or listed in the US Pharmacopoeia or other generally recognized pharmacopeia for use in animals. , and more particularly a carrier, excipient or diluent for use in humans. The term "carrier" refers to a diluent, adjuvant (eg, Freund's adjuvant (complete and incomplete)), excipient or vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Certain carriers for pharmaceutical compositions for aqueous intravenous administration. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. By way of example, the term pharmaceutically acceptable carrier, excipient or diluent includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition as disclosed herein is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0079] 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, dextrose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, monosodium glutamate, Glyceryl Stearate, Talc, Sodium Chloride, Skim Milk Powder, Glycerin, Propylene Glycol, Water, Ethanol, and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form will be administered to a patient and the particular active ingredients in the dosage form. Further provided herein are anhydrous pharmaceutical compositions and dosage forms comprising one or more compounds of formula (I), formula (II), formula (III) or formula (IV) or a pharmaceutically acceptable compound thereof as described herein. form, or a compound of formula (V) or formula (VI) or a pharmaceutically acceptable form thereof, such as formula (Ia), formula (Ib), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) compound, such as formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1) Or a compound of 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) compound, Or its pharmaceutically acceptable form, or formula (III-3), formula (IIIa-3), formula (IIIb-3), formula (V-1), formula (Va-1), formula (Vb- 1), a compound of formula (VI-1), formula (VIa-1) or formula (VIb-1), or a pharmaceutically acceptable form thereof. Compositions and single unit dosage forms may take the form of solutions or syrups (optionally with flavoring), suspensions (optionally with flavoring), emulsions, lozenges (such as chewable lozenges), pills, capsules, granules, powders (for reconstitution as appropriate), taste-masked or sustained-release formulations, and the like.

[0080] Pharmaceutical compositions provided herein suitable for oral administration may 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 may be prepared by methods of pharmacy well known to those skilled in the art.

[0081] Examples of excipients that may be used in the oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.

[0082] As used herein, the terms "prevention and preventing" are used herein to refer to methods of obtaining beneficial or desired results, including but not limited to prophylactic benefits. For prophylactic benefit, the compounds and pharmaceutical compositions disclosed herein can be administered to patients at risk for a particular disease, or to patients reporting one or more physical symptoms of a disease or disorder, even if the disease or disorder has not yet been diagnosed .

[0083] As used herein, the term "stereoisomer" is understood to mean 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. "Isomers" include, for example, geometric double bond cis and trans isomers, also known as E- and Z-isomers; R- and S-mirror isomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof if within the scope of the disclosure.

[0084] In some embodiments, the symbol Denotes a bond which may be a single bond or a double bond as described herein.

[0085] 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 surrounding a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures depicting a double bond encompass both "E" and "Z" isomers.

[0086] Substituents surrounding a carbon-carbon double bond may alternatively be referred to as "cis" or "trans", where "cis" indicates substituents on the same side of the double bond and "trans" indicates substitution on the opposite side of the double bond base. The arrangement of substituents around a carbocycle can 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. Mixtures of compounds in which the substituents are arranged on the same side as well as on opposite sides of the plane of the ring are designated "cis / trans".

[0087] As used herein, the term "individual" to which administration is contemplated includes, but is not limited to, a human (e.g., male or female of any age group, such as a pediatric individual (e.g., infant, child, adolescent) or an adult individual (e.g., adolescent, middle-aged years or older)) 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, quails and / or turkeys. The individual can be a patient, eg, a patient with a farnesylated protein-dependent cancer.

[0088] The term "therapeutic effect" as used herein encompasses therapeutic benefit and / or prophylactic benefit as described herein. A preventive effect includes delaying or eliminating the onset of a disease or disorder, delaying or eliminating the onset of symptoms of a disease or disorder, slowing, stopping or reversing the progression of a disease or disorder, or any combination thereof.

[0089] As used herein, the terms "treat, treating, treatment" and "improvement" are used interchangeably herein. These terms refer to means of obtaining beneficial or desired results including, but not limited to, therapeutic benefit. Therapeutic benefit means eradication or amelioration of the underlying condition being treated. Furthermore, therapeutic benefit is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying condition, such that improvement is observed in the patient, although the patient may still suffer from the underlying disease or condition. For example, when used in reference to a patient with a farnesylated protein-dependent cancer, refers to the act of reducing the severity of the cancer or delaying or slowing the progression of the cancer, including (a) inhibiting the growth of the cancer, or stopping the progression of the cancer development, and (b) cause regression of cancer, or delay or minimize one or more symptoms associated with the presence of cancer.

[0090] Definitions of specific functional groups and chemical terms are set forth in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS Edition, Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups are generally defined as described herein. Additionally, general principles of organic chemistry as well as specific functional moieties and reactivity are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th 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 ed., Cambridge University Press, Cambridge, 1987.

[0091] When a range of values ​​is stated, every value and subrange within that range is intended to be encompassed. For example, "C 1-6 alkyl" is intended to cover C 1, C 2, C 3, C 4, C 5, C 6, C 1-6, C 1-5, C 1-4, C 1- 3. C 1-2, C 2-6, C 2-5, C 2-4, C 2-3, C 3-6, C 3-5, C 3-4, C 4-6, C 4- 5 and C 5-6 alkyl.

[0092] "Alkyl" means a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, free of unsaturation, and in some embodiments, having from 1 to 10 carbon atoms (e.g., C 1 -C 10 alkyl). Straight-chain (linear or straight) alkyl refers to an alkyl group without branches, such as methyl, ethyl, n-propyl. Whenever appearing herein, a numerical range such as "1 to 10" refers to each integer in the given range; for example, "1 to 10 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 10 carbon atoms, but this definition also covers the term "alkyl" where it appears in an unspecified numerical range. In some embodiments, the alkyl group is C 1 -C 6 alkyl. 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, -second butyl, -isobutyl, -tertiary butyl, -isoamyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methyl pentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl and the like. The alkyl group is attached to the parent molecule by a single bond. Unless otherwise stated in this specification, an alkyl group is optionally substituted with one or more substituent(s) independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl Cycloalkyl, aralkyl, aryl, aryloxy, amine, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, Heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thio Carbonyl, nitro, side oxygen, phosphate, phosphonate, phosphinate, silicon, sulfinyl, sulfinyl, sulfonamide, 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) tR a (where t is 1 or 2), -S(O) tOR a (where t is 1 or 2), S(O) tN(R a) 2 (where t is 1 or 2), or -O-P(=O)(ORa) 2 , wherein each R is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

[0093] "Alkenyl" means a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and, in some embodiments, from two to ten carbon atoms (i.e., C 2-C 10 alkenyl). Whenever appearing herein, 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 consist of 2 carbon atoms, 3 carbon atoms, atoms, 4 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, alkenyl groups contain two to eight carbon atoms. In other embodiments, alkenyl groups contain two to five carbon atoms (eg, C2-C5 alkenyl). An alkenyl group is attached to the parent molecular structure by a single bond, such as ethenyl (also known as vinyl), prop-1-enyl (also known as allyl), but-1-enyl, pent-1-enyl, -1-enyl, pent-1,4-dienyl and the like. The one or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C 2-4 alkenyl include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), C4), butadienyl (C4) and the like. Examples of the C 2-6 alkenyl include the aforementioned C 2-4 alkenyl as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ) and the like. Other examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise stated in this specification, an alkenyl group is optionally substituted with one or more substituent(s) independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl Cycloalkyl, aralkyl, aryl, aryloxy, amine, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, Heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thio Carbonyl, nitro, side oxygen, phosphate, phosphonate, phosphinate, silicon, sulfinyl, sulfinyl, sulfonamide, 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) tR a (where t is 1 or 2), -S(O) tOR a (where t is 1 or 2), S(O) tN(R a) 2 (where t is 1 or 2), or -O-P(=O)(ORa) 2 , wherein each R 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.

[0094] "Alkynyl" means a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, and in some embodiments, from two to ten carbon atoms (i.e., C 2-C 10 alkynyl). Whenever appearing herein, numerical ranges such as "2 to 10" refer to each integer in the given range; for example, "2 to 10 carbon atoms" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, atoms, 4 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, alkynyl groups contain two to eight carbon atoms. In other embodiments, alkynyl groups have two to five carbon atoms (eg, C2-C5alkynyl). An alkynyl group is attached to the parent molecular structure by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless otherwise stated in this specification, an alkynyl group is optionally substituted with one or more substituent(s) independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl Cycloalkyl, aralkyl, aryl, aryloxy, amine, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, Heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thio Carbonyl, nitro, side oxygen, phosphate, phosphonate, phosphinate, silicon, sulfinyl, sulfinyl, sulfonamide, 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) tR a (where t is 1 or 2), -S(O) tOR a (where t is 1 or 2), -S(O) tN(R a) 2 (where t is 1 or 2), or -O-P(=O) (OR a ) 2, wherein each R is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, hetero Aryl or heteroarylalkyl, and each of these moieties may be optionally substituted as defined herein.

[0095] The term "alkoxy" refers to the group -O-alkyl (in some embodiments, including 1 to 10 carbon atom). Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, cyclohexyloxy, and the like. "Lower alkoxy" refers to an alkoxy group containing one to six carbons. In some embodiments, the C 1 -C 4 alkoxy group encompasses straight and branched chain alkyl groups of 1 to 4 carbon atoms. Unless otherwise stated in this specification, an alkoxy group is optionally substituted with one or more substituent(s) independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxy, Aryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl , heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, Thiocarbonyl, nitro, pendant oxygen, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamide, 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) tR a (where t is 1 or 2), -S(O) tOR a (where t is 1 or 2), -S(O) tN(R a) 2 (where t is 1 or 2) or -O-P(=O)(OR a) 2, wherein each R is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. The terms "alkenyloxy" and "alkynyloxy" reflect the description of "alkoxy" above, wherein the prefix "alk" is replaced by "alken" or "alkyn", respectively, and The parent "alkenyl" or "alkynyl" term is as described herein.

[0096] "Aryl" means a group having six to fourteen ring atoms (e.g., C6-C14 or C6-C10 aryl) having at least one carbocyclic ring with an aromatic conjugated π-electron system (eg, with 6, 10, or 14 π-electrons shared in a ring array) (eg, phenyl, fenyl, and naphthyl). In one embodiment, a divalent group formed from a substituted benzene derivative and having a free valence at a ring atom is named a substituted phenylene. In other embodiments, divalent radicals derived from monovalent monocyclic or polycyclic hydrocarbon radicals whose names end in "radical" by removal of a hydrogen atom from a carbon atom having a free valence by adding Add "idene" to the name to name, for example, naphthyl with two points of attachment is called naphthylene. Whenever appearing herein, a numerical range such as "6 to 10 aryl" refers to each integer in the given range; for example, "6 to 10 ring atoms" means that the aryl group can consist of 6 ring atoms, 7 ring atoms etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of ring atoms) groups. Unless otherwise stated in this specification, the aryl moiety is optionally substituted with one or more substituent(s), independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, Alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkane radical, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio , thiocarbonyl, nitro, side oxygen, phosphate, phosphonate, phosphinate, silicon, sulfinyl, sulfonyl, sulfonamide, 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) tR a (where t is 1 or 2), -S(O) tOR a (where t is 1 or 2), -S(O) tN(R a) 2 (where t is 1 or 2), or -O-P(=O) ( OR a) 2, wherein each R is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl , heteroaryl, or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. In one embodiment, unless otherwise stated, "aryl" also includes ring systems wherein 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 on the aromatic ring.

[0097] "Cycloalkyl" or alternatively "carbocyclyl" refers to a monocyclic or polycyclic group containing only carbon and hydrogen and which may be saturated or partially unsaturated. A partially unsaturated cycloalkyl group may be referred to as a "cycloalkenyl" if the carbocycle contains at least one double bond, or a "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl includes groups having 3 to 10 ring atoms (eg, C 3 -C 10 cycloalkyl). Whenever appearing herein, 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 consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 10 carbon atoms. The term "cycloalkyl" also includes bridged and spirofused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of ring atoms) groups. In some embodiments, it is C3-C8 cycloalkyl. In some embodiments, it is C 3 -C 5 cycloalkyl. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: C 3-6 carbocyclyl groups include, but are not limited to, cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), cyclopentyl (C 5 ), cyclo Pentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like. Examples of C 3-8 carbocyclyl include the above-mentioned C 3-6 carbocyclyl and cycloheptyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl and the like. Examples of the C 3-10 carbocyclyl include the aforementioned C 3-8 carbocyclyl as well as octahydro-1 H-indenyl, decahydronaphthyl, spiro[4.5]decyl and the like. Unless otherwise stated in this specification, cycloalkyl groups are optionally substituted with one or more substituent(s), independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkane Aryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl , heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, Thiocarbonyl, nitro, pendant oxygen, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamide, 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) tR a (where t is 1 or 2), -S(O) tOR a (where t is 1 or 2), -S(O) tN(R a) 2 (where t is 1 or 2) or -O-P(=O)(OR a) 2, wherein each R is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. In one embodiment, unless otherwise stated, "cycloalkyl" or "carbocyclyl" also includes ring systems in which a cycloalkyl or carbocyclyl ring as defined above is combined with one or more aryl or heteroaryl fused to a radical where the point of attachment to the parent molecular structure is on the cycloalkyl or carbocyclyl ring.

[0098] The term "halo", "halide" or alternatively "halogen" refers to fluorine, chlorine, bromine or iodine.

[0099] The terms "haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy groups substituted with one or more halo groups or combinations thereof structure. In certain embodiments, all hydrogen atoms of the alkyl group are replaced by halogen atoms. In certain embodiments, the alkyl group is substituted with 1, 2, 3, 4, 5 or 6 halogen atoms. In certain embodiments, the alkyl group is substituted with 1, 2 or 3 halogen atoms. In certain other instances, the alkyl group is substituted with 2 halogen atoms. In certain embodiments, an alkyl group is substituted with 1 halogen atom. In certain embodiments, haloalkyl includes trifluoromethyl, fluoromethyl, perfluoroethyl or chloromethyl. Certain other examples of haloalkyl include chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, or 1,1,1-trifluoroethoxy. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy, respectively, wherein halo 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 optionally be further substituted as defined herein.

[0100] "Heteroalkyl", "heteroalkenyl" and "heteroalkynyl" include alkyl, alkenyl and alkynyl, respectively, having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen , sulfur and phosphorus, or combinations thereof. A numerical range can be given, eg, C 1 -C 4 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 atomic chain length description. Attachment to the parent molecular structure can be through 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 a heteroalkyl group can optionally be oxidized. If present, one or more nitrogen atoms may also optionally be quaternized. For example, heteroalkyl also includes skeletal chains 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 (-CH 2CH 2-OCH 2OCH 3), (methoxymethoxy)methoxy (-CH 2OCH 2OCH 3) and (methoxyethoxy)methoxy-CH 2OCH 2CH 2OCH 3) and and the like; amines such as -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2NHCH2CH3, -CH2N(CH2CH3)(CH3) and the like. Each of heteroalkyl, heteroalkenyl, and heteroalkynyl may optionally be substituted with one or more substituent(s), independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, Alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkane radical, heteroaryl, heteroaralkyl, heterocycloalkyl, hydroxyl, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, Thiocarbonyl, nitro, pendant oxygen, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfinyl, sulfonate, urea , -Si(Ra) 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) tR a (where t is 1 or 2), -S(O) tOR a (where t is 1 or 2), -S(O) tN(R a) 2 (where t is 1 or 2), or -O-P(=O)(OR a ) 2, wherein each R is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, hetero Aryl or heteroarylalkyl, and each of these moieties may be optionally substituted as defined herein.

[0101] "Heteroaryl" or alternatively "heteroaromatic" refers to a 5- to 18-membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in an array) having ring carbon atoms and 1 to 6 ring heteroatoms provided in an aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ( "5- to 18-membered heteroaryl"). Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or more rings. Whenever appearing 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 can consist of 5 ring atoms, 6 ring atoms, 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 group derived from a valent heteroaryl group whose name ends in "radical" by removing a hydrogen atom from an atom having a free valence is identified by the name of the corresponding monovalent group Add "idene" to the name, for example, a pyridyl group with two points of attachment is a pyridinyl group.

[0102] For example, an N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one skeletal atom of the ring is a nitrogen atom. One or more heteroatoms in a heteroaryl group can optionally be oxidized. If present, one or more nitrogen atoms may also optionally be quaternized. Heteroaryl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents such as pyridyl N-oxide. The heteroaryl is attached to the parent molecular structure through any atom of the ring.

[0103] "Heteroaryl" also includes ring systems 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 at 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 at the heteroaryl ring. For polycyclic heteroaryls in which one ring contains no heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, and the like), the point of attachment to the parent molecular structure can be at any ring with a heteroatom (e.g., 2-indolyl) or on a ring containing no heteroatoms (for example, 5-indolyl). In some embodiments, heteroaryl 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, heteroaryl 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, heteroaryl 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 has 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0104] Examples of heteroaryl groups include, but are not limited to, azanyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxanyl Azolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxinyl, benzo[b][1,4]oxazinyl, 1,4- Benzodioxyl, benzonaphthofuryl, benzoxazolyl, benzobisoxazolyl, benzodiaxazolyl, benzoxazolyl, benzopyranyl, benzopyrone Base, benzofuryl, benzofuranone, benzofuranyl, benzothiazolyl, benzothienyl (benzothienyl, benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzo Triazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnamyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[ 4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnamyl, 6,7- Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuryl, dibenzothienyl, furyl, furanyl, furanonyl, furano [3,2-c]pyridyl, 5,6,7,8,9,10-hexahydrocyclooct[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooct[d] ]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooct[d]pyridyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl , indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-endomethylene-5,6,7,8-tetrahydroquinazolinyl, Naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazolyl, oxazolyl, oxirane, 5,6,6a,7,8,9,10 ,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1 H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl , pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidine Base, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydro Hydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta [4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiopyranyl base, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl and Thiophenyl (ie thienyl).

[0105] Unless otherwise stated in this specification, heteroaryl moieties are optionally substituted with one or more substituent(s), independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, Alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkane radical, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio , thiocarbonyl, nitro, side oxygen, phosphate, phosphonate, phosphinate, silicon, sulfinyl, sulfonyl, sulfonamide, 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) tR a (where t is 1 or 2), -S(O) tOR a (where t is 1 or 2), S(O) tN(R a) 2 (where t is 1 or 2), or -O-P(=O) (OR a) 2, wherein each R 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.

[0106] "Heterocyclyl", "heterocycloalkyl" or "heterocarbocyclyl" each refer to any 3 to 18 membered non-aromatic monocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen, phosphorus and sulfur or polycyclic moieties. The heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein the polycyclic ring system can be a fused, bridged or spiro ring system. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or more rings. A heterocyclyl group can be saturated or partially unsaturated. Partially unsaturated heterocycloalkyl groups may be referred to as "heterocycloalkenyl" if the heterocyclyl group contains at least one double bond, and "heterocycloalkynyl" if the heterocyclyl group contains at least one triple bond . Whenever appearing 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 heterocyclyl can consist of 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, etc., up to and including 18 ring atoms. In one embodiment, a divalent group derived from a valent heterocyclic group whose name ends in "radical" by removing a hydrogen atom from an atom having a free valence by adding Add "idene" to the name, for example, hexahydropyridyl is hexahydropyridyl with two points of attachment.

[0107] An N-containing heterocyclyl moiety refers to a non-aromatic group in which at least one ring atom is a nitrogen atom. A heteroatom in a heterocyclyl group is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heterocyclyl also includes ring systems substituted with one or more nitroxide (-O-) substituents, such as hexahydropyridyl N-oxide. The heterocyclyl is attached to the parent molecular structure through any atom of any ring.

