GAS41 inhibitors and methods of use thereof

Abstract

Provided herein are small molecules that bind to GAS41 and inhibit GAS41 activity, and methods of using such molecules for the treatment of cancer.

Description

Detailed Description of the Invention

[0001] [Technical Field] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 050,303, filed July 10, 2020, the entire contents of which are hereby incorporated by reference in their entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with United States government support under CA240514 awarded by the National Institutes of Health. The United States government has certain rights in this invention.

[0003] Provided herein are small molecules that bind to and inhibit the activity of GAS41, and methods of using such molecules for the treatment of cancer.

[0004] [Background technology] Proteins that recognize post-transcriptional modifications on histone proteins play an important role in transcriptional regulation (Allis et al. Nat. Rev. Genet. 17, 487-500 (2016)). YEATS domain-containing proteins belong to a relatively newly discovered family of epigenetic reader proteins, including four human paralogs: ENL, YEATS2, AF9, and GAS41. Biochemical studies have revealed that YEATS domains bind to chromatin by recognizing histones with acetylated or crotonylated lysine side chains.

[0005] Glioma amplified sequence 41 (GAS41) is an emerging oncogene that is overexpressed in several cancers and has been implicated in these cancers. GAS41 amplification has been identified in brain tumor patients, including 23% of glioblastomas and 80% of astrocytomas (Fischer et al., Hum. Genet. 98, 625-628 (1996), Fischer et al., Hum. Mol. Genet. 6, 1817-1822 (1997)). GAS41 is also frequently amplified in sarcomas (Italiano et al. Int. J. Cancer 122, 2233-2241 (2008), Barretina et al. Nat. Genet. 42, 715-721 (2010)), colorectal cancer (Tao et al. Am. J. Transl. Res. 7, 616-623 (2015)), lung cancer (Pikor et al. Cancer Res 73, 7301-7312 (2013), Hsu et al. Genes Dev 32, 58-69 (2018)), and gastric cancer (Kiuchi et al. Am J Cancer Res 8, 2436-2452 (2018)). For example, analysis of lung cancer samples confirmed amplification and overexpression of the GAS41 gene in 20% of non-small cell lung cancer cells compared with matched normal tissues (Pikor 2013). GAS41 overexpression was also detected in NSCLC but not in "normal" lung epithelial and fibroblast cell lines (Hsu 2018). Knockdown of GAS41 in a panel of GAS41-amplified NSCLC cell lines significantly reduced cell growth and colony formation (Pikor 2013, Hsu 2018). Furthermore, GAS41 binds to the promoter regions of actively transcribed genes, which are enriched in H3K27ac, suggesting that recognition of acetylated H3 is required for chromatin binding and GAS41 oncogenic activity (Hsu et al. Genes Dev 32, 58-69 (2018)).

[0006] Summary of the Invention Provided herein are small molecules that bind to GAS41 and inhibit GAS41 activity, and methods of using such molecules for the treatment of cancer.

[0007] In one aspect, the present disclosure provides a compound of formula (I):

[0008] [ka]

[0009] or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxy, acyl, amido, cyano, sulfonyl, and hydrogen; X is —C(O)—, —C(S)—, —CH—, —SO—, or absent; Y is -NR a - or -O-, R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl, and aminoalkyl, or R a is that R a and the nitrogen atom to which they are bonded form a fused ring with A, or R a and R 1 together with the atoms to which they are attached form an optionally substituted heterocyclic ring; Z is absent or -CR b R c - and R b and R c are each independently selected from hydrogen and alkyl; A is a 5-membered heteroaryl; Q is a 4-, 5-, or 6-membered heterocyclyl; R 2 is selected from hydrogen, halo, alkyl, amino and hydroxy; R 3 is hydrogen, halo, -OR d , -NR e R f , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl and groups of the formula:

[0010] [ka]

[0011] wherein B is aryl or heteroaryl; J is absent or is —CH—, —O—, —S—, or —NH—; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; and R g and R h are each independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl; Alternatively, R 2 and R 3 together with the carbon atom(s) to which they are attached form a ring selected from aryl, heteroaryl, cycloalkyl, and heterocycle, or R 2 and R 3 together with the carbon atom to which they are attached form an alkenyl group, R d , R e and R fare each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; each alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl independently is optionally substituted with 1, 2, 3, 4, or 5 substituents; However, Z is -CR b R c -When R 1 is not cycloalkyl.

[0012] In some embodiments, R 1 is selected from heterocyclyl, alkyl, and aryl. In some embodiments, R 1 is a monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, R 1 is pyrrolidinyl.

[0013] In some embodiments, X is -C(O)-. In some embodiments, Y is -NR a - and R a is hydrogen. In some embodiments, Z is absent.

[0014] In some embodiments, A is a 5-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, A is selected from thiophene and thiazole. In some embodiments, A is thiophene.

[0015] In some embodiments, Q is selected from azetidine, pyrrolidine, and piperidine. In some embodiments, Q is azetidine.

[0016] In some embodiments, R 2 is hydrogen.

[0017] In some embodiments, R 3 is a group of the formula:

[0018] [ka]

[0019] In some embodiments, B is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N and S; J is not present; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0 or 1; n is 0, 1, 2, or 3; and R g is C1-C6 alkyl, and each R h is independently selected from alkyl, halo, haloalkyl, amino, aminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, acyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl.

[0020] In some embodiments,

[0021] [ka]

[0022] The base is,

[0023] [ka]

[0024] having a formula selected from In the formula, R x , R y and R z are each independently -OR v, aryl, and heteroaryl; R v is selected from C1-C6 alkyl, aryl and heteroaryl.

[0025] In some embodiments, the compound has the following formula (Ia):

[0026] [ka]

[0027] In some embodiments, the compounds of the present invention have the following formula (Ib):

[0028] [ka]

[0029] In some embodiments, the compounds of the present invention have the following formula (Ic):

[0030] [ka]

[0031] During the ceremony, n is 0, 1, 2 or 3; Each R h is independently selected from C-C alkyl, halo, halo-C-C alkyl, amino, amino-C-C alkyl, hydroxy, hydroxy-C-C alkyl, C-C alkoxy, amido, amido-C-C alkyl, acyl, aryl, aryl-C-C alkyl, heteroaryl, heteroaryl-C-C alkyl, heterocyclyl, heterocyclyl-C-C alkyl, cycloalkyl, and cycloalkyl-C-C alkyl.

[0032] In some embodiments, at least one R h is -(CH2) r C(O)NRi R j or -(CH2) s NR k C(O)R m wherein: r and s are each independently selected from 0, 1, and 2; R i and R k are each independently selected from hydrogen and C1-C6 alkyl; R j is selected from C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, cycloalkyl, and cycloalkyl-C1-C6 alkyl; R m is selected from C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, cycloalkyl and cycloalkyl-C1-C6 alkyl, amino, C1-C6 alkylamino, arylamino, and aryl-C1-C6 alkylamino; Each alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is independently unsubstituted or substituted with one or two substituents independently selected from halo, C1-C6 alkyl, C1-C6-alkoxy, hydroxy, amino and oxo.

[0033] In some embodiments, the compound of the present invention is selected from the group consisting of the compounds shown in Table 1, or a pharmaceutically acceptable salt thereof.

[0034] In another aspect, the present disclosure provides a compound of formula (IIa):

[0035] [ka]

[0036] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 1’ are each independently selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxy, acyl, amido, cyano, sulfonyl, and hydrogen; X and X' are each independently selected from absent, -C(O)-, -C(S)-, -CH2-, and -SO2-; Y and Y' each independently represent -NR a - or -O-, R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl, and aminoalkyl, or R a is that R a and the nitrogen atom to which they are bonded form a fused ring with A, or R a and R 1 together with the atoms to which they are attached form an optionally substituted heterocyclic ring; Z and Z' are each independently absent or -CR b R c - and R b and R c are each independently selected from hydrogen and alkyl; A and A' are each independently a 5-membered heteroaryl ring; Q and Q' are each independently a 4-, 5-, or 6-membered heterocycle; R 2 and R 2 each ' is independently selected from hydrogen, halo, alkyl, amino, and hydroxy; R 3 and R 3each ' is independently selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, and a group of the formula:

[0037] [ka]

[0038] wherein B is aryl or heteroaryl; J is absent or is —CH—, —O—, —S—, or —NH—; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and R g and R h are each independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl; R d , R e and R f are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; L is a linker, Each alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl is independently optionally substituted with 1, 2, 3, 4, or 5 substituents.

[0039] In some embodiments, R 1 and R 1 ' is the same as R 2 and R 2 ' is the same as R 3 and R 3 In some embodiments, R' is the same, X and X' are the same, Y and Y' are the same, Z and Z' are the same, A and A' are the same, and Q and Q' are the same. 1 and R 1 Each R' is a 4- or 5-membered monocyclic heterocyclyl. 1 and R 1 ' is pyrrolidine.

[0040] In some embodiments, X and X' are -C(O)-. In some embodiments, Y and Y' are -NR a - and R a is hydrogen. In some embodiments, Z and Z' are each absent.

[0041] In some embodiments, A and A' are thiophene or thiazole.

[0042] In some embodiments, Q and Q' are selected from azetidine and pyrrolidine.

[0043] In some embodiments, R 2 and R 2 ' is hydrogen.

[0044] In some embodiments, R 3 and R 3’ is selected from aryl, heteroaryl and groups of the formula:

[0045] [ka]

[0046] In some embodiments, R3 and R 3’ are groups of the formula:

[0047] [ka]

[0048] wherein B is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N, S, or O; J is absent; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0 or 1; and R g is C1-C6 alkyl, n is 0, 1 or 2, and each R h is independently selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, amino, amino-C1-C6 alkyl, amido-C1-C6 alkyl, and heterocyclyl.

[0049] In some embodiments, L is a linker comprising one or more groups independently selected from methylene (-CH-), vinylene (-CH=CH-), acetylene (-C≡C-), ether (-O-), amine (-NH-), alkylamine (-NR-, where R is an optionally substituted C-C alkyl group), amide (-C(O)NH-), ester (-C(O)O-), carbamate (-OC(O)NH-), sulfonamide (-S(O)NH-), phenylene (-CH-), heteroarylene, heterocyclylene, and any combination thereof. In some embodiments, L is

[0050] [ka] JPEG0007758369000014.jpg75169

[0051] It is selected from wherein a, a1, and a2 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; b, b1, and b2 are each independently selected from 0, 1, 2, 3, 4, 5, and 6; c, c1, and c2 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; d and e are each independently selected from 0, 1, and 2; each G is independently selected from CH and N; and X 1 and X 2 each independently represents O or -NR x and the R x is hydrogen or optionally substituted alkyl, and Y 1 and Z 1 are each independently selected from —CH—, —NH—, and —O—.

[0052] In some embodiments, the compound of the present invention is selected from the group consisting of the compounds shown in Table 2 or a pharmaceutically acceptable salt thereof.

[0053] In another aspect, the present disclosure provides a compound of formula (IIb):

[0054] [ka]

[0055] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 1’ are each independently selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, and alkynyl; X and X' are each independently selected from absent, -C(O)-, -C(S)-, -CH2-, and -SO2-; Y and Y' each independently represent -NR a - or -O-; R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl, and aminoalkyl, or R a is that R a and together with the nitrogen atom bonded to form a condensed ring with A, Z and Z' are each independently absent or -CR b R c - and R b and R c are each independently selected from hydrogen and alkyl; A and A' are each independently a 5-membered heteroaryl ring; Q and Q' are each independently a 4-, 5-, or 6-membered heterocyclyl; R 2 and R 2 each ' is independently selected from hydrogen, halo, alkyl, amino, and hydroxy; R 3 and R 3 ' are each independently hydrogen, halo, -OR d , -NR e R f , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl and groups of the formula:

[0056] [ka]

[0057] wherein B is aryl or heteroaryl; J is absent or is —CH—, —O—, —S—, or —NH—; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and R g and R hare each independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl; Alternatively, R 2 and R 3 together with the carbon atom(s) to which they are attached form a ring selected from aryl, heteroaryl, cycloalkyl, and heterocycle, or R 2 and R 3 together with the carbon atom to which they are attached form an alkenyl group, R d , R e and R f are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; L is a linker, Each alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl is independently optionally substituted with 1, 2, 3, 4, or 5 substituents.

[0058] In some embodiments, R 1 and R 1 ' is the same as R 2 and R 2 ' is the same as R 3 and R 3In some embodiments, R' is the same, X and X' are the same, Y and Y' are the same, Z and Z' are the same, A and A' are the same, and Q and Q' are the same. 1 and R 1 Each R' is a 4- or 5-membered monocyclic heterocyclyl. 1 and R 1 ' is pyrrolidine.

[0059] In some embodiments, X and X' are -C(O)-. In some embodiments, Y and Y' are -NR a - and R a is hydrogen. In some embodiments, Z and Z' are each absent.

[0060] In some embodiments, A and A' are thiophene or thiazole.

[0061] In some embodiments, Q and Q' are selected from azetidine and pyrrolidine.

[0062] In some embodiments, R 2 and R 2 ' is hydrogen.

[0063] In some embodiments, R 3 and R 3’ is selected from hydrogen, aryl, heteroaryl and groups of the formula:

[0064] [ka]

[0065] In some embodiments, R 3 and R 3’ is selected from monocyclic and bicyclic heteroaryls having 1, 2 or 3 heteroatoms independently selected from N and S.

[0066] In some embodiments, R 3 and R 3’ are groups of the formula:

[0067] [ka]

[0068] wherein B is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N and S; J is absent; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0 or 1; and R g is C1-C6 alkyl, n is 0, 1 or 2, and each R h is independently selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, amino, amino-C1-C6 alkyl, amido-C1-C6 alkyl, and heterocyclyl.

[0069] In some embodiments, L is a linker comprising one or more groups independently selected from methylene (-CH-), vinylene (-CH=CH-), acetylene (-C≡C-), ether (-O-), amine (-NH-), alkylamine (-NR-, where R is an optionally substituted C-C alkyl group), amide (-C(O)NH-), ester (-C(O)O-), carbamate (-OC(O)NH-), sulfonamide (-S(O)NH-), phenylene (-CH-), heteroarylene, heterocyclylene, and any combination thereof. In some embodiments, L is

[0070] [ka] JPEG0007758369000020.jpg75169

[0071] It is selected from wherein a, a1, and a2 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; b, b1, and b2 are each independently selected from 0, 1, 2, 3, 4, 5, and 6; c, c1, and c2 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; d and e are each independently selected from 0, 1, and 2; each G is independently selected from CH and N; and X 1 and X 2 each independently represents O or -NR x and the R x is hydrogen or optionally substituted alkyl, and Y 1 and Z 1 are each independently selected from —CH—, —NH—, and —O—.

[0072] In some embodiments, the compound of the present invention is selected from the group consisting of the compounds shown in Table 2 or a pharmaceutically acceptable salt thereof.

[0073] In another aspect, the present disclosure provides a compound of formula (IIc):

[0074] [ka]

[0075] or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxy, acyl, amido, cyano, sulfonyl, and hydrogen; R 1’is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, and alkynyl; X and X' are each independently selected from absent, -C(O)-, -C(S)-, -CH2-, and -SO2-; Y and Y' each independently represent -NR a - or -O-; R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl, and aminoalkyl, or R a is that R a and the nitrogen atom to which they are bonded form a fused ring with A, or R a and R 1 together with the atoms to which they are attached form an optionally substituted heterocyclic ring; Z and Z' are each independently absent or -CR b R c - and R b and R c are each independently selected from hydrogen and alkyl; A and A' are each independently a 5-membered heteroaryl ring; Q and Q' are each independently a 4-, 5-, or 6-membered heterocycle; R 2 and R 2 each ' is independently selected from hydrogen, halo, alkyl, amino, and hydroxy; R 3 is selected from aryl, heteroaryl, heterocyclyl and groups of the formula:

[0076] [ka]

[0077] wherein B is aryl or heteroaryl; J is absent or is —CH—, —O—, —S—, or —NH—; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and R g and R h are each independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl; R 3 ' is hydrogen, halo, -OR d’ , -NR e’ R f’ , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl and groups of the formula:

[0078] [ka]

[0079] wherein B' is aryl or heteroaryl; J' is absent or is -CH2-, -O-, -S-, or -NH-; C' is selected from aryl, heteroaryl, and heterocyclyl; m' is 0, 1, 2, 3, or 4; n' is 0, 1, 2, 3, or 4; and R g’ and R h’are each independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl; R d’ , R e’ and R f’ are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; L is a linker, Each alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl is independently optionally substituted with 1, 2, 3, 4, or 5 substituents.

[0080] In some embodiments, R 1 and R 1 ' is the same as R 2 and R 2 ' is the same as R 3 and R 3 In some embodiments, R' is the same, X and X' are the same, Y and Y' are the same, Z and Z' are the same, A and A' are the same, and Q and Q' are the same. 1 and R 1 Each R' is a 4- or 5-membered monocyclic heterocyclyl. 1 and R 1 ' is pyrrolidine.

[0081] In some embodiments, X and X' are -C(O)-. In some embodiments, Y and Y' are -NR a - and R a is hydrogen. In some embodiments, Z and Z' are each absent.

[0082] In some embodiments, A and A' are thiophene.

[0083] In some embodiments, Q and Q' are selected from azetidine and pyrrolidine.

[0084] In some embodiments, R 2 and R 2 ' is hydrogen.

[0085] In some embodiments, R 3 is selected from aryl, heteroaryl and groups of the formula:

[0086] [ka]

[0087] In some embodiments, R 3 is a group of the formula:

[0088] [ka]

[0089] wherein B is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N and S; J is absent; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0 or 1; and R g is C1-C6 alkyl, n is 0, 1 or 2, and each R his independently selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, amino, amino-C1-C6 alkyl, amido-C1-C6 alkyl, and heterocyclyl.

[0090] In some embodiments, R 3’ is selected from hydrogen, aryl, heteroaryl and groups of the formula:

[0091] [ka]

[0092] In some embodiments, R 3’ is selected from monocyclic and bicyclic heteroaryls having 1, 2 or 3 heteroatoms independently selected from N and S.

[0093] In some embodiments, R 3’ is a group of the formula:

[0094] [ka]

[0095] wherein B' is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N and S; J' is absent; C' is selected from aryl, heteroaryl, and heterocyclyl; m' is 0 or 1; and R g’ is C1-C6 alkyl, n' is 0, 1 or 2, and each R h’ is independently selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, amino, amino-C1-C6 alkyl, amido-C1-C6 alkyl, and heterocyclyl.

[0096] In some embodiments, L is a linker comprising one or more groups independently selected from methylene (-CH-), vinylene (-CH=CH-), acetylene (-C≡C-), ether (-O-), amine (-NH-), alkylamine (-NR-, where R is an optionally substituted C-C alkyl group), amide (-C(O)NH-), ester (-C(O)O-), carbamate (-OC(O)NH-), sulfonamide (-S(O)NH-), phenylene (-CH-), heteroarylene, heterocyclylene, and any combination thereof. In some embodiments, L is

[0097] [ka] JPEG0007758369000029.jpg75169

[0098] It is selected from wherein a, a1, and a2 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; b, b1, and b2 are each independently selected from 0, 1, 2, 3, 4, 5, and 6; c, c1, and c2 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; d and e are each independently selected from 0, 1, and 2; each G is independently selected from CH and N; and X 1 and X 2 each independently represents O or -NR x and the R x is hydrogen or optionally substituted alkyl, and Y 1 and Z 1 are each independently selected from —CH—, —NH—, and —O—.

[0099] In one aspect, the disclosure provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for parenteral administration.

[0100] In one aspect, the disclosure provides a method of inhibiting GAS41 activity in a sample, the method comprising contacting the sample with an effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of Formula (I), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof).

[0101] In one aspect, the disclosure provides a method of reducing the proliferation of cancer cells in a sample, the method comprising contacting the sample with an effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of Formula (I), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof). In some embodiments, the cancer cells are selected from cells of a brain tumor (e.g., glioblastoma or astrocytoma), a sarcoma, a colorectal cancer, a lung cancer (e.g., non-small cell lung cancer), and a gastric cancer.

[0102] In one aspect, the disclosure provides a method of treating cancer in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of Formula (I), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof). In some embodiments, the cancer is selected from brain tumors (e.g., glioblastoma or astrocytoma), sarcoma, colorectal cancer, lung cancer (e.g., non-small cell lung cancer), and gastric cancer. In some embodiments, the method further comprises administering an additional chemotherapeutic agent to the subject. In some embodiments, the subject is human.

[0103] In one aspect, the present disclosure provides for the use of a compound disclosed herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of Formula (I), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof), in the treatment of cancer.

[0104] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the crystal structure of a compound disclosed herein (compound 85) in complex with the GAS41 YEATS domain. Figure 2, A-C, shows data on the activity of compounds disclosed herein. A) Results of a dimerization assay to determine GAS41 YEATS domain dimerization induced by bivalent inhibitors, as described in Example 6. B) Results of a dimerization assay to determine the dimerization of GAS41 YEATS domain induced by bivalent inhibitors, as described in Example 6. 15 N-labeled GAS41 YEATS domain (black) and in the presence of 60 μM compound 85 (red). 1 H- 15 C) 60 μM N HSQC spectrum in the presence of 30 μM compound 223. 15 N-labeled GAS41 YEATS domain1 H- 15 N HSQC spectrum (red). Figure 3 shows the activity of compound 221 in the NanoBiT assay after 24 hours of treatment in 293T cells co-transfected with SmBiT-H3.3 and LgBiT-GAS41-WT or W93A mutant, as described in Example 7. [Figure 4A] Shows the intracellular activity of certain compounds, as described in Example 8. Inhibition of cell proliferation of H1299 cells by Compound 221 and Compound 88. [Figure 4B] Shows the intracellular activity of certain compounds, as described in Example 8. Inhibition of growth by compound 221 in A549 or A549-KO cells. [Figure 4C] Shows the intracellular activity of certain compounds, as described in Example 8. Inhibition of growth in H1299 or H1993 cells by compound 221. Figure 4D shows the intracellular activity of certain compounds as described in Example 8. Relative mRNA levels of E2F2, FOXM1, and MCM6 in H1299 cells after 7 days of treatment with compound 221.

[0105] [Mode for Carrying Out the Invention] definition Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the embodiments described herein, certain preferred methods, compositions, devices, and materials are described herein. However, before describing the materials and methods of the present invention, it should be understood that this invention is not limited to the particular molecules, compositions, methods, or protocols described herein, as these may vary according to routine experimentation and optimization. It should also be understood that the terminology used herein is for the purpose of describing particular aspects or embodiments only, and is not intended to limit the scope of the embodiments described herein.

[0106] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. However, in case of conflict, the present specification, including definitions, will control. Therefore, in the context of the embodiments described herein, the following definitions apply:

[0107] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "GAS41 inhibitor" is a reference to one or more GAS41 inhibitors, and so forth.

[0108] As used herein, the term "comprising" and its linguistic variations indicate the presence of the recited feature(s), element(s), method step(s), etc., without excluding the presence of additional feature(s), element(s), method step(s), etc. In contrast, the term "consisting of" and its linguistic variations indicate the presence of the recited feature(s), element(s), method step(s), etc., but excluding any unrecited feature(s), element(s), method step(s), etc., except for impurities normally associated therewith. The phrase "consisting essentially of" refers to the recited feature(s), element(s), method step(s), etc., as well as any additional feature(s), element(s), method step(s), etc. that do not materially affect the basic nature of the composition, system, or method. Many of the embodiments herein are described using the open term "comprising." Such embodiments may include or may be claimed or described using the closed phrases "consisting of" and / or "consisting essentially of."

[0109] Any chemical names of substituents should be interpreted in light of IUPAC and / or revised nomenclature and with reference to the chemical structures depicted and / or described herein. In the compounds described herein, the groups and substituents may be selected according to the allowed valences of their atoms and substituents so that their selection and substitution results in stable compounds, e.g., compounds that do not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, and the like.

[0110] In the structural formulas herein, in accordance with the convention used in the art,

[0111] [ka]

[0112] is used to indicate the bond at which the moiety or substituent is attached to the core or backbone structure.

[0113] As used herein, the term "subject" refers broadly to any animal, including, but not limited to, humans and non-human animals (e.g., dogs, cats, cows, horses, sheep, poultry, fish, crustaceans, etc.). As used herein, the term "patient" refers to a subject who is typically undergoing treatment for a disease or condition.

[0114] As used herein, the term "subject at risk of cancer" refers to a subject who has one or more risk factors for developing cancer, which may include, but are not limited to, gender, age, genetic predisposition, environmental exposure, infection and past disease history, lifestyle, etc.

[0115] As used herein, the term "effective amount" refers to an amount of a compound or composition sufficient to produce beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration.

[0116] As used herein, the terms "administration" and "administering" refer to the act of delivering a drug, prodrug, or other agent, or therapeutic treatment to a subject, or to cells, tissues, and organs in vivo, in vitro, or ex vivo. Exemplary routes of administration to the human body can be via the subarachnoid space of the brain or spinal cord (intraceutical), eye (ophthalmic), mouth (oral), skin (topical or transdermal), nose (intranasal), lung (inhalant), oral mucosa (intrabucal), auricular, rectal, vaginal routes, by injection (e.g., intravenous injection, subcutaneous injection, intratumoral injection, intraperitoneal injection, etc.), and the like.

