GAS41 inhibitors and methods of use

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 050,303, filed on July 10, 2020, the entire contents of which are incorporated herein by reference.

[0003] Statement Regarding Federally Sponsored Research

[0004] This invention was made with government support under Grant No. CA240514 awarded by the National Institutes of Health. The government has certain rights in this invention. Technical Field

[0005] Provided herein are small molecules that bind to GAS41 and inhibit GAS41 activity, and methods of using the small molecules to treat cancer. Background Art

[0006] Proteins that recognize post-transcriptional modifications in histones play a key role in transcriptional regulation (Allis et al. Nat. Rev. Genet. 17, 487-500 (2016)). Proteins containing the YEATS domain belong to a relatively newly discovered family of epigenetic reader proteins and include four human paralogs: ENL, YEATS2, AF9, and GAS41. Biochemical studies have shown that the YEATS domain binds to chromatin by recognizing histones with acetylated or crotonylated lysine side chains.

[0007] GAS41 (glioma amplified sequence 41) is a newly discovered oncogene that is overexpressed and associated with a variety of cancers. It has been found that GAS41 is amplified in brain cancer patients, including in 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 found that the GAS41 gene was amplified and overexpressed in 20% of non-small cell lung cancer cells compared with matched normal tissues (Pikor 2013). Overexpression of GAS41 was also detected in NSCLC, but not in "normal" lung epithelial and fibroblast cell lines (Hsu 2018). In a panel of NSCLC cell lines with GAS41 amplification, knockdown of GAS41 severely impaired cell growth and colony formation (Pikor 2013; Hsu 2018). In addition, GAS41 binds to promoter regions of actively transcribed genes enriched in H3K27ac, suggesting that recognition of acetylated H3 is essential for chromatin binding and its oncogenic activity (Hsu et al. Genes Dev 32, 58-69 (2018)). Summary of the Invention

[0008] Provided herein are small molecules that bind to GAS41 and inhibit GAS41 activity, and methods of using the small molecules to treat cancer.

[0009] In one aspect, the present disclosure provides compounds of formula (I):

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein:

[0012] R 1is selected from the group consisting of heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxyl, acyl, amido, cyano, sulfonyl, and hydrogen;

[0013] X is -C(O)-, -C(S)-, -CH2- or -SO2-, or is absent;

[0014] Y is -NR a -or-O-;

[0015] R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl and aminoalkyl, or R a Together with the nitrogen atom to which it is attached, it forms 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;

[0016] Z does not exist or is -CR b R c -;

[0017] R b and R c are each independently selected from hydrogen and alkyl;

[0018] A is a five-membered heteroaryl group;

[0019] Q is a four-membered heterocyclic group, a five-membered heterocyclic group, or a six-membered heterocyclic group;

[0020] R 2 is selected from hydrogen, halo, alkyl, amino and hydroxy;

[0021] R 3 Selected from hydrogen, halogen, -OR d 、-NR e R f , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl and groups of the formula:

[0022]

[0023] 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, 4, or 5; and R g and R heach independently selected from the group consisting of 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, carboxyl, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl;

[0024] or R 2 and R 3 Together with the one or more carbon atoms to which they are attached, they 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; and

[0025] R d 、R e and R f each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl;

[0026] wherein 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,

[0027] The prerequisite is that when Z is -CR b R c -, R 1 Not a cycloalkyl group.

[0028] In some embodiments, R 1 is selected from heterocyclyl, alkyl and aryl. 1 is a monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S. In some embodiments, R 1 It is pyrrolidino.

[0029] In some embodiments, X is -C(O)-. In some embodiments, Y is -NR a -, and R a In some embodiments, Z is absent.

[0030] In some embodiments, A is a five-membered heteroaryl group 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.

[0031] In some embodiments, Q is selected from azetidine, pyrrolidine, and piperidine. In some embodiments, Q is azetidine.

[0032] In some embodiments, R 2 It's hydrogen.

[0033] In some embodiments, R 3 Is a group of the formula

[0034]

[0035] In some embodiments, 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; R g is a C1-C6 alkyl group; and each R h Independently selected from alkyl, halo, haloalkyl, amino, aminoalkyl, amido, amidoalkyl, sulfonamido, sulfonamidoalkyl, acyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl.

[0036] In some embodiments, the group The formula is selected from:

[0037]

[0038] where R x 、R y and R z are each independently selected from -OR v , aryl and heteroaryl substituents, wherein R v is selected from C1-C6 alkyl, aryl and heteroaryl.