[0108] "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or as defined above A heterocyclyl ring fused to one or more aryl or heteroaryl ring systems wherein the point of attachment to the parent molecular structure is at the heterocyclyl ring. In some embodiments, heterocyclyl is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ( "3 to 10 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ( "5- to 8-membered heterocyclyl"). In some embodiments, heterocyclyl is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ( "5- to 6-membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0109] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, aziridinyl, oxiranyl, thiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, tetrahydrofuryl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5 - Diketones. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, hexahydropyridyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, hexahydropyrazinyl, morpholinyl, dithianyl, dioxanyl, and triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azoalkyl, oxecanyl, and thiecanyl. Exemplary bicyclic heterocyclyl groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuryl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuryl, tetrahydrobenzofuryl, Indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, Decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimide, naphthalimide, chromanyl, Chromenyl, 1H-benzo[e][1,4]diazoxyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro - 4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2 , 3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridyl, 2,3-dihydrofuro[2,3-b]pyridyl, 4, 5 ,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridyl, 4,5,6,7 -tetrahydrothieno[3,2-b]pyridyl, 1,2,3,4-tetrahydro-1,6-naphthyridyl and the like.

[0110] Unless otherwise stated, heterocyclyl moieties are optionally substituted with one or more substituent(s) independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl , cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, hetero Aryl, heteroaralkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl , nitro, pendant oxygen, phosphate, phosphonate, phosphinate, silicon, sulfinyl, sulfonyl, sulfonamide, 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) tR a (wherein t is 1 or 2), -S(O) tOR a (where t is 1 or 2), S(O) tN(R a) 2 (where t is 1 or 2) or -O-P(=O)(OR a) 2, wherein each R 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.

[0111] "Hydroxyalkyl" means a radical of the formula -R-(OH)z, where R is alkyl as defined herein, and z is 1 or 2. In one embodiment, the hydroxyalkyl is -ROH. In one embodiment, hydroxyalkyl includes -CH 2 OH. In one embodiment, hydroxyalkyl is -R(OH)2.

[0112] 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 designated site. Unless otherwise specified, suitable non-limiting examples of such groups include halogen atoms, methanesulfonyloxy, o-nitrobenzenesulfonyloxy, p-nitrobenzenesulfonyloxy, trifluoromethoxy and Tosyloxy.

[0113] "Protecting group" has the customary meaning associated with it in organic synthesis, such as a group that selectively blocks one or more reactive sites in a polyfunctional The chemical reaction occurs selectively at the reactive site and allows for easy removal of the group after the selective reaction is complete. For example, a variety of protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, New York (2006), which is hereby incorporated by reference in its entirety. For example, a hydroxy-protected form is one in which at least one hydroxy group present in the compound is protected with a hydroxy-protecting group. Likewise, amines and other reactive groups can be similarly protected.

[0114] As used herein, the term "substituted" or "substituted" means that at least one hydrogen present on a group atom (such as a carbon or nitrogen atom) is replaced by a permissible substituent, for example, a stable compound (such as Substituents that do not undergo transformations spontaneously, such as in compounds that undergo 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 is at Each location can be the same or different. 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, aryl Alkyl, aryl, aryloxy, amine, amido, azide, carbonate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, Halo, haloalkoxy, haloalkyl, ester, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, side oxygen, phosphate, phosphonate, phosphinate, Silicon group, sulfinyl group, sulfonyl group, sulfonamide group, 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(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) tR a (where t is 1 or 2), -S(O) tOR a (where t is 1 or 2), -S (O)tN(Ra)2 (wherein t is 1 or 2) or -O-P(=O)(ORa)2, wherein each Ra is independently hydrogen, alkyl, haloalkyl, carbocyclyl , carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of these moieties may optionally be as described herein defined superseded. For example, cycloalkyl substituents may be substituted with halides and the like at one or more ring carbons. Protecting groups which can form protected derivatives of the above substituents are known to those skilled in the art and can be found in references such as Greene and Wuts, supra. [5.1] [compound]

[0115] In some embodiments, the compound is a compound of formula (I), formula (Ia) or formula (Ib) as disclosed herein, wherein A 1 is N or NR 1a. In some embodiments, a compound of formula (I), formula (Ia) or formula (Ib) as disclosed herein, wherein A 2 is CR 2b or -C(=O)-. In some embodiments, the bond between A1 and A2 is a single bond, A1 is NR1a, and A2 is -C(=O)-. In some embodiments, the bond between A 1 and A 2 is a double bond, A 1 is N, and A 2 is CR 2b.

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

[0117] In some embodiments, the compound is a compound of formula (I), formula (Ia) or formula (Ib) as disclosed herein, wherein for , , or . For example, in some instances, for . In some embodiments, for . In some embodiments, for .

[0118] In some embodiments, the compound is a compound of formula (I), formula (Ia) or formula (Ib) as disclosed herein, wherein for , , or . In some embodiments, for .

[0119] In some embodiments, the compound is a compound of formula (I), formula (Ia) or formula (Ib) as disclosed herein, wherein Y and the fused ring system containing A 1 , A 2 and A 3 are separated by 1,2- The relationship is connected to W. In some embodiments, Y and a fused ring system comprising A1, A2, and A3 are attached to W in a 1,3-relationship. In some embodiments, W is C 6-12 aryl. In some embodiments, W is phenyl. In some embodiments, W is 5-12 membered heteroaryl. In some embodiments, W is pyridyl. In some embodiments, W is substituted with one, two, three or four R substituents. In some embodiments, W is substituted with two R substituents. In some embodiments, W is substituted with one R substituent. 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 14R 15, wherein each R 4 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkane C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxy Alkoxy, C 1-6 heteroalkoxy, C 3-6 cycloalkoxy or 3-6 membered heterocycloalkoxy are optionally independently modified by one, two, three, four, five or Six are selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- Substituents of 6-membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and (O). For example, in some embodiments, R 4 is independently hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, wherein each R 4 of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 1- 6 Haloalkoxy is optionally independently selected from one, two, three, four, five or six halo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1 -6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and (O ) substituent substitution. In some embodiments, R4 is independently hydrogen.

[0120] 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 ) (containing A 4 , A 5 and A The condensed ring system)) group of 6 and Y is attached to Z in a 1,2-relationship. In some embodiments, the —(C(R 6 )(R 7 ) (a fused ring system containing A 4 , A 5 , and A 6 )) group and Y are attached to Z in a 1,3-relationship. In some embodiments, Z is C 6-12 aryl. In some embodiments, Z is phenyl. In some embodiments, Z is 5-12 membered heteroaryl. In some embodiments, Z is pyridyl. In some embodiments, Z is substituted with one, two, three or four R substituents. In some embodiments, Z is substituted with two R substituents. In some embodiments, Z is substituted with one R substituent. In some embodiments, R 5 is independently hydrogen, halo, or CN. In some embodiments, R 5 is independently hydrogen. In some embodiments, R 5 is independently an electron withdrawing group. In some embodiments, R 5 is independently chloro. In some embodiments, R 5 is independently CN.

[0121] 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 pharmaceutical compound thereof. The acceptable form above, wherein R 1a is independently R 9 . For example, in some embodiments, R 1a is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or the C 3-6 cycloalkyl are independently 1-6 independently selected from halo, hydroxyl, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, ( O), -C(O)R 12, -C(O)OR 12, -OC(O)R 12, -OC(O)OR 12, -C(O)NR 10R 11, -NR 10R 11, - NR 10C(O)R 12, -NR 10C(O)OR 12, -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 12, -S(O) pR 12 and -S(O) 2NR 10R 11 is substituted with a substituent. In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, R 1a is hydrogen, C 1-3 alkyl or C 3-4 cycloalkyl, wherein the C 1-3 alkyl or the C 3-4 cycloalkyl are independently One, two or three independently selected from halo, hydroxyl, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkane C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy radical, (O), -C(O)R 12, -C(O)OR 12, -OC(O)R 12, -OC(O)OR 12, -C(O)NR 10R 11, -NR 10R 11. -NR 10C(O)R 12, -NR 10C(O)OR 12, -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 12, -S(O) pR 12 and -S( O) The substituent of 2NR 10R 11 is substituted. For example, in some embodiments, R 1a is hydrogen, -CH 3 , -CD 3 , -CH 2CH 3 , -CD 2CD 3 , isopropyl, 2,3-dihydroxypropyl, or cyclopropyl. In some embodiments, R 1a is -CH 3 , -CD 3 or cyclopropyl. In some embodiments, R 1a is -CH 3 or -CD 3 . In some embodiments, R 1a is cyclopropyl. In some embodiments, the compound is a compound of formula (II-1) or formula (II-2), such as formula (IIa-1), formula (IIb-1), formula (IIa-2) or formula (IIb-2 ) compound, or a pharmaceutically acceptable form thereof.

[0122] In some embodiments, the compound is a compound of formula (I) or formula (III) as disclosed herein, such as a compound of formula (Ia), formula (Ib), formula (IIIa) or formula (IIIb), or a pharmaceutical compound thereof. or a compound of formula (V), formula (Va), formula (Vb), formula (VI), formula (VIa) or formula (VIb) or a pharmaceutically acceptable form thereof, wherein R 2b independently R 9 , -OR 9 , halo, CN, NO 2 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10R 11 , -NR 10R 11 , -NR 10C(O)R9, -S(O)pR9 or -S(O)2NR10R11. In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, R 2b is independently R 9 , -OR 9 , halo, CN, -C(O)NR 10R 11 , or -NR 10R 11 . In some embodiments, R 2b is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, hydroxyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 hetero Cycloalkoxy, halo, CN, -C(O)NR 10R 11 or -NR 10R 11; wherein R 10 and R 11 are each independently hydrogen, C 1-6 alkyl, 3- A 6-membered heterocycloalkyl group, or a 3-6-membered heterocycloalkyl group formed in combination with the respective connected Ns. In some embodiments, R 2b is independently hydrogen, C 1-3 alkyl, C 3-4 cycloalkyl, C 1-3 alkoxy, C 3-4 cycloalkoxy, C 3-4 hetero Cycloalkoxy, halo, CN, -C(O)NR 10R 11 or -NR 10R 11; wherein R 10 and R 11 are each independently hydrogen, C 1-3 alkyl, 3- A 4-membered heterocycloalkyl group, or combined with the respective connected Ns to form a 4-6 membered heterocycloalkyl group. In some embodiments, R 10 is H. In some embodiments, R 11 is C 1-3 haloalkyl, such as chloroethyl or fluoroethyl. For example, in some embodiments, R 2b is hydrogen, -CH 3 , -CD 3 , -CH 2CH 3 , -CD 2CD 3 , isopropyl, cyclopropyl, -OCH 3 , -OCD 3 , - OCH 2CH 3, -OCD 2CD 3, isopropoxy, cyclopropoxy, 3-oxetanyloxy, chlorine, CN, morpholinyl, hexahydropyrazinyl, 3-oxetanylamine group or -C(O)NH 2 . In some embodiments, R 2b is -NH 2 . In some embodiments, R 2b is independently an electron withdrawing group. Electron withdrawing groups may include, for example, halo, cyano, nitro, carbonyl, carboxylic acid, carboxylate, amide, sulfonyl, sulfonyl ester, or sulfonyl amide groups. For example, in some embodiments, R 2b is independently selected from halo, CN, NO 2 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10R 11 , The electron-withdrawing group of -S(O) pR 9 or -S(O) 2NR 10R 11. In some embodiments, R 2b is chlorine, CN, -C(O)H, -C(O)CH 3 , -C(O)OH, -C(O)OCH 3 , -C(O)NH 2 , -C(O)N(H)CH 3 , -C(O)N(CH 3 ) 2 , -S(O)CH 3 , -S(O) 2CH 3 , -S(O) 2NH 2 , - 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 formula (IIIa-1), formula (IIIb-1), formula (IIIa-2) or formula (IIIb-2 ) compound, 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.

[0123] 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 is CR 1b or -C (=O)-. In some embodiments, a compound of formula (I) as disclosed herein, eg, a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable form thereof, wherein A 2 is N or NR 2a. In some embodiments, the bond between A 1 and A 2 is a double bond, A 1 is CR 1b, and A 2 is N. In some embodiments, the bond between A 1 and A 2 is a single bond, A 1 is -C(=0)-, and A 2 is NR 2a. 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), or a pharmaceutically acceptable form thereof, respectively. academically acceptable form. 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 formula (V), formula (Va), formula (Vb), formula (V-1), formula (Va-1), formula (Vb-1), formula (VI), formula A compound of formula (VIa), formula (VIb), formula (VIa-1) or formula (VIb-1), or a pharmaceutically acceptable form thereof.

[0124] In some embodiments, the compound is a compound of formula (I) or formula (IV) as disclosed herein, such as a compound of formula (Ia), formula (Ib), formula (IVa) or formula (IVb), or a pharmaceutically Acceptable form, or a compound of formula (V) or formula (VI), such as a compound of formula (Va), formula (Vb), formula (VIa) or formula (VIb), or a pharmaceutically acceptable form thereof, wherein R 1b is independently R 9 , -OR 9 , halo, CN, NO 2 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10R 11 , -NR 10R 11 , -NR 10C(O)R 9 , -S(O)pR 9 or -S(O) 2NR 10R 11 . For example, in some embodiments, R 1b is R 9 , —OR 9 , halo, CN, —C(O)R 9 , or —C(O)OR 9 . In some embodiments, R 1b is R 9 , -OR 9 , halo or CN. For example, in some embodiments, R 1b is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, halo or CN, wherein the C 1-6 alkyl, the C 3-6 cycloalkyl, the C 1-6 alkoxy or the C 3-6 cycloalkoxy independently undergo one, two, three , four, five or six independently selected from halo, hydroxyl, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkane C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy radical, (O), -C(O)R 12, -C(O)OR 12, -OC(O)R 12, -OC(O)OR 12, -C(O)NR 10R 11, -NR 10R 11. -NR 10C(O)R 12, -NR 10C(O)OR 12, -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 12, -S(O) pR 12 and -S( O) The substituent of 2NR 10R 11 is substituted. 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 is 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 group, the C 3-4 cycloalkyl group, the C 1-3 alkoxy group or the C 3-4 cycloalkoxy group are independently replaced by one, two or three selected from halo, hydroxyl, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (O), -C(O) R 12, -C(O)OR 12, -OC(O)R 12, -OC(O)OR 12, -C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 12, -NR 10C(O)OR 12 , -NR 10C(O)NR 10R 11 , -NR 10S(O) 2R 12 , -S(O) pR 12 and -S(O) 2NR 10R 11 are substituted by substituents. For example, in some embodiments, R 1b is hydrogen, -CH 3 , -CD 3 , -CF 3 , -CH 2CH 3 , -CD 2CD 3 , isopropyl, 2,3-dihydroxypropyl, Cyclopropyl, -OCH 3 , -OCD 3 , -OCF 3 , -OCH 2CH 3 , -OCD 2CD 3 , isopropoxy, 2,3-dihydroxypropoxy, or cyclopropoxy. In some embodiments, the compound is a compound of formula (IV-1) or formula (IV-2), such as formula (IVa-1), formula (IVb-1), formula (IVa-2) or formula (IVb-2 ) compound 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.

[0125] In some embodiments, the compound is a compound of formula (I) as disclosed herein, eg, a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable form thereof, wherein R 2a is independently R 9 . For example, in some embodiments, R 2a is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or the C 3-6 cycloalkyl is independently One, two, three, four, five or six are independently selected from halo, hydroxyl, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy base, C 1-6 haloalkoxy, (O), -C(O)R 12, -C(O)OR 12, -OC(O)R 12, -OC(O)OR 12, -C( O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 12, -NR 10C(O)OR 12, -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 12, -S Substituents of (O) pR 12 and -S(O) 2NR 10R 11 are substituted. For example, in some embodiments, R 2a is hydrogen, C 1-3 alkyl or C 3-4 cycloalkyl, wherein the C 1-3 alkyl or the C 3-4 cycloalkyl are independently One, two or three selected from halo, hydroxyl, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (O), -C(O)R 12, -C(O)OR 12, -OC(O)R 12, -OC(O)OR 12, -C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 12, -NR 10C(O)OR 12, -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 12, -S(O) pR 12 and -S(O) 2NR 10R 11 is substituted with a substituent. In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, R 2a is hydrogen, -CH 3 , -CD 3 , -CH 2CH 3 , -CD 2CD 3 , isopropyl, 2,3-dihydroxypropyl, or cyclopropyl.

[0126] In some embodiments, the compound is a compound of formula (I), formula (II), formula (III) or formula (IV) as disclosed herein, such as formula (Ia), formula (Ib), formula (IIa), A compound of formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) or a pharmaceutically acceptable form thereof, or formula (VI), formula (VIa) or formula (VIb) Compound, wherein A 3 is CR 3. In some embodiments, R 3 is 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), formula (II), formula (III), formula (IV) or formula (VI), such as formula (Ia), formula (Ib), formula (IIa), A compound of formula (IIb), formula (IIIa), formula (IIIb), formula (IVa), formula (IVb), formula (VIa) or formula (VIb), wherein A 3 is N. In some embodiments, the compound is a compound of formula (Ia), formula (Ib), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) or A pharmaceutically acceptable form, or a compound of formula (VIa) or formula (VIb), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is 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) compound, or its pharmaceutically acceptable form, or formula (III -3), a compound of formula (IIIa-3), formula (IIIb-3), formula (VIa-1) or formula (VIb-1), or a pharmaceutically acceptable form thereof.

[0127] In some embodiments, the compound is a compound of formula (I), formula (II), formula (III) or formula (IV) as disclosed herein, such as formula (Ia), formula (Ib), formula (IIa), Formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) compound or its pharmaceutically acceptable form, or formula (V), formula (Va), formula (Vb) , a compound of formula (VI), formula (VIa) or formula (VIb), or a pharmaceutically acceptable form thereof, wherein A 4 is CR 8 . In some embodiments, A4 is N. In some embodiments, A4 is N, and no more than one of A5 and A6 is N. In some embodiments, A5 is CR8. In some embodiments, A is N. In some embodiments, A5 is N, and no more than one of A4 and A6 is N. In some embodiments, A6 is CR8. In some embodiments, A6 is N. In some embodiments, A6 is N, and no more than one of A4 and A5 is N. In some embodiments, A4, A5, and A6 are each independently CR8. In some embodiments, R 8 is independently R 9 , -OR 9 , halo, or CN. In some embodiments, R 8 is hydrogen. In some embodiments, A5 and A6 together are O, NR9 or S. For example, as a representative example in which A5 and A6 are combined together and replaced by O, NR9 or S in the compound of formula (I), as shown below respectively as formula (I-A1), formula (I-A2 ) and formula (I-A3) compound: Formula (I-A1) Formula (I-A2) Formula (I-A3) or a pharmaceutically acceptable form thereof.

[0128] In some embodiments, the compound is a compound of formula (I), formula (II), formula (III) or formula (IV) as disclosed herein, such as formula (Ia), formula (Ib), formula (IIa), Formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) compound, or its pharmaceutically acceptable form, or formula (V) or formula (VI), such as formula ( Va), a compound of formula (Vb), formula (VIa) or formula (VIb), or a pharmaceutically acceptable form thereof, wherein Y is a bond or is a compound having a length of up to 5 atoms, up to 4 atoms, up to 3 Atoms or linkers of up to 2 atoms. In some embodiments, Y is a bond. In some embodiments, Y is a linker that is 5 atoms in length. In some embodiments, Y is a linker that is 4 atoms in length. In some embodiments, Y is a linker that is 3 atoms in length. In some embodiments, Y is a linker that is 2 atoms in length. In some embodiments, Y is a linker that is 1 atom in length. In some embodiments, Y is a C 1-6 alkylene group, wherein one or more -CH 2- are optionally independently modified 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)- substitution. In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. In some embodiments, Y is in the direction of Z-Y-W (wherein Z refers to Z or a ring containing Z, W refers to W or a ring containing W, the foregoing can be used in formula (I), formula (II), formula (III) or formula (IV) and its sub-formula). For example, as a representative example of Y being written along the Z-Y-W direction in the compound of formula (I), wherein Y is -N(R 10 )C(O)- the following is a compound of formula (I-A4): Formula (I-A4); And Y is-C(O)N(R 10)-as shown below is the compound of formula (I-A5): Formula (I-A5).