[0117] As used herein, the terms "co-administration" and "co-administering" refer to the administration of at least two agents (e.g., a GAS41 inhibitor and one or more additional therapeutic agents) or therapies to a subject. In some embodiments, the co-administration of two or more agents or therapies is simultaneous. In other embodiments, a first agent / therapy is administered before a second agent / therapy. Those of skill in the art will understand that the formulations and / or routes of administration of the various agents or therapies used may vary. Those of skill in the art will readily be able to determine appropriate dosages for co-administration. In some embodiments, when agents or therapies are co-administered, each agent or therapy is administered at a lower dosage than would be appropriate if administered alone. That is, co-administration is particularly desirable in embodiments where the co-administration of agents or therapies reduces the required dosage of a potentially harmful (e.g., toxic) agent(s) and / or when co-administration of two or more agents sensitizes a subject to the beneficial effects of one agent by co-administration of another agent.

[0118] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier, making the composition particularly suitable for therapeutic use in vitro, in vivo or ex vivo.

[0119] The terms "pharmaceutically acceptable" or "pharmacologically acceptable," as used herein, refer to a composition that does not substantially produce an adverse reaction, e.g., a toxic, allergic, or immune response, when administered to a subject.

[0120] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, including, but not limited to, phosphate buffered saline, water, emulsions (e.g., oil-in-water emulsions or water-in-oil emulsions), various types of wetting agents, any solvents, dispersion media, coatings, sodium lauryl sulfate, isotonicity agents, absorption delaying agents, disintegrants (e.g., potato starch or sodium starch glycolate), and the like. The compositions of the present invention may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. (1975), incorporated herein by reference in its entirety.

[0121] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention that, upon administration to a subject, provides a compound of the present invention or its active metabolite or residue. As known to those skilled in the art, "salts" of the compounds of the present invention can be obtained from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be used to prepare salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0122] Examples of bases include hydroxides of alkali metals (e.g., sodium), hydroxides of alkaline earth metals (e.g., magnesium), ammonia, and NR4 + A compound of the formula (where each R is independently C 1-4 Examples include, but are not limited to, alkyl.

[0123] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include those formed by combining an anion of a compound of the present invention with Na + , NH4 + and NR4 + (Each R is independently 1-4 The examples include mixtures of suitable cations such as alkyl groups.

[0124] For therapeutic uses, salts of the compounds of the invention are contemplated to be pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0125] As used herein, the term "instructions for administering said compound to a subject" and its grammatical equivalents include instructions for using the compositions contained in the kit to treat a condition (e.g., instructions providing a decision tree for the treating physician to correlate administration, route of administration, patient-specific characteristics with a course of treatment).

[0126] "Amino" refers to the moiety -NH2.

[0127] "Carbonyl" refers to a moiety of the formula -C(=O)-.

[0128] "Carboxy" or "carboxyl" refers to the moiety -CO2H.

[0129] "Cyano" refers to the moiety -CN.

[0130] "Hydroxy" or "hydroxyl" refers to the moiety --OH.

[0131] "Imino" refers to the moiety =NH. Unless stated otherwise specifically in the specification, an imino group is optionally substituted.

[0132] "Nitro" refers to the -NO2 moiety.

[0133] "Oxo" refers to the =O moiety.

[0134] "Thioxo" refers to the =S part.

[0135] "Acyl" refers to the group -C(=O)R, where R is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and heteroalkyl. Unless stated otherwise specifically in the specification, an acyl group is optionally substituted.

[0136] "Alkyl" refers to an alkyl group having 1 to 30 carbon atoms, e.g., 1 to 16 carbon atoms (C1-C 16 alkyl), 1 to 12 carbon atoms (C1-C 12 "Ci-C alkyl" refers to a straight or branched saturated hydrocarbon chain having 1 to 8 carbon atoms (Ci-C alkyl), 1 to 6 carbon atoms (Ci-C alkyl), or 1 to 4 carbon atoms (Ci-C alkyl), such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specifically stated in the specification, an alkyl group is optionally substituted.

[0137] "Alkenyl" refers to an alkyl group having 2 to 30 carbon atoms, e.g., 2 to 16 carbon atoms (C-C 16 alkenyl), 2 to 12 carbon atoms (C2-C 12 "Alkenyl" refers to a straight or branched hydrocarbon chain containing 2 to 8 carbon atoms (C2-C8 alkenyl), 2 to 6 carbon atoms (C2-C6 alkenyl), or 2 to 4 carbon atoms (C2-C4 alkenyl) and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 1,4-pentadienyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted.

[0138] "Alkynyl" refers to an alkyl group having 2 to 30 carbon atoms, e.g., 2 to 16 carbon atoms (C-C 16 Alkynyl), 2 to 12 carbon atoms (C2-C 12"Alkynyl" refers to a straight or branched hydrocarbon chain containing 2 to 8 carbon atoms (C2-C8 alkynyl), 2 to 6 carbon atoms (C2-C6 alkynyl), or 2 to 4 carbon atoms (C2-C4 alkynyl) and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl. Unless stated otherwise specifically in the specification, alkynyl groups are optionally substituted.

[0139] "Alkylene" means a group of 1 to 30 carbon atoms (C1-C 30 alkylene), for example, refers to a divalent group derived from a straight or branched hydrocarbon chain of 1 to 6 carbon atoms (C1-C6 alkylene). Representative examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH2CH(CH3)-, -CH2CH2CH2CH2-, -CH2CH2CH(CH3)-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH(CH3)CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH(CH3)CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH(CH3)CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH(CH3)CH2CH2-, -CH2CH2CH2CH2CH2-, and -CH(CH3)CH2CH2CH2CH2-. Unless stated otherwise specifically in the specification, an alkylene group is optionally substituted.

[0140] "Alkoxy" refers to a moiety of the formula -OR, where R is an alkyl group, as defined herein, e.g., an alkyl group containing 1 to 12 carbon atoms. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[0141] "Alkenyloxy" refers to a moiety of the formula -OR, where R is an alkenyl group, as defined herein, e.g., an alkenyl group containing 2 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkenyloxy group is optionally substituted.

[0142] "Alkynyloxy" refers to a moiety of the formula -OR, where R is an alkynyl group, as defined herein, e.g., an alkynyl group containing 2 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkynyloxy group is optionally substituted.

[0143] "Alkylamino" refers to a moiety of the formula -NHR, where R is an alkyl group, as defined herein. Unless stated otherwise specifically in the specification, an alkylamino or dialkylamino group is optionally substituted.

[0144] "Alkylaminoalkyl" refers to an alkyl moiety that contains at least one alkylamino substituent. Unless stated otherwise specifically in the specification, an alkylaminoalkyl group is optionally substituted.

[0145] "Amide" or "amido" refers to a moiety having the formula -C(=O)NRR' or -NRC(=O)R', where R and R' are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, heterocyclyl, and heterocyclylalkyl. When the amide moiety is -C(=O)NRR', R and R' can optionally be joined together with the nitrogen to which they are attached to form a 4-, 5-, 6-, or 7-membered ring. Unless otherwise specifically stated herein, an amide group is optionally substituted.

[0146] "Amidoalkyl" refers to an alkyl moiety, as defined herein, in which at least one hydrogen atom is replaced by an amido group, as defined herein. Unless otherwise specifically stated herein, an amidoalkyl group is optionally substituted.

[0147] "Aminoalkyl" refers to an alkyl moiety, as defined herein, in which at least one hydrogen atom is replaced with an amino group, as defined herein. The amino group can be substituted on a tertiary, secondary, or primary carbon. Unless otherwise specifically stated herein, aminoalkyl groups are optionally substituted.

[0148] "Aryl" refers to a carbocyclic aromatic ring system having one ring (monocyclic) or multiple rings (bicyclic or tricyclic), including fused ring systems, and no heteroatoms. As used herein, aryl refers to a carbocyclic aromatic ring system having 6 to 20 carbon atoms (C6-C6). 20 aryl), 6 to 14 ring carbon atoms (C6-C 14 aryl), 6 to 12 ring carbon atoms (C6-C 12 aryl) or 6 to 10 ring carbon atoms (C6-C 10 Representative examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and phenanthrenyl. Unless stated otherwise specifically in the specification, the term "aryl" is intended to include optionally substituted aryl groups.

[0149] "Arylalkyl" refers to an alkyl group, as defined herein, in which at least one hydrogen atom is replaced by an aryl group, as defined herein. Exemplary arylalkyl groups include, but are not limited to, benzyl and phenethyl. Unless otherwise specifically stated herein, the term "arylalkyl" is intended to include groups in which the aryl and / or alkyl portions are optionally substituted.

[0150] "Arylene" refers to a divalent aryl group (e.g., phenylene). Unless specifically stated otherwise, the arylene is optionally substituted.

[0151] "Aryloxy" refers to the moiety -O-aryl. Unless stated otherwise specifically in the specification, the aryloxy is optionally substituted.

[0152] "Arylamino" is -NR a -aryl moiety, where R a refers to a moiety where is H or alkyl. Unless stated otherwise specifically in the specification, an arylamino is optionally substituted.

[0153] "Cycloalkyl" refers to a saturated carbocyclic ring system containing 3 to 10 carbon atoms per ring. Cycloalkyls can be monocyclic, bicyclic, tricyclic, bridged, fused, and / or spirocyclic rings. Representative examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, and bicyclo[5.2.0]nonanyl. Unless otherwise specifically stated herein, the term "cycloalkyl" is intended to include optionally substituted cycloalkyl groups.

[0154] "Cycloalkenyl" refers to a monocyclic or polycyclic non-aromatic ring system containing at least one carbon-carbon double bond and preferably having 5 to 10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl. Unless otherwise specifically stated herein, the term "cycloalkenyl" is intended to include optionally substituted cycloalkenyl groups.

[0155] "Cycloalkylalkyl" refers to an alkyl group, as defined herein, in which at least one hydrogen atom is replaced by a cycloalkyl group, as defined herein. Unless otherwise specifically stated in the specification, the term "cycloalkylalkyl" is intended to include groups in which the cycloalkyl and / or alkyl portions are optionally substituted.

[0156] "Cycloalkylalkylamino" refers to cycloalkylalkyl-NR a - and that R a is H or alkyl, and the cycloalkylalkyl moiety is attached via a carbon atom to a nitrogen, which serves as a linker attaching the cycloalkylalkyl moiety to the remainder of the molecule. Unless otherwise specifically stated herein, cycloalkylalkylamino is optionally substituted.

[0157] "Cycloalkylalkyloxy" refers to the moiety -O-cycloalkylalkyl, where the cycloalkylalkyl moiety is attached via a carbon atom to an oxygen that functions as a linker attaching the cycloalkylalkyl moiety to the remainder of the molecule. Unless otherwise specifically stated herein, the cycloalkylalkyloxy is optionally substituted.

[0158] "Cycloalkylamino" is -NR a -cycloalkyl moiety, where R a refers to a moiety where is H or alkyl. Unless stated otherwise specifically in the specification, a cycloalkylamino is optionally substituted.

[0159] "Cycloalkyloxy" refers to the moiety -O-cycloalkyl. Unless stated otherwise specifically in the specification, the cycloalkyloxy is optionally substituted.

[0160] "Dialkylamino" is -NRR ’ where R and R' are each independently an alkyl group, as defined herein. Unless stated otherwise specifically in the specification, an alkylamino or dialkylamino group is optionally substituted.

[0161] "Dialkylaminoalkyl" refers to an alkyl moiety that contains at least one dialkylamino substituent. Unless stated otherwise specifically in the specification, an alkylaminoalkyl group is optionally substituted.

[0162] "Halo" or "halogen" refers to fluoro, chloro, bromo or iodo.

[0163] "Haloalkyl" refers to an alkyl group, as defined herein, substituted with one or more halo atoms, as defined herein, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, -CHCF, -CHCHF, -CHCHF, -CHFCF, -CHFCHF, -CHFCHF, -CHFCH, -CFCF, -CFCHF, -CFCHF, -CFCH, -CHCFCH, -CHCHFCH, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

[0164] "Haloalkoxy" refers to an alkoxy group, as defined herein, that is substituted with one or more halo atoms, as defined herein.

[0165] As used herein, the term "heteroatom" or "ring heteroatom" is intended to include any element other than carbon or hydrogen. Suitable heteroatoms are oxygen (O), nitrogen (N), sulfur (S), and phosphorus (P).

[0166] "Heteroalkyl" means an alkyl group, as defined herein, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with a heteroatomic group such as -NR-, -O-, -S-, -S(O)-, -S(O)-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which may be optionally substituted. By way of example, one, two, or three carbon atoms may be independently replaced with the same or different heteroatomic groups. Examples of heteroalkyl groups include, but are not limited to, -OCH, -CHOCH, -SCH, -CHSCH, -NRCH, and -CHNRCH, in which R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. Heteroalkyl also includes groups in which the alkyl carbon atoms are oxidized (i.e., -C(O)-).

[0167] "Heteroalkylene" refers to an alkylene group, as defined herein, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with a heteroatom group such as -NR-, -O-, -S-, -S(O)-, -S(O)-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which may be optionally substituted. By way of example, one, two, or three carbon atoms may be independently replaced with the same or different heteroatom groups. Heteroalkylene also includes groups in which an alkyl carbon atom is oxidized (i.e., is -C(O)-). Examples of heteroalkylene groups include, but are not limited to, -CH-O-CH-, -CH-S-CH-, -CH-NR-CH-, -CH-NH-C(O)-CH-, etc., as well as polyethylene oxide chains, polypropylene oxide chains, and polyethyleneimine chains.

[0168] "Heteroaryl" refers to an aromatic group having one ring (monocyclic) or multiple rings (bicyclic or tricyclic) and one or more ring heteroatoms independently selected from O, N, and S. A monocyclic aromatic ring is a 5- or 6-membered ring containing at least one heteroatom independently selected from O, N, and S (e.g., 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S). A 5-membered monocyclic aromatic ring has two double bonds, and a 6-membered monocyclic aromatic ring has three double bonds. A bicyclic heteroaryl group is exemplified by a monocyclic heteroaryl ring fused to a monocyclic aryl group, as defined herein, or a monocyclic heteroaryl group, as defined herein. A tricyclic heteroaryl group is exemplified by a monocyclic heteroaryl ring fused to two rings independently selected from a monocyclic aryl group, as defined herein, and a monocyclic heteroaryl group, as defined herein. Representative examples of monocyclic heteroaryl include, but are not limited to, pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, thienyl, furanyl, oxazolyl, isoxazolyl, 1,2,4-triazinyl, and 1,3,5-triazinyl. Representative examples of bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzodioxolyl, benzofuranyl, benzoxadiazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxadiazolyl, benzoxazolyl, chromenyl, imidazopyridine, imidazothiazolyl, indazolyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, naphthyridinyl, purinyl, pyridoimidazolyl, quinazolinyl, quinolinyl, quinoxalinyl, thiazolopyridinyl, thiazolopyrimidinyl, thienopyrrolyl, and thienothienyl.Representative examples of tricyclic heteroaryl include, but are not limited to, dibenzofuranyl and dibenzothienyl. Monocyclic, bicyclic, and tricyclic heteroaryls are linked to the parent molecular moiety through any carbon atom or any nitrogen atom contained in the ring. Unless otherwise specifically stated herein, heteroaryl groups are optionally substituted.

[0169] "Heteroarylalkyl" refers to an alkyl group, as defined herein, in which at least one hydrogen atom is replaced by a heteroaryl group, as defined herein. Unless otherwise specifically stated in the specification, a heteroarylalkyl group is optionally substituted.

[0170] "Heteroarylalkylamino" refers to heteroarylalkyl-NR a - and that R a refers to a moiety where is H or alkyl. Unless stated otherwise specifically in the specification, a heteroarylalkylamino is optionally substituted.

[0171] "Heteroarylalkyloxy" refers to the moiety heteroarylalkyl-O-. Unless stated otherwise specifically in the specification, the heteroarylalkyloxy is optionally substituted.

[0172] "Heteroarylamino" refers to -NR a -heteroaryl moiety, where R a refers to a moiety where is H or alkyl. Unless stated otherwise specifically in the specification, a heteroarylamino is optionally substituted.

[0173] "Heteroaryloxy" refers to the moiety -O-heteroaryl. Unless stated otherwise specifically in the specification, heteroaryloxy is optionally substituted.

[0174] "Heteroarylene" refers to a divalent heteroaryl group. Unless otherwise specifically stated, the heteroarylene is optionally substituted.

[0175] "Heterocycle" or "heterocyclic" refers to a saturated or partially unsaturated non-aromatic cyclic group having one or more ring heteroatoms independently selected from O, N, and S, and refers to a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. A monocyclic heterocycle is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing at least one heteroatom independently selected from O, N, and S. A 3- or 4-membered monocyclic heterocycle contains zero or one double bond and one heteroatom selected from O, N, and S. A 5-membered monocyclic heterocycle contains zero or one double bond and one, two, or three heteroatoms selected from O, N, and S. A 6-membered monocyclic heterocycle contains zero, one, or two double bonds and one, two, or three heteroatoms selected from O, N, and S. Seven- and eight-membered monocyclic heterocycles contain zero, one, two, or three double bonds and one, two, or three heteroatoms selected from O, N, and S. Representative examples of monocyclic heterocycles include azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolidinyl, oxazolidinyl, oxetanyl, piperazinyl, piperizinyl, and cyclohexyl. Examples of thiazolinyl include, but are not limited to, thiazolinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl.A bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, a monocyclic heterocycle fused to a monocyclic cycloalkyl, a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, a spiro heterocyclic group, or a monocyclic bridged heterocyclic ring system in which two non-adjacent atoms of the ring are joined by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms. Representative examples of bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydroisoquinoline, 2-azaspiro[3.3]heptan-2-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), 2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclic heterocycles are exemplified by bicyclic heterocycles fused to a phenyl group, bicyclic heterocycles fused to a monocyclic cycloalkyl, bicyclic heterocycles fused to a monocyclic cycloalkenyl, bicyclic heterocycles fused to a monocyclic heterocycle, or bicyclic heterocycles in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms. Examples of tricyclic heterocycles include octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1-azatricyclo[3.3.1.1. 3,7 ]decane) and oxa-adamantane (2-oxatricyclo[3.3.1.1 3,7 ]decane). Monocyclic, bicyclic, and tricyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom within the ring. Unless stated otherwise specifically in the specification, a heterocyclyl group is optionally substituted.

[0176] "Heterocyclylalkyl" refers to an alkyl group, as defined herein, in which at least one hydrogen atom is replaced by a heterocyclyl group, as defined herein. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group is optionally substituted.

[0177] "Heterocyclylalkylamino" refers to heterocyclylalkyl-NR a - and that R a is H or alkyl, and the heterocyclylalkyl moiety is attached via a carbon atom to a nitrogen that functions as a linker attaching the heterocyclylalkyl moiety to the remainder of the molecule. Unless stated otherwise specifically in the specification, a heterocyclylalkylamino is optionally substituted.

[0178] "Heterocyclylalkyloxy" refers to the moiety -O-heterocycloalkyl, where the heterocyclylalkyl moiety is attached via a carbon atom to an oxygen, which acts as a linker attaching the heterocyclylalkyl moiety to the remainder of the molecule. Unless otherwise specifically stated herein, the heterocyclylalkyloxy is optionally substituted.

[0179] "Heterocyclylamino" is -NR a -heterocyclyl moiety, and the R a is H or alkyl, and the heterocyclyl moiety is attached via a carbon atom to a nitrogen that functions as a linker attaching the heterocyclyl moiety to the remainder of the molecule. Unless otherwise specifically stated herein, heterocyclylamino is optionally substituted.

[0180] "Heterocyclyloxy" refers to the moiety -O-heterocyclyl, where the heterocyclyl moiety is attached via a carbon atom to an oxygen, which acts as a linker attaching the heterocyclyl moiety to the remainder of the molecule. Unless otherwise specifically stated herein, the heterocyclyloxy is optionally substituted.

[0181] "Hydroxyalkyl" refers to an alkyl group containing at least one hydroxyl substituent. The -OH substituent may be at a primary, secondary, or tertiary carbon. Unless otherwise specifically stated herein, a hydroxylalkyl group is optionally substituted.

[0182] "Sulfonamide" refers to a moiety of the formula -SONR-R', where R and R' are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and heteroalkyl. R and R' can optionally be joined together with the nitrogen to which they are attached to form a 4-, 5-, 6-, or 7-membered ring. Unless stated otherwise specifically in the specification, a sulfonamide group is optionally substituted.

[0183] "Sulfonamidoalkyl" refers to an alkyl group, as defined herein, in which at least one hydrogen atom is replaced by a sulfonamido group, as defined herein. Unless otherwise specifically stated in the specification, a sulfonamidoalkyl group is optionally substituted.

[0184] "Thioalkyl" refers to a moiety of the formula -SR, where R is an alkyl moiety, as defined herein, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group is optionally substituted.

[0185] "Thiourea" refers to a moiety of the formula -NH-C(S)-NHR, where R is selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, each of which may be optionally substituted.

[0186] "Thiourea alkyl" refers to an alkyl group, as defined herein, in which at least one hydrogen atom is replaced by a thiourea group, as defined herein. Unless otherwise specifically stated in the specification, a thiourea alkyl group is optionally substituted.

[0187] "Urea" refers to a moiety of the formula -NH-C(O)-NHR, where R is selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, each of which may be optionally substituted.

[0188] "Urea alkyl" refers to an alkyl group, as defined herein, in which at least one hydrogen atom is replaced by a urea group, as defined herein. Unless otherwise specifically stated herein, a urea alkyl group is optionally substituted.

[0189] As used herein, the term "substituted" means that at least one hydrogen atom has been replaced with any of the above groups (e.g., amino, carboxy, hydroxy, imino, acyl, alkyl, alkoxy, alkylamino, alkylaminoalkyl, amido, aminoalkyl, aminocarbonyl, aryl, arylalkyl, arylalkylamino, arylalkyloxy, arylamino, aryloxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkyl, cycloalkylamino, cycloalkylalkyloxy, cycloalkylamino, cycloalkyloxy, halo, haloalkyl, heteroatom, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylamino, heteroarylalkyloxy, heteroarylamino, heteroaryloxy, heterobicycloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkylamino, heterocyclylalkyloxy, heterocyclylamino, heterocyclyloxy, hydroxyalkyl, thioalkyl, alkylene, alkylenecarbonyl, alkenylene, at least one hydrogen atom of the alkylene group is replaced by a bond to an atom other than hydrogen, and the non-hydrogen atom is selected from the group consisting of halogen atoms such as F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl groups, alkoxy groups, and ester groups; sulfur atoms in groups such as thiol groups, thioalkyl groups, sulfone groups (such as alkylsulfone groups), sulfonyl groups (such as sulfonylalkyl groups such as sulfonamide groups and sulfonylmethanes), and sulfoxide groups (such as alkylsulfoxide groups); nitrogen atoms in groups such as amino, amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine; silicon atoms in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups;"Substituted" also refers to any of the above groups in which one or more hydrogen atoms have been replaced by a higher bond (e.g., a double or triple bond) to a carbon atom or a heteroatom (such as oxygen) in oxo, carbonyl, carboxyl, and ester groups, and to a nitrogen in groups such as imines, oximes, hydrazones, and nitriles. ... group in which one or more hydrogen atoms have been replaced by a higher bond (e.g., a double or triple bond) to a nitrogen atom in groups such as -NR, g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g , -SO2NR g R h , -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g or -CH2SO2NR g R h and wherein R is any of the above groups replaced by g and R hare independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. "Substituted" also refers to the replacement of one or more hydrogen atoms with amino, carbonyl, carboxy, cyano, hydroxyl, imino, nitro, oxo, thioxo, acyl, alkyl, alkoxy, alkylamino, alkylaminoalkyl, amido, aminoalkyl, aminocarbonyl, aryl, arylalkyl, arylalkylamino, arylalkyloxy, arylamino, aryloxy, bicycloalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylamino, cycloalkyloxy, halo, haloalkyl, heteroatom, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylamino, heteroarylalkyloxy, heteroarylamino, heteroaryl aloxy, heterobicycloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkylamino, heterocyclylalkyloxy, heterocyclylamino, heterocyclyloxy, hydroxyalkyl, N-heteroaryl, N-heterocyclyl, thioalkyl, alkylene, alkylenecarbonyl, alkenylene, alkenylenecarbonyl, arylene, heteroalkylene, heteroalkylenecarbonyl, heteroarylene, heteroarylenecarbonyl, heterocyclylalkylene, heterocyclylalkylenecarbonyl, methylidene, trimethylsilanyl, dialkylphosphine oxide, -OR, -SR, -OC(O)-R, -N(R), -C(O)R, -C(O)OR, -C(O)N(R), -N(R)C(O)OR, -N(R)C(O)R, -N(R)S(O) t R (t is 1 or 2), -S(O) t OR (t is 1 or 2), -S(O) tmeans any of the above groups replaced by a bond to a group N(R) (where t is 1 or 2), -PO(R) or -PO(OR), where each R is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl group. In addition, each of the above substituents is optionally substituted with one or more of the above substituents.

[0190] The term "optionally substituted," as used herein, means that the group being referred to (e.g., alkyl, cycloalkyl, etc.) may be unsubstituted or substituted with one or more substituents.

[0191] Detailed Description Provided herein are small molecules that bind to GAS41 and inhibit GAS41 activity, and methods of using such molecules for the treatment of cancer.

[0192] Proteins that recognize post-transcriptional modifications on histone proteins play an important role in transcriptional regulation (Allis 2016). YEATS domain-containing proteins belong to the epigenetic reader protein family and include four human paralogs: ENL, YEATS2, AF9, and GAS41. Biochemical studies have revealed that YEATS domains bind to chromatin by recognizing histones with acetylated or crotonylated lysine side chains.