[0039] In some embodiments, the compound has Formula (Ia):

[0040]

[0041] In some embodiments, the compound has Formula (Ib):

[0042]

[0043] In some embodiments, the compound has Formula (Ic):

[0044]

[0045] in:

[0046] n is 0, 1, 2, or 3; and

[0047] Each R h Independently selected from C1-C6 alkyl, halo, halo-C1-C6-alkyl, amino, amino-C1-C6-alkyl, hydroxy, hydroxy-C1-C6-alkyl, C1-C6 alkoxy, amido, amido-C1-C6-alkyl, acyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, heterocyclyl, heterocyclyl-C1-C6-alkyl, cycloalkyl and cycloalkyl-C1-C6-alkyl.

[0048] In some embodiments, at least one R h Formula: -(CH2) r C(O)NR i R j or -(CH2) s NR k C(O)R m ,in:

[0049] r and s are each independently selected from 0, 1 and 2;

[0050] R i and R k are each independently selected from hydrogen and C1-C6 alkyl;

[0051] R j is selected from the group consisting of C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, heterocyclyl, heterocyclyl-C1-C6-alkyl, cycloalkyl and cycloalkyl-C1-C6-alkyl;

[0052] R m is selected from the group consisting of 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;

[0053] wherein each alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-C6-alkyl, C1-C6-alkoxy, hydroxy, amino and oxo.

[0054] In some embodiments, the compound is selected from the group consisting of the compounds shown in Table 1 or pharmaceutically acceptable salts thereof.

[0055] In another aspect, the present disclosure provides compounds of formula (IIa):

[0056]

[0057] or a pharmaceutically acceptable salt thereof, wherein:

[0058] R 1 and R 1’ each independently selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxyl, acyl, amido, cyano, sulfonyl, and hydrogen;

[0059] X and X' are each independently absent or selected from -C(O)-, -C(S)-, -CH2- and -SO2-;

[0060] Y and Y' are each independently -NR a -or-O-;

[0061] R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl and aminoalkyl, or R a Together with the nitrogen atom to which it is attached, it forms 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;

[0062] Z and Z' are each independently absent or -CR b R c -;

[0063] R b and R c are each independently selected from hydrogen and alkyl;

[0064] A and A' are each independently a five-membered heteroaromatic ring;

[0065] Q and Q' are each independently a four-membered heterocycle, a five-membered heterocycle or a six-membered heterocycle;

[0066] R 2 and R 2 ' are each independently selected from hydrogen, halo, alkyl, amino and hydroxy;

[0067] R 3 and R 3 ' are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyclyl and a group of the formula:

[0068]

[0069] 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 each independently selected from the group consisting of 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, carboxyl, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl;

[0070] R d 、R e and R f are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; and

[0071] L is the connector;

[0072] wherein 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.

[0073] In some embodiments, R 1 and R 1 ' is the same, R 2 and R 2 ' is the same, R 3 and R 3 ' are 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. In some embodiments, R 1 and R 1 ' are each a 4-membered monocyclic heterocyclyl or a 5-membered monocyclic heterocyclyl. In some embodiments, R 1 and R 1 'It's pyrrolidine.

[0074] In some embodiments, X and X' are -C(O)-. In some embodiments, Y and Y' are -NR a -, and R a In some embodiments, Z and Z' are each absent.

[0075] In some embodiments, A and A' are thiophene or thiazole.

[0076] In some embodiments, Q and Q' are selected from azetidine and pyrrolidine.

[0077] In some embodiments, R 2 and R 2 'It's hydrogen.

[0078] In some embodiments, R 3 and R 3' A group selected from aryl, heteroaryl and the following formula:

[0079]

[0080] In some embodiments, R 3 and R 3' Each is a group of the formula:

[0081]

[0082] wherein B is a 5-membered monocyclic heteroaryl group 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; R g is C1-C6 alkyl; n is 0, 1 or 2; and each R h Independently selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, amino, amino-C1-C6-alkyl, amido-C1-C6-alkyl and heterocyclyl.

[0083] In some embodiments, L is a linker comprising one or more groups independently selected from methylene (-CH2-), vinylene (-CH=CH-), acetylene (-C≡C-), ether (-O-), amine (-NH-), alkylamine (-NR-, wherein R is an optionally substituted C1-C6 alkyl group), amide (-C(O)NH-), ester (-C(O)O-), carbamate (-OC(O)NH-), sulfonamide (-S(O)2NH-), phenylene (-C6H4-), heteroarylene, heterocyclylene, and any combination thereof. In some embodiments, L is selected from:

[0084]

[0085]

[0086] 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; X 1 and X 2 are each independently O or -NR x , where R x is hydrogen or optionally substituted alkyl; and Y 1 and Z 1 are each independently selected from -CH2-, -NH- and -O-.

[0087] In some embodiments, the compound is selected from the group consisting of the compounds shown in Table 2 or pharmaceutically acceptable salts thereof.