[0129] In some embodiments, the compound is 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) compound, or its pharmaceutically acceptable form , or formula (III-3), formula (V-1) or formula (VI-1), such as formula (IIIa-3), formula (IIIb-3), formula (Va-1), formula (Vb- 1), a compound of formula (VIa-1) or formula (VIb-1), or a pharmaceutically acceptable form thereof.

[0130] In some embodiments, Y is -(CR 16R 17) q-, -(CR 16R 17) mO(CR 16R 17) n-, -(CR 16R 17) mC(O)(CR 16R 17) n-, -(CR 16R 17) mN(R 10)(CR 16R 17) n-, -(CR 16R 17) mN(R 10)C(O)(CR 16R 17) n-, -(CR 16R 17) mC( O)N(R 10)(CR 16R 17) n-, -(CR 16R 17) mN(R 10)C(O)N(R 11)(CR 16R 17) n-,-(CR 16R 17) mS (O) p(CR 16R 17) n-, -(CR 16R 17) mN(R 10)S(O) 2(CR 16R 17) n-, -(CR 16R 17) mS(O) 2N(R 10 )(CR 16R 17) n- or -(CR 16R 17) mN(R 10)S(O) 2N(R 11)(CR 16R 17) n-; wherein: R 16 and R 17 are each present at each occurrence independently hydrogen, halo, hydroxyl, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkane radical, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkane Oxygen, C 1-6 heteroalkoxy or 3-6 membered heterocycloalkoxy, or combined with the respective connected C to form C(O), C 3-6 cycloalkyl or 3-6 membered hetero Cycloalkyl; 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 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.

[0131] In some embodiments, Y is -(CR 16R 17) q-, -(CR 16R 17) mO(CR 16R 17) n-, -(CR 16R 17) mC(O)(CR 16R 17) n-, -(CR 16R 17) mN(R 10)(CR 16R 17) n-, -(CR 16R 17) mN(R 10)C(O)(CR 16R 17) n-, -(CR 16R 17) mC( O)N(R 10)(CR 16R 17) n-, -(CR 16R 17) mN(R 10)S(O) 2(CR 16R 17) n-or-(CR 16R 17) mS(O) 2N (R 10 )(CR 16R 17 ) n-. For example, in some embodiments, Y is -(CR 16R 17) q-, -(CR 16R 17) mO(CR 16R 17) n-, -(CR 16R 17) mN(R 10)C(O )(CR 16R 17) n- or -(CR 16R 17) mC(O)N(R 10)(CR 16R 17) n-. For example, in some embodiments, Y is -(CR 16R 17 )q-. For example, in some embodiments, Y is -(CR 16R 17 ) mO(CR 16R 17 ) n-. For example, in some embodiments, Y is -(CR 16R 17 ) mN(R 10 )C(O)(CR 16R 17 ) n-. For example, in some embodiments, Y is -(CR 16R 17 ) mC(O)N(R 10 )(CR 16R 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 hydrogen, halo, hydroxyl, CN, NO 2 , C 1-3 alkyl, C 2-3 alkenyl, C at each occurrence. 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 connected to each Combined to form C(O), C 3-5 cycloalkyl or 3-5 membered heterocycloalkyl. For example, in some embodiments, each occurrence of R 16 and R 17 is independently hydrogen, chlorine, hydroxyl, CN, NO 2 , methyl, ethyl, isopropyl, -CF 3 , - CH2CF3, -CH2OH, -(CH2)2OH, -(CH2)2OCH3, cyclopropyl, 3-oxetanyl, methoxy, ethoxy, isopropoxy, cyclo Propyloxy, -OCF 3 , -OCH 2CF 3 , -O(CH 2 ) 2OH, -O(CH 2 ) 2OCH 3 or 3-oxetanyloxy, or combined with the respective attached C C(O), cyclopropyl or 3-5 membered heterocycloalkyl. In some embodiments, R 16 and R 17 are each 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 -(CH 2 )O-. In some embodiments, Y is -O(CH2)-. In some embodiments, Y is -(CH 2 ) 2 O-. In some embodiments, Y is -O(CH 2 ) 2-. In some embodiments, Y is -(CH 2 ) 2-. In some embodiments, the compound is a compound of formula (I), formula (II), formula (III) or formula (IV) as disclosed herein, such as formula (Ia), formula (Ib), formula (IIa), Formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) compound or its pharmaceutically acceptable form, or formula (V), formula (Va), formula (Vb) , a compound of formula (VI), formula (VIa) or formula (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 formula (IIa-1), formula (IIb-1), formula (IIa-2) or formula (IIb-2 ) compound, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-1) or formula (III-2), such as formula (IIIa-1), formula (IIIb-1), formula (IIIa-2) or formula (IIIb-2 ) compound, 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 formula (IVa-1), formula (IVb-1), formula (IVa-2) or formula (IVb-2 ) compound, 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.

[0132] In some embodiments, the compound is a compound of formula (I), formula (II), formula (III) or formula (IV) as disclosed herein, such as formula (Ia), formula (Ib), formula (IIa), Formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) compound, or its pharmaceutically acceptable form, or formula (V), formula (Va), formula (Vb ), a compound of formula (VI), formula (VIa) or formula (VIb), or a pharmaceutically acceptable form thereof, wherein W 1 , W 2 , W 3 and W 4 are each independently N or CR 4 , or W 1 and W 2 together are O, NR 4A or S, or W 2 and W 3 together are O, NR 4A or S. In some embodiments, at least one of W 1 , W 2 , W 3 and W 4 is N. In some embodiments, W 1 , W 2 , and W 3 are each independently CR 4 , and W 4 is N. In some embodiments, W 1 , W 2 , and W 4 are each independently CR 4 , and W 3 is N. In some embodiments, W 1 , W 3 , and W 4 are each independently CR 4 , and W 2 is N. In some embodiments, W 2 , W 3 , and W 4 are each independently CR 4 , and W 1 is N. In some embodiments, W 1 , W 2 , W 3 and W 4 are each independently CR 4 . In some embodiments, W 2 and W 3 are each independently CR 4 , and W 1 and W 4 are each independently N. In some embodiments, W 1 and W 2 are each independently CR 4 , and W 3 and W 4 are each independently N. In some embodiments, W 1 and W 4 are each independently CR 4 , and W 2 and W 3 together are O, NR 4A or S. In some embodiments, W 3 and W 4 are each independently CR 4 , and W 1 and W 2 together are O, NR 4A or S. In some embodiments, W 1 is CR 4 , W 4 is N, and W 2 and W 3 together are O, NR 4A, or S. In some embodiments, W 3 is CR 4 , W 4 is N, and W 1 and W 2 together are O, NR 4A, or S.

[0133] In some embodiments, each occurrence of R is independently hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkane radical, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 1-6 hetero Alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy or -NR 14R 15, where each of R 4's 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, as the case may be, independently selected from 1-6 halo , hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl , C 1-6 alkoxy, C 1-6 haloalkoxy and substituents of (O). For example, in some embodiments, R 4 is independently hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cycloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, wherein each of R 4 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 1- 6 haloalkoxy groups are independently selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and (O) substituents. In some embodiments, R 4 is independently hydrogen, halo, C 1-3 alkyl, C 1-3 haloalkyl, C 3-5 cycloalkyl, C 1-3 alkoxy or C 1-3 3 Haloalkoxy. In some embodiments, R4 is independently hydrogen.

[0134] In some embodiments, R 4A is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkane radical, 3-6 membered heterocycloalkyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein each of R 4A’s 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, as the case may be, independently via one , two, three, four, five or six selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 hetero Substituents of alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and (O). For example, in some embodiments, R 4A is 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 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, as the case may be, independently through 1-6 independent is selected from halo, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 3-6 cycloalkyl, 3-6 Substituents of member heterocycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and (O). In some embodiments, R 4A is independently hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 3-6 cycloalkane group or 3-6 membered heterocycloalkyl. In some embodiments, R 4A is independently hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, or cyclopropyl.

[0135] In some embodiments, the compound is a compound of formula (I), formula (II), formula (III) or formula (IV) as disclosed herein, such as formula (Ia), formula (Ib), formula (IIa), Formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) compound or its pharmaceutically acceptable form, or formula (V), formula (Va), formula (Vb) , a compound of formula (VI), formula (VIa) or formula (VIb) or a pharmaceutically acceptable form thereof, wherein Z 1 , Z 2 , Z 3 and Z 4 are each independently N or CR 5 , or Z 2 Together with Z3 is O, NR5A or S, or Z3 and Z4 together are O, NR5A or S. In some embodiments, at least one of Z 1 , Z 2 , Z 3 and Z 4 is N. In some embodiments, Z 1 , Z 2 and Z 3 are each independently CR 5 and Z 4 is N. In some embodiments, Z 1 , Z 2 and Z 4 are each independently CR 5 and Z 3 is N. In some embodiments, Z 1 , Z 3 and Z 4 are each independently CR 5 and Z 2 is N. In some embodiments, Z2, Z3, and Z4 are each independently CR5, and Z1 is N. In some embodiments, Z 1 , Z 2 , Z 3 and Z 4 are each independently CR 5 . In some embodiments, each of Z2 and Z3 is independently CR5, and each of Z1 and Z4 is independently N. In some embodiments, each of Z3 and Z4 is independently CR5, and each of Z1 and Z2 is independently N. In some embodiments, Z1 and Z4 are each independently CR5, and Z2 and Z3 together are O, NR5A or S. In some embodiments, Z1 and Z2 are each independently CR5, and Z3 and Z4 together are O, NR5A or S. In some embodiments, Z1 is N, Z2 and Z3 together are O, NR5A or S, and Z4 is CR5. In some embodiments, Z1 is N, Z2 is CR5, and Z3 and Z4 together are O, NR5A or S. In some embodiments, each occurrence of R 5 is independently R 9 , —OR 9 , halo, CN, NO 2 , —C(O)R 9 , —C(O)OR 9 , —C( O)NR 10R 11 , —S(O)pR 9 or —S(O) 2NR 10R 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, each occurrence of R is independently hydrogen, halo, CN, NO, -C(O)(C 1-6 alkyl), -C(O)OH , -C(O)O(C 1-6 alkyl), -C(O)NR 10R 11 , -S(O)p(C 1-6 alkyl) or -S(O) 2NR 10R 11. In some embodiments, each occurrence of R is independently halo, CN, NO, -C(O)CH, -C(O)OH, -C(O)OCH, -C( O)N(CH3)2, -S(O)2CH3 or -S(O)2N(CH3)2. In some embodiments, R 5 is independently hydrogen, halo, or CN. In some embodiments, R 5 is independently hydrogen. In some embodiments, R 5 is independently an electron withdrawing group. In some embodiments, R 5 is independently chloro. In some embodiments, R 5 is independently CN.

[0136] In some embodiments, R 5A is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkane radical, 3-6 membered heterocycloalkyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein each of R 5A’s C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 hydroxyalkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C 6-12 aryl group or 5-12 membered heteroaryl group independently via 1 -6 independently selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl , 3-6 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and substituents of (O). For example, in some embodiments, R 5A is 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 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 as the case may be independently selected from 1-6 From halo, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered hetero Substituents of cycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and (O). In some embodiments, R 5A is independently hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 3-6 cycloalkane group or 3-6 membered heterocycloalkyl. In some embodiments, R 5A is independently hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, or cyclopropyl.

[0137] In some embodiments, the compound is a compound of formula (I), formula (II), formula (III) or formula (IV) as disclosed herein, such as formula (Ia), formula (Ib), formula (IIa), Formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) compound or its pharmaceutically acceptable form, or formula (V), formula (Va), formula (Vb) , a compound of formula (VI), formula (VIa) or formula (VIb) or a pharmaceutically acceptable form thereof, wherein 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 10R 11, -NR 10R 11, -NR 10OR 9, -NR 10C(O)R 9, - NR 10C(O)OR 9, -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 9, -NR 10C(NR 10)NR 10R 11, -S(O) pR 9, -S(O ) 2NR 10R 11 or -NR 10S(O) 2NR 10R 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 6 is CN, R 9 , -OR 9 , -OC(O)R 9 , -OC(O)OR 9 , -NR 10R 11 , -NR 10OR 9 , -NR 10C(O)R 9 or -NR 10C(NR 10)NR 10R 11. In some embodiments, R 6 is CN, R 9 , —OR 9 , —OC(O)R 9 , —OC(O)OR 9 , —NR 10R 11 , —NR 10OR 9 , or —NR 10C(O) R9. In some embodiments, R 6 is CN, R 9 , —OR 9 , —NR 10R 11 , or —NR 10OR 9 . In some embodiments, R 6 is CN, R 9 , -OR 9 or -NR 10R 11 . For example, in some embodiments, R 9 is 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 each independently hydrogen, C 1-6 alkyl or C 1-6 alkoxy. In some embodiments, R 10 and R 11 together form a divalent group, such as -(CH 2 ) x- (where x=2-5), -CH 2CH 2OCH 2CH 2- or -CH 2CH 2NR 18CH 2CH 2-, wherein R 18 is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, 3-6 membered heterocycloalkane Base or 5-12 membered heteroaryl. In some embodiments, R 6 is hydroxyl, -OCH 3 , CN, hydrogen, -CH 3 , -CH 2CN, -NH 2 , -NHCH 3 , or -NH(OCH 3 ). In some embodiments, R 6 is hydrogen, —CH 3 , hydroxyl, —OCH 3 , —OCD 3 , —NH 2 , —NHCH 3 , or —NH(OCH 3 ). In some embodiments, R 6 is hydrogen, hydroxyl, -OCH 3 , -OCD 3 , -NH 2 or -NHCH 3 . In some embodiments, R 6 is -NH(CH 2 CH 2 )Cl, -NH(CH 2CH 2 )F, or N-linked morpholinyl. In some embodiments, R 6 is hydroxyl. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is NH 2 . In some embodiments, the compound is a compound of formula (II-1) or formula (II-2), such as formula (IIa-1), formula (IIb-1), formula (IIa-2) or formula (IIb-2 ) compound, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-1) or formula (III-2), such as formula (IIIa-1), formula (IIIb-1), formula (IIIa-2) or formula (IIIb-2 ) compound 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 formula (IVa-1), formula (IVb-1), formula (IVa-2) or formula (IVb-2 ) compound, 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.

[0138] In some embodiments, the compound is a compound of formula (I), formula (II), formula (III) or formula (IV) as disclosed herein, such as formula (Ia), formula (Ib), formula (IIa), Formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) compound, or its pharmaceutically acceptable form, or formula (V), formula (Va), formula (Vb ), a compound of formula (VI), formula (VIa) or formula (VIb), or a pharmaceutically acceptable form thereof, wherein R is 5-12 membered heteroaryl, which, as the case may be, undergoes 1-4 independently selected from halo, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -OC(O)OR 9 , - C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 9, -NR 10C(O)OR 9, -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 9, Substituents of -S(O) pR 9 , -S(O) 2NR 10R 11 or -NR 10S(O) 2NR 10R 11 are substituted. For example, in some embodiments, R is imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, or pyrimidinyl, optionally 1-4 independently selected from halo, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -OC (O)OR 9, -C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 9, -NR 10C(O)OR 9, -NR 10C(O)NR 10R 11, -NR Substituents of 10S(O) 2R 9 , -S(O) pR 9 , -S(O) 2NR 10R 11 or -NR 10S(O) 2NR 10R 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 independently selected from halo, CN, NO 2 , R 9 , -OR 9 , -C( O)R 9, -C(O)OR 9, -C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 9, -S(O) pR 9, or -S(O) 2NR 10R 11 is substituted with a substituent. In some embodiments, R 7 is C-linked imidazolyl or C-linked triazolyl, which is optionally selected from 1-4 independently selected from halo, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9, -C(O)OR 9, -C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 9, -S(O)pR 9, or -S (O) 2NR 10R 11 is substituted by a substituent. In some embodiments, R 7 is N-linked imidazolyl or N-linked triazolyl, which is optionally selected from 1-4 independently selected from halo, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9, -C(O)OR 9, -C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 9, -S(O)pR 9, or -S (O) 2NR 10R 11 is substituted by a substituent. In some embodiments, R 7 is methyl-substituted imidazolyl or methyl-substituted triazolyl. In some embodiments, R is C-methyl substituted imidazolyl or C-methyl substituted triazolyl. In some embodiments, R is N-methyl substituted imidazolyl or N-methyl substituted triazolyl. In some embodiments, R7 is , , or . In some embodiments, R7 is or . In some embodiments, R7 is or . In some embodiments, R7 is or . In some embodiments, R7 is or . In some embodiments, the compound is a compound of formula (II-1) or formula (II-2), such as formula (IIa-1), formula (IIb-1), formula (IIa-2) or formula (IIb-2 ) compound, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of formula (III-1) or formula (III-2), such as formula (IIIa-1), formula (IIIb-1), formula (IIIa-2) or formula (IIIb-2 ) compound 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 formula (IVa-1), formula (IVb-1), formula (IVa-2) or formula (IVb-2 ) compound, 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.

[0139] In some embodiments, a compound disclosed herein is a compound of formula (I), such as a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable form thereof. In some embodiments, pharmaceutically acceptable forms of compounds of formula (I), such as compounds of formula (Ia) or formula (Ib), do not include salt forms (i.e., are not salts), and include formula (I ) pharmaceutically acceptable solvates, isomers and isotopologues (ie isotopically labeled derivatives) of compounds of formula (Ia) or formula (Ib).

[0140] 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. academically acceptable form. In some embodiments, the compound is a compound of formula (II-1) or formula (II-2) or a pharmaceutically acceptable form thereof, such as formula (IIa-1), formula (IIb-1), formula (IIa-2) or a compound of formula (IIb-2) or a pharmaceutically acceptable form thereof. In some embodiments, compounds of formula (II), formula (IIa) or formula (IIb) (for example, compounds of formula (II-1) or formula (II-2), such as formula (IIa-1), formula (IIb- 1), the pharmaceutically acceptable form of formula (IIa-2) or formula (IIb-2) compound) does not include salt form (that is not a salt), and includes formula (II), formula (IIa) respectively Or formula (IIb) compound (for example formula (II-1) or formula (II-2) compound, such as formula (IIa-1), formula (IIb-1), formula (IIa-2) or formula (IIb-2 ) compounds) pharmaceutically acceptable solvates, isomers and isotopologues (ie isotopically labeled derivatives).

[0141] 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. academically acceptable form. In some embodiments, the compound is a compound of formula (III-1) or formula (III-2) or a pharmaceutically acceptable form thereof, such as formula (IIIa-1), formula (IIIb-1), formula ( IIIa-2) or formula (IIIb-2) compound or its pharmaceutically acceptable form, or formula (III-3), formula (IIIa-3) or formula (IIIb-3) compound or its pharmaceutically acceptable form accepted form. In some embodiments, compounds of formula (III), formula (IIIa) or formula (IIIb) (for example, compounds of formula (III-1) or formula (III-2), such as formula (IIIa-1), formula (IIIb- 1), a pharmaceutically acceptable form of a compound of formula (IIIa-2) or formula (IIIb-2) or a compound of formula (III-3), formula (IIIa-3) or formula (IIIb-3)) does not include Salt form (that is, not a salt), and includes compounds of formula (III), formula (IIIa) or formula (IIIb), respectively (for example, compounds of formula (III-1) or formula (III-2), such as formula (IIIa -1), formula (IIIb-1), formula (IIIa-2) or formula (IIIb-2) compound, or formula (III-3), formula (IIIa-3) or formula (IIIb-3) compound) Pharmaceutically acceptable solvates, isomers and isotopologues (ie isotopically labeled derivatives).