[0193] Previous studies have reported molecular details of the GAS41 YEATS-mediated recognition of histone acetyl-lysine or crotonyl-lysine (Cho et al., ACS Chem. Biol. 13, 2739-2746 (2018)). GAS41 YEATS exhibits site-specific recognition of acetylated and crotonylated histone H3 peptides, albeit with moderate affinity in the mid-μM range (ibid.). Structural analysis revealed that acylated lysines bind within a channel on the GAS41 YEATS domain, which may constitute a targeting site for small molecule inhibitors. The compounds disclosed herein have been shown to be low-μM and sub-μM inhibitors of the GAS41 YEATS domain. GAS41 is a dimer intracellularly and can recognize diacylated histone peptides with enhanced affinity via a bivalent binding mode. Accordingly, some of the compounds disclosed herein are dimeric GAS41 inhibitors with enhanced potency and exhibit activity in non-small cell lung cancer (NSCLC) cells.

[0194] In some embodiments, the compounds described herein find use in treating or preventing cancer (e.g., brain tumors, sarcomas, colon cancer, lung cancer, or gastric cancer) and / or alleviating symptoms associated with cancer. In some embodiments, provided herein are pharmaceutical compositions comprising compounds described herein and / or within the scope of the invention. In some embodiments, a pharmaceutical composition comprising a compound described herein and / or within the scope of the invention is administered to a subject to treat cancer (e.g., brain tumors, sarcomas, colon cancer, lung cancer, or gastric cancer).

[0195] The present invention provides a compound of formula (I):

[0196] [ka]

[0197] or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxy, acyl, amido, cyano, sulfonyl, and hydrogen; X is —C(O)—, —C(S)—, —CH—, —SO—, or absent; Y is -NR a - or -O-, R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl, and aminoalkyl, or R a is that R a and the nitrogen atom to which they are bonded form a fused ring with A, or R a and R 1 together with the atoms to which they are attached form an optionally substituted heterocyclic ring; Z is absent or -CR b R c - and R b and R c are each independently selected from hydrogen and alkyl; A is a 5-membered heteroaryl; Q is a 4-, 5-, or 6-membered heterocyclyl; R 2 is selected from hydrogen, halo, alkyl, amino and hydroxy; R 3 is hydrogen, halo, -OR d , -NR e R f , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl and groups of the formula:

[0198] [ka]

[0199] wherein B is aryl or heteroaryl; J is absent or is —CH—, —O—, —S—, or —NH—; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; and R g and R h are each independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl; Alternatively, R 2 and R 3 together with the carbon atom(s) to which they are attached form a ring selected from aryl, heteroaryl, cycloalkyl, and heterocycle, or R 2 and R 3 together with the carbon atom to which they are attached form an alkenyl group, R d , R e and R f are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; each alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl independently is optionally substituted with 1, 2, 3, 4, or 5 substituents; However, Z is -CR b R c -When R 1 is not cycloalkyl.

[0200] In some embodiments, the present invention provides a compound of formula (I):

[0201] [ka]

[0202] or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxy, acyl, amido, cyano, sulfonyl, and hydrogen; X is —C(O)—, —C(S)—, —CH—, —SO—, or absent; Y is -NR a - or -O-, R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl, and aminoalkyl, or R a is that R a and together with the nitrogen atom bonded to form a condensed ring with A, Z is absent or -CR b R c - and R b and R c are each independently selected from hydrogen and alkyl; A is a 5-membered heteroaryl; Q is a 4-, 5-, or 6-membered heterocyclyl; R 2is selected from hydrogen, halo, alkyl, amino and hydroxy; R 3 is hydrogen, halo, -OR d , -NR e R f , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl and groups of the formula:

[0203] [ka]

[0204] wherein B is aryl or heteroaryl; J is absent or is —CH—, —O—, —S—, or —NH—; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; and R g and R h are each independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl; Alternatively, R 2 and R 3 together with the carbon atom(s) to which they are attached form a ring selected from aryl, heteroaryl, cycloalkyl, and heterocycle, or R 2 and R 3 together with the carbon atom to which they are attached form an alkenyl group, R d , Re and R f are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; each alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl independently is optionally substituted with 1, 2, 3, 4, or 5 substituents; However, Z is -CR b R c -When R 1 is not cycloalkyl.

[0205] In some embodiments, R 1 is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, and alkyl. In some embodiments, R 1 is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, and C1-C6 alkyl. 1 is selected from heterocyclyl, aryl, arylalkyl, heteroarylalkyl, and C1-C6 alkyl. In some embodiments, R 1 is selected from heterocyclyl (e.g., a monocyclic or bicyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S), aryl (e.g., phenyl), arylalkyl (e.g., phenethyl), heteroarylalkyl (e.g., the heteroaryl is a monocyclic heteroaryl having 1 or 2 nitrogen atoms), and C1-C4 alkyl (e.g., methyl, ethyl, or n-propyl). In some embodiments, R 1is a monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, R 1 is a monocyclic heterocyclyl having 1 or 2 nitrogen atoms. In some embodiments, R 1 is pyrrolidinyl. 1 may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents. For example, in some embodiments, R 1 is unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halo, hydroxy, amino, amino-C1-C6 alkyl, aryloxy, alkynyloxy, and methylidene. In some embodiments, R 1 is unsubstituted. In some embodiments, R 1 is unsubstituted pyrrolidinyl.

[0206] In some embodiments, R 1 teeth,

[0207] [ka]

[0208] is selected from.

[0209] In some embodiments, R 1 teeth,

[0210] [ka]

[0211] is.

[0212] In some embodiments, X is selected from -C(O)-, -CH2-, and -SO2-, or is absent. In some embodiments, X is selected from -C(O)-, -CH2-, and -SO2-. In some embodiments, X is selected from -C(O)- and -CH2-. In some embodiments, X is -C(O)-.

[0213] In some embodiments, Y is —NR a In some embodiments, Y is -NR a - and R a is selected from hydrogen and C1-C6 alkyl. In some embodiments, Y is -NR a - and R a is selected from hydrogen, methyl, and ethyl. In some embodiments, Y is —NR a - and R a is hydrogen. In some embodiments, Y is O. In some embodiments, Y is -NR a - and that R a is that R a and together with the nitrogen atom to which Y is bonded form a fused ring with A (e.g., a 5- or 6-membered ring fused with ring A). In some embodiments, Y is -NR a - and R a is that R a Together with the nitrogen atom bonded to R 1 and forming a fused ring (eg, a bicyclic ring system such as a 1,7-diazaspiro[4.4]nonane ring system), which ring is optionally substituted (eg, by an oxo group).

[0214] In some embodiments, Z is absent or selected from -CH2-, -CH(CH3)-, and -C(CH3)2-. In some embodiments, Z is absent or -CH2-. In some embodiments, Z is absent.

[0215] In some embodiments, A is a 5-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, A is a 5-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, A is a 5-membered heteroaryl having 1 or 2 heteroatoms independently selected from N and S. In some embodiments, A is selected from thiophene and thiazole. In some embodiments, A is thiophene. In some embodiments, A has the formula:

[0216] [ka]

[0217] wherein E is selected from N and CH. In some embodiments, E is CH. In some embodiments, E is N. In some embodiments, A has the formula:

[0218] [ka]

[0219] In some embodiments, Q is a 4-, 5-, or 6-membered heterocyclyl having one nitrogen atom (i.e., the nitrogen atom shown in Formula (I)), wherein the heterocyclyl is optionally substituted. In some embodiments, Q is selected from azetidinyl, pyrrolidinyl, and piperidinyl. In some embodiments, Q is selected from azetidinyl and pyrrolidinyl. In some embodiments, Q is azetidinyl. In some embodiments, Q is pyrrolidinyl.

[0220] In some embodiments, R 2 is selected from hydrogen, halo, amino, and hydroxy. In some embodiments, R 2is selected from hydrogen, halo, and hydroxy. In some embodiments, R 2 is hydrogen.

[0221] In some embodiments, R 3 is hydrogen, -OR d , -NR e R f , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl and groups of the formula:

[0222] [ka]

[0223] In the formula, R d is selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl, benzyl, and heteroaryl; R e is hydrogen and R f is selected from hydrogen, C-C alkyl, and heteroaryl; B is monocyclic heteroaryl; J is absent; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0 or 1; n is 0, 1, 2, or 3; and R g and R h are each independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl.

[0224] In some embodiments, R 3is hydrogen, -OR d , -NR e R f phenyl, benzyl, heteroaryl, heteroarylalkyl, and heterocyclyl, wherein R d is selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl, benzyl, and heteroaryl; R e is hydrogen and R f is selected from hydrogen, C1-C6 alkyl and heteroaryl.

[0225] In some embodiments, R 3 is hydrogen, -OR d , -NR e R f phenyl, benzyl, heteroaryl, heteroarylalkyl, and heterocyclyl, wherein R d is selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl, benzyl, and heteroaryl; R e is hydrogen and R f is selected from hydrogen, C1-C6 alkyl, and heteroaryl, wherein each heteroaryl is independently a monocyclic or bicyclic heteroaryl having 1 or 2 heteroatoms independently selected from N, S, and O, and each heterocyclyl is independently a monocyclic or bicyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, S, and O.

[0226] In some embodiments, R 3 is a group of the formula:

[0227] [ka]

[0228] In some embodiments, R 3 is a group of the formula:

[0229] [ka]

[0230] wherein B is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N and S; J is absent; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0 or 1; n is 0, 1, 2, or 3; and R g is C1-C6 alkyl, and each R h are independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl. In some embodiments, B is thiazole or thiophene. In some embodiments, m is 0. In some embodiments, J is absent. In some embodiments, C is selected from phenyl and monocyclic heteroaryl having 1 or 2 nitrogen atoms. In some embodiments, C is selected from phenyl and pyridyl.

[0231] In some embodiments, at least one R h is -(CH2) r C(O)NR i R j or -(CH2) s NR k C(O)R m is an amide or amidoalkyl having the formula: r and s are each independently selected from 0, 1, and 2; R i and R kare each independently selected from hydrogen and C1-C6 alkyl; R j is selected from C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, cycloalkyl, and cycloalkyl-C1-C6 alkyl; R m is selected from C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, cycloalkyl and cycloalkyl-C1-C6 alkyl, amino, C1-C6 alkylamino, arylamino and aryl-C1-C6 alkylamino; Each alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is independently unsubstituted or substituted with one or two substituents independently selected from halo, C1-C6 alkyl, C1-C6-alkoxy, hydroxy, amino and oxo.

[0232] In some embodiments, R 2 and R 3 together with the carbon atom(s) to which they are attached form a ring selected from aryl, heteroaryl, cycloalkyl, and heterocycle, any of which can be optionally substituted (e.g., with 1, 2, or 3 substituents independently selected from alkyl, halo, amino, alkylamino, dialkylamino, alkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, aminoalkyl, and amidoalkyl).

[0233] In some embodiments, R 2 and R 3 substitutes adjacent carbon atoms of ring Q, and the R 2 and R 3and together with the carbon atom to which they are bonded form a phenyl ring fused to ring Q, which phenyl ring is optionally substituted. In some embodiments, the phenyl ring is unsubstituted.

[0234] In some embodiments, R 2 and R 3 substitutes the same carbon atom of ring Q, and the R 2 and R 3 and the carbon atom to which they are attached form a spiro ring, which is optionally substituted. 2 and R 3 substitutes the same carbon atom of ring Q, and the R 2 and R 3 and together with the carbon atom to which they are attached form a 4-membered spiro ring selected from cyclobutyl and azetidinyl, each of which is optionally substituted with one substituent selected from -OR' and heteroaryl, where R' is selected from C-C alkyl, aryl, and heteroaryl. In some embodiments, the spiro ring is substituted with one substituent selected from -OR', where R' is selected from methyl, phenyl, and a monocyclic 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N and S (e.g., pyridyl). In some embodiments, the spiro ring is substituted with a monocyclic 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N and S (e.g., pyridyl or thiazolyl).

[0235] In some embodiments, R 2 and R 3 substitutes the same carbon atom of ring Q, and the R 2 and R 3 together with the carbon atom to which it is attached form an alkenyl group (for example, a methylidene group or a substituted version thereof).

[0236] In some embodiments,

[0237] [ka]

[0238] The base is,

[0239] [ka]

[0240] having a formula selected from In the formula, R x , R y and R z are each independently -OR v , aryl, and heteroaryl; R v is selected from C1-C6 alkyl, aryl, and heteroaryl. In some embodiments, R x , R y and R z are independently -OR v phenyl, and monocyclic 5- or 6-membered heteroaryl (e.g., pyridyl or thiazolyl) having 1 or 2 heteroatoms independently selected from N and S, wherein R v is selected from C1-C6 alkyl (e.g., methyl), aryl (e.g., phenyl), and 5- or 6-membered monocyclic heteroaryl (e.g., pyridyl or thiazolyl) having 1 or 2 heteroatoms independently selected from N and S. In some embodiments, R x is aryl (e.g., phenyl). In some embodiments, R y -OR v and 5- or 6-membered monocyclic heteroaryl (e.g., pyridyl or thiazolyl) having 1 or 2 heteroatoms independently selected from N and S, wherein R vis selected from C1-C6 alkyl (e.g., methyl), aryl (e.g., phenyl), and 5- or 6-membered monocyclic heteroaryl (e.g., pyridyl or thiazolyl) having 1 or 2 heteroatoms independently selected from N and S. In some embodiments, R z is a 5- or 6-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N and S, such as a 6-membered monocyclic heteroaryl (eg, pyridyl).

[0241] In some embodiments,

[0242] [ka]

[0243] The group has the formula:

[0244] [ka]

[0245] In the formula, B, J, C, R g , R h , m and n are as defined herein.

[0246] In some embodiments,

[0247] [ka]

[0248] The group has the formula:

[0249] [ka]

[0250] In the formula, R hand n is as defined herein. For example, in some embodiments, n is 0, 1, 2, or 3, and each R h are independently selected from C-C alkyl, halo, halo-C-C alkyl, amino, amino-C-C alkyl, hydroxy, hydroxy-C-C alkyl, C-C alkoxy, amido, amido-C-C alkyl, acyl, aryl, aryl-C-C alkyl, heteroaryl, heteroaryl-C-C alkyl, heterocyclyl, heterocyclyl-C-C alkyl, cycloalkyl, and cycloalkyl-C-C alkyl. h is -(CH2) r C(O)NR i R j or -(CH2) s NR k C(O)R m wherein: r and s are each independently selected from 0, 1, and 2; R i and R k are each independently selected from hydrogen and C1-C6 alkyl; R j is selected from C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, cycloalkyl, and cycloalkyl-C1-C6 alkyl; R m is selected from C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, cycloalkyl and cycloalkyl-C1-C6 alkyl, amino, C1-C6 alkylamino, arylamino, aryl-C1-C6 alkylamino; Each alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is independently unsubstituted or substituted with one or two substituents independently selected from halo, C1-C6 alkyl, C1-C6-alkoxy, hydroxy, amino and oxo.

[0251] In some embodiments,

[0252] [ka]

[0253] The base is,

[0254] [ka] JPEG0007758369000050.jpg170169JPEG0007758369000051.jpg161169JPEG000 7758369000052.jpg168169JPEG0007758369000053.jpg181169JPEG00077583690 00054.jpg196169JPEG0007758369000055.jpg191169JPEG0007758369000056.j pg197169JPEG0007758369000057.jpg196169JPEG0007758369000058.jpg112169

[0255] is selected from.

[0256] In some embodiments, the compound of formula (I) is a compound of formula (Ia):

[0257] [ka]

[0258] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 3has any of the meanings disclosed herein.

[0259] In some embodiments, the compound of formula (I) is a compound of formula (Ib):

[0260] [ka]

[0261] or a pharmaceutically acceptable salt thereof, wherein B, J, C, R g , R h , m and n have any of the meanings disclosed herein.

[0262] In some embodiments, the compound of formula (I) is a compound of formula (Ic):

[0263] [ka]

[0264] or a pharmaceutically acceptable salt thereof, wherein R h and c has any of the meanings disclosed herein.

[0265] As used herein, when referring to a compound of formula (I) (e.g., a pharmaceutical composition comprising a compound of formula (I), or a method of treatment using a compound of formula (I)), such reference also includes compounds of formula (Ia), (Ib), and (Ic).

[0266] In some embodiments, the compound is selected from the compounds shown in Table 1 herein, or a pharmaceutically acceptable salt thereof.

[0267] The present invention discloses a compound of formula (IIa):

[0268] [ka]

[0269] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 1’ are each independently selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxy, acyl, amido, cyano, sulfonyl, and hydrogen; X and X' are each independently selected from absent, -C(O)-, -C(S)-, -CH2-, and -SO2-; Y and Y' each independently represent -NR a - or -O-, R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl, and aminoalkyl; a is that R a and the nitrogen atom to which they are bonded form a fused ring with A, or R a and R 1 together with the atoms to which they are attached form an optionally substituted heterocyclic ring; Z and Z' are each independently absent or -CR b R c - and R b and R c are each independently selected from hydrogen and alkyl; A and A' are each independently a 5-membered heteroaryl ring; Q and Q' are each independently a 4-, 5-, or 6-membered heterocycle; R 2 and R 2 each ' is independently selected from hydrogen, halo, alkyl, amino, and hydroxy; R 3 and R 3each ' is independently selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, and a group of the formula:

[0270] [ka]

[0271] wherein B is aryl or heteroaryl; J is absent or is —CH—, —O—, —S—, or —NH—; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and R g and R h are each independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl; R d , R e and R f are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; L is a linker, Each alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl is independently optionally substituted with 1, 2, 3, 4, or 5 substituents.

[0272] In some embodiments, disclosed herein is a compound of formula (IIa):

[0273] [ka]

[0274] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 1’ are each independently selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxy, acyl, amido, cyano, sulfonyl, and hydrogen; X and X' are each independently selected from absent, -C(O)-, -C(S)-, -CH2-, and -SO2-; Y and Y' each independently represent -NR a - or -O-, R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl, and aminoalkyl, or R a is that R a and together with the nitrogen atom bonded to form a condensed ring with A, Z and Z' are each independently absent or -CR b R c - and R b and R c are each independently selected from hydrogen and alkyl; A and A' are each independently a 5-membered heteroaryl ring; Q and Q' are each independently a 4-, 5-, or 6-membered heterocycle; R 2 and R 2each ' is independently selected from hydrogen, halo, alkyl, amino, and hydroxy; R 3 and R 3 each ' is independently selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, and a group of the formula:

[0275] [ka]

[0276] wherein B is aryl or heteroaryl; J is absent or is —CH—, —O—, —S—, or —NH—; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and R g and R h are each independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl; R d , R e and R f are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; L is a linker, Each alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl is independently optionally substituted with 1, 2, 3, 4, or 5 substituents.

[0277] In some embodiments, R 1 and R 1 ' is the same as R 2 and R 2 ' is the same as R 3 and R 3 X and X' are the same, Y and Y' are the same, Z and Z' are the same, A and A' are the same, and Q and Q' are the same.

[0278] In some embodiments, R 1 and R 1 In some embodiments, R ' is heterocyclyl and is optionally substituted. 1 and R 1 In some embodiments, R ' is a 4-6 membered monocyclic heterocyclyl having 1 or 2 nitrogen atoms and is optionally substituted. 1 and R 1 Each R' is a 4- or 5-membered monocyclic heterocyclyl, such as a 4- or 5-membered heterocyclyl having one nitrogen atom, and is optionally substituted. In some embodiments, R 1 and R 1 In some embodiments, R 1 and R 1 ' is unsubstituted pyrrolidine.

[0279] In some embodiments, X and X' are -C(O)-.

[0280] In some embodiments, Y and Y′ are —NR a - and R ais selected from hydrogen and C1-C6 alkyl. In some embodiments, Y and Y' are -NR a - and R a is selected from hydrogen and methyl. In some embodiments, Y and Y' are -NR a - and R a is hydrogen.

[0281] In some embodiments, each of Z and Z' is absent.

[0282] In some embodiments, A and A' are each 5-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from S and N. In some embodiments, A and A' are selected from thiophene and thiazole. In some embodiments, A and A' are thiophene.

[0283] In some embodiments, Q and Q' are each a 4-, 5-, or 6-membered heterocyclyl having one nitrogen atom (i.e., the nitrogen atom shown in Formula (IIa)). In other words, in some embodiments, Q and Q' are selected from azetidine, pyrrolidine, and piperidine. In some embodiments, Q and Q' are selected from azetidine and pyrrolidine. In some embodiments, Q and Q' are azetidine. In some embodiments, Q and Q' are pyrrolidine.

[0284] In some embodiments, R 2 and R 2 ' is hydrogen.

[0285] In some embodiments, R 3 and R 3’ is selected from aryl, heteroaryl and groups of the formula:

[0286] [ka]

[0287] In some embodiments, R 3 and R 3’ are groups of the formula:

[0288] [ka]

[0289] wherein B is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N, S, or O; J is absent; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0 or 1; and R g is C1-C6 alkyl, n is 0, 1 or 2, and each R h are independently selected from C-C alkyl, halo, C-C haloalkyl, amino, amino-C-C alkyl, amido-C-C alkyl, and heterocyclyl. In some embodiments, B is selected from thiazole and thiophene. In some embodiments, B is thiazole. In some embodiments, C is selected from aryl and monocyclic heteroaryl. In some embodiments, C is selected from phenyl and pyridyl. In some embodiments, at least one R h is -(CH2) r C(O)NR i R j or -(CH2) s NR k C(O)R m wherein: r and s are each independently selected from 0, 1, and 2; R i and R k are each independently selected from hydrogen and C1-C6 alkyl; R jis selected from C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, cycloalkyl, and cycloalkyl-C1-C6 alkyl; R m is selected from C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, cycloalkyl and cycloalkyl-C1-C6 alkyl, amino, C1-C6 alkylamino, arylamino, aryl-C1-C6 alkylamino; Each alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is independently unsubstituted or substituted with one or two substituents independently selected from halo, C1-C6 alkyl, C1-C6-alkoxy, hydroxy, amino and oxo.

[0290] In some embodiments, L is a linker that includes one or more groups independently selected from methylene (-CH-), vinylene (-CH=CH-), acetylene (-C≡C-), ether (-O-), amine (-NH-), alkylamine (-NR-, where R is an optionally substituted C-C alkyl group), amide (-C(O)NH-), ester (-C(O)O-), carbamate (-OC(O)NH-), sulfonamide (-S(O)NH-), phenylene (-CH-), heteroarylene, heterocyclylene, and any combination thereof.

[0291] In some embodiments, L is

[0292] [ka] JPEG0007758369000069.jpg76169

[0293] It is selected from wherein a, a1, and a2 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; b, b1, and b2 are each independently selected from 0, 1, 2, 3, 4, 5, and 6; c, c1, and c2 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; d and e are each independently selected from 0, 1, and 2; each G is independently selected from CH and N; and X 1 and X 2 each independently represents O or -NR x and the R x is hydrogen or optionally substituted alkyl, and Y 1 and Z 1 are each independently selected from —CH—, —NH—, and —O—.

[0294] In some embodiments, the compound is selected from the compounds shown in Table 2 herein, or a pharmaceutically acceptable salt thereof.

[0295] The present invention discloses a compound of formula (IIb):

[0296] [ka]

[0297] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 1’ are each independently selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, and alkynyl; X and X' are each independently selected from absent, -C(O)-, -C(S)-, -CH2-, and -SO2-; Y and Y' each independently represent -NR a - or -O-; R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl, and aminoalkyl, or R a is that R a and together with the nitrogen atom bonded to form a condensed ring with A, Z and Z' are each independently absent or -CR b R c - and R b and R c are each independently selected from hydrogen and alkyl; A and A' are each independently a 5-membered heteroaryl ring; Q and Q' are each independently a 4-, 5-, or 6-membered heterocyclyl; R 2 and R 2 each ' is independently selected from hydrogen, halo, alkyl, amino, and hydroxy; R 3 and R 3 ' are each independently hydrogen, halo, -OR d , -NR e R f , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl and groups of the formula:

[0298] [ka]

[0299] wherein B is aryl or heteroaryl; J is absent or is —CH—, —O—, —S—, or —NH—; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and R g and R hare each independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl; Alternatively, R 2 and R 3 together with the carbon atom(s) to which they are attached form a ring selected from aryl, heteroaryl, cycloalkyl, and heterocycle, or R 2 and R 3 together with the carbon atom to which they are attached form an alkenyl group, R d , R e and R f are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; L is a linker, Each alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl is independently optionally substituted with 1, 2, 3, 4, or 5 substituents.

[0300] In some embodiments, R 1 and R 1 ' is the same as R 2 and R 2 ' is the same as R 3 and R 3X and X' are the same, Y and Y' are the same, Z and Z' are the same, A and A' are the same, and Q and Q' are the same.

[0301] In some embodiments, R 1 and R 1 In some embodiments, R ' is heterocyclyl and is optionally substituted. 1 and R 1 In some embodiments, R ' is a 4-6 membered monocyclic heterocyclyl having 1 or 2 nitrogen atoms and is optionally substituted. 1 and R 1 Each R' is a 4- or 5-membered monocyclic heterocyclyl, such as a 4- or 5-membered heterocyclyl having one nitrogen atom, and is optionally substituted. In some embodiments, R 1 and R 1 In some embodiments, R 1 and R 1 ' is unsubstituted pyrrolidine.

[0302] In some embodiments, X and X' are -C(O)-.

[0303] In some embodiments, Y and Y′ are —NR a - and R a is selected from hydrogen and C1-C6 alkyl. In some embodiments, Y and Y' are -NR a - and R a is selected from hydrogen and methyl. In some embodiments, Y and Y' are -NR a - and R a is hydrogen.