[0088] In another aspect, the present disclosure provides compounds of formula (IIb):

[0089]

[0090] or a pharmaceutically acceptable salt thereof, wherein:

[0091] R 1 and R 1' each independently selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, and alkynyl;

[0092] X and X' are each independently absent or selected from -C(O)-, -C(S)-, -CH2- and -SO2-;

[0093] Y and Y' are each independently selected from -NR a -or-O-;

[0094] R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl and aminoalkyl, or R a Together with the nitrogen atom to which it is attached, it forms a fused ring with A;

[0095] Z and Z' are each independently absent or -CR b R c -;

[0096] R b and R c are each independently selected from hydrogen and alkyl;

[0097] A and A' are each independently a five-membered heteroaromatic ring;

[0098] Q and Q' are each independently a four-membered heterocyclic group, a five-membered heterocyclic group or a six-membered heterocyclic group;

[0099] R 2 and R 2 ' are each independently selected from hydrogen, halo, alkyl, amino and hydroxy;

[0100] R 3 and R 3 ' are each independently selected from hydrogen, halogen, -OR d 、-NR e R f , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, and groups of the formula:

[0101]

[0102] 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 each independently selected from the group consisting of 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, carboxyl, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl;

[0103] or R 2 and R 3 Together with the one or more carbon atoms to which they are attached, they 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, they form an alkenyl group;

[0104] R d 、R e and R f are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; and

[0105] L is the connector;

[0106] wherein 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.

[0107] In some embodiments, R 1 and R 1 ' is the same, R 2 and R 2 ' is the same, R 3 and R 3 ' are 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. In some embodiments, R 1 and R 1 ' are each a 4-membered monocyclic heterocyclyl or a 5-membered monocyclic heterocyclyl. In some embodiments, R 1 and R 1 'It's pyrrolidine.

[0108] In some embodiments, X and X' are -C(O)-. In some embodiments, Y and Y' are -NR a -, and R a In some embodiments, Z and Z' are each absent.

[0109] In some embodiments, A and A' are thiophene or thiazole.

[0110] In some embodiments, Q and Q' are selected from azetidine and pyrrolidine.

[0111] In some embodiments, R 2 and R 2 'It's hydrogen.

[0112] In some embodiments, R 3 and R 3' A group selected from hydrogen, aryl, heteroaryl and the following formula:

[0113]

[0114] In some embodiments, R 3 and R 3' is selected from monocyclic heteroaryl and bicyclic heteroaryl groups having 1, 2 or 3 heteroatoms independently selected from N and S.

[0115] In some embodiments, R 3 and R 3' Each is a group of the formula:

[0116]

[0117] wherein B is a 5-membered monocyclic heteroaryl group 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; R g is C1-C6 alkyl; n is 0, 1 or 2; and each R h Independently selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, amino, amino-C1-C6-alkyl, amido-C1-C6-alkyl and heterocyclyl.

[0118] In some embodiments, L is a linker comprising one or more groups independently selected from methylene (-CH2-), vinylene (-CH=CH-), acetylene (-C≡C-), ether (-O-), amine (-NH-), alkylamine (-NR-, wherein R is an optionally substituted C1-C6 alkyl group), amide (-C(O)NH-), ester (-C(O)O-), carbamate (-OC(O)NH-), sulfonamide (-S(O)2NH-), phenylene (-C6H4-), heteroarylene, heterocyclylene, and any combination thereof. In some embodiments, L is selected from:

[0119]

[0120]

[0121] 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; X 1 and X 2 are each independently O or -NR x , where R x is hydrogen or optionally substituted alkyl; and Y 1 and Z 1 are each independently selected from -CH2-, -NH- and -O-.

[0122] In some embodiments, the compound is selected from the group consisting of the compounds shown in Table 2 or pharmaceutically acceptable salts thereof.

[0123] In another aspect, the present disclosure provides compounds of formula (IIc):

[0124]

[0125] or a pharmaceutically acceptable salt thereof, wherein:

[0126] R 1 is selected from the group consisting of heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxyl, acyl, amido, cyano, sulfonyl, and hydrogen;

[0127] R 1' is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, and alkynyl;

[0128] X and X' are each independently absent or selected from -C(O)-, -C(S)-, -CH2- and -SO2-;

[0129] Y and Y' are each independently selected from -NR a -or-O-;

[0130] R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl and aminoalkyl, or R a Together with the nitrogen atom to which it is attached, it forms 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;

[0131] Z and Z' are each independently absent or -CR b R c -;

[0132] R b and R c are each independently selected from hydrogen and alkyl;

[0133] A and A' are each independently a five-membered heteroaromatic ring;