[0142] 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), or a pharmaceutically acceptable form thereof, respectively. academically acceptable form. In some embodiments, the compound is a compound of formula (IV-1) or formula (IV-2) or a pharmaceutically acceptable form thereof, such as formula (IVa-1), formula (IVb-1), formula (IVa-2) or a compound of formula (IVb-2) or a pharmaceutically acceptable form thereof. In some embodiments, compounds of formula (IV), formula (IVa) or formula (IVb) (for example, compounds of formula (IV-1) or formula (IV-2), such as formula (IVa-1), formula (IVb- 1), the pharmaceutically acceptable form of formula (IVa-2) or formula (IVb-2) compound) does not include salt form (that is not a salt), and includes formula (IV), formula (IVa) respectively Or formula (IVb) compound (for example formula (IV-1) or formula (IV-2) compound, such as formula (IVa-1), formula (IVb-1), formula (IVa-2) or formula (IVb-2 ) compounds) pharmaceutically acceptable solvates, isomers and isotopologues (ie isotopically labeled derivatives).

[0143] 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 in a pharmaceutically acceptable form. 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) or a pharmaceutically acceptable form thereof, respectively. form. In some embodiments, the pharmaceutical compound of formula (V), formula (Va) or formula (Vb) (e.g., formula (V-1) compound, such as formula (Va-1) or formula (Vb-1) compound) Acceptable forms above do not include salt forms (i.e., are not salts), and include compounds of formula (V), formula (Va) or formula (Vb) (for example, compounds of formula (V-1), such as compounds of formula (Va- 1) or the pharmaceutically acceptable solvates, isomers and isotopologues (ie isotopically labeled derivatives) of the compound of formula (Vb-1).

[0144] In some embodiments, the compound of formula (I), formula (Ia) or formula (Ib), or a pharmaceutically acceptable form thereof, is a compound of formula (VI), formula (VIa) or formula (VIb), or a pharmaceutically acceptable form thereof, respectively. academically acceptable form. In some embodiments, the compound is a compound of formula (VI-1) or a pharmaceutically acceptable form thereof, such as a compound of formula (VIa-1) or formula (VIb-1) or a pharmaceutically acceptable form thereof, respectively. form. In some embodiments, the pharmaceutical compound of formula (VI), formula (VIa) or formula (VIb) (e.g., formula (VI-1) compound, such as formula (VIa-1) or formula (VIb-1) compound) Acceptable forms above do not include salt forms (i.e., are not salts), and include compounds of formula (VI), formula (VIa) or formula (VIb) (e.g., compounds of formula (VI-1), such as compounds of formula (VIa- 1) or the pharmaceutically acceptable solvates, isomers and isotopologues (ie isotopically labeled derivatives) of the compound of formula (VIb-1).

[0145] 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) Compounds or pharmaceutically acceptable forms thereof, wherein: Y is -(CR 16R 17) q- or -(CR 16R 17) mO(CR 16R 17) n-; R 1a is independently R 9 , —OR 9 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 10R 11 , —S(O) pR 9 , or —S(O) 2NR 10R 11; Each occurrence of R 2b and R 5 is independently R 9 , -OR 9 , halo, CN, NO 2 , -C(O)R 9 , -C(O)OR 9 , -OC(O) R 9, -OC(O)OR 9, -C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 9, -NR 10C(O)OR 9, -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 9, -S(O) pR 9, -S(O) 2NR 10R 11 or -NR 10S(O) 2NR 10R 11; 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 10R 11, -NR 10R 11, -NR 10OR 9, -NR 10C(O)R 9, -NR 10C(O)OR 9, -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 9, -NR 10C(NR 10)NR 10R 11, -S(O) pR 9, -S(O) 2NR 10R 11 or -NR 10S(O) 2NR 10R 11; R 7 is a 5-12 membered heteroaryl group, which is independently selected from halo, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O )OR 9, -OC(O)R 9, -OC(O)OR 9, -C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 9, -NR 10C(O)OR 9. Substituents of -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 9, -S(O) pR 9, -S(O) 2NR 10R 11 or -NR 10S(O) 2NR 10R 11 replace; Each occurrence of R 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 3-5 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-9 membered heteroaryl, wherein each C 1-4 alkyl, C 2-4 alkene Base, 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 is independently selected from halogen, hydroxyl, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, C 3-5 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-4 alkane Oxygen, C 1-4 haloalkoxy, (O), -C(O)R 12, -C(O)OR 12, -OC(O)R 12, -OC(O)OR 12, -C (O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 12, -NR 10C(O)OR 12, -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 12, - S(O) pR 12, -S(O) 2NR 10R 11 and -NR 10S(O) 2NR 10R 11 are substituted by substituents; R 10 and R 11 are each independently hydrogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 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 Combined with the respective connected N to form a 3-6 membered heterocycloalkyl group, wherein each of R 10 and R 11 is 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 The 5-9 membered heteroaryl groups are independently selected from halo, hydroxyl, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyn C 1-4 haloalkyl group, C 1-4 heteroalkyl group, C 3-5 cycloalkyl group, 3-6 membered heterocycloalkyl group, C 1-4 alkoxy group, C 1-4 haloalkane group Oxygen, (O), -C(O)R 13, -C(O)OR 13, -OC(O)R 13, -OC(O)OR 13, -C(O)NR 14R 15, -NR 14R 15, -NR 14C(O)R 13, -NR 14C(O)OR 13, -NR 14C(O)NR 14R 15, -NR 14S(O) 2R 13, -S(O) pR 13, -S Substituents of (O) 2NR 14R 15 and -NR 14S(O) 2NR 14R 15; Each occurrence of R 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 3-5 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-9 membered heteroaryl, wherein each of R 12's 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 heterocycle Alkyl, phenyl or 5-9 membered heteroaryl are independently selected from halogen, hydroxyl, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, C 3-5 cycloalkyl, 3-6 membered heterocycloalkyl, C 1 -4 alkoxy, C 1-4 haloalkoxy, (O), -C(O)R 13, -C(O)OR 13, -OC(O)R 13, -OC(O)OR 13 , -C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 13, -NR 10C(O)OR 13, -NR 10C(O)NR 10R 11, -NR 10S(O) 2R 13. The substituents of -S(O) pR 13, -S(O) 2NR 10R 11 and -NR 10S(O) 2NR 10R 11 are substituted; Each occurrence of R is independently hydrogen, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 3-5 cycloalkyl or 3-6 membered heterocycloalkyl; R 14 and R 15 are each independently hydrogen, hydroxyl, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 haloalkyl, C 1-3 3 hydroxyalkyl, C 1-3 heteroalkyl, C 3-5 cycloalkyl, 3-6 membered heterocycloalkyl or C 1-4 alkoxy, or combined with the respective connected N to form 3- 6-membered heterocycloalkyl; R 16 and R 17 are each independently hydrogen, halo, hydroxyl, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 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 combined with the respective connected C to form C(O), C 3 -5 cycloalkyl or 3-6 membered heterocycloalkyl; each m is independently an integer of 0, 1, 2 or 3; each n is independently an integer of 0, 1, 2 or 3; 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.

[0146] 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 ) compound or a pharmaceutically acceptable form thereof, wherein: Y is -(CH 2) q- or -(CH 2) mO(CH 2) n-; R 1a is independently R 9; R 2b is independently R 9, -OR 9, halo, CN, -C(O)NR 10R 11 or -NR 10R 11; R 5 is independently R 9 , -OR 9 , halo, CN, NO 2 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10R 11 , -S(O) pR 9 or -S(O) 2NR 10R 11; R 6 is CN, R 9, -OR 9, -NR 10R 11 or -NR 10OR 9; R 7 is a 5-12 membered heteroaryl group, which is independently selected from halo, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O )OR 9, -C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 9, -NR 10C(O)OR 9, -NR 10C(O)NR 10R 11, -NR 10S( O) 2R 9, -S(O) pR 9, -S(O) 2NR 10R 11 or -NR 10S(O) 2NR 10R 11 are substituted by substituents; Each occurrence of R is independently hydrogen, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, C 3-5 cycloalkyl or 3-6 membered heterocycloalkane wherein each C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, C 3-5 cycloalkyl or 3-6 membered heterocycloalkyl is independently modified by 1 -5 independently selected from halo, hydroxyl, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 3-5 ring Substituents of alkyl, 3-6 membered heterocycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, (O) and -NR 10R 11; R 10 and R 11 are each independently hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 3- 5-cycloalkyl, 3-6-membered heterocycloalkyl or C 1-3 alkoxy, or combined with the N connected to each to form a 3-6-membered heterocycloalkyl, wherein each of R 10 and R 11 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 groups are independently selected from halo, hydroxyl, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 3- Substituents of 5 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, (O) and -NR 14R 15; Each occurrence of R 14 and R 15 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 combined with each connected N to form a 3-6-membered heterocycloalkyl; each m is independently an integer of 0, 1, 2 or 3; each n is independently an integer of 0, 1, 2 or 3; The sum of m and n is 0, 1, 2, 3, 4 or 5; each p is independently an integer of 0, 1 or 2; and Each q is independently an integer of 0, 1, 2, 3, 4 or 5.

[0147] 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) Compounds or pharmaceutically acceptable forms, wherein: Y is -(CH 2) q- or -(CH 2) mO(CH 2) n-; R 1a is independently R 9; R 2b is independently R 9, -OR 9, halo, CN, -C(O)NR 10R 11 or -NR 10R 11; R 5 is independently R 9, -OR 9, halo, CN, NO 2, -C(O)R 9, -C(O)OR 9, -C(O)NR 10R 11, -S(O) pR 9 or -S(O) 2NR 10R 11; R 6 is R 9, -OR 9, -NR 10R 11 or -NR 10OR 9; R 7 is a 5-12 membered heteroaryl group, which is independently selected from halo, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O )OR 9, -C(O)NR 10R 11, -NR 10R 11, -NR 10C(O)R 9, -NR 10S(O) 2R 9, -S(O)pR 9, or -S(O) 2NR The substituent of 10R 11 is substituted; Each occurrence of R is independently hydrogen, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, C 3-5 cycloalkyl or 3-6 membered heterocycloalkane wherein each C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, C 3-5 cycloalkyl or 3-6 membered heterocycloalkyl is independently modified by 1 -5 independently selected from halo, hydroxyl, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 3-5 ring Substituents of alkyl, 3-6 membered heterocycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, (O) and -NR 10R 11; R 10 and R 11 are each independently hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 3- 5-cycloalkyl, 3-6-membered heterocycloalkyl or C 1-3 alkoxy, or combined with the N connected to each to form a 3-6-membered heterocycloalkyl, wherein each of R 10 and R 11 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 groups are independently selected from halo, hydroxyl, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C Substituents of 3-5 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, (O) and -NR 14R 15; Each occurrence of R 14 and R 15 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 combined with each connected N to form a 3-6-membered heterocycloalkyl; each m is independently an integer of 0, 1, 2 or 3; each n is independently an integer of 0, 1, 2 or 3; The sum of m and n is 0, 1, 2, 3, 4 or 5; each p is independently an integer of 0, 1 or 2; and Each q is independently an integer of 0, 1, 2, 3, 4 or 5.

[0148] 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) Compounds or pharmaceutically acceptable forms thereof, wherein: Y is -(CH 2) q- or -(CH 2) mO(CH 2) n-; R 1a is independently R 9; R 2b is independently R 9, -OR 9, halo, CN, -C(O)NR 10R 11 or -NR 10R 11; R 5 is independently R 9, halo, CN, NO 2, -C(O)R 9, -S(O) pR 9 or -S(O) 2NR 10R 11; R 6 is R 9, -OR 9 or -NR 10OR 11; R 7 is a 5-9 membered heteroaryl group, which is independently selected from halogen, CN, NO 2 , R 9 , -OR 9 , -C(O)R 9 , -C(O) through 1-4 as the case may be. ) NR 10R 11, -NR 10R 11, -NR 10C(O)R 9, -NR 10S(O) 2R 9, -S(O) pR 9 or -S(O) 2NR 10R 11 are substituted by substituents; Each occurrence of R is independently hydrogen, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 3-5 cycloalkyl or 3-6 membered heterocycloalkane wherein each C 1-3 alkyl group, C 1-3 hydroxyalkyl group, C 1-3 heteroalkyl group, C 3-5 cycloalkyl group or 3-6 membered heterocycloalkyl group is independently passed through a , two or three substituents independently selected from halo, hydroxyl, CN, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl or C 1-3 alkoxy replace; R 10 and R 11 are each independently hydrogen, C 1-3 alkyl, C 1-3 heteroalkyl or 3-6 membered heterocycloalkyl in each occurrence, or combined with the N to which they are attached to form 3-6 membered heterocycloalkyl, wherein each of R 10 and R 11 each C 1-3 alkyl, C 1-3 heteroalkyl or 3-6 membered heterocycloalkyl independently passes through one or two One or three substituents independently selected from halo, hydroxyl, CN, C 1-3 alkyl, C 1-3 heteroalkyl or 3-6 membered heterocycloalkyl; each m is independently an integer of 0, 1, 2 or 3; each n is independently an integer of 0, 1, 2 or 3; The sum of m and n is 0, 1, 2, 3, 4 or 5; each p is independently an integer of 0, 1 or 2; and Each q is independently an integer of 0, 1, 2, 3, 4 or 5.

[0149] 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) Compounds or pharmaceutically acceptable forms thereof, wherein: Y is -(CH 2) q- or -(CH 2) mO(CH 2) n-; R 1a is hydrogen, -CH 3 , -CD 3 , -CH 2CH 3 , -CD 2CD 3 , isopropyl, 2,3-dihydroxypropyl or cyclopropyl; R 2b is (a) hydrogen, -CH 3 , -CD 3 , -CH 2CH 3 , -CD 2CD 3 , isopropyl, cyclopropyl, -OCH 3 , -OCD 3 , -OCH 2CH 3 , -OCD 2CD 3. Isopropoxy, cyclopropoxy, 3-oxetanyloxy, chlorine, CN, morpholinyl, hexahydropyrazinyl, 3-oxetanylamino or -C(O) NH 2 ; or R 2b is (b)-NH 2 ; R 5 is hydrogen, halo, CN, NO 2 , -C(O)CH 3 , -S(O)CH 3 , -S(O) 2CH 3 , -S(O) 2NH 2 , -S(O) 2NHCH 3 or -S(O) 2N(CH 3 ) 2; R 6 is hydrogen, -CH 3 , hydroxyl, -OCH 3 , -OCD 3 , -NH 2 , -NHCH 3 or -NH(OCH3); or R 6 is -NH(CH 2CH 2 )Cl, -NH(CH 2CH 2) F or N-linked morpholinyl. R is imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyrimidyl, which are independently selected from - CH 3, -CD 3, -CH 2CH 3, -CD 2CD 3, isopropyl, cyclopropyl, -OCH 3, -OCD 3, -OCH 2CH 3, -OCD 2CD 3, isopropoxy, cyclopropyl Oxygen, chlorine and CN substituents are substituted; each m is independently an integer of 0, 1 or 2; each n is independently an integer of 0, 1 or 2; where the sum of m and n is 0, 1, 2, 3 or 4; and Each q is independently an integer of 0, 1, 2, 3, 4 or 5.

[0150] 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) Compounds or pharmaceutically acceptable forms thereof, wherein: Y is -(CH 2) 2-, -O(CH 2)-, -O(CH 2) 2-, -(CH 2)O- or -(CH 2) 2O-; R 1a is hydrogen, -CH 3 , -CD 3 , 2,3-dihydroxypropyl or cyclopropyl; R 2b is (a) -OCH 3, -OCD 3, 3-oxetanyloxy, chlorine, CN, morpholinyl, hexahydropyrazinyl, 3-oxetanylamino or -C( O) NH 2 ; or R 2b is (b) -NH 2 ; R 5 is hydrogen, chlorine, bromine or CN; R 6 is hydrogen, hydroxyl, -OCH 3 , -OCD 3 , -NH 2 or -NHCH 3 ; and R is imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyrimidyl, which are independently selected from - CH 3, -CD 3, -CH 2CH 3, -CD 2CD 3, isopropyl, cyclopropyl, -OCH 3, -OCD 3, -OCH 2CH 3, -OCD 2CD 3, isopropoxy, cyclopropyl Substituents of oxy, chloro and CN are substituted.

[0151] 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) Compounds or pharmaceutically acceptable forms thereof, wherein: Y is -(CH 2) 2-, -O(CH 2)-, -O(CH 2) 2-, -(CH 2)O- or -(CH 2) 2O-; R 1a is hydrogen, -CH 3 , -CD 3 , 2,3-dihydroxypropyl or cyclopropyl; R 2b is (a) -OCH 3, -OCD 3, 3-oxetanyloxy, chlorine, CN, morpholinyl, hexahydropyrazinyl, 3-oxetanylamino or -C( O) NH 2 ; or R 2b is (b)-NH 2 ; R 5 is hydrogen, chlorine, bromine or CN; R 6 is hydrogen, hydroxyl, -OCH 3 , -OCD 3 , -NH 2 or -NHCH 3 ; and R 7 is methyl-substituted imidazolyl or methyl-substituted triazolyl.

[0152] 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) Compounds or pharmaceutically acceptable forms thereof, wherein: Y is -(CH 2) 2-, -O(CH 2)-, -O(CH 2) 2-, -(CH 2)O- or -(CH 2) 2O-; R 1a is hydrogen, -CH 3 , -CD 3 , 2,3-dihydroxypropyl or cyclopropyl; R 2b is (a) -OCH 3, -OCD 3, 3-oxetanyloxy, chlorine, CN, morpholinyl, hexahydropyrazinyl, 3-oxetanylamino or -C( O) NH 2 ; or R 2b is (b) -NH 2 ; R 5 is hydrogen, chlorine, bromine or CN; R 6 is hydrogen, hydroxyl, -OCH 3 , -OCD 3 , -NH 2 or -NHCH 3 ; and R 7 is , , , , or .

[0153] 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) Compounds or pharmaceutically acceptable forms thereof, wherein: Y is -(CH 2) 2-, -O(CH 2)-, -O(CH 2) 2-, -(CH 2)O- or -(CH 2) 2O-; R 1a is hydrogen, -CH 3 , -CD 3 , 2,3-dihydroxypropyl or cyclopropyl; R 2b is (a) -OCH 3, -OCD 3, 3-oxetanyloxy, chlorine, CN, morpholinyl, hexahydropyrazinyl, 3-oxetanylamino or -C( O) NH 2 ; or R 2b is (b) -NH 2 ; R 5 is hydrogen, chlorine, bromine or CN; R 6 is hydrogen, hydroxyl, -OCH 3 , -OCD 3 , -NH 2 or -NHCH 3 ; and R 7 is or .

[0154] 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, compounds of formula (II-1), formula (II-2), formula (III-1) or formula (III-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) compound) or formula (III-3) , the pharmaceutically acceptable form of the compound of formula (IIIa-3) or formula (IIIb-3) does not include salt form (i.e. is not a salt), and includes formula (II-1), formula (II-2) , formula (III-1) or formula (III-2) compound (such as being respectively formula (IIa-1), formula (IIb-1), formula (IIa-2), formula (IIb-2), formula (IIIa -1), formula (IIIb-1), formula (IIIa-2), formula (IIIb-2) compound) or formula (III-3), formula (IIIa-3) or formula (IIIb-3) compound medicine Pharmaceutically acceptable solvates, isomers and isotopologues (ie isotopically labeled derivatives).

[0155] In some embodiments, the compound is a compound of formula (I), formula (II), formula (III) or formula (IV) as disclosed herein, such as formula (Ia), formula (Ib), formula (IIa), Formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) compound, or its pharmaceutically acceptable form, or formula (V), formula (Va), formula (Vb ), a compound of formula (VI), formula (VIa) or formula (VIb), or a pharmaceutically acceptable form thereof, wherein the compound has a MW of not more than 1,000 g / mol. In some embodiments, the compound has a MW of no greater than 900 g / mol, no greater than 800 g / mol, no greater than 700 g / mol, no greater than 600 g / mol, or no greater than 500 g / mol. In some embodiments, the compound has a MW no greater 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 Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (IV-1 ) or Formula ( IV-2) Compounds, 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) compound or its pharmaceutically acceptable form , or formula (III-3), formula (IIIa-3), formula (IIIb-3), formula (V-1), formula (Va-1), formula (Vb-1), formula (VI-1) , a compound of formula (VIa-1 ) or formula (VIb-1 ), or a pharmaceutically acceptable form thereof.