[0304] In some embodiments, each of Z and Z' is absent.

[0305] In some embodiments, A and A' are each 5-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from S and N. In some embodiments, A and A' are selected from thiophene and thiazole. In some embodiments, A and A' are thiophene.

[0306] In some embodiments, Q and Q' are each a 4-, 5-, or 6-membered heterocyclyl having one nitrogen atom (i.e., the nitrogen atom shown in Formula (IIa)). In other words, in some embodiments, Q and Q' are selected from azetidine, pyrrolidine, and piperidine. In some embodiments, Q and Q' are selected from azetidine and pyrrolidine. In some embodiments, Q and Q' are azetidine. In some embodiments, Q and Q' are pyrrolidine.

[0307] In some embodiments, R 2 and R 2 ' is hydrogen.

[0308] In some embodiments, R 3 and R 3’ is selected from aryl, heteroaryl and groups of the formula:

[0309] [ka]

[0310] In some embodiments, R 3 and R 3’ is selected from monocyclic and bicyclic heteroaryls having 1, 2 or 3 heteroatoms independently selected from N and S.

[0311] In some embodiments, R 3 and R 3’ are groups of the formula:

[0312] [ka]

[0313] wherein B is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N, S, or O; J is absent; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0 or 1; and R g is C1-C6 alkyl, n is 0, 1 or 2, and each R h are independently selected from C-C alkyl, halo, C-C haloalkyl, amino, amino-C-C alkyl, amido-C-C alkyl, and heterocyclyl. In some embodiments, B is selected from thiazole and thiophene. In some embodiments, B is thiazole. In some embodiments, C is selected from aryl and monocyclic heteroaryl. In some embodiments, C is selected from phenyl and pyridyl. In some embodiments, at least one R h is -(CH2) r C(O)NR i R j or -(CH2) s NR k C(O)R m wherein: r and s are each independently selected from 0, 1, and 2; R i and R k are each independently selected from hydrogen and C1-C6 alkyl; R j is selected from C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, cycloalkyl, and cycloalkyl-C1-C6 alkyl; R mis selected from C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, cycloalkyl and cycloalkyl-C1-C6 alkyl, amino, C1-C6 alkylamino, arylamino, aryl-C1-C6 alkylamino; Each alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is independently unsubstituted or substituted with one or two substituents independently selected from halo, C1-C6 alkyl, C1-C6-alkoxy, hydroxy, amino and oxo.

[0314] In some embodiments, L is a linker that includes one or more groups independently selected from methylene (-CH-), vinylene (-CH=CH-), acetylene (-C≡C-), ether (-O-), amine (-NH-), alkylamine (-NR-, where R is an optionally substituted C-C alkyl group), amide (-C(O)NH-), ester (-C(O)O-), carbamate (-OC(O)NH-), sulfonamide (-S(O)NH-), phenylene (-CH-), heteroarylene, heterocyclylene, and any combination thereof.

[0315] In some embodiments, L is

[0316] [ka] JPEG0007758369000075.jpg76169

[0317] It is selected from wherein a, a1, and a2 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; b, b1, and b2 are each independently selected from 0, 1, 2, 3, 4, 5, and 6; c, c1, and c2 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; d and e are each independently selected from 0, 1, and 2; each G is independently selected from CH and N; and X 1 and X 2 each independently represents O or -NR x and the R x is hydrogen or optionally substituted alkyl, and Y 1 and Z 1 are each independently selected from —CH—, —NH—, and —O—.

[0318] In some embodiments, the compound is selected from the compounds shown in Table 2 herein, or a pharmaceutically acceptable salt thereof.

[0319] The present invention discloses a compound of formula (IIc):

[0320] [ka]

[0321] or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxy, acyl, amido, cyano, sulfonyl, and hydrogen; R 1’is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, and alkynyl; X and X' are each independently selected from absent, -C(O)-, -C(S)-, -CH2-, and -SO2-; Y and Y' each independently represent -NR a - or -O-; R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl, and aminoalkyl, or R a is that R a and the nitrogen atom to which they are bonded form a fused ring with A, or R a and R 1 together with the atoms to which they are attached form an optionally substituted heterocyclic ring; Z and Z' are each independently absent or -CR b R c - and R b and R c are each independently selected from hydrogen and alkyl; A and A' are each independently a 5-membered heteroaryl ring; Q and Q' are each independently a 4-, 5-, or 6-membered heterocycle; R 2 and R 2 each ' is independently selected from hydrogen, halo, alkyl, amino, and hydroxy; R 3 is selected from aryl, heteroaryl, heterocyclyl and groups of the formula:

[0322] [ka]

[0323] wherein B is aryl or heteroaryl; J is absent or is —CH—, —O—, —S—, or —NH—; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and R g and R h are each independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl; R 3 ' is hydrogen, halo, -OR d’ , -NR e’ R f’ , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl and groups of the formula:

[0324] [ka]

[0325] wherein B' is aryl or heteroaryl; J' is absent or is -CH2-, -O-, -S-, or -NH-; C' is selected from aryl, heteroaryl, and heterocyclyl; m' is 0, 1, 2, 3, or 4; n' is 0, 1, 2, 3, or 4; and R g’ and R h’are each independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl; R d’ , R e’ and R f’ are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; L is a linker, Each alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl is independently optionally substituted with 1, 2, 3, 4, or 5 substituents.

[0326] The present invention discloses a compound of formula (IIc):

[0327] [ka]

[0328] or a pharmaceutically acceptable salt thereof, wherein: R 1is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxy, acyl, amido, cyano, sulfonyl, and hydrogen; R 1’ is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, and alkynyl; X and X' are each independently selected from absent, -C(O)-, -C(S)-, -CH2-, and -SO2-; Y and Y' each independently represent -NR a - or -O-; R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl, and aminoalkyl, or R a is that R a and together with the nitrogen atom bonded to form a condensed ring with A, Z and Z' are each independently absent or -CR b R c - and R b and R c are each independently selected from hydrogen and alkyl; A and A' are each independently a 5-membered heteroaryl ring; Q and Q' are each independently a 4-, 5-, or 6-membered heterocycle; R 2 and R 2 each ' is independently selected from hydrogen, halo, alkyl, amino, and hydroxy; R 3 is selected from aryl, heteroaryl, heterocyclyl and groups of the formula:

[0329] [ka]

[0330] wherein B is aryl or heteroaryl; J is absent or is —CH—, —O—, —S—, or —NH—; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and R g and R h are each independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl; R 3 ' is hydrogen, halo, -OR d’ , -NR e’ R f’ , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl and groups of the formula:

[0331] [ka]

[0332] wherein B' is aryl or heteroaryl; J' is absent or is -CH2-, -O-, -S-, or -NH-; C' is selected from aryl, heteroaryl, and heterocyclyl; m' is 0, 1, 2, 3, or 4; n' is 0, 1, 2, 3, or 4; and R g’and R h’ are each independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, urea, ureaalkyl, thiourea, thioureaalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, thioalkyl, acyl, carboxy, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl; R d’ , R e’ and R f’ are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; L is a linker, Each alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl is independently optionally substituted with 1, 2, 3, 4, or 5 substituents.

[0333] In some embodiments, R 1 and R 1 ' is the same as R 2 and R 2 ' is the same as R 3 and R 3 X and X' are the same, Y and Y' are the same, Z and Z' are the same, A and A' are the same, and Q and Q' are the same.

[0334] In some embodiments, R 1 and R 1 In some embodiments, R ' is heterocyclyl and is optionally substituted. 1 and R1 In some embodiments, R ' is a 4-6 membered monocyclic heterocyclyl having 1 or 2 nitrogen atoms and is optionally substituted. 1 and R 1 Each R' is a 4- or 5-membered monocyclic heterocyclyl, such as a 4- or 5-membered heterocyclyl having one nitrogen atom, and is optionally substituted. In some embodiments, R 1 and R 1 In some embodiments, R 1 and R 1 ' is unsubstituted pyrrolidine.

[0335] In some embodiments, X and X' are -C(O)-.

[0336] In some embodiments, Y and Y′ are —NR a - and R a is selected from hydrogen and C1-C6 alkyl. In some embodiments, Y and Y' are -NR a - and R a is selected from hydrogen and methyl. In some embodiments, Y and Y' are -NR a - and R a is hydrogen.

[0337] In some embodiments, each of Z and Z' is absent.

[0338] In some embodiments, A and A' are each 5-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from S and N. In some embodiments, A and A' are selected from thiophene and thiazole. In some embodiments, A and A' are thiophene.

[0339] In some embodiments, Q and Q' are each a 4-, 5-, or 6-membered heterocyclyl having one nitrogen atom (i.e., the nitrogen atom shown in Formula (IIa)). In other words, in some embodiments, Q and Q' are selected from azetidine, pyrrolidine, and piperidine. In some embodiments, Q and Q' are selected from azetidine and pyrrolidine. In some embodiments, Q and Q' are azetidine. In some embodiments, Q and Q' are pyrrolidine.

[0340] In some embodiments, R 2 and R 2 ' is hydrogen.

[0341] In some embodiments, R 3 is selected from hydrogen, aryl, heteroaryl and groups of the formula:

[0342] [ka]

[0343] In some embodiments, R 3 is a group of the formula:

[0344] [ka]

[0345] wherein B is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N and S; J is absent; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0 or 1; and R g is C1-C6 alkyl, n is 0, 1 or 2, and each R his independently selected from C-C alkyl, halo, C-C haloalkyl, amino, amino-C-C alkyl, amido-C-C alkyl, and heterocyclyl. In some embodiments, B is selected from thiazole and thiophene. In some embodiments, B is thiazole. In some embodiments, C is selected from aryl and monocyclic heteroaryl. In some embodiments, C is selected from phenyl and pyridyl. In some embodiments, C is phenyl.

[0346] In some embodiments, R 3’ is selected from hydrogen, aryl, heteroaryl and groups of the formula:

[0347] [ka]

[0348] In some embodiments, R 3’ is selected from monocyclic and bicyclic heteroaryls having 1, 2 or 3 heteroatoms independently selected from N and S.

[0349] In some embodiments, R 3’ is a group of the formula:

[0350] [ka]

[0351] wherein B' is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N and S; J' is absent; C' is selected from aryl, heteroaryl, and heterocyclyl; m' is 0 or 1; and R g’ is C1-C6 alkyl, n' is 0, 1 or 2, and each R h’are independently selected from C-C alkyl, halo, C-C haloalkyl, amino, amino-C-C alkyl, amido-C-C alkyl, and heterocyclyl. In some embodiments, B is selected from thiazole and thiophene. In some embodiments, B is thiazole. In some embodiments, C is selected from aryl and monocyclic heteroaryl. In some embodiments, C is selected from phenyl and pyridyl. In some embodiments, C is phenyl. In some embodiments, at least one R h is -(CH2) r C(O)NR i R j or -(CH2) s NR k C(O)R m wherein: r and s are each independently selected from 0, 1, and 2; R i and R k are each independently selected from hydrogen and C1-C6 alkyl; R j is selected from C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, cycloalkyl, and cycloalkyl-C1-C6 alkyl; R m is selected from C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, cycloalkyl and cycloalkyl-C1-C6 alkyl, amino, C1-C6 alkylamino, arylamino, aryl-C1-C6 alkylamino; Each alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is independently unsubstituted or substituted with one or two substituents independently selected from halo, C1-C6 alkyl, C1-C6-alkoxy, hydroxy, amino and oxo.

[0352] In some embodiments, L is a linker that includes one or more groups independently selected from methylene (-CH-), vinylene (-CH=CH-), acetylene (-C≡C-), ether (-O-), amine (-NH-), alkylamine (-NR-, where R is an optionally substituted C-C alkyl group), amide (-C(O)NH-), ester (-C(O)O-), carbamate (-OC(O)NH-), sulfonamide (-S(O)NH-), phenylene (-CH-), heteroarylene, heterocyclylene, and any combination thereof.

[0353] In some embodiments, L is

[0354] [ka] JPEG0007758369000087.jpg76169

[0355] It is selected from wherein a, a1, and a2 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; b, b1, and b2 are each independently selected from 0, 1, 2, 3, 4, 5, and 6; c, c1, and c2 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; d and e are each independently selected from 0, 1, and 2; each G is independently selected from CH and N; and X 1 and X 2 each independently represents O or -NR x and the R x is hydrogen or optionally substituted alkyl, and Y 1 and Z 1 are each independently selected from —CH—, —NH—, and —O—.

[0356] The compounds of the present invention can be synthesized in various ways. For example, compounds of formula (I) can be synthesized as shown in Schemes 1 and 2. Generally, the compounds can be synthesized by coupling an appropriate amine with an acid using a suitable coupling agent such as HATU. (In Schemes 1 and 2, HATU refers to (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, DIPEA is N,N-diisopropylethylamine, DCM is dichloromethane, and Mt is a metal selected from Li, Na, K, etc.)

[0357] [ka]

[0358] The compounds and intermediates of the present invention may be isolated and purified by methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, recrystallization at high or low temperatures (with optional pretreatment with activated carbon), thin-layer chromatography, distillation at various pressures, vacuum sublimation, and trituration, as described, for example, in "Vogel's Textbook of Practical Organic Chemistry," 5th edition (1989) by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

[0359] The reaction conditions and reaction times for each individual step may vary depending on the specific reactants used and the substituents present in the reactants used. Specific procedures are provided in the Examples section. Workup of the reaction can be carried out in a conventional manner, for example by removing the solvent from the residue, and further purification can be carried out according to methods generally known in the art, such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise specified, starting materials and reagents are commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. If the starting materials are not commercially available, they can be prepared by procedures selected from standard organic chemistry techniques, techniques analogous to the synthesis of known structurally similar compounds, or procedures analogous to those described in the Schemes or Synthetic Examples section above.

[0360] Routine experimentation is within the scope of this disclosure, including appropriate manipulation of reaction conditions, reagents, and synthetic route sequences, protection of any chemical functional groups incompatible with the reaction conditions, and deprotection at appropriate points in the reaction sequence of the method. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art, examples of which can be found in Protective Groups in Organic Synthesis by PGM Wuts and TW Greene (4 th ed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. The compounds of the present disclosure can be synthesized by methods analogous to those described in the synthetic schemes above and in the specific examples below.

[0361] The compounds described herein may, in some cases, exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and stereoisomeric forms, as well as the appropriate mixtures thereof. Separation of stereoisomers may be carried out by chromatography, by formation of diastereomers and recrystallization or chromatographic separation, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981, incorporated herein by reference for the present disclosure.) Stereoisomers may also be obtained by stereoselective synthesis.

[0362] In some embodiments, compounds may exist as tautomers, and all tautomers are included in the formulas described herein.

[0363] Unless otherwise specified, a divalent variable or group described herein may be bonded in the orientation depicted or in the opposite orientation.

[0364] The methods and compositions described herein include the use of amorphous and crystalline forms (also known as crystalline polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, active metabolites of these compounds that have the same type of activity are also included within the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0365] In some embodiments, the compounds or salts described herein may be prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. A prodrug may be bioavailable, for example, by oral administration, while the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. Examples of prodrugs include, but are not limited to, compounds described herein that are administered as esters ("prodrugs") to facilitate permeability across cell membranes (where water solubility would hinder transport, but once inside cells where water solubility is beneficial, they are metabolically hydrolyzed to the active carboxylic acid). Another example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group, where the peptide is metabolized to reveal the active moiety. In certain embodiments, a prodrug, upon in vivo administration, is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[0366] To create a prodrug, a pharmaceutically active compound is modified so that the active compound is regenerated upon administration in vivo. Prodrugs can be designed to alter the metabolic stability or transport properties of the drug, mask side effects or toxicity, improve the flavor of the drug, or change other characteristics or properties of the drug. In some embodiments, once a pharmaceutically active compound is identified based on knowledge of in vivo pharmacodynamic processes and drug metabolism, a prodrug of that compound is designed (see, e.g., Nogrady (1985) Medicinal Chemistry: A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992) The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401; Saulnier et al., (1994) Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985; Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Miller et al., J. Med. Chem., Vol. 46, no. 24, pp. 5097-5116, 2003; Aesop Cho, "Recent Advances in Oral (See "Prodrug Discovery", Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006).

[0367] The compounds described herein may be labeled isotopically (e.g., radioisotopes) or by other means, including, but not limited to, the use of chromophores, fluorescent moieties, bioluminescent labels, photoactivatable labels, chemiluminescent labels, affinity labels (e.g., biotin), and the like.

[0368] The compounds and salts described herein include isotopically labeled compounds.Generally, isotopically labeled compounds are the same as the compounds described in various formulas and structures shown herein, except that one or more atoms are replaced by atoms with different atomic masses or mass numbers from the most common atomic masses or mass numbers in nature.Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F or 36 Certain isotopically labeled compounds described herein, for example, 3 H and 14 Compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. Additionally, deuterium, i.e. 2 Substitution with isotopes such as H may confer certain therapeutic advantages due to increased metabolic stability (eg, increased in vivo half-life or reduced dosage requirements).

[0369] In additional or further embodiments, the compounds described herein, when administered to an organism in need thereof, are metabolized to produce metabolites that are then used to provide a desired effect, including a desired therapeutic effect.

[0370] The compounds described herein may be formed and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include: (1) salts of a compound in free base form with a pharmaceutically acceptable inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, etc.) or organic acid (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]octo-2 (1) acid addition salts formed by reacting the parent compound with an acidic proton such as 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertbutylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, etc.; (2) salts formed by replacing an acidic proton present in the parent compound with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), alkaline earth ion (e.g., magnesium or calcium), or aluminum ion. Optionally, the compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, etc. Alternatively, the compounds described herein may form salts with amino acids, such as, but not limited to, arginine, lysine, etc. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0371] It should be understood that a reference to a pharmaceutically acceptable salt includes its solvent addition forms or crystalline forms, particularly solvates or crystalline polymorphs. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent and can be formed during the process of crystallization using a pharmaceutically acceptable solvent such as water, ethanol, etc. When the solvent is water, a hydrate is formed, and when the solvent is alcohol, an alcoholate is formed. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated and solvated forms. Generally, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0372] In some embodiments, the compounds described herein are in various forms, including, but not limited to, amorphous, milled, and nanoparticulate forms. In addition, the compounds described herein include crystalline forms (also known as polymorphs). Polymorphs include compounds with the same elemental composition that have different crystal packing arrangements. Polymorphs typically differ in X-ray diffraction patterns, melting points, density, hardness, crystal shape, optical properties, stability, and solubility. Various factors, such as recrystallization solvent, crystallization rate, and storage temperature, can result in a single crystalline form predominating.

[0373] Screening and characterization of pharmaceutically acceptable salts, crystalline polymorphs, and / or solvates may be performed using a variety of techniques, including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods examine heat-induced chemical decomposition or heat-induced physical processes (including, but not limited to, polymorphic transformations), and are used to analyze relationships between crystalline polymorphs, determine weight loss, identify glass transition temperatures, or for excipient compatibility testing. Such methods include, but are not limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), and thermogravimetric and infrared analysis (TG / IR). X-ray diffraction methods include, but are not limited to, single crystal diffractometers, powder diffractometers, and synchrotron radiation sources. Various spectroscopic techniques used include, but are not limited to, Raman spectroscopy, FTIR, UV-VIS, and NMR (liquid and solid phase). Various microscopy techniques include, but are not limited to, polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX), environmental scanning electron microscopy (under a gas or water vapor atmosphere) with EDX, infrared microscopy, and Raman microscopy.

[0374] Pharmaceutical Composition In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc)) or a pharmaceutically acceptable salt thereof is combined with one or more additional agents to form a pharmaceutical composition. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers containing excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically usable preparation. Proper formulation will depend on the chosen route of administration. Further details regarding suitable excipients for the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0375] As used herein, a pharmaceutical composition refers to a mixture of a compound disclosed herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc)) or a pharmaceutically acceptable salt thereof with other chemical components, such as a carrier, stabilizer, diluent, dispersant, suspending agent, thickener, and / or excipient. The pharmaceutical composition facilitates administration of the compound of the present invention to a subject. In practicing the treatment methods or uses provided herein, a therapeutically effective amount of a compound described herein is administered in a pharmaceutical composition to a subject having a disease, disorder, or condition (e.g., cancer) to be treated. In some embodiments, the subject is a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compound of the present invention or a pharmaceutically acceptable salt thereof can be used alone or in combination with one or more therapeutic agents as a component of a mixture (as in combination therapy).

[0376] The pharmaceutical formulations described herein can be administered to a subject by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration. Furthermore, the pharmaceutical compositions described herein (comprising a compound disclosed herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc)) or a pharmaceutically acceptable salt thereof) can be formulated into any suitable dosage form, including, but not limited to, oral aqueous dispersions, solutions, gels, syrups, elixirs, slurries, suspensions, aerosols, fast-dissolving formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, and capsules.

[0377] The compounds and / or compositions of the present invention may be administered in a local rather than systemic manner, for example, by injecting the compound directly into an organ or tissue, often in a depot preparation or sustained-release formulation. Such long-acting formulations may be administered by implantation (e.g., subcutaneous or intramuscular implantation) or intramuscular injection. Furthermore, the drug may be administered in a targeted drug delivery system, for example, a liposome coated with an organ-specific antibody. The liposome will be selectively directed to the organ and taken up by that organ. In addition, the drug may be provided in the form of a rapid-release formulation, a sustained-release formulation, or a formulation with a moderate release rate.

[0378] Pharmaceutical compositions containing the compounds described herein may be manufactured in conventional manner, including, by way of example only, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compressing processes.

[0379] In certain embodiments, the compositions provided herein may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0380] Oral pharmaceutical preparations can be prepared by mixing one or more solid excipients with one or more compounds disclosed herein (e.g., compounds of Formula (I), (IIa), (IIb), or (IIc)) or pharmaceutically acceptable salts thereof, optionally pulverizing the resulting mixture, and, if desired, adding suitable adjuvants, processing the granular mixture to obtain tablets, pills, or capsules. Suitable excipients include, for example, fillers such as sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose; or other excipients such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0381] The core of the sugar-coated tablets is provided with a suitable coating.For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.For identification or to characterize different combinations of active compound doses, dyes or pigments can be added to the tablets or sugar coatings.

[0382] Orally usable pharmaceutical preparations include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Push-fit capsules can contain the active ingredient mixed with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate), and optionally, a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added.

[0383] In some embodiments, the solid dosage forms disclosed herein may be in the form of a tablet (including a suspension tablet, a fast-dissolving tablet, a chewable tablet, a fast-disintegrating tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile-packed powder, a disposable powder, or an effervescent powder), a capsule (including both soft and hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), a solid dispersion, a solid solution, a bioerodible dosage form, a multiparticulate dosage form, a pellet, a granule, or an aerosol. In another embodiment, the pharmaceutical formulation is in the form of a powder. In yet another embodiment, the pharmaceutical formulation is in the form of a tablet, including, but not limited to, a fast-dissolving tablet. In addition, the pharmaceutical formulation of the compounds described herein may be administered as a single capsule or in a multi-capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, three, or four capsules or tablets.

[0384] In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing particles of a compound disclosed herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc)) or a pharmaceutically acceptable salt thereof with one or more pharmaceutical excipients to form a bulk blend composition. These bulk blend compositions are referred to as homogeneous, meaning that the particles of the compound are uniformly dispersed throughout the composition, allowing the composition to be subdivided into equally effective unit dosage forms (e.g., tablets, pills, and capsules). Individual unit dosage forms may also include a film coating that disintegrates upon oral ingestion or contact with a diluent. These formulations can be manufactured by conventional pharmaceutical techniques.

[0385] The solid pharmaceutical dosage forms described herein can comprise a compound disclosed herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc)) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, such as one or more of a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, humectant, plasticizer, stabilizer, permeation enhancer, wetting agent, antifoaming agent, antioxidant, preservative, or combinations thereof. In yet another aspect, a film coating is applied around a formulation of a compound described herein using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In one embodiment, some or all of the particles of a compound described herein are coated. In another embodiment, some or all of the particles of a compound described herein are microencapsulated. In yet another embodiment, the particles of a compound described herein are not microencapsulated and are not coated.

[0386] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0387] Fillers suitable for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0388] In order to release the compound from the solid dosage form matrix as efficiently as possible, disintegrants are often used in formulations, especially when the dosage form is compressed with a binder. Disintegrants help rupture the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Disintegrants suitable for use in the solid dosage forms described herein include natural starches such as cornstarch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, wood products, crystalline methylcellulose, such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Examples of suitable surfactants include, but are not limited to, celluloses such as Tia® and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked celluloses (such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose), crosslinked starches such as sodium starch glycolate, crospovidone, crosslinked polymers such as crosslinked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid (such as sodium alginate), clays such as Veegum® HV (magnesium aluminum silicate), gums such as agar, guar, locust bean, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in mixed starches, and the like.

[0389] Binders impart cohesion to solid oral dosage formulations; in powder-filled capsule formulations, they aid in the formation of a plug that can be filled into soft or hard capsules; and in tablet formulations, they help to maintain tablet integrity after compression and ensure blend uniformity prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603), hydroxypropyl methylcellulose acetate stearate (Aqoate®), and hydroxypropyl methylcellulose acetate stearate (Aqoate®). HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), ethyl cellulose (e.g., Ethocel®) and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, acid polysaccharides, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugars (sucrose (e.g., Dipac®), glucose, dextrin, Examples of suitable glycerin-based additives include, but are not limited to, sugar, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, etc.), natural or synthetic gums (acacia, tragacanth, gum ghatti, isapol mucilage, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethylene glycol, wax, sodium alginate, etc.