[0156] In some embodiments, the compound is a compound of formula (I), formula (II), formula (III) or formula (IV) as disclosed herein, such as formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1) or formula (IV-2) compound, or its pharmaceutically acceptable form, or formula (III-3), formula (V) , a compound of formula (V-1), formula (VI) or formula (VI-1), or a pharmaceutically acceptable form thereof, wherein the compound is a racemate or a mixture of diastereomers, or a stereoisomer A mixture of structures. 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 Formula (Ia), Formula (Ib), Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb), Formula (IVa) as disclosed herein ) or a compound of formula (IVb), 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) compound, or its pharmaceutically acceptable Accepted forms, or compounds of formula (IIIa-1), formula (IIIb-1), formula (Va-1), formula (Vb-1), formula (VIa-1) or formula (VIb-1), or in a pharmaceutically acceptable form. In some embodiments, the compound is the (R)-enantiomer. In some embodiments, the compound has an (R)-enantiomer in excess of greater than 10%. In some embodiments, the compound has an enantiomer 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 enantiomer excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% (R)-enantiomer. In some embodiments, the compound is the (S)-enantiomer. In some embodiments, the compound has an (S)-enantiomer in excess of greater than 10%. In some embodiments, the compound has an enantiomer 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 enantiomer excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% (S)-enantiomer.

[0157] 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 Racemate, and selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 , 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96 ,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121 , 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, and 135, or a pharmaceutically acceptable form thereof. 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 Single enantiomer. In some embodiments, the compound is compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 , 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 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 (R)-enantiomers or pharmaceutically acceptable forms thereof. For example, in some embodiments, the compound is 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 (R)-mirror isomerism substance or its pharmaceutically acceptable form. In some embodiments, the compound is compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 , 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 86, 89, 90 or 91 (S)-enantiomer or a pharmaceutically acceptable form thereof. For example, in some embodiments, the compound is 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 (S)-enantiomer or a pharmaceutically acceptable form thereof.

[0158] 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, 41, 42, 43, 44, 45, 46, 47, 50, 51, 54, 55, 56, 57, 61, 62, 63, 65, 69, 76, 77, 79, 80, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, and 110, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is 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 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 (S)-enantiomer, or a pharmaceutically acceptable form thereof.

[0159] 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 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 their pharmaceutical acceptable form. In some embodiments, the compound is the (R)-enantiomer of compound 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.

[0160] 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, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 36, 37, 40, 41, 42, 43, 44, 45, 46, 47, 48, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 81, 82, 83, 84, 85, 86, 87, 88, 89, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, and 135, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is 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 (R)-enantiomer, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is 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 (S)-enantiomer, or a pharmaceutically acceptable form thereof.

[0161] 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 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.

[0162] 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, 26, 28, 29, 31, 32, 36, 38, 40, 41, 42, 43, 44, 45, 49, 52, 53, 54, 55, 59, 60, 61, 63, 64, 65, 71, 72, 73, 78, 81, 83, 84, 85, 87, 88, 93, 94, 95, 112, 113, 114, 115, 117, 118, 119 and 120, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is the (R)-enantiomer of compound 6, 14, 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.

[0163] 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 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 compound 4, 7, 8, 9, 15, 19, 20, 21, 27, 30, 34, 35, 37, 39, 46, 48, 51, 56, 57, 58, 66 , the (R)-enantiomer of 70, 86 or 89, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is 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 (S)-enantiomer, or a pharmaceutically acceptable form thereof.

[0164] 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 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 substance, or its pharmaceutically acceptable form. In some embodiments, the compound is the (S)-mirror image of compound 3, 4, 14, 15, 25, 27, 28, 29, 30, 34, 35, 46, 47, 48, 51, 71, 77 or 80 isomers, or pharmaceutically acceptable forms thereof.

[0165] 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 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 compound 6, 7, 8, 9, 18, 19, 20, 21, 36, 37, 39, 55, 56, 57, 58, 66, 70, 78, 86, 89, 90 or the (R)-enantiomer of 91, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is compound 6, 7, 8, 9, 18, 19, 20, 21, 36, 37, 39, 55, 56, 57, 58, 66, 69, 70, 78, 86, 89 , the (S)-enantiomer of 90 or 91, or a pharmaceutically acceptable form thereof.

[0166] 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, 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.

[0167] 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 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.

[0168] 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 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 compound 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.

[0169] 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, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,95,100,105,110,115,120,125,130 and 135, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is the (R) - an enantiomer, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is ( S)-enantiomer, or a pharmaceutically acceptable form thereof.

[0170] 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 63, 64, 65, 94, 99, 104, 109, 114, 119, 124, 129 and 134, or a pharmaceutically acceptable form thereof.

[0171] 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 pharmaceutical In an acceptable form, it is a farnesyl transferase inhibitor. For example, in some embodiments, the compounds disclosed herein inhibit farnesyl transferase with an IC50 of 300 nM or less, such as 250 nM or less, 200 nM or less, 150 nM or less, 125 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 25 nM or less, 20 nM or less, 15 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less. In some embodiments, the compounds disclosed herein are selective farnesyl transferase inhibitors. In some embodiments, compounds disclosed herein selectively inhibit farnesyltransferase with greater potency (lower IC50 values) relative to the level of inhibition of geranylgeranyltransferase type 1 . For example, in some embodiments, compounds disclosed herein inhibit geranylgeranyltransferase type 1 with an IC50 of 100 nM or greater, such as 300 nM or greater, 500 nM or greater, 750 nM nM or higher or 1,000 nM or higher. For example, in some embodiments, a compound disclosed herein selectively inhibits farnesyl transferase relative to type 1 geranylgeranyl transferase, wherein the compound has an IC 50 (farnesyl transferase ) to IC50 (geranylgeranyltransferase type 1) with an IC50 ratio of at least 1:5, for example an IC50 ratio of 1:10, 1:25, 1:50, 1:100, 1:300 , 1:500, 1:750 or 1:1000 or higher.

[0172] 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 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 their pharmaceutical acceptable form. 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 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 (S)-enantiomer, or a pharmaceutically acceptable form thereof.

[0173] 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 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 in a pharmaceutically acceptable form.

[0174] 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 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.

[0175] 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 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.

[0176] 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 the following compounds: 3-Hydroxy-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-2(4,6)-quinoline-1,4(1,3)- Diphenylcyclohexyl-2 2-one [(001)]; 3-Hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-2(4,6)-quinoline-1,4 (1,3)-Diphenylcyclohexyl-2 2-one [(002)]; 4 4-chloro-3-hydroxyl-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-2(4,6)-quinone Phenyl-1,4(1,3)-diphenylcyclohexifane-2 2-one [(003)]; 3-amino-4 4-chloro-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-2(4,6)- Quinoline-1,4(1,3)-Diphenylcyclohexifane-2 2-one [(004)]; 3-Hydroxy-2 2-methoxy-3-(1-methyl-1 H-imidazol-5-yl)-2(4,6)-quinoline-1,4(1,3)-diphenyl Cyclohexene-4 4-carbonitrile [(005)]; 3-Hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-2(4,6) -Quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(006)]; 3-amino-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-2(4,6 )-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(007)]; 3-amino-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-22-oxo-2 1,2 2-dihydro-2 (4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(008)]; 3-amino-3-(1-methyl-1 H-imidazol-5-yl)-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2 ,4 4-Dicarbonitrile [(009)]; 2 2-methoxy-3-(1-methyl-1 H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1,3)-di phencyclohexan-3-ol [(010)]; 3-Hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa-2(4,6)-quinone Phenyl-1,4(1,3)-diphenylcyclohexifane-2 2-one [(011)]; 4 4-chloro-2 2-methoxy-3-(1-methyl-1 H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1 ,3)-Diphenylcyclohexyl-3-ol [(012)]; 4 4-chloro-3-hydroxy-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa-2(4,6)-quinoline -1,4(1,3)-Diphenylcyclohexane-2 2-one [(013)]; 4 4-chloro-3-hydroxyl-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa-2(4 ,6)-quinolin-1,4(1,3)-diphenylcyclohexyl-2 2-one [(014)]; 3-amino-4 4-chloro-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa-2( 4,6)-quinolin-1,4(1,3)-diphenylcyclohexyl-2 2-one [(015)]; 3-Hydroxy-2 2-methoxy-3-(1-methyl-1 H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1, 3)-Diphenylcyclohexane-4 4-carbonitrile [(016)]; 3-Hydroxy-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-5-oxa-2(4,6)- Quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(017)]; 3-Hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-5-oxa-2 (4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(018)]; 3-amino-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-5-oxa- 2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(019)]; 3-amino-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro- 5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(020)]; 3-Amino-3-(1-methyl-1 H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclo Hexafan-2 2,4 4-dicarbonitrile [(021)]; 3-Hydroxy-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa-2(4,6)-quinoline-1,4( 1,3)-Diphenylcycloheptan-2 2-one [(022)]; 3-Hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa-2(4,6)-quinone Phenyl-1,4(1,3)-Diphenylcycloheptafan-2 2-one [(023)]; 4 4-chloro-2 2-methoxy-3-(1-methyl-1 H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1 ,3)-Diphenylcycloheptafan-3-ol [(024)]; 4 4-chloro-3-hydroxy-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa-2(4,6)-quinoline -1,4(1,3)-Diphenylcycloheptafan-2 2-one [(025)]; 4 4-chloro-3-hydroxyl-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa-2(4 ,6)-quinoline-1,4(1,3)-diphenylcycloheptafan-2 2-one [(026)]; 3-amino-4 4-chloro-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa-2( 4,6)-quinoline-1,4(1,3)-diphenylcycloheptafan-2 2-one [(027)]; 4 4-chloro-3-hydroxyl-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxo Hetero-2(4,6)-quinolin-1,4(1,3)-diphenylcycloheptan-2 2-one [(028)]; 4 4-chloro-2 1-cyclopropyl-3-hydroxyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa-2( 4,6)-quinoline-1,4(1,3)-diphenylcycloheptafan-2 2-one [(029)]; 3-amino-4 4-chloro-2 1-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa-2 (4,6)-Quinoline-1,4(1,3)-Diphenylcycloheptafan-2 2-one [(030)]; 4 4-chloro-3-hydroxyl-3-(4-methyl-4 H-1,2,4-triazol-3-yl)-2 1,2 2-dihydro-5-oxa-2( 4,6)-quinoline-1,4(1,3)-diphenylcycloheptafan-2 2-one [(031)]; 4 4-chloro-3-hydroxyl-2 1-(methyl-d 3)-3-(4-methyl-4 H-1,2,4-triazol-3-yl)-2 1,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptafan-2 2-one [(032)]; 4 4-Chloro-3-(methoxy-d3)-21-(methyl-d3)-3-(4-methyl-4H-1,2,4-triazol-3-yl) -21,22-Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2-one [(033)]; 3-amino-4 4-chloro-2 1-(methyl-d 3)-3-(4-methyl-4 H-1,2,4-triazol-3-yl)-2 1,2 2-Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2-one [(034)]; 3-amino-4 4-chloro-2 1-cyclopropyl-3-(4-methyl-4 H-1,2,4-triazol-3-yl)-2 1,2 2-dihydro -5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptafan-2 2-one [(035)]; 3-Hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-5-oxa-2 (4,6)-quinoline-1,4(1,3)-diphenylcycloheptafan-4 4-carbonitrile [(036)]; 3-amino-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-5-oxa- 2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptafan-4 4-carbonitrile [(037)]; 3-Hydroxy-2 1-methyl-3-(4-methyl-4 H-1,2,4-triazol-3-yl)-2 2-oxo-2 1,2 2-dihydro -5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptafan-4 4-carbonitrile [(038)]; 3-amino-21-methyl-3-(4-methyl-4 H-1,2,4-triazol-3-yl)-2 2-oxo-2 1,2 2-dihydro -5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptafan-4 4-carbonitrile [(039)]; 2 2-methoxy-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-di phencyclohexan-3-ol [(040)]; 3-Hydroxy-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-6-oxa-2(4,6)-quinoline-1,4( 1,3)-Diphenylcyclohexane-2 2-one [(041)]; 3-Hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-6-oxa-2(4,6)-quinone Phenyl-1,4(1,3)-diphenylcyclohexifane-2 2-one [(042)]; 4 4-chloro-2 2-methoxy-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1 ,3)-Diphenylcyclohexyl-3-ol [(043)]; 4 4-chloro-3-hydroxy-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-6-oxa-2(4,6)-quinoline -1,4(1,3)-Diphenylcyclohexane-2 2-one [(044)]; 4 4-chloro-3-hydroxyl-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-6-oxa-2(4 ,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one [(045)]; 3-amino-4 4-chloro-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-6-oxa-2( 4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one [(046)]; 3-amino-4 4-chloro-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-6- Oxa-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexyl-2 2-one [(047)]; 3-amino-4 4-chloro-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3 )-diphenylcyclohexane-2 2-carbonitrile [(048)]; 4 4-chloro-2 2-methoxy-3-(4-methyl-4 H-1,2,4-triazol-3-yl)-6-oxa-2(4,6)-quinone Phenyl-1,4(1,3)-diphenylcyclohexan-3-ol [(049)]; 4 4-chloro-2 1-methyl-3-(4-methyl-4 H-1,2,4-triazol-3-yl)-3-(methylamino)-2 1,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one [(050)]; 3-amino-4 4-chloro-2 1-methyl-3-(4-methyl-4 H-1,2,4-triazol-3-yl)-2 1,2 2-dihydro- 6-Oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one [(051)]; 4 4-bromo-2 2-methoxy-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1 ,3)-Diphenylcyclohexyl-3-ol [(052)]; 3-Hydroxy-2 2-methoxy-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1, 3)-Diphenylcyclohexane-4 4-carbonitrile [(053)]; 3-Hydroxy-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-6-oxa-2(4,6)- Quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(054)]; 3-Hydroxy-21-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-6- Oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(055)]; 3-amino-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro- 6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(056)]; 3-amino-21-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-6-oxa- 2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(057)]; 3-Amino-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclo Hexafan-2 2,4 4-dicarbonitrile [(058)]; 4 6-chloro-2 2-methoxy-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-4(3,5 )-pyridine-1(1,3)-benzcyclohexan-3-ol [(059)]; 3-Hydroxy-2 2-methoxy-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-4(3,5) -pyridine-1(1,3)-benzenecyclohexacene-4 6-carbonitrile [(060)]; 3-Hydroxy-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-22-oxo-2 1,2 2-dihydro-6- Oxa-2(4,6)-quinoline-4(3,5)-pyridine-1(1,3)-benzenecyclohexacene-4 6-carbonitrile [(061)]; 3-amino-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro- 6-oxa-2(4,6)-quinoline-4(3,5)-pyridine-1(1,3)-benzenecyclohexacene-4 6-carbonitrile [(062)]; 3-Hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-7-oxa-2(4,6)-quinone Phenyl-1,4(1,3)-Diphenylcycloheptafan-2 2-one [(063)]; 4 4-chloro-2 2-methoxy-3-(1-methyl-1 H-imidazol-5-yl)-7-oxa-2(4,6)-quinoline-1,4(1 ,3)-Diphenylcycloheptafan-3-ol [(064)]; 4 4-chloro-3-hydroxyl-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-7-oxa-2(4 ,6)-quinoline-1,4(1,3)-diphenylcycloheptafan-2 2-one [(065)]; 3-amino-3-(1-methyl-1 H-imidazol-5-yl)-2 2-morpholinyl-6-oxa-2(4,6)-quinoline-1,4(1 ,3)-Diphenylcyclohexane-4 4-carbonitrile [(066)]; 3-amino-3-(1-methyl-1 H-imidazol-5-yl)-2 2-(hexahydropyrazin-1-yl)-6-oxa-2(4,6)-quinolin Phenyl-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(067)]; 3-amino-3-(1-methyl-1 H-imidazol-5-yl)-2 2-(oxetan-3-ylamino)-6-oxa-2(4,6) -Quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(068)]; 3-amino-2 1-(2,3-dihydroxypropyl)-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2- Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(069)]; 3-Amino-3-(1-(methyl-d3)-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3 )-diphenylcyclohexane-2 2,4 4-dicarbonitrile [(070)]; 4 4-bromo-2 2-chloro-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3 )-Diphenylcyclohexyl-3-ol [(071)]; 3-Hydroxy-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl Fan-2 2,4 4-dicarbonitrile [(072)]; 4 4-cyano-3-hydroxy-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3 )-Diphenylcyclohexane-2 2-carboxamide [(073)]; 4 4-bromo-2 2-chloro-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3 )-Diphenylcyclohexan-3-amine [(074)]; 4 4-bromo-3-(1-methyl-1 H-imidazol-5-yl)-2 2-(oxetane-3-oxyl)-6-oxa-2(4,6)- Quinoline-1,4(1,3)-diphenylcyclohexan-3-amine [(075)]; 4 4-chloro-2 1-(methyl-d 3)-3-(5-methyl-1 H-imidazol-1-yl)-2 1,2 2-dihydro-6-oxa-2( 4,6)-quinolin-1,4(1,3)-diphenylcyclohexyl-2 2-one [(076)]; and 4 4-chloro-2 1-(methyl-d 3)-3-(4-methyl-1 H-imidazol-1-yl)-2 1,2 2-dihydro-6-oxa-2( 4,6)-quinolin-1,4(1,3)-diphenylcyclohexyl-2 2-one [(077)]; or a pharmaceutically acceptable form thereof.

[0177] In some embodiments, the compound is selected from: (R)-3-Hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-2( 4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(( , R , )-006) ]; (R)-3-amino-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-2 (4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(( , R , )-007) ]; (R)-3-amino-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-22-oxo-2 1,2 2- Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(( , R , )-008) ]; (R)-3-Amino-3-(1-methyl-1 H-imidazol-5-yl)-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl Fan-2 2,4 4-dicarbonitrile [(( , R , )-009) ]; and (R)-4 4-chloro-2 1-(methyl-d 3)-3-(4-methyl-1 H-imidazol-1-yl)-2 1,2 2-dihydro-6-oxo Hetero-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexan-2 2-one [(( , R , )-077) ]; or a pharmaceutically acceptable form thereof.