[0390] Typically, powder-filled gelatin capsule formulations use binder levels of 20-70%. Binder usage levels in tablet formulations vary depending on whether the formulation is direct compression, wet granulation, roller compaction, or the use of other excipients, such as fillers, which may themselves function as modest binders. In some embodiments, the formulator determines the binder level for the formulation, but binder usage levels of up to 70% are common in tablet formulations.

[0391] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal and alkaline earth salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol (such as Carbowax™, PEG 4000, PEG 5000, PEG 6000), propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium lauryl sulfate, sodium lauryl sulfate, and the like.

[0392] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrins), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like.

[0393] Suitable humectants for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, and the like.

[0394] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF), and the like.

[0395] Suitable suspending agents for use in the solid dosage forms described herein include polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol (e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, about 3350 to about 4000, or about 5400 to about 7000), vinylpyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyisopropylcellulose, methyl ... Examples of suitable cellulose derivatives include, but are not limited to, polysorbate 80, hydroxyethyl cellulose, sodium alginate, gums (e.g., tragacanth gum and acacia gum, guar gum, xanthans including xanthan gum, etc.), sugars, cellulose derivatives (e.g., sodium carboxymethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, etc.), polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0396] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0397] There is considerable overlap among the excipients used in the solid dosage forms described herein, and therefore the excipients listed above should be considered exemplary only and not limiting of the types of excipients that can be included in the solid dosage forms of the pharmaceutical compositions described herein.

[0398] In another embodiment, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, plasticizers are generally high-boiling solids or liquids. Suitable plasticizers can be added in amounts of about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearates, and castor oil.

[0399] Compressed tablets are solid dosage forms prepared by compressing a bulk blend of the formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth will contain one or more flavoring agents. In another embodiment, compressed tablets will contain a film surrounding the final compressed tablet. In some embodiments, the film coating aids in patient compliance (e.g., Opadry® coating or sugar coating). Film coatings, including Opadry®, typically range from about 1% to about 3% of the tablet weight. In another embodiment, compressed tablets contain one or more excipients.

[0400] Capsules may be prepared, for example, by placing a bulk blend of the compound formulation into a capsule. In some embodiments, the formulation (non-aqueous suspensions and solutions) is placed into a soft gelatin capsule. In other embodiments, the formulation is placed into a standard gelatin capsule or a non-gelatin capsule (such as a capsule containing HPMC). In other embodiments, the formulation is placed into a sprinkle capsule, which may be swallowed whole or opened and its contents sprinkled on food before eating. In some embodiments, the therapeutic agent amount is divided into multiple (e.g., 2, 3, or 4) capsules. In some embodiments, the entire dose of the formulation is delivered in capsule form.

[0401] In various embodiments, particles of a compound disclosed herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof) and one or more excipients are dry blended and compressed into a mass (e.g., a tablet) of sufficient hardness to provide a pharmaceutical composition that releases the formulation into gastrointestinal fluids by substantially disintegrating in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration.

[0402] In another aspect, the dosage form may comprise a microencapsulated formulation. In some embodiments, the microencapsulated material may contain one or more other compatible materials. Exemplary materials include, but are not limited to, pH adjusters, disintegration accelerators, antifoaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0403] Materials useful for microencapsulation as described herein include materials that are compatible with the compounds described herein and that sufficiently isolate the compounds from other incompatible excipients.

[0404] In yet another embodiment, effervescent powders are also prepared in accordance with the present disclosure. Effervescent salts are used to disperse medications in water for oral administration. Effervescent salts are granules or coarse powders containing a drug in a dry mixture typically composed of sodium bicarbonate, citric acid, and / or tartaric acid. When such salts are added to water, the acid and base react to liberate carbon dioxide gas, thereby creating an "effervescent" effect. Examples of effervescent salts include sodium bicarbonate or a mixture of sodium bicarbonate with sodium carbonate, citric acid, and / or tartaric acid. Instead of the combination of sodium bicarbonate with citric acid and tartaric acid, any combination of acids and bases that liberate carbon dioxide can be used, as long as the components are suitable for pharmaceutical use and provide a pH of about 6.0 or higher.

[0405] In another embodiment, the formulations described herein are solid dispersions. Methods for making such solid dispersions include, but are not limited to, U.S. Patent Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269, and U.S. Patent Application Publication No. 2004 / 0013734. In yet another embodiment, the formulations described herein are solid solutions. Solid solutions incorporate a substance along with an active agent and other excipients, and upon heating the mixture, the drug dissolves. The resulting composition is then cooled to provide a solid blend that can be further compounded, added directly to capsules, or compressed into tablets. Methods for making such solid solutions include, but are not limited to, U.S. Patent Nos. 4,151,273, 5,281,420, and 6,083,518.

[0406] In some embodiments, a pharmaceutical formulation is provided for oral administration to a subject, comprising particles of a compound disclosed herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc)) or a pharmaceutically acceptable salt thereof, and at least one dispersing or suspending agent. The formulation may be a powder and / or granules for suspension, which upon addition of water and mixing provides a substantially uniform suspension.

[0407] The dosage form of the liquid formulation for oral administration can be an aqueous suspension selected from the group including, but not limited to, pharmaceutically acceptable oral aqueous dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).

[0408] The aqueous suspensions and dispersions described herein can maintain a homogeneous state for at least 4 hours, as defined in The USP Pharmacists' Pharmacopeia (2005 Edition, Chapter 905). Homogeneity should be determined by a consistent sampling method with respect to determining the homogeneity of the entire composition. In one embodiment, the aqueous suspension can be resuspended to a homogeneous suspension by physical agitation lasting less than 1 minute. In another embodiment, the aqueous suspension can be resuspended to a homogeneous suspension by physical agitation lasting less than 45 seconds. In yet another embodiment, the aqueous suspension can be resuspended to a homogeneous suspension by physical agitation lasting less than 30 seconds. In yet another embodiment, agitation is not required to maintain a homogeneous aqueous dispersion.

[0409] The pharmaceutical compositions described herein may include a sweetening agent, which may be selected from the group consisting of acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarois, berry, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, and cyclamate. , Silamate, Dextrose, Eucalyptus, Eugenol, Fructose, Fruit Punch, Ginger, Glycyrrhetinate, Licorice Syrup, Grapes, Grapefruit, Honey, Isomalt, Lemon, Lime, Lemon Cream, Monoammonium Glycyrrhizinate (MagnaSweet®), Maltol, Mannitol, Maple, Marshmallow, Menthol, Mint Cream, Mixed Berry, Neohesperidin DC, Neotame, Orange, Se Pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talc, sucralose, sorbitol, Swiss cream, tagatose, tannins Flavoring ingredients include, but are not limited to, anise, thaumatin, tutti-frutti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

[0410] In some embodiments, the pharmaceutical formulations described herein can be self-emulsifying drug delivery systems (SEDDS). Emulsions are a dispersion of one immiscible phase in another, usually in the form of droplets. Generally, emulsions are created by strong mechanical dispersion. In contrast to emulsions or microemulsions, SEDDSs spontaneously form emulsions when added to excess water without any external mechanical dispersion or agitation. The advantage of SEDDSs is that gentle mixing is all that is required to distribute the droplets throughout the solution. In addition, water or an aqueous phase can be added immediately before administration, thereby ensuring the stability of unstable or hydrophobic active ingredients. Thus, SEDDSs provide an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDSs can improve the bioavailability of hydrophobic active ingredients. Methods for making self-emulsifying dosage forms include, but are not limited to, those described in US Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.

[0411] There is some overlap among the above-listed additives for use in the aqueous dispersions or suspensions described herein, as a given additive is often classified differently by different practitioners in the art or is commonly used for any of several different functions. Thus, the above-listed additives should be considered exemplary only and not limiting of the types of additives that can be included in the formulations described herein.

[0412] Pharmaceutical excipients for intranasal formulations include, for example, U.S. Patent Nos. 4,476,116, 5,116,817, and 6,391,452. For formulation solutions in saline, benzyl alcohol or other suitable preservatives, fluorocarbons, and / or other solubilizing or dispersing agents are used. See, for example, Ansel, H.C. et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably, these compositions and formulations are prepared with suitable non-toxic pharmaceutically acceptable ingredients. The selection of an appropriate carrier largely depends on the exact nature of the desired intranasal dosage form, e.g., a solution, suspension, ointment, or gel. Intranasal dosage forms generally contain a large amount of water in addition to the active ingredient. Minor amounts of other ingredients, such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffers, and other stabilizers and solubilizers, may also be present. Preferably, the dosage form for nasal administration should be isotonic with nasal secretions.

[0413] For administration by inhalation, the compounds described herein may be in the form of aerosol, mist, or powder.The pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount.By way of example only, capsules and cartridges, such as gelatin, for use in an inhaler or insufflator can be formulated to contain a powder mix of the compounds described herein and a suitable powder base, such as lactose or starch.

[0414] Oral formulations containing the compounds described herein may be administered using a variety of formulations, including, but not limited to, those described in U.S. Patent Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136. In addition, the oral dosage forms described herein can further include a biodegradable (hydrolyzable) polymer carrier that also serves to adhere the dosage form to the oral mucosa. The oral dosage form is designed to gradually degrade over a predetermined period of time, essentially delivering the compound throughout this period. Drug delivery into the oral cavity avoids the problems associated with oral drug administration, such as slow absorption, degradation of the active agent due to fluids present in the gastrointestinal tract and / or first-pass inactivation in the liver. With regard to bioerodible (hydrolyzable) polymeric carriers, virtually any polymeric carrier can be used, so long as the desired drug release profile is not compromised and the carrier is compatible with the compounds described herein and any other ingredients that may be present in the buccal dosage unit. Generally, polymeric carriers include hydrophilic (water-soluble and water-swellable) polymers that adhere to the moist surface of the oral mucosa. Examples of polymeric carriers useful in the present invention include acrylic acid polymers and, for example, polymers known as "carbomers" (Carbopol®, available from BFGoodrich, is one such polymer). Other ingredients may also be incorporated into the buccal dosage forms described herein, including, but not limited to, disintegrants, diluents, binders, lubricants, flavoring agents, coloring agents, preservatives, and the like. For buccal or sublingual administration, the compositions of the present invention may take the form of tablets, lozenges, or gels formulated in a conventional manner.

[0415] The transdermal formulations described herein may be administered using a variety of devices, including those described in U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, and 4,031,899. 4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144.

[0416] The transdermal dosage forms described herein may incorporate certain pharmaceutically acceptable excipients conventional in the art. In one embodiment, the transdermal formulations described herein comprise at least three components: (1) a formulation of a compound disclosed herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc)) or a pharmaceutically acceptable salt thereof, (2) a permeation enhancer, and (3) an aqueous adjuvant. In addition, the transdermal formulations may comprise additional components, such as, but not limited to, gelling agents, cream and ointment bases, etc. In some embodiments, the transdermal formulations may further comprise a woven or nonwoven backing to enhance absorption and prevent the transdermal formulation from peeling off the skin. In another embodiment, the transdermal formulations described herein may maintain a saturated or supersaturated state to facilitate diffusion into the skin.

[0417] Formulations suitable for transdermal administration of the compounds described herein may be transdermal delivery devices and transdermal delivery patches, which may be lipophilic emulsions or aqueous buffered solutions dissolved and / or dispersed in polymers or adhesives. Such patches may be constructed for sustained, pulsatile, or on-demand delivery of pharmaceutical agents. Furthermore, transdermal delivery of the compounds described herein may be achieved by iontophoretic patches and the like. Additionally, transdermal patches may provide controlled delivery of the compounds described herein. Absorption rates can be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption can be enhanced by using absorption enhancers. The absorption enhancer or carrier can include absorbable pharmaceutically acceptable solvents to aid passage through the skin. For example, a transdermal device may be in the form of a bandage containing a reservoir containing the compound, along with a backing member, optional carrier, and optionally a rate-controlling barrier for delivering the compound of the present invention to the skin of the recipient at a controlled, predetermined rate over an extended period of time, along with a means for securing the device to the skin.

[0418] Formulations suitable for intramuscular, subcutaneous, or intravenous injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, cremophor, etc.), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preservatives, wetting agents, emulsifying agents, and dispensing agents. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.

[0419] For intravenous injection, the compounds described herein may be formulated in aqueous solution, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution or physiological saline buffer.For transmucosal administration, a penetrant suitable for the barrier to be permeated is used in the formulation.Such penetrants are generally recognized in the art.For other parenteral injection, suitable formulations may include aqueous or non-aqueous solutions, preferably with physiologically compatible buffers or excipients.Such excipients are generally recognized in the art.

[0420] Parenteral injections may include bolus injections or continuous infusions. Injectable preparations may be provided in unit dosage form, e.g., in ampoules, or in multi-dose containers with added preservatives. The pharmaceutical compositions described herein may be in a form suitable for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending agents, stabilizers, and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. Additionally, suspensions of the active compound may be prepared as suitable oily suspensions for injection. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous suspensions for injection may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0421] In certain embodiments, delivery systems for pharmaceutical compounds, such as liposomes and emulsions, may be used. In certain embodiments, the compositions provided herein also include a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0422] In some embodiments, the compounds described herein may be administered topically and are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compounds can include solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives.

[0423] The compounds described herein may be formulated in rectal compositions (such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas) containing conventional suppository bases (cocoa butter or other glycerides) and synthetic polymers (such as polyvinylpyrrolidone, PEG, etc.) In suppository forms, a low-melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally combined with cocoa butter, is first melted.

[0424] Generally, agents such as the compounds disclosed herein (e.g., compounds of Formula (I), (IIa), (IIb), or (IIc) or pharmaceutically acceptable salts thereof) are administered in an amount effective to ameliorate a disease or disorder or prevent the onset of its symptoms (i.e., a therapeutically effective amount). Thus, a therapeutically effective amount can be an amount that can at least partially prevent or reverse a disease or disorder. The dosage required to achieve an effective amount can vary depending on the agent, formulation, disease or disorder, and the individual receiving the agent.

[0425] Determining the effective amount may also involve in vitro assays in which various doses of the drug are administered to cultured cells to determine the concentration of the drug effective to ameliorate some or all symptoms in order to calculate the concentration needed in vivo. Effective amounts may also be based on in vivo animal studies.

[0426] The agent can be administered before, concurrently with, and after the onset of symptoms of the disease or disorder, hi some embodiments, the agent is administered to a subject with a family history of the disease or disorder, a subject with a phenotype that may indicate a predisposition to the disease or disorder, or a subject with a genetic type that predisposes the subject to the disease or disorder.

[0427] In some embodiments, the compositions described herein are provided as pharmaceutical and / or therapeutic compositions. The pharmaceutical and / or therapeutic compositions of the present invention can be administered in a variety of ways, depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be topical (including ophthalmic, vaginal, and rectal administration to mucous membranes), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including administration by nebulizer, intratracheal, intranasal, epidermal, and transdermal administration), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion, or intracranial administration, e.g., intrathecal or intraventricular administration. Compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional carriers, aqueous bases, powder bases, oily bases, thickeners, and the like, may be necessary or desirable. Compositions and formulations for oral administration include powders, granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids, or binders may be desirable. Compositions and formulations for parenteral, intrathecal, or intracerebroventricular administration may include sterile aqueous solutions, which may also contain buffers, diluents, and other additives, such as, but not limited to, permeation enhancers, carrier compounds, and other pharmaceutically acceptable carriers or excipients. Pharmaceutical and / or therapeutic compositions of the present invention include, but are not limited to, solutions, emulsions, and liposomes containing the formulation. These compositions can be generated from a variety of components, including, but not limited to, preformed liquids, self-emulsifying solids, and self-emulsifying semisolids.

[0428] Pharmaceutical and / or therapeutic formulations, which can conveniently be provided in unit dosage form, can be prepared according to conventional techniques well known in the pharmaceutical / nutraceutical industries. Such techniques include the step of bringing into association the active ingredient with the pharmaceutical carrier(s) or excipient(s). Generally, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if desired, shaping the product. The compositions of the present invention can be formulated into any of many possible dosage forms, including, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present invention can also be formulated as suspensions in aqueous, non-aqueous, oil-based, or mixed media. Suspensions can further contain substances that increase the viscosity of the suspension, including, for example, sodium carboxymethylcellulose, sorbitol, and / or dextran. Suspensions can also contain stabilizers. In one embodiment of the present invention, the pharmaceutical compositions of the present invention can be formulated and used as effervescent agents. Pharmaceutical foaming agents include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies, and liposomes, which are essentially similar in nature but differ in the composition and consistency of the final product.

[0429] The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of a precise dosage. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dosage may be in the form of a package containing discrete amounts of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be in non-reclosable single-dose containers. Alternatively, reclosable multi-dose containers can be used, in which case preservatives are typically included in the composition. By way of example only, formulations for parenteral injection may be provided in unit dosage form, including, but not limited to, in ampoules or multi-dose containers with added preservatives.

[0430] Dosage and administration regimens are adjusted by a clinician or other skilled in the art of pharmacology based on well-known pharmacological and therapeutic considerations, including, but not limited to, the desired level of therapeutic effect and the actual level of therapeutic effect that can be achieved. Generally, it is prudent to follow well-known pharmacological principles regarding the administration of chemotherapeutic agents (e.g., it is generally prudent not to change the dosage by more than 50% at a time and more frequently than every 3-4 half-lives of the drug). For compositions where dose-related toxicity considerations are relatively minor or nonexistent, and where maximal efficacy is desired, dosing above the average required dose is not uncommon. This dosing approach is commonly referred to as a "maximum dose" strategy. In certain embodiments, the compounds of the present invention are administered to a subject at a dose of about 0.01 mg / kg to about 200 mg / kg, more preferably about 0.1 mg / kg to about 100 mg / kg, and even more preferably about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are administered in combination with another agent (e.g., a sensitizing agent), the effective amount may be less than when the agent is used alone. Dosing may be once daily or multiple times daily for one or more consecutive days.

[0431] Usage / Treatment The present disclosure provides methods of using the compounds and compositions described herein (e.g., compounds of Formula (I), (IIa), (IIb), and (IIc) or pharmaceutically acceptable salts thereof), including methods of inhibiting GAS41 and treating diseases such as cancer.

[0432] In certain embodiments, the present disclosure provides a method of inhibiting GAS41 activity in a sample, the method comprising contacting the sample with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof). The sample can be an in vitro sample or an ex vivo sample (e.g., a sample comprising cells, tissues, or organs).

[0433] In some embodiments, the present disclosure provides methods for inhibiting GAS41 activity by contacting an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt thereof) with GAS41, e.g., by contacting a cell, tissue, or organ expressing GAS41 with a compound of the present invention or a salt thereof. In some embodiments, the present disclosure provides methods for inhibiting GAS41 activity in a subject (including, but not limited to, a rodent and a mammal (e.g., a human)) by administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt thereof). In some embodiments, the inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0434] In some embodiments, the disclosure provides a method of inhibiting GAS41 activity in a cell, the method comprising contacting the cell with a compound described herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof) in an amount sufficient to inhibit the activity. In some embodiments, the disclosure provides a method of inhibiting GAS41 activity in a tissue by contacting the tissue with a compound described herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof) in an amount sufficient to inhibit GAS41 activity in the tissue. In some embodiments, the disclosure provides a method of inhibiting GAS41 activity in an organism (e.g., a mammal, a human, etc.) by contacting the organism with a compound described herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof) in an amount sufficient to inhibit GAS41 activity in the organism.

[0435] Inhibition of GAS41 activity may be assessed and demonstrated by a variety of methods known in the art. Non-limiting examples include measures of (a) a direct reduction in GAS41 activity, (b) a reduction in cell proliferation and / or cell viability, (c) an increase in cell differentiation, (d) a reduction in the levels of downstream targets of GAS41 activity, and (e) a reduction in tumor volume and / or a reduction in the rate of tumor volume growth. Kits and commercially available assays are available to determine one or more of the above.

[0436] The present disclosure also provides a method of treating cancer in a subject in need thereof (e.g., a subject suffering from cancer), comprising administering to the subject a compound or pharmaceutical composition described herein (e.g., a compound of Formula (I), (IIa) or (IIb) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), (IIa) or (IIb) or a pharmaceutically acceptable salt thereof). In certain embodiments, the cancer is associated with GAS41 expression (e.g., aberrant expression, overexpression, etc.) and / or activity. In certain embodiments, the cancer is a brain tumor (e.g., astrocytoma or glioblastoma), a sarcoma, colon cancer, lung cancer (e.g., non-small cell lung cancer), or gastric cancer.

[0437] In certain embodiments, the present disclosure provides a method of treating cancer in a subject, the method comprising determining whether the subject has a GAS41-mediated cancer and administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt thereof).

[0438] Determining whether a tumor or cancer expresses (e.g., overexpresses, aberrantly expresses, etc.) GAS41 can be done by evaluating the nucleotide sequence encoding GAS41 or by evaluating the amino acid sequence of GAS41. Methods for detecting GAS41 nucleotide sequences are known to those of skill in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, variant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. Methods for detecting GAS41 protein are known to those of skill in the art. These methods include, but are not limited to, detection using GAS41-specific binding agents, such as antibodies, protein electrophoresis and Western blots, and direct peptide sequencing.

[0439] Methods for determining whether a tumor or cancer expresses (e.g., overexpresses, aberrantly expresses, etc.) GAS41 or is mediated by GAS41 activity can use a variety of samples. In some embodiments, the sample is obtained from a subject with cancer or a tumor. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed, paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0440] The present disclosure also relates to a method of treating a hyperproliferative disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt thereof).In some embodiments, the methods of the present invention are directed to treating acute myeloid leukemia, adolescent cancers, childhood adrenocortical carcinoma, AIDS-related cancers such as lymphoma and Kaposi's sarcoma, anal cancer, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, chondrosarcoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, Colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic bile duct carcinoma in situ (DCIS), germinoma, CNS cancer, uterine cancer, ependymoma, epithelioid sarcoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational choriocarcinoma, glioblastoma, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, leiomyosarcoma , lip and oral cavity cancer, liposarcoma, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer of unknown primary site, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma, myxofibrosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer , papillomatosis, paraganglioma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, renal pelvis and ureteral transitional cell carcinoma, trophoblastic tumor, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer or virus-induced cancer.In some embodiments, the methods of the invention relate to the treatment of non-cancerous hyperproliferative disorders such as benign skin hyperplasia, e.g., psoriasis, restenosis, or prostate, e.g., benign prostatic hyperplasia (BPH). In some embodiments, the methods of the invention relate to the treatment of brain tumors (e.g., astrocytoma or glioblastoma), sarcoma, colon cancer, lung cancer (e.g., non-small cell lung cancer), or gastric cancer.

[0441] Subjects that can be treated with the compounds of the present disclosure according to the methods of the present disclosure include, for example, acute myeloid leukemia, adolescent cancers, childhood adrenocortical carcinoma, AIDS-related cancers such as lymphoma and Kaposi's sarcoma, anal cancer, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, chondrosarcoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), ), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic bile duct carcinoma in situ (DCIS), germinoma, CNS cancer, uterine cancer, ependymoma, epithelioid sarcoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational choriocarcinoma, glioblastoma, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, Laryngeal cancer, leiomyosarcoma, lip and oral cavity cancer, liposarcoma, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer of unknown primary, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma, myxofibrosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer These include subjects who have been diagnosed with focal carcinoma, pancreatic cancer, papillomatosis, paraganglioma, nasal / sinonasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, renal pelvis / ureter transitional cell carcinoma, trophoblastic tumor, rare pediatric cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.In some embodiments, the methods of the invention relate to the treatment of non-cancerous hyperproliferative disorders such as benign skin hyperplasia, e.g., psoriasis, restenosis, or prostate, e.g., benign prostatic hyperplasia (BPH). In some embodiments, the subject has been diagnosed with a brain tumor (e.g., astrocytoma or glioblastoma), a sarcoma, colon cancer, lung cancer (e.g., non-small cell lung cancer), or gastric cancer.

[0442] The compositions containing the compounds described herein or their salts can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compounds or compositions are administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease. Amounts effective for this application will depend on the severity and course of the disease, previous treatments, the patient's health status, weight, and response to drugs, and the judgment of the treating clinician.

[0443] In prophylactic applications, compositions containing the compounds described herein or salts thereof are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." Again, the precise amount for this application will depend on the patient's health, weight, and the like. When used in patients, the effective amount for this application will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health, and response to the drugs, as well as the judgment of the treating clinician.

[0444] If the patient's condition does not improve, administration of the compounds of the invention may be chronic, i.e., for an extended period of time, including the entire lifespan of the patient, at the discretion of the clinician, to ameliorate or otherwise control or limit the symptoms of the patient's disease.

[0445] If the patient's condition improves, at the discretion of the clinician, administration of the compounds of the invention may continue, or the administered drug dose may be temporarily reduced or discontinued for a specified period of time (i.e., a "drug holiday"). The length of the drug holiday may vary from 2 days to 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during the drug holiday period may be from about 10% to about 100%, including, by way of example only, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 100%.

[0446] Once the patient's condition has improved, a maintenance dose is administered if necessary. Thereafter, the dosage or frequency of administration, or both, can be reduced depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. However, the patient may require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0447] The amount of a given agent corresponding to such an amount will vary depending on factors such as the particular compound, the disease and its severity, and the characteristics (e.g., body weight) of the subject or recipient requiring treatment, but can be determined in an art-recognized manner according to the particular circumstances surrounding the case, including, for example, the specific agent being administered, the route of administration, the condition being treated, and the subject or recipient being treated. In general, however, dosages used for adult human treatment will typically range from about 0.02 to about 5000 mg per day, and in some embodiments, from about 1 to about 1500 mg per day. The desired dosage may conveniently be provided in a single dose or as divided doses administered simultaneously (or closely spaced) or at appropriate intervals, e.g., two, three, four or more subdoses per day.