[0178] In some embodiments, the compound is selected from: (S)-4 4-chloro-3-hydroxyl-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-2(4, 6)-Quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one [(( , S , )-003) ]; (S)-3-amino-4 4-chloro-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-2(4 ,6)-quinolin-1,4(1,3)-diphenylcyclohexyl-2 2-one [(( , S , )-004) ]; (S)-4 4-chloro-3-hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa -2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexan-2 2-one [(( , S , )-014) ]; (S)-3-amino-4 4-chloro-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxo Hetero-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexan-2 2-one [(( , S , )-015) ]; (S)-3-Hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-5- Oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(( , S , )-018) ]; (S)-3-amino-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-5 -Oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(( , S , )-019) ]; (S)-3-amino-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile [(( , S , )-020) ]; (S)-3-Amino-3-(1-methyl-1 H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1,3) -Diphenylcyclohexane-2 2,4 4-dicarbonitrile [(( , S , )-021) ]; (S)-4 4-chloro-3-hydroxy-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa-2(4,6 )-quinoline-1,4(1,3)-diphenylcycloheptafan-2 2-one [(( , S , )-025) ]; (S)-3-amino-4 4-chloro-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxo Hetero-2(4,6)-quinolin-1,4(1,3)-diphenylcycloheptan-2 2-one [(( , S , )-027) ]; (S)-4 4-chloro-3-hydroxy-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro -5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptafan-2 2-one [(( , S , )-028) ]; (S)-4 4-chloro-2 1-cyclopropyl-3-hydroxyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxo Hetero-2(4,6)-quinolin-1,4(1,3)-diphenylcycloheptan-2 2-one [(( , S , )-029) ]; (S)-3-amino-4 4-chloro-2 1-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5- Oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2-one [(( , S , )-030) ]; (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-one [(( , S , )-034) ]; (S)-3-amino-4 4-chloro-2 1-cyclopropyl-3-(4-methyl-4 H-1,2,4-triazol-3-yl)-2 1,2 2-Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptan-2 2-one [(( , S , )-035) ]; (S)-3-Hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-5- Oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptafan-4 4-carbonitrile [(( , S , )-036) ]; (S)-3-amino-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-5 -Oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptafan-4 4-carbonitrile [(( , S , )-037) ]; (S)-3-amino-21-methyl-3-(4-methyl-4 H-1,2,4-triazol-3-yl)-2 2-oxo-2 1,2 2-Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptapan-4 4-carbonitrile [(( , S , )-039) ]; (S)-3-amino-4 4-chloro-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-6-oxo Hetero-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-2 2-one ( [( , S , )-046 ]); (S)-3-amino-4 4-chloro-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-di Hydrogen-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one ( [( , S , )-047 ]); (S)-3-amino-4 4-chloro-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4 (1,3)-Diphenylcyclohexane-2 2-carbonitrile ( [( , S , )-048 ]); (S)-3-amino-4 4-chloro-2 1-methyl-3-(4-methyl-4 H-1,2,4-triazol-3-yl)-2 1,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one ( [( , S , )-051 ]); (S)-3-Hydroxy-21-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-di Hydrogen-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile ( [( , S , )-051 ]); (S)-3-amino-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile ( [( , S , )-056 ]); (S)-3-Amino-21-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-6 -Oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile ( [( , S , )-057 ]); (S)-3-Amino-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3) -Diphenylcyclohexane-2 2,4 4-dicarbonitrile ( [( , S , )-058 ]); (S)-3-Amino-3-(1-methyl-1 H-imidazol-5-yl)-2 2-morpholinyl-6-oxa-2(4,6)-quinoline-1 ,4(1,3)-diphenylcyclohexane-4 4-carbonitrile ( [( , S , )-066 ]); (S)-3-amino-2 1-(2,3-dihydroxypropyl)-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1 ,2 2-dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile ( [( , S , )-069 ]); and (S)-3-Amino-3-(1-(methyl-d3)-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4 (1,3)-Diphenylcyclohexane-2 2,4 4-dicarbonitrile ( [( , S , )-070 ]); or a pharmaceutically acceptable form thereof.

[0179] In some embodiments, the compound is selected from: (R)-3-Hydroxy-3-(1-(methyl-d 3)-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4( 1,3)-Diphenylcyclohexane-2 2,4 4-dicarbonitrile ( [( , R , )-078 ]); (S)-3-Hydroxy-3-(1-(methyl-d 3)-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4( 1,3)-Diphenylcyclohexane-2 2,4 4-dicarbonitrile ( [( , S , )-078 ]); (R)-4 4-chloro-21-(methyl-d 3)-3-(5-methyl-1 H-1,2,4-triazol-1-yl)-2 1,2 2- Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one ( [( , R , )-079 ]); (S)-4 4-chloro-2 1-(methyl-d 3)-3-(5-methyl-1 H-1,2,4-triazol-1-yl)-2 1,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one ( [( , S , )-079 ]); (R)-4 4-chloro-2 1-(methyl-d 3)-3-(3-methyl-1 H-1,2,4-triazol-1-yl)-2 1,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one ( [( , R , )-080 ]); (S)-4 4-chloro-2 1-(methyl-d 3)-3-(3-methyl-1 H-1,2,4-triazol-1-yl)-2 1,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one ( [( , S , )-080 ]); 4 4-bromo-2 2-chloro-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3 )-Diphenylcyclohexane-3-ol (

[0081] ); 4 4-Bromo-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenyl ring Hexafan-2 2,3-diamine (

[0082] ); 4 4-Bromo-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-isoquinoline-1,4(1,3)-diphenyl Cyclohexafan-3-ol (

[0083] ); 4 4-Bromo-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinoline-1,4(1,3)-diphenyl Cyclohexafan-3-ol (

[0084] ); 3-Hydroxy-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinoline-1,4(1,3)-diphenylcyclo Hexafan-44-carbonitrile (

[0085] ); 3-Amino-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinoline-1,4(1,3)-diphenyl Cyclohexene-4 4-carbonitrile (

[0086] ); (R)-3-amino-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinoline-1,4(1,3 )-Diphenylcyclohexane-44-carbonitrile ( [( , R , )-086 ]); (S)-3-amino-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinoline-1,4(1,3 )-Diphenylcyclohexane-44-carbonitrile ( [( , S , )-086 ]); 4 4-bromo-2 7-methoxy-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(5,3)-quinoline-1,4(1 ,3)-Diphenylcyclohexyl-3-ol (

[0087] ); 3-Hydroxy-2 7-methoxy-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(5,3)-quinoline-1,4(1, 3)-Diphenylcyclohexane-4 4-carbonitrile (

[0088] ); (R)-3-amino-3-(1-methyl-1 H-imidazol-5-yl)-2 2-(oxetane-3-oxyl)-6-oxa-2(4 ,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile ( [( , R , )-089 ]); (S)-3-amino-3-(1-methyl-1 H-imidazol-5-yl)-2 2-(oxetane-3-oxyl)-6-oxa-2(4 ,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile ( [( , S , )-089 ]); (S)-3-(4-Methyl-1 H-imidazol-1-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl Fan-2 2,4 4-dicarbonitrile ( [( , S , )-090 ]); (R)-3-(4-methyl-1 H-imidazol-1-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl Fan-2 2,4 4-dicarbonitrile ( [( , R , )-090 ]); (S)-3-(5-Methyl-1 H-imidazol-1-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl Fan-2 2,4 4-dicarbonitrile ( [( , S , )-091 ]); (R)-3-(5-methyl-1 H-imidazol-1-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl Fan-2 2,4 4-dicarbonitrile ( [( , R , )-091 ]); (R)-3-amino-4 4-chloro-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-2(4 ,6)-quinolin-1,4(1,3)-diphenylcyclohexyl-2 2-one; [( , R , )-004 ] (S)-3-Hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-2( 4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile; [( , S , )-006 ] (S)-3-amino-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-2 (4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile; [( , S , )-007 ] (S)-3-amino-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-22-oxo-2 1,2 2- Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile; [( , S , )-008 ] (S)-3-Amino-3-(1-methyl-1 H-imidazol-5-yl)-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl Fan-2 2,4 4-dicarbonitrile; [( , S , )-009 ] (R)-4 4-chloro-3-hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa -2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexyl-2-2-one; [( , R , )-014 ] (R)-3-amino-4 4-chloro-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxo Hetero-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexifane-2 2-one; [( , R , )-015 ] (R)-3-Hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-5- Oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile; [( , R , )-018 ] (R)-3-amino-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-5 -oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile; [( , R , )-019 ] (R)-3-amino-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2 -Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile; [( , R , )-020 ] (R)-3-amino-3-(1-methyl-1 H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1,3) -Diphenylcyclohexane-2 2,4 4-dicarbonitrile; [( , R , )-021 ] (R)-4 4-chloro-3-hydroxy-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa-2(4,6 )-quinoline-1,4(1,3)-diphenylcyclohexane-2 2-one; [( , R , )-025 ] (R)-3-amino-4 4-chloro-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxo Hetero-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexifane-2 2-one; [( , R , )-027 ] (R)-4 4-chloro-3-hydroxy-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro -5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one; [( , R , )-028 ] (R)-4 4-chloro-2 1-cyclopropyl-3-hydroxy-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxo Hetero-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexifane-2 2-one; [( , R , )-029 ] ( R )-3-amino-4 4-chloro-2 1-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5- Oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one; [( , R , )-030 ] (R)-3-amino-4 4-chloro-2 1-(methyl-d 3)-3-(4-methyl-4 H-1,2,4-triazol-3-yl)- 2 1,2 2-dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one; [( , R , )-034 ] (R)-3-amino-4 4-chloro-2 1-cyclopropyl-3-(4-methyl-4 H-1,2,4-triazol-3-yl)-2 1,2 2-Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one; [( , R , )-035 ] (R)-3-Hydroxy-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-5- Oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile; [( , R , )-036 ] (R)-3-amino-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-5 -oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile; [( , R , )-037 ] (R)-3-amino-21-methyl-3-(4-methyl-4 H-1,2,4-triazol-3-yl)-2 2-oxo-2 1,2 2-Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile; [( , R , )-039 ] (R)-3-amino-4 4-chloro-2 1-methyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-6-oxo Hetero-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexifane-2 2-one; [( , R , )-046 ] (R)-3-amino-4 4-chloro-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-di Hydrogen-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexan-2 2-one; [( , R , )-047 ] (R)-3-amino-4 4-chloro-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4 (1,3)-Diphenylcyclohexane-2 2-carbonitrile; [( , R , )-048 ] (R)-3-amino-4 4-chloro-2 1-methyl-3-(4-methyl-4 H-1,2,4-triazol-3-yl)-2 1,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one; [( , R , )-051 ] (R)-3-Hydroxy-21-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-di Hydrogen-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile; [( , R , )-055 ] (R)-3-amino-2 1-(methyl-d 3)-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2 -Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile; [( , R , )-056 ] (R)-3-Amino-21-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-2 2-oxo-2 1,2 2-dihydro-6 -oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-4 4-carbonitrile; [( , R , )-057 ] (R)-3-amino-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3) -Diphenylcyclohexane-2 2,4 4-dicarbonitrile; [( , R , )-058 ] (R)-3-amino-3-(1-methyl-1 H-imidazol-5-yl)-2 2-morpholinyl-6-oxa-2(4,6)-quinoline-1 ,4(1,3)-Diphenylcyclohexane-4 4-carbonitrile; [( , R , )-066 ] (R)-3-Amino-3-(1-(methyl-d 3)-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4 (1,3)-Diphenylcyclohexane-2 2,4 4-dicarbonitrile; [( , R , )-070 ] (S)-4 4-chloro-2 1-(methyl-d 3)-3-(5-methyl-1 H-imidazol-1-yl)-2 1,2 2-dihydro-6-oxo Hetero-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexifane-2 2-ones; and [( , S , )-076 ] (S)-4 4-chloro-2 1-(methyl-d 3)-3-(4-methyl-1 H-imidazol-1-yl)-2 1,2 2-dihydro-6-oxo Hetero-2(4,6)-quinolin-1,4(1,3)-diphenylcyclohexifane-2 2-one; [( , S , )-077 ] or a pharmaceutically acceptable form thereof.

[0180] In some embodiments, the compound is selected from: 3-amino-4 4-chloro-21-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-5-oxa-2( 4,6)-quinolin-1,4(1,3)-diphenylcyclohexyl-2 2-one;

[0092] 4 4-chloro-2 1-cyclopropyl-3-hydroxyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-2(4,6)- Quinoline-1,4(1,3)-diphenylcyclohexane-2 2-one;

[0093] 4 4-chloro-2 1-cyclopropyl-3-hydroxyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-7-oxa-2( 4,6)-quinolin-1,4(1,3)-diphenylcyclohexyl-2 2-one;

[0094] 4 4-chloro-2 1-cyclopropyl-3-hydroxyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2-dihydro-6-oxa-2( 4,6)-quinolin-1,4(1,3)-diphenylcyclohexyl-2 2-one;

[0095] 4 4-chloro-2 1-cyclopropyl-3-((2-fluoroethyl)amino)-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2- Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one;

[0096] 4 4-chloro-2 1-cyclopropyl-3-((2-fluoroethyl)amino)-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2- Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one;

[0097] 4 4-chloro-2 1-cyclopropyl-3-((2-fluoroethyl)amino)-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2- Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexan-2 2-one;

[0098] 4 4-chloro-2 1-cyclopropyl-3-((2-fluoroethyl)amino)-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2- Dihydro-7-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one;

[0099] 4 4-chloro-2 1-cyclopropyl-3-((2-fluoroethyl)amino)-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2- Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one;

[0100] 4 4-chloro-3-((2-chloroethyl)amino)-2 1-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2- Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one;

[0101] 4 4-chloro-3-((2-chloroethyl)amino)-2 1-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2- Dihydro-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one;

[0102] 4 4-chloro-3-((2-chloroethyl)amino)-2 1-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2- Dihydro-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexan-2 2-one;

[0103] 4 4-chloro-3-((2-chloroethyl)amino)-2 1-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2- Dihydro-7-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one;

[0104] 4 4-chloro-3-((2-chloroethyl)amino)-2 1-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-2 1,2 2- Dihydro-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2 2-one;

[0105] 4 4-chloro-21-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-3-morpholinyl-2 1,2 2-dihydro-5-oxa-2 (4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2-2-one;

[0106] 4 4-chloro-2 1-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-3-morpholinyl-2 1,2 2-dihydro-5-oxa- 2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2-2-one;

[0107] 4 4-chloro-21-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-3-morpholinyl-2 1,2 2-dihydro-2(4,6) -quinoline-1,4(1,3)-diphenylcyclohexifane-2 2-one;

[0108] 4 4-chloro-2 1-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-3-morpholinyl-2 1,2 2-dihydro-7-oxa- 2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexyl-2-2-one;

[0109] 4 4-chloro-2 1-cyclopropyl-3-(1-methyl-1 H-imidazol-5-yl)-3-morpholinyl-2 1,2 2-dihydro-6-oxa- 2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane;

[0110] 4 4-Chloro-3-(1-methyl-1 H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenyl ring Hexafan-3-amine;

[0111] 4 4-Chloro-3-(1-methyl-1 H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenyl ring Hexafene-3-ol;

[0112] 4 4-Chloro-3-(1-methyl-1 H-imidazol-5-yl)-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexane-3- alcohol;

[0113] 4 4-Chloro-3-(1-methyl-1 H-imidazol-5-yl)-7-oxa-2(4,6)-quinoline-1,4(1,3)-diphenyl ring Hexafene-3-ol;

[0114] 4 4-Chloro-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenyl ring Hexafene-3-ol;

[0115] 4 4-Chloro-3-(1-methyl-1 H-imidazol-5-yl)-5-oxa-2(1,7)-isoquinoline-1,4(1,3)-diphenyl Cyclohexafan-3-amine;

[0116] 4 4-Chloro-3-(1-methyl-1 H-imidazol-5-yl)-5-oxa-2(1,7)-isoquinoline-1,4(1,3)-diphenyl Cyclohexafan-3-ol;

[0117] 4 4-Chloro-3-(1-methyl-1 H-imidazol-5-yl)-2(1,7)-isoquinoline-1,4(1,3)-diphenylcyclohexane-3 -alcohol;

[0118] 4 4-Chloro-3-(1-methyl-1 H-imidazol-5-yl)-7-oxa-2(1,7)-isoquinoline-1,4(1,3)-diphenyl Cyclohexafan-3-ol;

[0119] 4 4-Chloro-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinoline-1,4(1,3)-diphenyl Cyclohexafan-3-ol;

[0120] 4 4-Chloro-N-(2-fluoroethyl)-3-(1-methyl-1 H-imidazol-5-yl)-5-oxa-2(1,7)-isoquinoline-1 ,4(1,3)-Diphenylcyclohexan-3-amine;

[0121] 4 4-Chloro-N-(2-fluoroethyl)-3-(1-methyl-1 H-imidazol-5-yl)-5-oxa-2(1,7)-isoquinoline-1 ,4(1,3)-Diphenylcyclohexan-3-amine;

[0122] 4 4-Chloro-N-(2-fluoroethyl)-3-(1-methyl-1 H-imidazol-5-yl)-2(1,7)-isoquinoline-1,4(1, 3)-Diphenylcyclohexyl-3-amine;

[0123] 4 4-Chloro-N-(2-fluoroethyl)-3-(1-methyl-1 H-imidazol-5-yl)-7-oxa-2(1,7)-isoquinoline-1 ,4(1,3)-Diphenylcyclohexan-3-amine;

[0124] 4 4-Chloro-N-(2-fluoroethyl)-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinoline-1 ,4(1,3)-Diphenylcyclohexan-3-amine;

[0125] 4 4-Chloro-N-(2-chloroethyl)-3-(1-methyl-1 H-imidazol-5-yl)-5-oxa-2(1,7)-isoquinoline-1 ,4(1,3)-Diphenylcyclohexan-3-amine;

[0126] 4 4-Chloro-N-(2-chloroethyl)-3-(1-methyl-1 H-imidazol-5-yl)-5-oxa-2(1,7)-isoquinoline-1 ,4(1,3)-Diphenylcyclohexan-3-amine;

[0127] 4 4-Chloro-N-(2-chloroethyl)-3-(1-methyl-1 H-imidazol-5-yl)-2(1,7)-isoquinoline-1,4(1, 3)-Diphenylcyclohexyl-3-amine;

[0128] 4 4-Chloro-N-(2-chloroethyl)-3-(1-methyl-1 H-imidazol-5-yl)-7-oxa-2(1,7)-isoquinoline-1 ,4(1,3)-Diphenylcyclohexan-3-amine;

[0129] 4 4-Chloro-N-(2-chloroethyl)-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinoline-1 ,4(1,3)-Diphenylcyclohexan-3-amine;

[0130] 4 4-chloro-3-(1-methyl-1 H-imidazol-5-yl)-3-morpholinyl-5-oxa-2(1,7)-isoquinoline-1,4(1 ,3)-Diphenylcyclohexane;

[0131] 4 4-chloro-3-(1-methyl-1 H-imidazol-5-yl)-3-morpholinyl-5-oxa-2(1,7)-isoquinoline-1,4(1 ,3)-Diphenylcyclohexane;

[0132] 4-(4 4-chloro-3-(1-methyl-1 H-imidazol-5-yl)-2(1,7)-isoquinoline-1,4(1,3)-diphenylcyclohexyl Fan-3-yl)morpholine;

[0133] 4 4-chloro-3-(1-methyl-1 H-imidazol-5-yl)-3-morpholinyl-7-oxa-2(1,7)-isoquinoline-1,4(1 ,3)-Diphenylcyclohexane; and

[0134] 4 4-chloro-3-(1-methyl-1 H-imidazol-5-yl)-3-morpholinyl-6-oxa-2(1,7)-isoquinoline-1,4(1 ,3)-Diphenylcyclohexane;

[0135] Stereoisomers thereof, and pharmaceutically acceptable forms thereof. 5.2 [Pharmaceutical composition]

[0181] In some embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound having any of formula (I), formula (II), formula (III) or formula (IV) or Its pharmaceutically acceptable form (for example, its pharmaceutically acceptable salt, solvate, isomer or isotope), or formula (V) or formula (VI) compound, or its pharmaceutically acceptable acceptable form, and 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 formula (Ia), formula (Ib), formula (IIa), formula (IIb), formula (IIIa), formula ( IIIb), a compound of any one of formula (IVa) or formula (IVb), or a pharmaceutically acceptable form thereof, or a compound of formula (Va), formula (Vb), formula (VIa) or formula (VIb) ) compound, or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient. For example, in some embodiments, the pharmaceutical composition provided herein contains a therapeutically effective amount of , formula (IV-1) or any compound of the structure of 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 formula (III-3), formula (IIIa-3), formula (IIIb-3), formula (V-1), formula ( Va-1), formula (Vb-1), formula (VI-1), formula (VIa-1) or formula (VIb-1) compound, or its pharmaceutically acceptable form, and pharmaceutically acceptable carrier, diluent or excipient.

[0182] 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 Pharmaceutically acceptable forms can be formulated into suitable pharmaceutical preparations, such as solutions, suspensions, troches, dispersible lozenges, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile Solution or suspension for ophthalmic or parenteral administration, as well as transdermal patch formulations and dry powder inhalers. Generally, the compounds disclosed herein are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, eg, Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition, 1999).

[0183] Compositions can be formulated for single dose administration. To formulate the composition, the weight fraction of the compound disclosed herein is dissolved, suspended, dispersed or otherwise mixed in the selected vehicle at an effective concentration, so that the disease to be treated can be alleviated or improved. The pharmaceutical carriers or vehicles provided herein suitable for administering the compounds disclosed herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.