[0448] The toxicity and therapeutic efficacy of such treatment regimens can be determined in cultured cells or experimental animals by standard pharmaceutical procedures, including LD 50 (lethal dose in 50% of the population) and ED 50 Examples of useful measurements include, but are not limited to, determining the dose that is therapeutically effective in 50% of a population. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 Compounds with a high therapeutic index are preferred. Data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for human use. The dosage of such compounds can be selected to achieve an ED 100 with minimal toxicity. 50 The dosage may vary within this range depending on the dosage form and route of administration employed.

[0449] Combination therapy Provided herein are methods of combination therapy using agents known to modulate other pathways or other components of the same pathway, or even an overlapping set of target enzymes, in combination with a compound described herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt thereof). In one aspect, such therapy includes, but is not limited to, combining one or more of the disclosed compounds with chemotherapeutic agents, targeted agents, therapeutic antibodies, and / or radiation therapy to provide a synergistic or additive therapeutic effect.

[0450] Generally, in embodiments using the compounds and compositions described herein and combination therapies, the other agent need not be administered in the same pharmaceutical composition, but may need to be administered by a different route due to different physical and chemical characteristics. When administration in the same pharmaceutical composition is possible, the method of administration and the determination of the appropriateness of administration are well within the knowledge of the clinician. Initial administration can be performed according to established protocols recognized in the art, and thereafter the dosage, method of administration, and time of administration can be modified by the clinician based on the observed effects.

[0451] In certain cases, it may be appropriate to administer at least one of the compounds described herein in combination with another therapeutic agent. By way of example only, if nausea is one of the side effects experienced by a patient upon administration of a compound described herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof), it may be appropriate to administer an antiemetic agent in combination with the initial therapeutic agent. Alternatively, by way of example only, the therapeutic efficacy of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., the adjuvant itself may have minimal therapeutic effect, but when combined with another therapeutic agent, the overall therapeutic effect on the patient is increased). Alternatively, by way of example only, a patient may experience an increased benefit from administration of one of the compounds described herein with another therapeutically effective therapeutic agent (including a treatment regimen). In either case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may simply be the additive effect of the two therapeutic agents, or the patient may experience a synergistic effect.

[0452] The specific choice of compounds to be used will depend on the diagnosis and assessment of the patient's condition and the appropriate treatment protocol. The compounds of the present invention may be administered concomitantly (e.g., simultaneously, essentially simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the patient's disease, disorder, or condition and the actual choice of compounds to be used. After evaluating the disease to be treated and the patient's condition, the decision of the order of administration of each therapeutic agent during the treatment protocol and the number of times administration should be repeated is well within the knowledge of the clinician.

[0453] When drugs are used in combination therapy, the therapeutically effective dosage may vary. Methods for experimentally determining the therapeutically effective dosage of drugs and other agents used in combination therapy regimens are described in the literature. For example, the use of metronomic dosing, i.e., delivering smaller doses more frequently, to minimize toxic side effects has been widely described in the literature. Combination therapy also includes intermittent therapy, which is started and stopped at various times to aid in the clinical management of patients.

[0454] In the combination therapies described herein, the dosage of the co-administered compounds will, of course, vary depending on the type of co-medication used, the specific drug used, the disease being treated, etc. Additionally, when co-administered with one or more bioactive agents, the compounds provided herein may be administered simultaneously with the bioactive agent(s) or sequentially. If administered sequentially, the attending physician will determine the appropriate sequence for administering the protein in combination with the bioactive agent(s).

[0455] In either case, the multiple therapeutic agents (one of which is a compound described herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt thereof)) may be administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form or in multiple forms (by way of example only, either as a single pill or two separate pills). One of the therapeutic agents may be administered in multiple doses, or both may be administered in multiple doses. If not simultaneously, the timing between the multiple administrations may vary from more than zero weeks to less than four weeks. Additionally, the combination methods, compositions, and formulations are not limited to the use of only two agents, but also contemplate the use of multiple therapeutic agents in combination.

[0456] It is understood that the dosage regimen for treating, preventing or ameliorating the condition(s) for which relief is sought can be modified according to various factors. These factors include the disorder or condition from which the subject suffers, as well as the age, weight, sex, diet and medical condition of the subject. That is, the dosage regimen actually used can vary widely and therefore may deviate from the dosage regimen set forth herein.

[0457] The pharmaceutical agents constituting the combination therapy disclosed herein may be in a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. The pharmaceutical agents constituting the combination therapy may be administered sequentially, with each therapeutic compound being administered by a regimen requiring two-step administration. The two-step administration regimen may require sequential administration of the active agents or separate administration of the active agents at intervals. The interval between multiple administration steps may range from minutes to hours, depending on the properties of each agent, such as drug potency, solubility, bioavailability, plasma half-life, and kinetic profile. Circadian variations in target molecule concentrations may determine optimal dose intervals.

[0458] In addition, the compounds described herein may be used in combination with procedures that may provide an additive or synergistic effect to the patient. By way of example only, it is expected that patients will find therapeutic and / or prophylactic benefit in methods described herein that combine pharmaceutical compositions of the compounds disclosed herein in combination with other therapeutic agents with genetic testing to determine whether the individual is a carrier of a variant gene known to be correlated with a particular disease or condition.

[0459] The compounds and combination therapies described herein can be administered before, during, or after the onset of a disease, and the timing of administering a composition containing the compound can vary. For example, the compounds can be used prophylactically and administered continuously to a subject prone to developing a condition or disease to prevent the onset of the disease. The compounds and compositions of the present invention can be administered to a subject during or as soon as possible after the onset of symptoms. Administration of the compounds of the present invention can begin within the first 48 hours of the onset of symptoms, preferably within the first 48 hours of the onset of symptoms, more preferably within the first 6 hours of the onset of symptoms, and most preferably within 3 hours of the onset of symptoms. Initial administration can be by any practical route, such as intravenous injection, bolus injection, infusion over about 5 minutes to about 5 hours, pill, capsule, transdermal patch, buccal delivery, or the like, or a combination thereof. The compounds are preferably administered as soon as practicable after the onset of the disease is detected or suspected, for the period required to treat the disease (e.g., 1 day to about 3 months). The length of treatment may vary from subject to subject, and can be determined using known criteria. For example, the compound of the present invention or a formulation containing the compound can be administered for at least 2 weeks, preferably from about 1 month to about 5 years.

[0460] The compounds and pharmaceutical compositions disclosed herein may be administered in combination with one or more chemotherapeutic agents. Currently, many chemotherapeutic agents are known in the art and can be used in combination with the compounds of the present invention. In some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, protein-protein interaction inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0461] Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules (such as Gleevec® (imatinib mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and adriamycin), as well as numerous chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents (such as thiotepa and cyclophosphamide (CYTOXAN™)), alkyl sulfonates (such as busulfan, improsulfan, and piposulfan), aziridines (such as benzodopa, carboquone, meturedopa, and uredopa), ethylenimines, and methylmelamines (including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine). , nitrogen mustards (chlorambucil, chlornafazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, uracil mustard, etc.), nitrosoureas (carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, etc.), antibiotics (aclacinomycin, actinomycin, australis) Mycobacterium difficile, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potofilomycin anti-metabolites (methotrexate and 5-fluorouracil (5-FU) etc.), folic acid analogs (denopterin, methotrexate, pteropterin, trimetrexate etc.), purine analogs (fludarabine, 6-mercaptopurine, thiamiprine, thioguanine etc.), pyrimidine analogs (ancitabine,Azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, etc.), androgens (calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone, etc.), antiadrenal agents (aminoglutethimide, mitotane, trilostane, etc.), folic acid supplements (floric acid, etc.), aceglatone, aldophosphamide glycoside, aminolevulinic acid, amsacrine, bestravcil, bisantrene, edatrexate, defofamine, demecolcine, diaziquone, elfornithine, elliptinium acetate, etoglucide, gallium nitrate, hydroxybenzoates Urea, lentinan, lonidamine, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenamet, pirarubicin, podophyllic acid, 2-ethylhydrazide, procarbazine, PSK®, razoxane, sizofiran, spirogermanium, tenuazonic acid, triazicon, 2,2′,2″-trichlorotriethylamine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside (“Ara-C”), cyclophosphamide, thiotepa, taxanes, e.g., paclitaxel (TAXOL®, Bristol-Myers Squibb), Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France), retinoic acid, esperamicin, capecitabine, and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Suitable chemotherapeutic cell regulators include antihormonal agents that regulate or inhibit the effects of hormones on tumors (e.g., antiestrogens including tamoxifen (Nolvadex™), raloxifene, 4(5)-imidazoles that inhibit aromatase, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston), etc.), antiandrogens (e.g., flutamide, nilutamide, bicalutamide, leuprolide, and goserelin), chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine,Also included are methotrexate, platinum analogs (such as cisplatin and carboplatin), vinblastine, platinum, etoposide (VP-16), ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, navelbine, novantrone, teniposide, daunomycin, aminopterin, xeloda, ibandronate, camptothecin-11 (CPT-11), the topoisomerase inhibitor RFS2000, and difluoromethylornithine (DMFO). If desired, the compounds or pharmaceutical compositions of the present invention may be used in combination with other drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alfa, cefotaxime ... Phalazine, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antitumor agent, antitumor herbal medicine, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, biricodal, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle non-specific antitumor agent, diclofenac loracetate, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucantone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nephrotic steroids Daplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan,It can be used in combination with commonly prescribed anti-cancer drugs such as vinflunine, ZD6126, or zosuquidar.

[0462] Embodiments of the present invention further relate to methods of using a compound disclosed herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition provided herein, in combination with radiation therapy to inhibit abnormal cell growth or treat a hyperproliferative disorder in a mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. Administration of a compound of the present invention in this combination therapy can be determined as described herein.

[0463] Radiation therapy can be administered by one of several methods, or a combination of methods, including, but not limited to, external beam radiation therapy, internal radiation therapy, interstitial irradiation, stereotactic radiotherapy, systemic radiotherapy, radiotherapy, and permanent or temporary interstitial brachytherapy. The term "brachytherapy," as used herein, refers to radiation therapy administered by a spatially confined radioactive material inserted within the body or near the site of a tumor or proliferative diseased tissue. This term is intended to include, but is not limited to, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as cell regulators of the present invention include both solid and liquid sources. By way of non-limiting example, the radioactive source can be a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid radioactive source, I-125 as a solid radioactive source, or other radionuclides that emit photons, beta particles, gamma rays, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of the radionuclide(s), e.g., a solution of I-125 or I-131, or a radioactive fluid can be made using a slurry of an appropriate fluid containing microparticles of a solid radionuclide, such as Au-198, Y-90. Additionally, the radionuclide(s) can be embodied in a gel or radioactive microspheres.

[0464] The compounds or pharmaceutical compositions of the invention are also used in combination with an amount of one or more agents selected from an anti-angiogenic agent, a signal transduction inhibitor, an anti-proliferative agent, a glycolysis inhibitor, or an autophagy inhibitor.

[0465] Antiangiogenic agents such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors can be used in conjunction with the compounds of the present disclosure and the pharmaceutical compositions described herein. Antiangiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include CELEBREX™ (celecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors include those disclosed in WO96 / 33172 (published October 24, 1996), WO96 / 27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO98 / 07697 (published February 26, 1998), WO98 / 03516 (published February 26, 1998), and WO98 / 03516 (published March 7, 1996). WO98 / 34918 (published January 29, 1998), WO98 / 34915 (published August 13, 1998), WO98 / 33768 (published August 6, 1998), WO98 / 30566 (published July 16, 1998), European Patent Publication No. 606,046 (published July 13, 1994), European Patent Publication No. 931,788 (published July 28, 1999), WO90 / 0 5719 (published May 31, 1990), WO99 / 52910 (published October 21, 1999), WO99 / 52889 (published October 21, 1999), WO99 / 29667 (published June 17, 1999), International Application PCT / IB98 / 01113 (filed July 21, 1998), European Patent Application Publication No. 99302232.1 (filed March 25, 1999), UK Patent Application No. 991296 No. 1.1, filed June 3, 1999, U.S. Provisional Patent Application No. 60 / 148,464, filed August 12, 1999, U.S. Patent No. 5,863,949, issued January 26, 1999, U.S. Patent No. 5,861,510, issued January 19, 1999, and European Patent Publication No. 780,386, published June 25, 1997, all of which are incorporated herein by reference in their entireties.Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred are inhibitors that selectively inhibit MMP-2 and / or MMP-9 relative to other matrix metalloproteinases (e.g., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO32-3555, and RS13-0830.

[0466] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibitory algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels (such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine). Additionally, antisense or siRNA inhibitors that inhibit the expression of proteins, including, but not limited to, ATG5 (involved in autophagy), may also be used.

[0467] In some embodiments, the compounds described herein are formulated or administered in conjunction with a liquid or solid tissue barrier (also known as a lubricant). Examples of tissue barriers include, but are not limited to, polysaccharides, polyglycans, Seprafilm, Interceed, and hyaluronic acid.

[0468] In some embodiments, the pharmaceutical agents administered in conjunction with the compounds described herein can be any suitable drug typically delivered by inhalation, for example, analgesics such as codeine, dihydromorphine, ergotamine, fentanyl, or morphine; antianginal preparations such as diltiazem; antiallergic agents such as cromoglycate, ketotifen, or nedocromil; anti-infectives such as cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines, or pentamidine; antihistamines such as methapyrilene; anti-inflammatory agents such as beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide, or fluticasone; antitussives such as noscapine; bronchodilators such as ephedrine, adrenaline, fenoterol, formoterol, or the like. anticholinergics such as ipratropium, atropine or oxitropium; hormones such as cortisone, hydrocortisone or prednisolone; xanthines such as aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides such as insulin or glucagon. It will be apparent to those skilled in the art that, where appropriate, pharmaceutical agents may be used in the form of a salt (e.g., as an alkali metal or amine salt, or as an acid addition salt), an ester (e.g., a lower alkyl ester), or a solvate (e.g., a hydrate) in order to optimize the activity and / or stability of the pharmaceutical agent.

[0469] Other exemplary therapeutic agents useful in combination therapy include those described above, radiation therapy, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid drugs, estrogens and progestins, androgens, adrenocorticotropic hormones, corticosteroids and their synthetic analogs, inhibitors of corticosteroid synthesis and action, insulin, oral hypoglycemic agents, pharmacological agents of the endocrine pancreas, agents affecting calcification and bone turnover, i.e., calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitamins (water-soluble vitamins), and the like. These include, but are not limited to, vitamins, B-complex vitamins, ascorbic acid, fat-soluble vitamins, vitamin A, vitamin K, and vitamin E), growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists, anticholinesterase agents, drugs acting on the neuromuscular junction and / or autonomic ganglia, catecholamines, sympathomimetic drugs, adrenergic receptor agonists or antagonists, and 5-hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists.

[0470] Other therapeutic agents suitable for administration in combination with the compounds of the invention include agents for pain and inflammation (such as histamine and histamine antagonists), bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances produced by the biotransformation of products of selective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory drugs, analgesics and antipyretics, agents that inhibit the synthesis of prostaglandins and thromboxanes, derivatized cyclooxygenase inhibitors (DHAs), and the like. Also included are selective inhibitors of cyclooxygenase, selective inhibitors of inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, β-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers, and leukotriene inhibitors.

[0471] Additional therapeutic agents contemplated for co-administration with the compounds and compositions of the invention include diuretics, vasopressin, agents that affect renal water retention, rennin, angiotensin, agents useful in the treatment of myocardial ischemia, antihypertensive agents, angiotensin-converting enzyme inhibitors, beta-adrenergic receptor antagonists, agents for the treatment of hypercholesterolemia, and agents for the treatment of dyslipidemia.

[0472] Other therapeutic agents contemplated for co-administration with the compounds and compositions of the invention include drugs used to control gastric acidity, drugs to treat peptic ulcers, drugs to treat gastroesophageal reflux disease, prokinetic agents, antiemetic agents, drugs used in irritable bowel syndrome, drugs used for diarrhea, drugs used for constipation, drugs used in inflammatory bowel disease, drugs used in biliary tract disease, drugs used in pancreatic disease, drugs to treat protozoal infections, drugs to treat malaria, amebic dysentery, giardiasis, trichomoniasis, trypanosomiasis and / or leishmaniasis, and / or drugs used in the chemotherapy of helminthic diseases. Other therapeutic agents include antimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, agents for urinary tract infections, penicillins, cephalosporins and the like, beta-lactam antibiotics, agents including aminoglycosides, protein synthesis inhibitors, drugs used in chemotherapy for tuberculosis, Mycobacterium avium complex disease and leprosy, antifungal agents, antiviral agents including non-retroviral agents and antiretroviral agents.

[0473] Examples of therapeutic antibodies that can be combined with the compounds of the invention include, but are not limited to, anti-receptor tyrosine kinase antibodies (cetuximab, panitumumab, trastuzumab), anti-CD20 antibodies (rituximab, tositumomab), and other antibodies such as alemtuzumab, bevacizumab, and gemtuzumab.

[0474] Additionally, therapeutic agents used for immunomodulation are also contemplated by the methods of the present invention, such as immunomodulators, immunosuppressants, tolerogens, and immunostimulants, as well as therapeutic agents acting on blood and blood-forming organs, hematopoietic agents, growth factors, minerals and vitamins, anticoagulants, thrombolytic, and antiplatelet drugs.

[0475] Additional therapeutic agents that can be combined with the compounds of the invention can be found in "The Pharmacological Basis of Therapeutics," by Goodman and Gilman, 10th Edition, edited by Hardman, Limbird and Gilman, or the Physician's Desk Reference, both of which are incorporated herein by reference in their entireties.

[0476] In some embodiments, the compounds described herein are administered in combination with another therapeutic agent effective in treating brain tumors, such as glioblastoma or astrocytoma. In some embodiments, the other therapeutic agent can be bevacizumab, carmustine (e.g., carmustine wafers), cisplatin, everolimus, lomustine, procarbazine, temozolomide, vincristine, or any combination thereof (e.g., procarbazine hydrochloride, lomustine, and vincristine sulfate in combination).

[0477] In some embodiments, the compounds described herein are administered in combination with one or more therapeutic agents approved for the treatment of sarcoma, such as adriamycin, bevacizumab, carboplatin, cisplatin, cyclophosphamide, dacarbazine, dactinomycin, docetaxel, doxorubicin (e.g., doxorubicin hydrochloride liposomal), epirubicin, eribulin, etoposide, gemcitabine, ifosfamide, imatinib, ixabepilone, methotrexate, paclitaxel, pazopanib, pomalidomide, recombinant interferon alpha-2b, tazemetostat, temozolomide, topotecan, trabectedin, vinblastine, vincristine, vinorelbine, or any combination thereof.

[0478] In some embodiments, the compounds described herein are administered in combination with one or more therapeutic agents approved for the treatment of colorectal cancer, such as 5-fluorouracil, bevacizumab, capecitabine, cetuximab, ipilimumab, irinotecan, leucovorin, nivolumab, oxaliplatin, panitumumab, pembrolizumab, ramucirumab, regorafenib, tipiracil, trifluridine, ziv-aflibercept, or any combination thereof.

[0479] In some embodiments, the compounds described herein are administered in combination with one or more therapeutic agents approved for the treatment of lung cancer, such as non-small cell lung cancer. In such embodiments, the additional therapeutic agent can be afatinib, alectinib, atezolizumab, bevacizumab, brigatinib, capmatinib, carboplatin, ceritinib, cisplatin, crizotinib, dabrafenib, dacomitinib, docetaxel, doxorubicin, durvalumab, entrectinib, erlotinib, everolimus, gefitinib, gemcitabine, ipilimumab, lorlatinib, mechlorethamine, methotrexate, necitumumab, nivolumab, osimertinib, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, selpercatinib, trametinib, vinorelbine, or any combination thereof.

[0480] In some embodiments, the compounds described herein are administered in combination with one or more therapeutic agents approved for the treatment of gastric cancer, such as 5-fluorouracil, capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, irinotecan, oxaliplatin, paclitaxel, trifluridine, tipiracil, trastuzumab, or any combination thereof.

[0481] In some embodiments, the compounds described herein are administered in combination with one or more alkylating agents (e.g., for the treatment of cancer) selected from, for example, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, thiotepa, ranimustine, nimustine, temozolomide, altretamine, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, mafosfamide, bendamustine, mitolactol, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin, and satraplatin.

[0482] In some embodiments, a compound described herein is administered in combination with one or more antimetabolites (e.g., for the treatment of cancer) selected from, for example, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, gemcitabine, fludarabine, 5-azacytidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethinylcytidine, cytosine arabinoside, hydroxyurea, melphalan, nelarabine, nolatrexed, ocfosfate, pemetrexed disodium, pentostatin, peritrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, and vinorelbine.

[0483] In some embodiments, a compound described herein is administered in combination with one or more hormone therapy agents (e.g., for the treatment of cancer) selected from, for example, exemestane, lupron, anastrozole, doxercalciferol, fadrozole, formestane, abiraterone acetate, finasteride, epristeride, tamoxifen citrate, fulvestrant, trelstar, toremifene, raloxifene, lasofoxifene, letrozole, sagopilone, ixabepilone, epothilone B, vinblastine, vinflunine, docetaxel, and paclitaxel.

[0484] In some embodiments, the compounds described herein are administered in combination with one or more cytotoxic topoisomerase inhibitors (e.g., for the treatment of cancer) selected from, for example, aclarubicin, doxorubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan, topotecan, edotecarin, epirubicin, etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, tafluposide, etc.

[0485] In some embodiments, the compounds described herein are administered in combination with one or more anti-angiogenic compounds (e.g., for the treatment of cancer) selected from, for example, acitretin, aflibercept, angiostatin, aplidine, asentar, axitinib, resentin, bevacizumab, brivanib alaninate, cilengitide, combretastatin, DAST, endostatin, fenretinide, halofuginone, pazopanib, ranibizumab, revimastat, rimuvab, revlimid, sorafenib, vatalanib, squalamine, sunitinib, telatinib, thalidomide, ukrain, and vitaxin.

[0486] In some embodiments, the compounds described herein are administered in combination with one or more antibodies (e.g., for the treatment of cancer) selected from, for example, trastuzumab, cetuximab, bevacizumab, rituximab, ticilimumab, ipilimumab, lumiliximab, catumaxomab, atacicept, oregovomab, and alemtuzumab.

[0487] In some embodiments, the compounds described herein are administered in combination with one or more VEGF inhibitors (e.g., for the treatment of cancer) selected from, for example, sorafenib, DAST, bevacizumab, sunitinib, resentin, axitinib, aflibercept, telatinib, brivanib alaninate, vatalanib, pazopanib, and ranibizumab.

[0488] In some embodiments, the compounds described herein are administered in combination with one or more EGFR inhibitors (e.g., for the treatment of cancer) selected from, for example, cetuximab, panitumumab, vectibix, gefitinib, erlotinib, and zactima.

[0489] In some embodiments, the compounds described herein are administered in combination with one or more HER2 inhibitors (e.g., for the treatment of cancer) selected from, e.g., lapatinib, trastuzumab, and pertuzumab, and the CDK inhibitor is selected from roscovitine and flavopiridol.

[0490] In some embodiments, the compounds described herein are administered in combination with one or more proteasome inhibitors (e.g., for the treatment of cancer), for example, selected from bortezomib and carfilzomib.

[0491] In some embodiments, the compounds described herein are administered in combination with one or more serine / threonine kinase inhibitors (e.g., for the treatment of cancer), such as a MEK inhibitor and a Raf inhibitor (such as sorafenib).

[0492] In some embodiments, a compound described herein is administered in combination with one or more tyrosine kinase inhibitors (e.g., for the treatment of cancer) selected from, for example, dasatinib, nilotinib, DAST, bosutinib, sorafenib, bevacizumab, sunitinib, AZD2171, axitinib, aflibercept, telatinib, imatinib mesylate, brivanib alaninate, pazopanib, ranibizumab, vatalanib, cetuximab, panitumumab, vectibix, gefitinib, erlotinib, lapatinib, trastuzumab, and pertuzumab.

[0493] In some embodiments, the compounds described herein are administered in combination with one or more androgen receptor antagonists (e.g., for the treatment of cancer) selected from, for example, nandrolone decanoate, fluoxymesterone, android, prostoid, andromustine, bicalutamide, flutamide, apocyproterone, apoflutamide, chlormadinone acetate, androcur, tabi, cyproterone acetate, and nilutamide.

[0494] In some embodiments, the compounds described herein are administered in combination with one or more aromatase inhibitors (e.g., for the treatment of cancer) selected from, for example, anastrozole, letrozole, testolactone, exemestane, aminoglutethimide, and formestane.

[0495] In some embodiments, the compounds described herein are administered in combination with one or more other anti-cancer agents, including, for example, alitretinoin, ampligen, atrasentan, bexarotene, bortezomib, bosentan, calcitriol, exisulind, fotemustine, ibandronic acid, miltefosine, mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotene, velcade, gallium nitrate, canfosfamide, darinaparsin, and tretinoin. In preferred embodiments, the compounds of the present disclosure may be used in combination with chemotherapeutic agents (e.g., cytotoxic agents), antihormonal agents, and / or targeted therapeutic agents such as other kinase inhibitors, mTOR inhibitors, and angiogenesis inhibitors.

[0496] In embodiments where the compounds and pharmaceutical compositions of the invention are used to treat or prevent diseases and / or conditions other than cancer, the compounds and pharmaceutical compositions of the invention may be administered in combination with therapeutic agents and / or therapies known in the art as suitable for treating such diseases and / or conditions.