[0184] In addition, 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 Its pharmaceutically acceptable form can be formulated in a composition as the sole pharmaceutically active ingredient or can be combined with other therapeutically active ingredients.

[0185] 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 A pharmaceutically acceptable form is included in a pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect without undesired side effects in the patient being treated. Therapeutically effective concentrations can be determined empirically by testing the compounds in the in vitro and in vivo systems described herein and then extrapolating the doses for use in humans therefrom.

[0186] 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 A pharmaceutically acceptable form may be administered at one time, or may be divided into smaller doses administered at intervals. It is understood that the precise dosage and duration of treatment will vary with the disease being treated and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values ​​may also vary with the severity of the condition to be alleviated. It is further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges described herein are exemplary only and are not intended to be limiting. Claims the scope or practice of composition.

[0187] Accordingly, an effective concentration or amount of one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, is admixed with a suitable pharmaceutical carrier or vehicle for systemic, topical, or local administration. to form a pharmaceutical composition. Compounds are included in amounts effective to ameliorate one or more symptoms, or for treatment, delay of progression or prevention. The concentration of active compound in the composition will depend on the absorption, tissue distribution, metabolism, rate of excretion of the active compound, dosage schedule, amount administered, the particular formulation and other factors known to those skilled in the art.

[0188] Compositions are intended to be administered by a suitable route including, but not limited to, oral, parenteral, rectal, topical and topical. For oral administration, capsules and lozenges can be formulated. Compositions are in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.

[0189] Solutions or suspensions for parenteral, intradermal, subcutaneous or topical application may contain any of the following components: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerol , propylene glycol, dimethylacetamide, or other synthetic solvents; antimicrobials, such as benzyl alcohol and methylparaben; 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. The parenteral preparation can be enclosed in ampoules, pens, disposable syringes, or single- or multiple-dose vials made of glass, plastic, or other suitable material.

[0190] Provides pharmaceutical compositions for administration to humans and animals in unit dosage form, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and containing an appropriate amount of the compound or an oil-water emulsion of a pharmaceutically acceptable salt thereof. Pharmaceutically active compounds and salts thereof are formulated and administered in unit dosage form or in multiple dosage forms. Unit-dosage form as used herein refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit dosage forms include ampoules and syringes, and individually packaged tablets or capsules. Unit dosage forms may be administered in fractions or in multiples. Multiple dosage form is a plurality of the same unit dosage form packaged in a single container for administration in separate unit dosage forms. Examples of multiple dosage forms include vials, bottles of lozenges or capsules, or pint or gallon bottles. Thus, multiple dosage forms are multiple unit-doses that are not segregated in packaging.

[0191] Sustained release formulations may also be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds provided herein, such matrices being in the form of shaped articles, such as films or microcapsules. Examples of sustained release matrices include iontophoretic patches, polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactic acid, L-glutamic acid Copolymers with ethyl L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic-glycolic acid copolymers, such as LUPRON DEPOT™ (consisting of lactic-glycolic acid copolymer and leuprolide acetate injectable microspheres) and poly-D-(-)-3-hydroxybutyrate. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid are capable of releasing molecules for over 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 a loss of biological activity and possibly changing its structure. A reasonable stabilization strategy can be designed depending on the mechanism of action involved. For example, if the aggregation mechanism is found to be via sulfhydryl-disulfide exchange to form intermolecular S-S bonds, it may be possible to modify sulfhydryl residues, lyophilize from acidic solutions, control moisture content, use appropriate additives, and develop specific aggregates. material matrix composition to achieve stability.

[0192] Dosage forms or compositions can be prepared containing the active ingredient in the range of 0.001% to 100%, with non-toxic carriers making up the balance. For oral administration, pharmaceutically acceptable nontoxic compositions are formed by incorporating any of the commonly employed excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, Talc, cellulose derivatives, croscarmellose sodium, dextrose, 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 Protein, ethylene vinyl acetate, polyanhydride, polyglycolic acid, polyorthoester, polylactic acid, etc. Methods for preparing such 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%.

[0193] 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 Pharmaceutically acceptable forms can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a delayed release formulation or coatings.

[0194] The compositions may include other active compounds to obtain the desired combination of properties. The compounds provided herein, or their pharmaceutically acceptable salts as described herein, may also be valuable in the treatment of one or more of the above-mentioned diseases or medical conditions as known in the ordinary art (such as diseases associated with oxidative stress) with another pharmacological agent.

[0195] Oral pharmaceutical dosage forms can be solid, gel or liquid. Solid dosage forms are tablets, capsules, granules and bulk powders. Types of oral lozenges include compressed chewable lozenges and lozenges which may be enteric-coated, sugar-coated or film-coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in unfoamed or expanded form in combination with other ingredients known to those skilled in the art.

[0196] In certain embodiments, the formulations are solid dosage forms, such as capsules or lozenges. Tablets, pills, capsules, dragees and the like may contain any of the following ingredients or compounds of a similar nature: binders; diluents; disintegrants; lubricants; glidants; sweeteners; and flavoring agents.

[0197] Examples of binders include microcrystalline cellulose, tragacanth, dextrose solution, acacia mucilage, gelatin solution, sucrose, and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol, and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrants include croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose. Colorants include, for example, any of the approved certified water-soluble FD and C dyes, mixtures thereof; and water-insoluble FD and C dyes suspended on alumina hydrate. Sweeteners include sucrose, lactose, mannitol, and artificial sweeteners such as saccharin, as well as a variety of spray-dried flavors. Flavors include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds that produce a pleasant sensation, such as, but not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laurate. Enteric coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalate. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate.

[0198] When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds may also be administered as components of elixirs, suspensions, syrups, wafers, sprays, chewing gum, or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

[0199] Pharmaceutically acceptable carriers included in tablets are binders, lubricants, diluents, disintegrants, coloring agents, flavoring agents and wetting agents. Enteric-coated lozenges are resistant to gastric acid and dissolve or disintegrate in neutral or alkaline intestines due to the enteric coating. Sugar-coated lozenges are compressed lozenges to which different layers of pharmaceutically acceptable substances have been applied. Film-coated tablets are compressed tablets coated with a polymer or other suitable coating. Multiple compressed lozenges are compressed lozenges produced by more than one compression cycle using the previously mentioned pharmaceutically acceptable substances. Coloring agents can also be used in the above dosage forms. Flavoring and sweetening agents are used in compressed lozenges, sugar-coated lozenges, multiple compressed lozenges and chewable lozenges. Flavoring and sweetening agents are especially useful in the formation of chewable lozenges and lozenges.

[0200] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-foaming particles and effervescent formulations reconstituted from foaming particles. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

[0201] Elixirs are clear, sweetened hydroalcoholic preparations. Pharmaceutically acceptable carriers for elixirs include solvents. Syrups are concentrated aqueous solutions of sugar such as sucrose and may contain preservatives. An emulsion is a two-phase system in which one liquid is dispersed as globules in another liquid. Pharmaceutically acceptable carriers for emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non-effervescent granules intended to be reconstituted into liquid oral dosage forms include diluents, sweeteners and wetting agents. Pharmaceutically acceptable substances used in effervescent granules intended to be reconstituted into liquid oral dosage forms include organic acids and carbon dioxide sources. Coloring and flavoring agents can be used in all of the above dosage forms.

[0202] 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, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic additives include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Colorants 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.

[0203] 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 US Patent Nos. 4,328,245; 4,409,239; and 4,410,545. For liquid dosage forms, a solution, eg, in polyethylene glycol, can be diluted with sufficient pharmaceutically acceptable liquid carrier (eg, water) for easy measurement for administration.

[0204] Alternatively, liquid or semisolid oral formulations can be formulated by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (such as propylene carbonate), and other such carriers and dissolving them Solutions or suspensions are encapsulated in hard or soft gelatin capsule shells. Other useful formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene glycol (including, but not limited to, 1,2-dimethoxy Methane, 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 (where 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol) and one or more antioxidants (such as butylated hydroxytoluene (BHT), butyl Hydroxyanisole (BHA), Propyl Gallate, Vitamin E, Hydroquinone, Hydroxycoumarin, Ethanolamine, Lecithin, Cephalin, Ascorbic Acid, Malic Acid, Sorbitol, Phosphoric Acid, Thiodipropionic Acid and Its Esters and dithiocarbamate).

[0205] Other formulations include, but are not limited to, aqueous alcoholic solutions including 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, lower alkyl aldehyde bis(lower alkyl) acetals, such as acetaldehyde diethyl acetal.

[0206] In all embodiments, tablet and capsule formulations may be coated as known by those skilled in the art to regulate or maintain dissolution of the active ingredient. Thus, for example, they may be coated with customary enteric digestible coatings such as phenyl salicylate, waxes and cellulose acetate phthalate.

[0207] Also provided herein is parenteral administration, which is typically characterized by subcutaneous, intramuscular or intravenous injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, stabilizing agents, solubilizing agents and other such agents, such as sodium acetate, Sorbitan Monolaurate, Triethanolamine Oleate and Cyclodextrin. Also contemplated herein is the implantation of slow-release or sustained-release systems enabling maintenance of a constant level of dosage. Briefly, the compounds provided herein are dispersed in a solid internal matrix, for example, polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized Polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, Silicone carbonate copolymers, hydrophilic polymers (such as hydrogels of acrylic and methacrylic acid esters), collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate, the solid interior The matrix is ​​surrounded by an outer polymeric film, e.g., polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane , neoprene, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epoxy Chloropropane rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, the outer polymeric film is insoluble in body fluids. In a release rate controlling step, the compound diffuses across the outer polymeric membrane. The percentage of active compound contained in such parenteral compositions is highly dependent on its particular nature and activity of the compound and the needs of the individual.

[0208] Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administration. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products ready to be combined with a solvent immediately before use (such as lyophilized powders, including subcutaneous lozenges), sterile suspensions ready for injection solutions, sterile dry insoluble products and sterile emulsions to be combined with a vehicle immediately before use. Solutions can be aqueous or non-aqueous.

[0209] 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.

[0210] 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, emulsifying agents agent, chelating agent or chelating agent and other pharmaceutically acceptable substances.

[0211] Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents at bacteriostatic or fungistatic concentrations must be added to parenteral formulations packaged in multi-dose containers, including phenol or cresol, mercury, benzyl alcohol, chlorobutanol, methylparaben, and propylene glycol. esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Emulsifiers include Polysorbate 80 (TWEEN® 80). Sequestering or chelating agents for metal ions 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.

[0212] Injectables are designed for local and systemic administration. Typically, a therapeutically effective agent is formulated to contain the active compound at a concentration of at least about 0.1% w / w to about 90% w / w or higher, such as more than 1% w / w to the tissue being treated. The active ingredient may be administered at one time, or may be divided into smaller doses administered at intervals. It is understood that the precise dosage and duration of treatment will vary with the tissue being treated and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values ​​may also vary with the age of the individual treated. It is further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering or supervising the administration of the formulation, and that the concentration ranges described herein are exemplary only and are not intended to be limiting. The scope or practice of the claimed formulation.

[0213] 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 Pharmaceutically acceptable forms can be suspended in micronized form or other suitable form to produce a more soluble active product. The form of the resulting mixture will depend on a number of factors including the intended mode of administration and the solubility of the compound in the chosen carrier or vehicle. Effective concentrations are sufficient to ameliorate the symptoms of the disorder and can be determined empirically.

[0214] Topical mixtures are prepared as described for topical and systemic administration. The resulting mixture may be a solution, suspension, emulsion, or the like, and formulated as a cream, gel, ointment, lotion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, rinse, Sprays, suppositories, bandages, skin patches or any other formulations suitable for topical administration.

[0215] 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 Pharmaceutically acceptable forms, or pharmaceutical compositions comprising them, may be formulated for topical or topical application (such as in the form of gels, creams, and lotions to the skin and mucous membranes, such as in the eye), and with 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, may be formulated as 0.01% - 10% isotonic solutions containing appropriate salts at a pH of about 5-7.

[0216] Other routes of administration, such as transdermal patches and rectal administration, are also contemplated herein. Pharmaceutical dosage forms for rectal administration are, for example, rectal suppositories, capsules, and lozenges, for systemic effects. Rectal suppository as used herein means a solid for insertion into the rectum which melts or softens at body temperature to release one or more pharmacologically or therapeutically active ingredients. The pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and melting point raising agents. Examples of bases include cocoa butter (cocoa butter), glycerinated gelatin, carbowax (polyoxyethylene glycol) and suitable mixtures of mono-, diglycerides and triglycerides of fatty acids. Combinations of various substrates can be used. Agents to raise the melting point of suppositories include spermaceti and waxes. Rectal suppositories can be prepared by the compressed method or by moulding. An exemplary weight for a rectal suppository is about 2 to 3 grams. Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substances and by the same methods as formulations for oral administration.

[0217] 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 The pharmaceutically acceptable form, 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 set forth in the following U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; , No. 5,073,543, No. 5,639,476, No. 5,354,556, No. 5,639,480, No. 5,733,566, No. 5,739,108, No. 5,891,474, No. 5,922,356, No. 5,972,891, No. 5,980,945, No. 5 ,993,855, 6,045,830, 6,087,324 No. 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 No. 6,740,634, the U.S. Patents Each is incorporated herein by reference. Such dosage forms can use, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide the Slow or controlled release of compounds is revealed to provide desired release characteristics in varying proportions. Suitable controlled-release formulations known to those skilled in the art, including those described herein, can readily be selected for use with the active ingredients provided herein.

[0218] In certain embodiments, the compound of any one of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable form thereof, or formula (V) or formula The (VI) compound, or a pharmaceutically acceptable form thereof, can be administered using intravenous infusion, implantable osmotic pumps, transdermal patches, liposomes, 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, polymeric materials may be used. In another embodiment, the controlled release system can be placed near the therapeutic target, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, Vol. 2, pp. 115-138 ( 1984)).

[0219] 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 it packaged into an article containing packaging material for the treatment, prevention or amelioration of one or more symptoms of cancers dependent on farnesylated proteins or Advances in the compounds provided herein or pharmaceutically acceptable forms thereof and indications that the compounds or pharmaceutically acceptable forms thereof are useful in the treatment, prevention or amelioration of one or more of the cancers dependent on farnesylated proteins A label for a symptom or progression.

[0220] The articles of manufacture provided herein contain packaging materials. Packaging materials for packaging pharmaceutical products are well known to those skilled in the art. See, eg, US 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 suitable for the selected formulation and intended mode of administration and treatment Material. A wide variety of formulations of the compounds and compositions provided herein are contemplated herein.

[0221] In some embodiments, the article of manufacture is a kit. A kit may include a compound or pharmaceutical composition as described herein in suitable packaging, and may include written material such as instructions for use, discussions of clinical studies, lists of side effects, and the like. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results and / or summaries of such items and the like, which indicate or determine the activity and / or advantages of the pharmaceutical composition, and / or describe Administration, administration, side effects, drug interactions, or other information useful to healthcare providers. Such information may 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.

[0222] In some embodiments, the kit provides memory aids, for example in the form of numbers next to the lozenges or capsules, whereby the numbers correspond to the days in the regimen that the designated lozenges or capsules should be ingested. A "daily dose" may be a single tablet or capsule or several tablets or capsules to be taken on a given day.

[0223] Suitable packaging and additional articles for use (eg, measuring cups for liquid formulations, foil wraps to minimize exposure to air, and the like) are known in the art and can be included in the kit. In other embodiments, the kit can further comprise 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 may be provided, sold and / or promoted to health providers, including physicians, nurses, pharmacists, prescribing personnel, and the like. In some embodiments, kits may also be sold directly to consumers.

[0224] An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are becoming widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of preferably transparent plastic material. During the packaging process, grooves are formed in the plastic foil. The groove has the size and shape of the tablet or capsule to be packaged. Next, the tablet or capsule is placed in the groove, and a relatively hard sheet of material is sealed to the plastic foil at the side of the foil opposite to the direction in which the groove was formed. As a result, the lozenge or capsule is sealed in the groove between the plastic foil and the sheet. The strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the indentation, thereby creating an opening in the sheet at the indentation. The lozenge or capsule can then be removed through this opening.

[0225] The kit may further comprise a pharmaceutically acceptable vehicle useful for administering the active agent. For example, if the active agent is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active agent can be dissolved to form a formulation suitable for parenteral administration. It is administered as a particulate-free sterile solution. Examples of pharmaceutically acceptable vehicles include, but are not limited to: USP Water for Injection; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Chloride 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. [5.3] [Use and method] [5.3.1] [Therapeutic uses and methods]

[0226] RAS isoforms associate with the inner surface of the plasma membrane to transduce extracellular signals. To become active, RAS undergoes several post-translational modifications. The first step in activation is farnesylation of the cysteine ​​at the C-terminus of the CAAX box (where C represents cysteine, A represents an aliphatic amino acid, and X represents any amino acid). Rowinsky, E.K. et al., J. Clin. Oncol. 1999, 17, 3631-3652. Farnesyltransferase (FTase) recognizes the CAAX motif and transfers the 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, I.A. et al., J. Cell Sci. 2001, 114, 1603-1608. Further palmitoylation (presence of KRAS4A, NRAS and HRAS or a multi-domain (KRAS4B)) leads to anchoring of the protein in the plasma membrane. Hancock, J.F. et al., Cell 1990, 63, 133-139. Observations indicate that prenylation is required for the function of all RAS isoforms, including mutant forms thereof. However, some farnesylated proteins, including KRAS and NRAS, can be regenerated by alternative prenylation by geranylgeranyltransferase (GGTase) in the presence of farnesyltransferase inhibitors (FTIs). Freedom from membrane displacement. Zhang, F.L. et al., J. Biol. Chem. 1997, 272, 10232-10239; Whyte, D.B. et al., J. Biol. Chem. 1997, 272, 14459-14464. In contrast, the third family member, HRAS, is not a substrate for GGTase, and thus FTI impairs its membrane localization and cellular function. Whyte, D.B. et al. Therefore, the use of FTIs to target enriched patient populations of tumors (eg, tumors that depend on farnesylated proteins, such as HRAS, eg, tumors that carry HRAS mutations) should provide clinical benefit.

[0227] One specific FTI in clinical development is tipifarnib. The efficacy of tipifarnib was 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. Genome analysis revealed that 6% of HNSCC had HRAS mutations at the time of initial diagnosis (Hoadley, K.A. et al., Cell 2018, 173, 291-304), and 15% of patients were diagnosed after receiving cetuximab. HRAS mutations occur during resistance (Braig, F. et al., Oncotarget 2016, 7, 42988-42995) and have been shown to be associated with reduced response to cetuximab therapy in HNSCC patients. Rampias, T. et al., Clin. Cancer Res. 2014, 20, 2933-2946.

[0228] HRAS is also recurrently mutated in other cancer types, including urothelial cell carcinoma and salivary gland tumors, and 24% of patients with HRAS-mutant metastatic urothelial carcinoma treated with tipifarnib experienced an objective response. Furthermore, among 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 best response. Ho, A.L. et al., J. Clin. Oncol. 2020, 38, 6504. Other tumor types exhibiting recurrent HRAS driver mutations include lung squamous cell carcinoma, thyroid carcinoma, pheochromocytoma, and paraganglioma. Hoadley, K.A. et al.

[0229] In certain embodiments, a compound as disclosed herein is Formula (Ia), Formula (Ib), Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb), Formula (IVa), or Formula (IVb) compounds, for example compounds 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 is a farnesyl transferase inhibitor . In some embodiments, the compound as disclosed herein is Formula (III-3), Formula (IIIa-3), Formula (IIIb-3), Formula (Va), Formula (Vb), Formula (V-1) , a compound of formula (Va-1), formula (Vb-1), formula (VIa), formula (VIb), formula (VIa-1) or formula (VIb-1) or a pharmaceutically acceptable form thereof, which Inhibitor of farnesyl transferase. In certain embodiments, relative to inhibition of geranylgeranyltransferase type 1 (such as geranylgeranyltransferase type 1), a compound as disclosed herein, or a pharmaceutically acceptable equivalent thereof, The form is a selective farnesyl transferase inhibitor.