[0497] kit Kits and articles of manufacture containing the compounds or pharmaceutical compositions described herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof) for use in the therapeutic applications described herein are also provided. In some embodiments, such kits include a carrier, package, or container partitioned to contain one or more containers, such as vials, tubes, etc., each of which contains a separate element for use in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers may be formed from a variety of materials, such as glass or plastic.

[0498] The articles of manufacture provided herein include packaging materials. Packaging materials used to package pharmaceutical products include, for example, those found in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended method of administration and treatment. For example, in some embodiments, the container(s) contain a compound of Formula (I), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (e.g., the container is an intravenous solution bag or vial with a stopper pierceable by a hypodermic injection needle). Such kits optionally include the compounds along with identifying information or labels or instructions for use in the methods described herein.

[0499] For example, a kit typically includes one or more additional containers each containing one or more of various materials (such as reagents and / or equipment, optionally in concentrated form) that are commercially and user-desirable for use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers, packages, containers, vials, and / or tube labels listing the contents, and / or instructions for use, and package inserts containing the instructions for use. Typically, a set of instructions will also be included. The label is optionally on or associated with the container. For example, the label is on the container when letters, numbers, or other symbols forming the label are attached, molded, or etched into the container itself; the label is associated with the container when it is present in a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, the label is used to indicate that the contents should be used for a predetermined therapeutic application. In addition, the label indicates how to use the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical compositions of the present invention are provided in a pack or dispenser device containing one or more unit dosage forms comprising a compound provided herein. The pack, for example, comprises metal or plastic foil (such as a blister pack). Alternatively, the pack or dispenser device is accompanied by instructions for administration. Alternatively, the pack or dispenser device is accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, the notice reflecting approval by that agency of the drug form for administration to humans or animals. Such notice, for example, is labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. In some embodiments, compositions comprising a compound provided herein, formulated in a compatible pharmaceutical carrier, are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. [Example]

[0500] Abbreviations used in the examples below include the following: ACN is acetonitrile, Boc is tert-butyloxycarbonyl, DCM is dichloromethane, DIPEA is N,N-diisopropylethylamine, DMA is dimethylacetamide, dppf is 1,1′-bis(diphenylphosphino)ferrocene, EtOAc is ethyl acetate, HATU is (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), MeOH is methanol, RPH refers to reverse phase chromatography, RT is room temperature, and TFA is trifluoroacetic acid.

[0501] General synthesis method General Procedure A: To a 10 dr screw-capped vial was added carboxylic acid (1.1 equiv.), DIPEA (2 equiv., 3 equiv. in the case of amine hydrochlorides), HATU (1.2 equiv.), and anhydrous DCM (5 mL). The mixture was stirred for 15 min at RT, then the corresponding amine or its hydrochloride (1.2 equiv.) was added, the vial was sealed, and the reaction mixture was heated at 45 °C overnight. After cooling to RT, the mixture was diluted with DCM (20 mL) and washed sequentially with water, saturated aqueous NaHCO3, and brine. The organic phase was dried over Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography (DCM:EtOAc or DCM:MeOH) followed, if necessary, by RPH chromatography (10 to 100% gradient of MeOH in water) to give the title compound.

[0502] General procedure B: To a solution of the corresponding methyl ester (1 mmol, 1 equiv.) in MeOH (2 mL / mmol), 1 M LiOH solution (2 equiv.) was added, and the mixture was stirred at RT for 4 h (for proline esters) or overnight (for aromatic esters). The mixture was concentrated in vacuo, and the crude was diluted with water (5 mL) and acidified with 1 M HCl to pH 4. The resulting mixture was extracted with EtOAc (3 × 10 mL), and the combined organics were washed with brine (3 × 10 mL), dried over NaSO, and concentrated to give the product, which was either used directly in the next step without further purification or purified by silica gel column chromatography.

[0503] General Procedure C: To a degassed suspension of zinc powder (217 mg, 3.338 mmol, 1.8 equiv.) in DMA (2 mL) in a screw-cap vial, a mixture of chlorotrimethylsilane (67.3 μL, 57.6 mg, 0.53 mmol, 0.3 equiv.) and 1,2-dibromoethane (45.9 μL, 99.6 mg, 0.53 mmol, 0.3 equiv.) was added dropwise, and the resulting mixture was stirred at room temperature under Ar for 15 min. Subsequently, neat 3-iodoazetidine-1-carboxylic acid tert-butyl ester (753 mg, 2.661 mmol, 1.4 equiv.) was added dropwise, and the resulting mixture was stirred at room temperature for 15 min. In a separate vial, PdCl2(dppf)×DCM (65.2 mg, 0.08 mmol, 0.04 equiv.) and copper iodide (30 mg, 0.157 mmol, 0.08 mmol) were added to a degassed solution of the corresponding heta(aryl) bromide (1.862 mmol, 1 equiv.) in DMA (1 mL). After stirring for 30 min, the above zinc suspension was added to the suspension of the heta(aryl) bromide, PdCl2(dppf)×DCM, and copper iodide, and the reaction mixture was stirred at 80 °C for 2 h under argon. The resulting mixture was cooled to RT, diluted with EtOAc, filtered through a pad of Celite, the pad was washed with EtOAc, and the combined organics were washed with a mixture of saturated ammonium chloride and ammonium hydroxide (15:1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0→100% ethyl acetate in hexanes), and fractions containing the corresponding product in LC-MS were combined, concentrated, and used in the next step without further purification.

[0504] General procedure D: To a solution of the Boc-protected substituted azetidine (1 mmol) in 3 mL of 1,4-dioxane was added dropwise 4 M HCl in 1,4-dioxane (3 mL), and the mixture was stirred overnight at RT. After removing all volatiles under reduced pressure, the residue was triturated with dry ACN, the ACN was decanted, and the remaining solid was dried in vacuo to give the corresponding dihydrochloride salt as a white solid in quantitative yield.

[0505] General Procedure E: To a degassed suspension of boronic acid or boronic acid pinacol ester (1.3 equiv., 0.65 mmol), bromide (1 equiv., 0.5 mmol), and NaHCO (3 equiv., 1.5 mmol) in a mixture of 1,4-dioxane:water (10:1) was added PdCl(dppf) × DCM (0.025 mmol) in one portion. The resulting suspension was degassed again, backfilled with Ar, and stirred at 80 °C overnight under argon. The resulting mixture was cooled to RT, diluted with EtOAc, filtered through a pad of Celite, the pad was washed with EtOAc, and the combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0→100% ethyl acetate in hexanes, then 0→20% methanol in dichloromethane), and the fractions containing the corresponding purified product by LC-MS were combined and concentrated, and the residue was redissolved in DCM (5 mL). To this mixture, TFA (30 equiv.) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 60 minutes. The mixture was concentrated in vacuo, and the crude product was triturated with 7N ammonia in methanol and concentrated again. The resulting residue was purified by silica gel column chromatography (0→100% hexanes / EtOAc, then DCM / MeOH) and then by RPH (0→100% MeOH / water) to give the title compound as an off-white solid.

[0506] General Procedure F: To a 10 dr screw-capped vial was added the amine (1 equiv.), DIPEA (2 equiv.), and anhydrous DCM (5 mL). The mixture was stirred for 15 min at 0 °C, then the corresponding acyl chloride was added, the vial was sealed, and the reaction mixture was stirred at RT overnight. After cooling to RT, the mixture was diluted with DCM (20 mL) and washed successively with water, saturated aqueous NaHCO3, and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was redissolved in DCM (2 mL) at 0 °C. TFA (30 equiv.) was added dropwise, and the mixture was stirred at 0 °C for 60 min. The mixture was concentrated in vacuo, and the crude was triturated with 7N ammonia in methanol and concentrated again. The resulting residue was purified by silica gel column chromatography (0→100% hexanes / EtOAc followed by DCM / MeOH) and then by RPH (0→100% MeOH / water) to afford the title compound as an off-white solid.

[0507] General Procedure G: The Boc-protected compound was dissolved in DCM (2 mL) at 0 °C and TFA (30 equiv.) was added dropwise. The mixture was stirred at 0 °C for 60 min, then concentrated in vacuo, and the crude material was triturated with 7N ammonia in methanol and concentrated again. The resulting residue was purified by silica gel column chromatography (0 → 100% hexanes / EtOAc, then DCM / MeOH) and then by RPH (0 → 100% MeOH / water) to give the title compound as an off-white solid.

[0508] Example 1 Compound Synthesis - Monomer Compound 14: N-((5-(pyrrolidine-1-carbonyl)thiophen-2-yl)methyl)azetidine-3-carboxamide

[0509] [ka]

[0510] Synthesis according to general procedure A using (5-aminothiophen-2-yl)(pyrrolidin-1-yl)methanone and 1-Boc-azetidine-3-carboxylic acid, as well as general procedure G, afforded compound 14 (10 mg, 72%) as an off-white solid. 1 H NMR (600 MHz, CD3OD): δ 7.46 (d, J = 3.8 Hz, 1H), 7.00 (d, J = 3.8 Hz, 1H), 4.56 (s, 2H), 3.96 (br.s, 2H), 3.78 (br.s, 4H), 3.59 (br.s, 3H), 2.02 (br.s, 2H), 1.95 (br.s, 2H). 13 C NMR (125 MHz, CD3OD): δ 174.9, 163.6, 148.3, 139.1, 131.4, 127.1, 118.1, 68.1, 50.3, 49.6, 39.0, 27.6, 24.9. HR-MS (ESI): [M+H + ] Calculated value 294.1271, Measured value 294.1270 Compound 37: N-(5-(pyrrolidine-1-carbonyl)thiophen-2-yl)azetidine-2-carboxamide

[0511] [ka]

[0512] Synthesis according to general procedure A using (5-aminothiophen-2-yl)(pyrrolidin-1-yl)methanone and (rac)-1-Boc-azetidine-2-carboxylic acid, as well as general procedure G, afforded compound 20 (13 mg, 79%) as an off-white solid. 1H NMR (600 MHz, CD3OD): δ 7.44 (d, J = 4.2 Hz, 1H), 6.79 (d, J = 4.2 Hz, 1H), 4.46 (dd, J = 9.1, 7.1 Hz, 1H), 3.82 (s, 2H), 3.69 (q, J = 7.9 Hz, 1H), 3.61 (s, 2H), 3.49 (td, J = 8.5, 5.1 Hz, 1H), 2.70 (ddt, J = 8.9, 6.2, 4.4 Hz, 1H), 2.48 - 2.36 (m, 1H), 2.04 (s, 2H), 1.96 (s, 2H). 13 C NMR (125 MHz, CD3OD): δ 173.0, 164.3, 145.5, 130.6, 129.9, 113.4, 60.0, 50.2, 47.5 (from HSQC) 44.6, 27.6, 26.8, 24.9. HR-MS (ESI): [M+H + ] Calculated value 280.1114, Measured value 280.1117 Compound 44: (S)-N-(5-(pyrrolidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide

[0513] [ka]

[0514] Synthesized according to general procedure A from the corresponding amine and N-Boc-L-proline and general procedure G to give the title compound as an off-white solid (18 mg, 83%). 1H NMR MeOD (600 MHz): δ 7.44 (d, J = 4.2 Hz, 1H), 6.78 (d, J = 4.2 Hz, 1H), 3.89-3.77 (m, 3H), 3.60 (s, 2H), 3.06 (dt, J = 10.5, 6.5 Hz, 1H), 2.97 (dt, J = 10.5, 6.5 Hz, 1H), 2.19 (dt, J = 12.7, 6.8 Hz, 1H), 2.04 (s, 2H), 1.95 (s, 2H), 1.91-1.85 (m, 1H), 1.82-1.75 (m, 2H); 13 C NMR MeOD (150 MHz), mixture of rotamers (1:1): δ 174.1, 164.4, 145.5, 130.5, 129.9, 113.3, 61.6, 49.8, 48.1, 32.0, 27.6, 27.0, 24.9;HR-ESI-MS: C 14 H 20 N3O2S [M+H] + m / z calculated 294.1271, observed 294.1275 Compound 85. (S)-N-(5-(3-(thiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide

[0515] [ka]

[0516] Step 1. tert-Butyl (S)-2-((5-(methoxycarbonyl)thiophen-2-yl)carbamoyl)pyrrolidine-1-carboxylate: Synthesized from methyl 5-amino-2-thiophenecarboxylate and N-Boc-L-proline according to general procedure A. The resulting residue was purified by silica gel column chromatography (0→100% DCM / EtOAc) to afford the title compound as a semi-solid (182 mg, 73%). 1 H NMR DMSO- d6(600 MHz) (mixture of rotamers (2:1)): δ 11.66 (s, 1H), 7.60 (d, J = 4.1 Hz, 1H), 6.75 (d, J = 4.1 Hz, 1H), 4.34 - 4.18 (m, 1H), 3.77 (s, 3H), 3.50 - 3.40 (m, 1H), 3.40 - 3.32 (m, 1H), 2.30 - 2.13 (m, 1H), 1.95 - 1.76 (m, 3H), 1.40 (s, 3H), 1.23 (s, 6H); 13 C NMR DMSO- d6 (150 MHz) (mixture of rotamers (2:1)): δ 170.7, 170.2, 162.5, 153.6, 152.9, 146.3, 146.2, 132.0, 131.9, 121.9, 121.8, 112.0, 111.9, 78.9,78.7,59.8,59.4,51.7,46.7,46.8,30.8,30.6,30.0,28.1,27.9,27.8,24.0,23.4;HR-ESI-MS: C 16 H 23 N2O5S [M+H] + m / z calculated 355.1322, found 355.1336 Step 2. (S)-5-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)thiophene-2-carboxylic acid: Synthesized from tert-butyl (S)-2-((5-(methoxycarbonyl)thiophen-2-yl)carbamoyl)pyrrolidine-1-carboxylate according to general procedure B. The resulting residue was purified by silica gel column chromatography (0→100% DCM / EtOAc) to afford the title compound (120 mg, 93%) as a semi-solid. 1 H NMR DMSO- d6(600 MHz) (mixture of isomers (2:1)): δ 12.54 (s, 1H), 11.56 (s, 1H), 7.51 (d, J = 4.1 Hz, 1H), 6.72 (d, J = 4.1 Hz, 1H), 4.28 (dd, J = 8.2, 4.8 Hz, 0.3H), 4.21 (dd, J = 8.2, 4.8 Hz, 0.7H), 3.51 - 3.40 (m, 1H), 3.40 - 3.31 (m, 1H, HDO purification and repeat), 2.29 - 2.14 (m, 1H), 1.96 - 1.79 (m, 3H), 1.40 (s, 3H), 1.24 (s, 6H); 13 C NMR DMSO- d6 (150 MHz) 1 H NMR base, heterogeneous mixture (2:1)): δ 170.5, 170.1, 163.6, 153.6, 152.9, 145.8, 145.7, 131.4, 131.4, 123.8, 123.7, 111.8, 111.8, 78.9, 78.7, 59.8, 59.4, 46.7, 46.5, 30.9, 30.1, 28.1, 27.8, 24.0, 23.4;HR-ESI-MS: C 15 H 21 N2O5S [M+H] + m / z calculated value 341.1166, measured value 341.1179 Step 3. (S)—N-(5-(3-(thiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide (compound 85): Synthesized from (S)-5-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamide)thiophene-2-carboxylic acid and 2-(azetidin-3-yl)thiazole dihydrochloride according to general procedure A. The resulting residue was used in the next step without further purification. To a solution of the residue from the previous step in DCM (2 mL) at 0° C., TFA (0.5 mL) was added dropwise, and the mixture was stirred at 0° C. for 30 min. After removing all the volatiles under reduced pressure, the residue was triturated with a 7N solution of ammonia in methanol, re-concentrated, and purified by silica gel column chromatography (0→100% DCM / MeOH+0.5% ammonia (v / v)) to afford the title compound as an off-white solid (9 mg, 75%). 1 H NMR MeOD (600 MHz) δ: 7.80 (d, J = 3.3 Hz, 1H), 7.56 (d, J = 3.3 Hz, 1H), 7.40 (d, J = 4.2 Hz, 1H), 6.80 (d, J = 4.2 Hz, 1H), 4.96 (s, 1H), 4.67 (s, 2H), 4.41 (m, 2H), 3.83 (dd, J = 8.7, 5.9 Hz, 1H), 3.05 (dt, J = 10.5, 6.5 Hz, 1H), 2.97 (dt, J = 10.5, 6.5 Hz, 1H), 2.20 (td, J = 15.6, 12.7, 7.3 Hz, 1H), 1.88 (td, J = 15.6, 12.7, 7.3 Hz, 1H), 1.80 (p, J = 6.9 Hz, 2H); 13C NMR MeOD (150 MHz) δ: 174.3, 172.1, 165.7, 146.3, 143.8, 130.4, 127.5, 120.9, 113.6, 61.6, 60.3 (azetidine CH2, identified from HSQC spectrum), 56.8 (azetidine CH2, identified from HSQC spectrum), 48.1, 33.3, 32.0, 27.0. HR-ESI-MS: C 16 H 19 N4O2S2[M+H] + m / z calculated 363.0944, observed 363.0952 Compound 90. ((S)-N-(5-(3-(5-phenylthiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide

[0517] [ka]

[0518] Step 1. 2-(Azetidin-3-yl)-5-phenylthiazole hydrochloride: Synthesized according to general procedures C and D to afford 2-(azetidin-3-yl)-5-phenylthiazole hydrochloride (70 mg, 15%) as an off-white solid. 1 H NMR (600 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.22 (s, 1H), 8.24 (s, 1H), 7.70 - 7.63 (m, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.41 - 7.34 (m, 1H), 4.50 (p, J = 8.3 Hz, 1H), 4.38 - 4.28 (m, 2H), 4.26 - 4.18 (m, 2H). 13 C NMR (150 MHz, DMSO-d6): δ 166.6, 139.4, 138.5, 130.6, 129.3, 128.5, 126.4, 50.6, 33.5. MS (m / z) [M+H + ]: Calculated value 217, Measured value 217 (S)—N-(5-(3-(5-phenylthiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide (compound 91): Synthesized according to general procedure A using (S)-5-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamide)thiophene-2-carboxylic acid and 2-(azetidin-3-yl)-5-phenylthiazole hydrochloride, as well as general procedure G, to afford compound 90 (8 mg, 79%) as an off-white solid. 1 H NMR (600 MHz, CD3OD) δ 7.91 (s, 1H), 7.55 (d, J = 9.6 Hz, 1H), 7.41 - 7.37 (m, 3H), 7.33 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 4.2 Hz, 1H), 4.94 (s, 1H), 4.81 (s, 2H), 4.48 (s, 2H), 4.33 (tt, J = 8.8, 5.8 Hz, 1H), 3.86 - 3.80 (m, 1H), 3.07 (dt, J = 11.1, 6.5 Hz, 1H), 3.04 - 2.96 (m, 1H), 2.28 - 2.16 (m, 1H), 1.92 (dq, J = 12.9, 6.6 Hz, 1H), 1.81 (p, J = 6.9 Hz, 2H). HR-MS (ESI): [M+H + ] Calculated value 439.1257, Measured value 439.1259 Compound 123. (S)-N-(5-(3-(5-(4-(acetamidomethyl)phenyl)thiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide

[0519] [ka]

[0520] Synthesis according to general procedure F using (S)—N-(5-(3-(5-(4-(aminomethyl)phenyl)thiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide (obtained by general procedure E. Boc-intermediate was used directly) and acetyl chloride to give compound 123 (8 mg, 86%) as an off-white solid. 1 H NMR (600 MHz, CD3OD+30%DMSO-d6) δ 8.07 (s, 1H), 7.64 - 7.58 (m, 2H), 7.39 - 7.33 (m, 3H), 6.84 (d, J = 4.2 Hz, 1H), 4.90 (br.s, 1H), 4.65 (br.s, 2H), 4.40 - 4.36 (m, 1H), 4.34 (s, 3H), 3.90 (dd, J = 8.8, 5.9 Hz, 1H), 3.02 (dtd, J = 17.1, 10.5, 6.7 Hz, 2H), 2.19 (dq, J = 12.6, 7.5 Hz, 1H), 1.96 (s, 3H), 1.93 - 1.84 (m, 1H), 1.78 (p, J = 7.0 Hz, 2H). 13 C NMR (150 MHz, CD3OD+30%DMSO-d6): δ 173.2, 172.2, 170.7, 165.0, 146.0, 141.1, 140.6, 139.5, 131.1, 130.0, 129.5, 128.0, 127.8, 113.8, 61.5, 60.0, 56.3, 48.0, 43.5, 33.6, 31.7, 26.8, 23.1. HR-MS (ESI): [M+H + ] Calculated value 510.1628, Measured value 510.1628 Compound 125. (S)-N-(5-(3-(5-(4-(aminomethyl)phenyl)thiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide

[0521] [ka]

[0522] Step 1. tert-Butyl 3-(5-bromothiazol-2-yl)azetidine-1-carboxylate: The corresponding Boc-intermediate was synthesized according to General Procedure C and used in the next step without further purification. To a solution of tert-butyl 3-(thiazol-2-yl)azetidine-1-carboxylate (1 g, 4.17 mmol, 1 equiv.) in 20 mL of anhydrous DMF was added NBS (890 mg, 5 mmol, 1.2 equiv.) in portions at RT. The mixture was stirred for 12 h at RT, poured onto ice, and extracted with EtOAc (3 × 50 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0→60% ethyl acetate in hexanes) to afford tert-butyl 3-(5-bromothiazol-2-yl)azetidine-1-carboxylate (665 mg, 50%) as a clear oil. 1 H NMR (600 MHz, CDCl3) δ 7.62 (s, 1H), 4.33 (t, J = 8.6 Hz, 2H), 4.14 (dd, J = 8.6, 5.9 Hz, 2H), 4.02 (tt, J = 8.7, 5.9 Hz, 1H), 1.45 (s, 9H). 13 C NMR (150 MHz, CDCl3): δ 172.3, 156.3, 144.1, 108.6, 80.1, 55.5, 32.4, 28.5. MS (m / z) [M+H + ]: Calculated values ​​262, 264, Measured values ​​262, 264 Step 2. tert-Butyl (S)-2-((5-(3-(5-bromothiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)carbamoyl)pyrrolidine-1-carboxylate: (S)-5-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)thiophene-2-carboxylic acid and 3-(5-bromothiazol-2-yl)azetidin-1-ium trifluoroacetate (tert-butyl 3-(5-bromothiazol-2-yl)azetidine-1-in DCM) The carboxylate solution was treated with TFA (30 equiv.) at 0° C., stirred at 0° C. for 60 min, and all volatiles were removed in vacuo to afford tert-butyl (S)-2-((5-(3-(5-bromothiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)carbamoyl)pyrrolidine-1-carboxylate (58 mg, 57%) as an off-white solid, synthesized according to general procedure A with the residue (which was used in the HATU-assisted coupling reaction without further purification). 1 H NMR (600 MHz, CDCl3, mixture of rotamers) δ 10.72 (s, 1H), 7.61 (s, 1H), 7.31 (br.s, 1H), 6.54 (br.s, 0.5H), 6.45 (br.s, 0.5H), 4.71 (br.s, 2H), 4.49 (br.s, 2H), 4.20 (tt, J = 8.8, 5.9 Hz, 1H), 3.78 - 3.68 (m, 1H), 3.46 (s, 1H), 3.36 (s, 1H), 3.24 - 3.14 (m, 1H), 1.98 (s, 1H), 1.91 (s, 2H), 1.48 (s, 9H).MS (m / z) [M+H + ]: Calculated values ​​541 and 543, Measured values ​​541 and 543 Step 3. (S)—N-(5-(3-(5-(4-(aminomethyl)phenyl)thiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide (Compound 125): Synthesized according to general procedure E using tert-butyl (S)-2-((5-(3-(5-bromothiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)carbamoyl)pyrrolidine-1-carboxylate and (4-aminomethylphenyl)boronic acid hydrochloride, the resulting Boc-analogue was further redissolved in DCM (2 mL) at 0° C., treated with TFA (0.5 mL), and the mixture was stirred at 0° C. for 30 min. After this time, all volatiles were removed under reduced pressure, and the residue was triturated with a 7N solution of ammonia in methanol, re-concentrated, and purified by silica gel column chromatography (0→100% DCM / MeOH+0.5% ammonia (v / v)) to afford the title compound as an off-white solid (8 mg, 53%). 1 H NMR (600 MHz, CD3OD) δ 8.09 (s, 1H), 7.71 (d, J = 7.8 Hz, 2H), 7.55 (d, J = 7.9 Hz, 2H), 7.41 (d, J = 4.1 Hz, 1H), 6.86 (d, J = 4.0 Hz, 1H), 4.99 (s, 1H), 2H is the water peak, present at 59.8 in HSQC, 4.65 (s, 1H), 4.57 - 4.49 (m, 1H), 4.49 - 4.25 (m, 1H), 4.16 (s, 2H), 3.48 (q, J = 6.5, 5.9 Hz, 1H), 3.44 (q, J = 5.6, 5.0 Hz, 1H), 2.65 - 2.48 (m, 1H), 2.20 - 2.08 (m, 3H). 13C NMR (150 MHz, CD3OD): δ 171.5, 166.7, 165.3, 145.4, 140.3, 139.9, 134.7, 133.1, 131.0, 130.4, 128.6, 128.3, 114.6, 61.3, 60.2, 56.5, 47.5, 43.9, 33.6, 30.8, 25.0. HR-MS (ESI): [M+H + ] Calculated value 468.1522, Measured value 468.1499 Other compounds Additional compounds were synthesized following similar procedures using appropriate starting materials, and their structures and HR-MS data are shown in Table 1.