[0230] In some embodiments, provided herein is a method of inhibiting farnesyl transferase, comprising combining farnesyl transferase with an effective amount of formula (I), formula (II), formula (III) or formula (IV) The compound or its pharmaceutically acceptable form is contacted. In some embodiments, provided herein is a method of inhibiting farnesyl transferase, comprising combining farnesyl transferase with an effective amount of a compound of formula (V) or formula (VI) as disclosed herein, or a pharmaceutically acceptable compound thereof. Accepted Form Contact. In some embodiments, the compound is a compound of formula (Ia), formula (Ib), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb), such as Compounds 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. In some embodiments, the compound is formula (III-3), formula (IIIa-3), formula (IIIb-3), formula (Va), formula (Vb), formula (V-1), formula (Va- 1), a compound of formula (Vb-1), formula (VIa), formula (VIb), formula (VIa-1) or formula (VIb-1) or a pharmaceutically acceptable form thereof. In some embodiments, the method of inhibiting farnesyl transferase comprises contacting farnesyl transferase with an effective amount of a pharmaceutical composition as disclosed herein, the pharmaceutical composition comprising formula (I), formula (II), A compound of formula (III) or formula (IV) or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the method of inhibiting farnesyl transferase comprises contacting farnesyl transferase with an effective amount of a pharmaceutical composition as disclosed herein, the pharmaceutical composition 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), formula (Ib), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) , such as formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1) or formula (IV-2) compound, 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. In some embodiments, the pharmaceutical composition contains formula (III-3), formula (IIIa-3), formula (IIIb-3), formula (Va), formula (Vb), formula (V-1), formula ( A compound of Va-1), formula (Vb-1), formula (VIa), formula (VIb), formula (VIa-1) or formula (VIb-1), or a pharmaceutically acceptable form thereof. In some embodiments, the contacting of the farnesyl transferase occurs in a cell. In some embodiments, the farnesyl transferase is present in the cell. In some embodiments, the cells are in an individual. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are human cells. In some embodiments, the individual has a cancer that is dependent on a farnesylated protein. In some embodiments, the individual is a human.

[0231] In some embodiments, the method inhibits farnesylation of H-Ras protein. In some embodiments, the H-Ras protein has mutations. In some embodiments, the H-Ras protein is mutated to or comprises a modification in a codon encoding a corresponding mutant H-Ras protein selected from the group consisting of G12, G13, Q61, Q22, K117, A146, and Amino acid substitutions at specific positions in any combination. In some embodiments, 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 cells are in an individual. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are human cells. In some embodiments, the inhibition of farnesyltransferase present in the cell occurs in an individual with a cancer that is dependent on a farnesylated protein. In some embodiments, the farnesylated protein-dependent cancer is a solid tumor. In some embodiments, the farnesylated protein-dependent cancer is a cancer dependent on one or more farnesylated proteins. In some embodiments, the farnesylated protein-dependent cancer is dependent on the farnesylated protein for progression and / or survival of the cancer. In some embodiments, the farnesylated protein dependent cancer is a farnesylated H-Ras protein dependent cancer. In some embodiments, the farnesylated protein dependent cancer has a mutation in the H-Ras protein. In some embodiments, the H-Ras protein is mutated to or comprises a modification in a codon encoding a corresponding mutant H-Ras protein selected from the group consisting of G12, G13, Q61, Q22, K117, A146, and Amino acid substitutions at specific positions in any combination. In some embodiments, the farnesylated protein-dependent cancer is head and neck cancer. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, head and neck cancer (eg, HNSCC) is dependent on one or more farnesylated proteins, such as dependent on farnesylated H-Ras protein. In some embodiments, the head and neck cancer (eg, HNSCC) has a mutation in the H-Ras protein. In some embodiments, the farnesylated protein-dependent cancer is carcinoma, melanoma, sarcoma, or chronic granulomatous disease. For example, in some embodiments, the farnesylated protein-dependent cancer is thyroid cancer, head and neck cancer, urothelial cancer, salivary cancer, upper gastrointestinal cancer, bladder cancer, breast cancer, ovarian cancer, brain cancer, Cancer of the stomach, prostate, lung, colon, skin, liver, or pancreas. In some embodiments, the cancer is squamous cell carcinoma (SCC). For example, in some embodiments, the SCC is head and neck SCC (HNSCC), lung SCC (LSCC), thyroid SCC (TSCC), esophagus SCC (ESCC), bladder SCC (BSCC), or urothelial carcinoma (UC ). In some embodiments, the SCC is a HNSCC. In some embodiments, the SCC is a 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, HNSCC is dependent on one or more farnesylated proteins, such as dependent on farnesylated H-Ras protein. In some embodiments, the SCC (eg, HNSCC, lung SCC, thyroid SCC, esophageal SCC, bladder SCC, or urothelial carcinoma) has a mutation in the H-Ras protein. In some embodiments, HNSCC has a mutation in the H-Ras protein. In some embodiments, the individual is a human.

[0232] In some embodiments, the method inhibits farnesylation of N-Ras protein. In some embodiments, the N-Ras protein has mutations. In some embodiments, the N-Ras protein is mutated to or comprises a modification in a codon encoding a corresponding mutant N-Ras protein selected from the group consisting of G12, G13, Q61, Q22, K117, A146, and Amino acid substitutions at specific positions in any combination. In some embodiments, inhibition of farnesylation of an N-Ras protein, such as an N-Ras protein with a mutation, occurs in a cell. In some embodiments, the cells are in an individual. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are human cells. In some embodiments, inhibition of farnesyltransferase present in the cell occurs in an individual with a farnesylated protein-dependent cancer. In some embodiments, the farnesylated protein-dependent cancer is a solid tumor. In some embodiments, the farnesylated protein-dependent cancer is a cancer dependent on one or more farnesylated proteins. In some embodiments, the farnesylated protein-dependent cancer is dependent on the farnesylated protein for progression and / or survival of the cancer. In some embodiments, the farnesylated protein dependent cancer is a farnesylated N-Ras protein dependent cancer. In some embodiments, the farnesylated protein-dependent cancer has a mutation in the N-Ras protein. In some embodiments, the N-Ras protein is mutated to or comprises a modification in a codon encoding a corresponding mutant N-Ras protein selected from the group consisting of G12, G13, Q61, Q22, K117, A146 and Amino acid substitutions at specific positions in any combination thereof. In some embodiments, the farnesylated protein-dependent cancer is melanoma, acute myeloid leukemia (AML), thyroid cancer, lung adenocarcinoma, rectal cancer, endometrial cancer, or colorectal cancer. In some embodiments, melanoma, acute myelogenous leukemia (AML), thyroid cancer, lung adenocarcinoma, rectal cancer, en...

Claims

1. A compound of formula (III) or a pharmaceutically acceptable stereoisomer or tautomer thereof or a pharmaceutically acceptable salt and / or hydrate thereof, wherein: A3 is CR3 or N, where R3 is hydrogen; A4 is CR8, where R8 is hydrogen; A5 is CR8, where R8 is hydrogen; A6 is CR8 or N, where R8 is hydrogen; W1, W2, W3, and W4 are each CR4, where R4 is hydrogen; Y is a linker with a maximum length of 3 atoms, where Y is in the ZYW direction, and Y is -(CH2)1-3-, -O(CH2)1-2-, or -(CH2)1-2O-; Z1 is CR5, where R5 is hydrogen; Z2 is CR5, where R5 is hydrogen, a halogen, or CN; Z3 is N or CR5, where R5 is hydrogen; Z4 is CR5, where R5 is hydrogen. R2b is R9, -OR9, a halogroup, CN, -C(O)NR10R11, or -NR10R11, wherein R9 is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or 3-6-membered heterocyclic alkyl, and wherein R10 and R11 are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or 3-6-membered heterocyclic alkyl, or combined with their respective attached N to form a 3-6-membered heterocyclic alkyl; R6 is hydrogen, -OR9, or -NR10R11, wherein R9 is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or 3-6-membered heterocyclic alkyl, and wherein R10 and R11 are each independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or 3-6-membered heterocyclic alkyl, or combined with their respective attached N to form 3-6-membered heterocyclic alkyl; and R7 is imidazolyl or triazolyl, each of which is substituted by one or two R9 substituents as appropriate, wherein R9 is independently C1-6 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable stereoisomer or tautomer or a pharmaceutically acceptable salt and / or hydrate thereof, wherein the compound is a compound of formula (IIIa) or formula (IIIb): Formula (IIIa) Formula (IIIb) 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, wherein A3 is CR3 and R3 is hydrogen.

4. The compound of claim 1 or claim 2, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, wherein A6 is CR8 and R8 is hydrogen.

5. The compound of claim 1 or claim 2, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, wherein Z3 is N.

6. The compound of claim 1 or claim 2, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, wherein Z2 is CR5 and R5 is hydrogen.

7. The compound of claim 1 or claim 2, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, wherein Z2 is CR5, and R5 is a halogen or CN.

8. A compound of claim 1 or claim 2, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, wherein R2b is: (a) hydrogen, C1-3 alkyl, C3-4 cycloalkyl, C1-3 alkoxy, C3-4 cycloalkoxy, C3-4 heterocycloalkoxy, halogen, CN, -C(O)NR10R11 or -NR10R11; wherein R10 and R11, each in each occurrence, are independently hydrogen, C1-3 alkyl, 3-4-membered heterocycloalkyl, or combined with their respective attached N to form a 4-6-membered heterocycloalkyl; or (b) Hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, cyclopropyl, -OCH3, -OCD3, -OCH2CH3, -OCD2CD3, isopropoxy, cyclopropoxy, 3-oxacyclobutaneoxy, chlorine, CN, morpholino, hexahydropyrazinyl, 3-oxacyclobutaneamino or -C(O)NH2; or (c) -NH2.

9. The compound of claim 8 or a pharmaceutically acceptable stereoisomer or tautomer thereof or a pharmaceutically acceptable salt and / or hydrate thereof, wherein R2b is -OCH3.

10. The compound of claim 8 or a pharmaceutically acceptable stereoisomer or tautomer thereof or a pharmaceutically acceptable salt and / or hydrate thereof, wherein R2b is CN.

11. The compound of claim 1 or claim 2, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, 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-.

12. A compound of claim 1 or claim 2, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, wherein R7 is a C-linked imidazole group or a C-linked triazole group, wherein the C-linked imidazole group or the C-linked triazole group is substituted by one or two R9 substituents, wherein R9 is independently a C1-6 alkyl group.

13. A compound of claim 1 or claim 2, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, wherein R7 is an N-linked imidazole group or an N-linked triazole group, wherein the N-linked imidazole group or the N-linked triazole group is substituted by one or two R9 substituents, wherein R9 is independently a C1-6 alkyl group.

14. The compound of claim 1 or claim 2, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, wherein R7 is a methyl-substituted imidazolyl or a methyl-substituted triazolyl.

15. The compound of claim 14 or a pharmaceutically acceptable stereoisomer or tautomer or a pharmaceutically acceptable salt and / or hydrate thereof, wherein R7 is a C-methyl-substituted imidazolyl or a C-methyl-substituted triazolyl.

16. The compound of claim 14 or a pharmaceutically acceptable stereoisomer or tautomer or a pharmaceutically acceptable salt and / or hydrate thereof, wherein R7 is, , or.

17. The compound of claim 14 or a pharmaceutically acceptable stereoisomer or tautomer or a pharmaceutically acceptable salt and / or hydrate thereof, wherein R7 is an N-methyl-substituted imidazolyl or an N-methyl-substituted triazolyl.

18. The compound of claim 14 or a pharmaceutically acceptable stereoisomer or tautomer or a pharmaceutically acceptable salt and / or hydrate thereof, wherein R7 is, , , or.

19. A compound of claim 1 or claim 2, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, wherein R6 is hydrogen, -OR9, or -NR10R11, wherein R9 is hydrogen or a C1-3 alkyl, C3-6 cycloalkyl, or 3-4 member heterocyclic alkyl, and wherein R10 and R11 are each independently hydrogen, a C1-3 alkyl, a C1-3 haloalkyl, a C3-4 cycloalkyl, or a 3-6 member heterocyclic alkyl, or combined with the N to which they are attached to to form a 3-6 member heterocyclic alkyl.

20. A compound of claim 19 or a pharmaceutically acceptable stereoisomer or tautomer or a pharmaceutically acceptable salt and / or hydrate thereof, wherein R6 is hydrogen, hydroxyl, -OCH3, -OCD3, -NH2, -NHCH3, -NH(CH2CH2)Cl, -NH(CH2CH2)F or an N-linked morpholino group.

21. The compound of claim 19 or a pharmaceutically acceptable stereoisomer or tautomer or a pharmaceutically acceptable salt and / or hydrate thereof, wherein R6 is a hydroxyl group or -NH2.

22. The compound of claim 1 or a medically acceptable stereoisomer or tautomer or a medically acceptable salt and / or hydrate thereof, wherein the compound is of formula (III-1), (III-2) or (III-3): Formula (III-1) Formula (III-2) or (III-3).

23. The compound of claim 22 or a pharmaceutically acceptable stereoisomer or tautomer or a pharmaceutically acceptable salt and / or hydrate thereof, wherein the compound is: (a) a compound of formula (IIIa-1) or (IIIb-1): Formula (IIIa-1) Formula (IIIb-1); (b) a compound of formula (IIIa-2) or (IIIb-2): Formula (IIIa-2) Formula (IIIb-2); or (c) a compound of formula (IIIa-3) or (IIIb-3): Formula (IIIa-3) Formula (IIIb-3).

24. The compound of claim 22 or 23, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, wherein: Y is -(CH2)2-, -O(CH2)-, -O(CH2)2-, -(CH2)O-, or -(CH2)2O-; R2b is -OCH3, -OCD3, 3-oxetaneoxy, chlorine, CN, morpholino, hexahydropyrazinyl, 3-oxetanebutylamine, -C(O)NH2, or -NH2; R5 is hydrogen, chlorine, bromine, or CN; R6 is hydrogen, hydroxyl, -OCH3, -OCD3, -NH2, or -NHCH3; and R7 is a methyl-substituted imidazolyl or a methyl-substituted triazolyl.

25. The compound of claim 24 or a pharmaceutically acceptable stereoisomer or tautomer thereof or a pharmaceutically acceptable salt and / or hydrate thereof, wherein: R7 can be any of the following characters: 、、、、 or 、 ...

26. The compound of claim 24 or a pharmaceutically acceptable stereoisomer or tautomer thereof or a pharmaceutically acceptable salt and / or hydrate thereof, wherein: R7 is OR.

27. The compound of claim 22 or 23, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, wherein the compound is a compound of formula (III-1), formula (IIIa-1), or formula (IIIb-1), or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof.

28. The compound of claim 1 or claim 2, or its pharmaceutically acceptable stereoisomer or tautomer or its pharmaceutically acceptable salt and / or hydrate, wherein the pharmaceutically acceptable stereoisomer or tautomer or its pharmaceutically acceptable salt and / or hydrate does not include the salt form.

29. The compound of claim 1 or claim 2, or a pharmaceutically acceptable stereoisomer or tautomer or a pharmaceutically acceptable salt and / or hydrate thereof, wherein the compound is a racemic mixture, a mixture of non-mirror image isomers, or a mixture of stereoisomers, or a pharmaceutically acceptable stereoisomer or tautomer or a pharmaceutically acceptable salt and / or hydrate thereof.

30. The compound of claim 1 or claim 2, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, wherein the compound is a single mirror-image isomer or a single non-mirror-image isomer thereof, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof.

31. The compound of claim 1 or claim 2, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, wherein the compound is a single mirror-image isomer having an R6 / R7 substituted carbon atom in an (R) configuration, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof.

32. The compound of claim 1 or claim 2, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, wherein the compound is a single mirror-image isomer having an R6 / R7 substituted carbon atom in an (S) configuration, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof.

33. A pharmaceutical composition comprising a compound of any one of claims 1 to 32 or a pharmaceutically acceptable stereoisomer or tautomer thereof or a pharmaceutically acceptable salt and / or hydrate thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

34. A compound selected from the group consisting of: 3-hydroxy-22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-44-carboxynitrile; 3-amino-3-(1-methyl-1H-imidazol-5-yl)-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-22,44-dicarboxynitrile; 22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-3-ol; 4,4-Chloro-2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexano-3-ol; 3-hydroxy-2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexano-4,4-carboxynitrile; 3-amino-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexano-22,4,4-dicarboxynitrile; 4,4-Chloro-2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohepta-3-ol; 2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexa-3-ol; 4,4-Chloro-2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexa-3-ol; 3-Amino-4,4-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexano-22-carboxynitrile; 4,4-chloro-2,2-methoxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexano-3-ol; 4,4-bromo-2,2-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexano-3-ol; 3-Hydroxy-22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-44-carboxynitrile; 3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-22,44-dicarboxynitrile;46-Chloro-22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-4(3,5)-pyridine-1(1,3)-benzenecyclohexane-3-ol; 3-hydroxy-22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-4(3,5)-pyridine-1(1,3)-benzenecyclohexane-46-carboxynitrile; 44-Chloro-22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-7-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcycloheptafen-3-ol; 3-amino-3-(1-methyl-1H-imidazol-5-yl)-22-morpholino-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexano-44-carboxynitrile; 3-amino-3-(1-methyl-1H-imidazol-5-yl)-22-(hexahydropyrazin-1-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexano-44-carboxynitrile; 3-amino-3-(1-methyl-1H-imidazol-5-yl)-22-(oxacyclobut-3-ylamino)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexano-44-carboxynitrile; 3-Amino-3-(1-(methyl-d3)-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-22,44-dicarboxynitrile; 4,4-bromo-22-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-3-ol; 3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-22,44-dicarboxynitrile; 4,4-Cyano-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexano-22-methylamine; 4,4-bromo-22-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexano-3-amine; 4,4-bromo-3-(1-methyl-1H-imidazol-5-yl)-22-(oxacyclobut-3-oxy)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexano-3-amine; 3-Hydroxy-3-(1-(methyl-d3)-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-22,44-dicarboxynitrile; 4,4-bromo-22-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-3-ol;4,4-Bromo-3-(1-Methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-22,3-diamine; 3-amino-3-(1-methyl-1H-imidazol-5-yl)-22-(oxacyclobut-3-oxy)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-44-carboxynitrile; 3-(4-methyl-1H-imidazol-1-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-22,44-dicarboxynitrile; 3-(5-methyl-1H-imidazol-1-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-22,44-dicarboxynitrile; 4,4-chloro-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-3-amine; 4,4-chloro-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-3-ol; 4,4-chloro-3-(1-methyl-1H-imidazol-5-yl)-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexanoate-3-ol; 4,4-Chloro-3-(1-methyl-1H-imidazol-5-yl)-7-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexano-3-ol; and 4,4-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexano-3-ol; including its (R)- or (S)- mirror-image isomers or racemates; or pharmaceutically acceptable stereoisomers or tautomers thereof or their pharmaceutically acceptable salts and / or hydrates.

35. A pharmaceutical composition comprising a compound as claimed in claim 34, or a pharmaceutically acceptable stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and / or hydrate thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

36. The compound of claim 34 or a pharmaceutically acceptable stereoisomer or tautomer thereof or a pharmaceutically acceptable salt and / or hydrate thereof, wherein the compound is: 3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexano-22,44-dicarboxynitrile; or its (R)- or (S)- mirror isomer thereof.

37. A pharmaceutical composition comprising the compound of claim 36 or a pharmaceutically acceptable stereoisomer or tautomer thereof or a pharmaceutically acceptable salt and / or hydrate thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

38. The compound of claim 1 or a pharmaceutically acceptable stereoisomer or tautomer or a pharmaceutically acceptable salt and / or hydrate thereof, wherein the compound is: .

39. A pharmaceutical composition comprising the compound of claim 38 or a pharmaceutically acceptable stereoisomer or tautomer thereof or a pharmaceutically acceptable salt and / or hydrate thereof, and a pharmaceutically acceptable carrier, excipient or diluent.