[0523] [Table 1] JPEG0007758369000097.jpg209169JPEG0007758369000098.jpg207169JPEG0007758369000099.jpg202169JPEG0007758369000100.jpg202169JPEG0007758369000101.jpg204169JPEG0007758369000102.jpg206169JPEG0007758369000103.jpg176169JPEG0007758369000104.jpg197169JPEG0 007758369000105.jpg207169JPEG0007758369000106.jpg195169JPEG0007758369000107.jpg171169JPEG0007758369000108.jpg201169JPEG000 7758369000109.jpg208169JPEG0007758369000110.jpg208169JPEG0007758369000111.jpg188169JPEG0007758369000112.jpg173169JPEG000775 8369000113.jpg165169JPEG0007758369000114.jpg161169JPEG0007758369000115.jpg198169JPEG0007758369000116.jpg163169JPEG00077583 69000117.jpg196169JPEG0007758369000118.jpg199169JPEG0007758369000119.jpg168169JPEG0007758369000120.jpg177169JPEG00077583690 00121.jpg163169JPEG0007758369000122.jpg189169JPEG0007758369000123.jpg189169JPEG0007758369000124.jpg191169JPEG0007758369000125.jpg186169JPEG0007758369000126.jpg193169JPEG0007758369000127.jpg176169JPEG0007758369000128.jpg202169JPEG0007758369000129.jpg196169JPEG0007758369000130.jpg196169JPEG0007758369000131.jpg193169JPEG0007758369000132.jpg205169J PEG0007758369000133.jpg193169JPEG0007758369000134.jpg186169JPEG0007758369000135.jpg189169JPEG0007758 369000136.jpg188169JPEG0007758369000137.jpg188169JPEG0007758369000138.jpg208169JPEG0007758369000139. jpg190169JPEG0007758369000140.jpg195169JPEG0007758369000141.jpg197169JPEG0007758369000142.jpg171169.

[0524] Example 2 Compound Synthesis - Dimer Compound 223. (2S,2'S,4R,4'R)-4,4'-(hexane-1,6-diylbis(oxy))bis(N-(5-(3-(thiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide)

[0525] [ka]

[0526] Step 1. 1-Di-tert-butyl 2-dimethyl 4,4'-(hexane-1,6-diylbis(oxy))(2S,2'S,4R,4'R)-bis(pyrrolidine-1,2-dicarboxylate)

[0527] [ka]

[0528] To a suspension of NaH (60% dispersion in mineral oil, 400 mg, 0.01 mol) in anhydrous DMF (10 mL) at 0 °C was added dropwise a solution of 1-(tert-butyl) 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.45 g, 0.01 mol). The mixture was stirred for 30 min at 0 °C, and then 1,6-diiodohexane (1.54 g, 750 μL, 4.55 mmol) was added. The temperature was slowly raised to RT, and the reaction mixture was stirred for 16 h before being treated with saturated aqueous NH4Cl. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (10 to 100% EtOAc in hexanes gradient) to give the target 1-di-tert-butyl 2-dimethyl 4,4′-(hexane-1,6-diylbis(oxy))(2S,2′S,4R,4′R)-bis(pyrrolidine-1,2-dicarboxylate) as a clear oil. Yield: 521 mg (20%). 1 H NMR (600 MHz, methanol-d4, mixture of rotamers) δ 4.40–4.25 (m, 2H), 4.14–4.01 (m, 2H), 3.78–3.67 (m, 6H), 3.62–3.34 (m, 8H), 2.41–2.20 (m, 2H), 2.07–1.99 (m, 2H), 1.60–1.53 (m, 2H), 1.50–1.40 (m, 18H), 1.40–1.27 (m, 6H). 13C NMR (125 MHz, methanol-d4, mixture of rotamers) δ 175.2, 174.9, 174.3, 174.1, 172.9, 156.3, 156.2, 155.9, 155.7, 81.7, 81.6, 81.5, 78.7, 78.5, 77.9, 77.8, 70.1, 70.0, 70.0, 69.9, 69.8, 61.5, 59.5, 59.2, 59.1, 58.8, 53.4, 53.2, 52.8, 52.7, 52.7, 52.7, 52.6, 52.6, 52.6, 37.4, 37.4, 36.9, 36.6, 36.6, 36.0, 32.7, 30.9, 30.8, 30.8, 30.8, 30.7, 30.1, 28.7, 28.7, 28.6, 28.6, 27.1, 27.0, 26.9, 26.9, 23.7, 20.9, 14.5, 14.4;HR-ESI-MS: C 28 H 49 N2O 10 [M+H] + m / z calculated 573.3382, found 573.3356 Step 2. (2'S,4R,4'R)-4,4'-(hexane-1,6-diylbis(oxy))bis(1-(tert-butoxycarbonyl)-L-proline)

[0529] [ka]

[0530] Synthesized from 1-di-tert-butyl 2-dimethyl 4,4'-(hexane-1,6-diylbis(oxy))(2S,2'S,4R,4'R)-bis(pyrrolidine-1,2-dicarboxylate) according to general procedure B. Clear oil. Yield 485 mg (98%). 1H NMR (600 MHz, methanol-d4, mixture of rotamers) δ = 4.37 - 4.20 (m, 2H), 4.17 - 4.02 (m, 2H), 3.65 - 3.34 (m, 8H), 2.42 - 2.18 (m, 2H), 2.11 - 2.01 (m, 2H), 1.59 - 1.50 (m, 4H), 1.49 - 1.41 (m, 18H), 1.40 - 1.30 (m, 4H). 13 C NMR (125 MHz, methanol-d4, mixture of rotamers) δ = 176.6, 176.2, 175.7, 175.6, 175.4, 175.4, 156.4, 156.3, 156.0, 155.9, 81.8, 81.8, 81.5, 81.4, 78.7, 78.5, 77.9, 77.7, 77.7, 70.1, 70.1, 70.1, 70.0, 70.0, 70.0, 69.9, 59.5, 59.1, 58.9, 58.7, 53.5, 53.2, 53.2, 52.7, 52.7, 37.5, 37.5, 36.8, 36.8, 36.8, 36.7, 35.9, 30.8, 30.8, 30.7, 30.7, 29.9, 28.8, 28.7, 28.6, 28.6, 27.0, 27.0, 26.9, 26.9, 24.2. HR-ESI-MS: C 26 H 45 N2O 10 [M+H] + m / z calculated 545.3069, observed 545.3075 Step 3. 5,5'-(((2S,2'S,4R,4'R)-4,4'-(hexane-1,6-diylbis(oxy))bis(1-(tert-butoxycarbonyl)pyrrolidine-4,2-diyl-2-carbonyl))bis(azanediyl))bis(thiophene-2-carboxylic acid)

[0531] [ka]

[0532] Synthesized from (2'S,4R,4'R)-4,4'-(hexane-1,6-diylbis(oxy))bis(1-(tert-butoxycarbonyl)-L-proline) and methyl 5-amino-2-thiophenecarboxylate according to general procedure A. The crude material obtained was directly subjected to hydrolysis (general procedure B) and then purified by silica gel column chromatography (0→100% EtOAc in DCM) to give the title compound as an off-white solid. Yield 87 mg (61% for two steps). 1 H NMR (600 MHz, methanol-d4, mixture of rotamers) δ 7.60 - 7.54 (m, 2H), 6.76 - 6.70 (m, 2H), 4.49 - 4.33 (m, 2H), 4.17 - 4.00 (m, 2H), 3.65 - 3.55 (m, 4H), 3.52 - 3.41 (m, 4H), 2.50 - 2.35 (m, 2H), 2.14 - 1.97 (m, 2H), 1.64 - 1.54 (m, 4H), 1.50 - 1.42 (m, 4H), 1.40 - 1.31 (m, 18H). 13 C NMR (125 MHz, methanol-d4, mixture of rotamers) δ 172.4, 166.7, 155.8, 147.0, 132.6, 126.8, 113.7, 113.6, 113.5, 82.0, 82.0, 82.0, 78.7, 78.1, 78.0, 70.0, 70.0, 69.9, 60.8, 60.8, 60.3, 53.3, 53.3, 38.0, 37.9, 31.0, 30.8, 30.8, 28.7, 28.6, 28.5, 27.1, 27.1, 26.9. HR-ESI-MS: C 36 H 51 N4O 12 S2 [M+H] + m / z calculated 795.2939, observed 795.2948 Step 4. (2S,2'S,4R,4'R)-4,4'-(hexane-1,6-diylbis(oxy))bis(N-(5-(3-(thiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide) (Compound 223) Synthesized according to general procedure A from 5,5'-(((2S,2'S,4R,4'R)-4,4'-(hexane-1,6-diylbis(oxy))bis(1-(tert-butoxycarbonyl)pyrrolidine-4,2-diyl-2-carbonyl))bis(azanediyl))bis(thiophene-2-carboxylic acid) and 2-(azetidin-3-yl)thiazole dihydrochloride. The resulting residue was used in the next step without further purification. To a solution of the residue from the previous step in DCM (2 mL) at 0°C, TFA (0.5 mL) was added dropwise and the mixture was stirred at 0°C for 30 min. After removing all the volatiles under reduced pressure, the residue was triturated with a 7N solution of ammonia in methanol, reconcentrated, and purified by silica gel column chromatography (0→100% DCM / MeOH+0.5% ammonia (v / v)) to give the title compound in the form of the free base, which was redissolved in 1 mL of DCM and treated with 200 μL of TFA at 0° C. After stirring for 10 min, the mixture was concentrated under reduced pressure, the residue was redissolved in MeOH, passed through a pad containing Amberlite IRA402 (Cl form), and the resulting solution was reconcentrated to give the title compound in the form of the dihydrochloride salt (23 mg, 52% over two steps). 1H NMR (600 MHz, methanol-d4) δ 7.80 (d, J = 3.3 Hz, 2H), 7.56 (d, J = 3.3 Hz, 2H), 7.38 (d, J = 4.2 Hz, 2H), 6.84 (d, J = 4.2 Hz, 2H), 4.97 (s, 2H), 4.76-4.56 (br.s., 4H), 4.53 (dd, J = 10.4, 7.4 Hz, 2H), 4.46 - 4.37 (m, 3H), 4.36 - 4.28 (m, 3H), 3.59 - 3.48 (m, 4H), 3.46 (s, 4H), 2.70 (dd, J = 13.7, 7.4 Hz, 2H), 2.11 (ddd, J = 14.2, 10.4, 4.3 Hz, 2H), 1.63 (t, J = 6.9 Hz, 4H), 1.51 - 1.40 (m, 4H). 13 C NMR (151 MHz, methanol-d4) δ 171.9, 167.5, 165.3, 145.3, 143.8, 130.2, 128.8, 121.0, 114.5, 79.4, 70.2, 60.4 (two overlapping carbons, one of which is the CH2 of azetidine, identified from the HSQC spectrum), 56.7 (CH2 of azetidine, identified from the HSQC spectrum), 52.8, 49.8, 37.0, 33.3, 30.8, 27.1. HR-ESI-MS: C 38 H 47 N8O6S4[M+H] + m / z calculated 839.2496, observed 839.2498 Other compounds Additional dimeric compounds were synthesized following similar procedures using appropriate starting materials, and their structures and HR-MS data are shown in Table 2.

[0533] [Table 2] JPEG0007758369000148.jpg185169JPEG0007758369000149.jpg140169JPEG0007758369000150.jpg197169JPEG0007758369000151.jpg190169

[0534] Example 3 Fluorescence polarization assay A fluorophore-conjugated dicrotonylated histone H3-derived peptide (FAM-H3K23crK27cr) binds to the GST-fused GAS41 YEATS domain with submicromolar affinity (K D Fluorescence polarization anisotropy (FP) assays were developed using peptides binding at 500 ng / mL (0.9 μM). A 5'6-fluorescein (FAM)-labeled dicrotonylated histone H3 peptide probe, H3K23crK27cr, was synthesized and used in competition experiments with 1 μM GST-GAS41(1-148) incubated with a competitor (e.g., a compound of the present disclosure) for 1 hour in an assay buffer containing 50 mM Tris (pH 7.5), 150 mM sodium chloride, 1 mM TCEP, 0.01% BSA, and 0.01% Tween-20, in 1% DMSO. 25 nM FAM-H3K23crK27cr peptide was added, and the plate was incubated for an additional hour. Fluorescence polarization data were then measured at 525 nM on a Pherastar plate reader (BMG Labtech).

[0535] We validated this assay by testing competition with H3K27ac peptide, resulting in an IC 50 = 243 μM, which is consistent with the relatively weak affinity of monoacetylated peptides (Cho 2018). Compound 134 ((5-(tert-butyl)thiophen-2-yl)(pyrrolidin-1-yl)methanone) showed comparable activity against H3K27ac in this assay, with an IC 50 =210 μM.

[0536] Fluorescence polarization assays using GAS41-YEATS and FAM-H3K23crK27cr were used to measure the IC of selected compounds of the disclosure. 50 Table 3 shows the biological activity (IC for inhibition of GAS41 YEATS) in the fluorescence polarization assay for selected compounds in Table 1. 50 The compound numbers correspond to the numbers and structures shown in Table 1.

[0537] [Table 3]

[0538] Example 4 AlphaScreen assay An AlphaScreen competition assay was also developed using His6-tagged, full-length GAS41 and biotinylated dicrotonylated H3 peptide (biotin-H3K23crK27cr). For full-length protein competition experiments, 100 nM MOCR-his6-Gas41 protein was incubated with 100x competitor in 50 mM HEPES (pH 7.5), 100 mM NaCl, 1 mM TCEP, 0.05% BSA, and 0.01% Tween-20 in 1% DMSO for 1 hour in a 96-well ½-Area AlphaPlate. H3K23crK27cr-biotin was added to a final concentration of 25 nM and incubated for 1 hour. Nickel Chelate Acceptor AlphaScreen beads were added to a final concentration of 10 μg / mL and incubated for 1 hour. Streptavidin Donor AlphaScreen beads were added to a final concentration of 10 μg / mL and incubated for 2 hours. Alpha signals were measured using a Pherastar plate reader. For the compound (5-(tert-butyl)thiophen-2-yl)(pyrrolidin-1-yl)methanone (compound 134 in Table 1), the IC 50 = 73 μM, and for H3K27ac, IC 50 We found that = 24 μM.

[0539] Table 4 shows the biological activity (IC for inhibition of GAS41) in the AlphaScreen assay for selected compounds from Table 2. 50 The compound numbers correspond to the numbers and structures shown in Table 2.

[0540] [Table 4]

[0541] Example 5 Crystal structure The crystal structure of compound 85 in complex with GAS41 YEATS was determined at 2.10 Å resolution (Figure 1). Compound 85 forms a recognition site for acetyl-lysine (Cho 2018) and binds through a channel composed of side chains consisting of H43, H71, S73, Y74, W93, and F96, and main chains consisting of G92, G94, and E95 (Figure 1).

[0542] Example 6 Dimeric compounds induce dimerization of the GAS41 YEATS domain An AlphaScreen assay based on His-tagged and biotin-labeled Avi-tagged GAS41 YEATS domain constructs was developed. For dimerization experiments, 500 nM his6-Gas41(13-158) and 250 nM avi-Gas41-YEATS were incubated in 50 mM HEPES (pH 7.5), 100 mM NaCl, 1 mM TCEP, 0.05% BSA, and 0.01% Tween-20 in a 96-well ½-Area AlphaPlate for 30 min. Compounds 221 and 223 were added to a final concentration of 250 nM in 1% DMSO. Nickel Chelate Acceptor AlphaScreen beads were added to a final concentration of 10 μg / mL and incubated for 1 hour. Streptavidin Donor AlphaScreen beads were added to a final concentration of 10 μg / mL and incubated for 2 hours. For competition experiments with the dimeric complex, 500 nM his-Gas41(13-158) and 250 nM avi-Gas41-YEATS were incubated with 250 nM dimeric inhibitor in assay buffer for 30 min before the addition of monomeric competitor. AlphaScreen beads were added as in the previous experiment. Alpha signals were measured on a Pherastar plate reader.

[0543] Increasing the concentration of either compound 223 or 221 in his6-Gas41(13-158) and avi-Gas41-YEATS resulted in an increase in the luminescence signal, reflecting the formation of a dimeric complex (Figure 2A). Furthermore, at the highest compound concentrations, the signal decreased, indicating saturation of the YEATS domain by the independent inhibitor molecules (Hook effect). NMR revealed: 15 We also compared the binding of compound 85 and compound 223 to the N-labeled GAS41 YEATS domain and found that only dimeric compound 223, but not monomeric compound 85, induced a significant broadening of the signal, suggesting the formation of a larger dimeric complex (Fig. 2B,C).

[0544] Example 7 Inhibition of GAS41 interactions in cells A NanoBiT assay (Promega Corporation, Madison, WI) was developed to detect compound-mediated inhibition of protein-protein interactions in HEK293T cells. GAS41-WT and GAS41-W93A mutants were cloned into the pBiT1.1-C[TK / LgBiT] vector. SmBiT-H3.3 was purchased from Promega. HEK293T cells (4 × 10E5) were seeded in 6-well plates (DMEM containing 10% FBS) and incubated for 5 hours. LgBiT-GAS41 and SmBiT-H3.3 plasmids were cotransfected for 42 hours using FuGENE HD. 5 × 104 cells were transferred to 96-well white plates (DMEM containing 10% FBS and 1% penicillin and streptomycin) and treated with compounds for 24 hours. Nano-Glo Live Cell Reagent was added to each well and luminescence was immediately measured using a PHERAstar FS instrument.

[0545] Co-expression of both proteins resulted in a strong luciferase signal, reflecting the interaction of GAS41 with acetylated H3.3 in cells. The NanoBit assay was validated by the introduction of a point mutation, W93A, in LgBit GAS41, which abolishes histone recognition (Hsu 2018), resulting in a significant decrease in luminescence signal. The activity of dimeric compound 221 was then tested in the NanoBit assay, and a dose-dependent inhibition of the luminescence signal was observed, with an IC 50 = 6 μM (Figure 3). Importantly, treatment with compound 221 did not reduce the signal in the W93A GAS41 mutant, further supporting its specific activity (Figure 3).

[0546] Example 8 Activity in NSCLS cells To examine the intracellular activity of GAS41 inhibitors, H1299 cells were treated for 4 days with monomeric Compound 88 and dimeric Compound 221. Only dimeric Compound 221 inhibited the GI 50 At approximately 3 μM, compound 221 induced dose-dependent growth inhibition (Figure 4A). To determine whether growth inhibition was dependent on the presence of GAS41, we used the CRISPR / CAS9 system to generate A549 GAS41 knockout cells. We found that GAS41-KO cells survived but grew more slowly than parental A549 cells, with growth reduced by approximately 70% by day 14 (Figure 4B). Treatment with compound 221 at 12 μM partially inhibited A549 cell growth by approximately 40%, but had no effect on GAS41-KO cells (Figure 4B), demonstrating specific growth inhibition. Next, we evaluated the effect of compound 221 on the growth of two NSCLC cell lines, H1299 and H1933, based on GAS41 amplification. Treatment with compound 221 resulted in a GI phenotype at day 14. 50 At approximately 6 μM, growth of both cell lines was reduced (Figure 4C). This effect closely correlates with the activity of compound 221 in the NanoBit assay (Figure 3). To further validate the on-target activity of compound 221, we examined the expression of GAS41 target genes in H1299 cells (Hsu 2018). Treatment with compound 221 resulted in a statistically significant decrease in the expression of E2F2, FOXM1, and MCM6 (Figure 4D). Taken together, the dimeric inhibitor compound 221 reduces GAS41 binding to acetylated H3.3 in cells, inducing on-target growth inhibition in NSCLC lines. [Brief explanation of the drawings]

[0547] [Figure 1] 1 shows the crystal structure of a compound disclosed herein (compound 85) in complex with the GAS41 YEATS domain. [Figure 2A-C]Figures A-C show data on the activity of compounds disclosed herein. A) Results of a dimerization assay to determine dimerization of the GAS41 YEATS domain induced by bivalent inhibitors, as described in Example 6. B) 1H-15N HSQC spectra of 60 μM 15N-labeled GAS41 YEATS domain (black) and in the presence of 60 μM Compound 85 (red). C) 1H-15N HSQC spectrum of 60 μM 15N-labeled GAS41 YEATS domain in the presence of 30 μM Compound 223 (red). [Figure 3] FIG. 1 shows the activity of compound 221 in the NanoBiT assay after 24 hours of treatment in 293T cells co-transfected with SmBiT-H3.3 and LgBiT-GAS41-WT or W93A mutant, as described in Example 7. [Figure 4A] The intracellular activity of certain compounds is demonstrated as described in Example 8. Inhibition of cell proliferation of H1299 cells by Compound 221 and Compound 88. [Figure 4B] The intracellular activity of certain compounds is shown as described in Example 8. Inhibition of growth by compound 221 in A549 or A549-KO cells. [Figure 4C] The intracellular activity of certain compounds is demonstrated as described in Example 8. Inhibition of growth by compound 221 in H1299 or H1993 cells. [Figure 4D] 1 shows the intracellular activity of certain compounds as described in Example 8. Relative mRNA levels of E2F2, FOXM1, and MCM6 in H1299 cells after 7 days of treatment with Compound 221.

Claims

1. A compound of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein: R １ is selected from heterocyclyl, alkyl, and aryl; X is —C(O)—, Y is -NR ａ - and R ａ is hydrogen and C １― C ６ alkyl, Z does not exist, A is selected from thiophene and thiazole; Q is selected from azetidine, pyrrolidine and piperidine; R ２ is selected from hydrogen, halo, alkyl, amino, and hydroxy; R ３ is the base of the formula: 【Chemistry 2】 wherein B is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N and S; J is absent; C is selected from aryl, heteroaryl, and heterocyclyl; m is 0 or 1; n is 0, 1, 2, or 3; and R ｇ is C １ -C ６ alkyl, and each R ｈ is independently selected from alkyl, halo, haloalkyl, amino, aminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, acyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl; The compound or the salt.

2. R １ is a monocyclic heterocyclyl having one or two heteroatoms independently selected from N, O, and S.

3. R １ 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein is pyrrolidinyl.

4. R ａ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

5. The compound of any one of claims 1 to 4, wherein A is thiophene.

6. 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Q is azetidine.

7. R ２ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. 【Request 8】 【Chemical 3】 The basis is, 【Chemistry 4】 8. The compound of any one of claims 1 to 7, having a formula selected from: or a pharmaceutically acceptable salt thereof.

9. 2. The compound of claim 1, wherein the compound has the following formula (Ia): or a pharmaceutically acceptable salt thereof: 【Chemistry 5】

10. 2. The compound of claim 1, wherein the compound has the following formula (Ib): or a pharmaceutically acceptable salt thereof: 【Chemistry 6】

11. The compound has the following formula (Ic): 【Chemistry 7】 During the ceremony, n is 0, 1, 2 or 3; Each R ｈ became independent and C １ -C ６ Alkyl, halo, halo-C １ -C ６ Alkyl, amino, amino-C １ -C ６ Alkyl, hydroxy, hydroxy-C １ -C ６ Alkyl, C １ -C ６ Alkoxy, Amido, Amido-C １ -C ６ Alkyl, acyl, aryl, aryl-C １ -C ６ Alkyl, heteroaryl, heteroaryl-C １ -C ６ Alkyl, heterocyclyl, heterocyclyl-C １ -C ６ Alkyl, cycloalkyl and cycloalkyl-C １ -C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R is selected from the group consisting of alkyl, aryl, arylsulfonyl ...

12. At least one R ｈ But -(CH ２ ) ｒ C(O)NR ｉ R ｊ or -(CH ２ ) ｓ NR ｋ C(O)R ｍ wherein: r and s are each independently selected from 0, 1, and 2; R ｉ and R ｋ are each independently hydrogen and C １ -C ６ alkyl, R ｊ But C １ -C ６ Alkyl, aryl, aryl-C １ -C ６ Alkyl, heteroaryl, heteroaryl-C １ -C ６ Alkyl, heterocyclyl, heterocyclyl-C １ -C ６ Alkyl, cycloalkyl and cycloalkyl-C １ -C ６ alkyl, R ｍ But C １ -C ６ Alkyl, aryl, aryl-C １ -C ６ Alkyl, heteroaryl, heteroaryl-C １ -C ６ Alkyl, heterocyclyl, heterocyclyl-C １ -C ６ Alkyl, cycloalkyl and cycloalkyl-C １ -C ６ Alkyl, amino, C １ -C ６ Alkylamino, arylamino and aryl-C １ -C ６ alkylamino; Each alkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl is independently unsubstituted or independently selected from halo, C １ -C ６ Alkyl, C １ -C ６ The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which is substituted by one or two substituents selected from alkoxy, hydroxy, amino and oxo.

13. The compound is 【Chemistry 8】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 2. The compound of claim 1, selected from the group consisting of:

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

15. 15. The pharmaceutical composition of claim 14, formulated for oral administration.

16. 15. The pharmaceutical composition of claim 14, formulated for parenteral administration.

17. 17. A method for inhibiting GAS41 activity in a sample, comprising contacting the sample with an effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 14 to 16.

18. A method for reducing the proliferation of cancer cells in a sample, the method comprising contacting the sample with an effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 14 to 16.

19. 19. The method of claim 18, wherein the cancer cells are selected from cells of a brain tumor (e.g., glioblastoma or astrocytoma), a sarcoma, a colon cancer, a lung cancer (e.g., non-small cell lung cancer), and a gastric cancer.

20. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 14 to 16, in the manufacture of a medicament for the treatment of cancer.

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