[0134] Q and Q' are each independently a four-membered heterocycle, a five-membered heterocycle or a six-membered heterocycle;

[0135] R 2 and R 2 ' are each independently selected from hydrogen, halo, alkyl, amino and hydroxy;

[0136] R 3 A group selected from aryl, heteroaryl, heterocyclic and the following formula:

[0137]

[0138] 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 each independently selected from the group consisting of 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, carboxyl, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl;

[0139] R 3 'Selected from hydrogen, halogen, -OR d’ 、-NR e’ R f’ , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, and groups of the formula:

[0140]

[0141] 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’ each independently selected from the group consisting of 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, carboxyl, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl;

[0142] R d’ 、R e’ and R f’ are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; and

[0143] L is the connector;

[0144] wherein 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.

[0145] In some embodiments, R 1 and R 1 ' is the same, R 2 and R 2 ' is the same, R 3 and R 3 ' are 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. In some embodiments, R 1 and R 1 ' are each a 4-membered monocyclic heterocyclyl or a 5-membered monocyclic heterocyclyl. In some embodiments, R 1 and R 1 'It's pyrrolidine.

[0146] In some embodiments, X and X' are -C(O)-. In some embodiments, Y and Y' are -NR a -, and R a In some embodiments, Z and Z' are each absent.

[0147] In some embodiments, A and A' are thiophene.

[0148] In some embodiments, Q and Q' are selected from azetidine and pyrrolidine.

[0149] In some embodiments, R 2 and R 2 'It's hydrogen.

[0150] In some embodiments, R 3 A group selected from aryl, heteroaryl and the following formula:

[0151]

[0152] In some embodiments, R 3 is a group of the formula:

[0153]

[0154] wherein B is a 5-membered monocyclic heteroaryl group 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; R g is C1-C6 alkyl; n is 0, 1 or 2; and each R hIndependently selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, amino, amino-C1-C6-alkyl, amido-C1-C6-alkyl and heterocyclyl.

[0155] In some embodiments, R 3' A group selected from hydrogen, aryl, heteroaryl and the following formula:

[0156]

[0157] In some embodiments, R 3’ is selected from monocyclic heteroaryl and bicyclic heteroaryl groups having 1, 2 or 3 heteroatoms independently selected from N and S.

[0158] In some embodiments, R 3’ is a group of the formula:

[0159]

[0160] wherein B' is a 5-membered monocyclic heteroaryl group 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; R g’ is C1-C6 alkyl; n' is 0, 1 or 2; and each R h’ Independently selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, amino, amino-C1-C6-alkyl, amido-C1-C6-alkyl and heterocyclyl.

[0161] In some embodiments, L is a linker comprising one or more groups independently selected from methylene (-CH2-), vinylene (-CH=CH-), acetylene (-C≡C-), ether (-O-), amine (-NH-), alkylamine (-NR-, wherein R is an optionally substituted C1-C6 alkyl group), amide (-C(O)NH-), ester (-C(O)O-), carbamate (-OC(O)NH-), sulfonamide (-S(O)2NH-), phenylene (-C6H4-), heteroarylene, heterocyclylene, and any combination thereof. In some embodiments, L is selected from:

[0162]

[0163]

[0164] 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; X 1 and X 2 are each independently O or -NR x , where R x is hydrogen or optionally substituted alkyl; and Y 1 and Z 1 are each independently selected from -CH2-, -NH- and -O-.

[0165] In one aspect, the present 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.

[0166] In one aspect, the present disclosure provides a method for inhibiting GAS41 activity in a sample, 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).

[0167] In one aspect, the present disclosure provides 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 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 brain cancer (e.g., glioblastoma or astrocytoma), sarcoma, colorectal cancer, lung cancer (e.g., non-small cell lung cancer), and gastric cancer cells.

[0168] In one aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject 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 is selected from brain cancer (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 to the subject an additional chemotherapeutic agent. In some embodiments, the subject is human.

[0169] In one aspect, the present disclosure provides 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) for treating cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0170] Figure 1 Shown is the crystal structure of a compound disclosed herein (Compound 85) in complex with the GAS41 YEATS domain.

[0171] Figures 2A-2C Activity data for compounds disclosed herein are shown. A) Results of a dimerization assay as described in Example 6 to determine dimerization induced by bivalent inhibitors of the GAS41 YEATS domain. B) 60 μM 15 N-labeled GAS41 YEATS domain 1 H- 15 N HSQC spectrum (black) and spectrum in the presence of 60 μM compound 85 (red). C) 60 μM in the presence of 30 μM compound 223. 15 N-labeled GAS41 YEATS domain 1 H- 15 N HSQC spectrum (red).

[0172] Figure 3 The activity of compound 221 in the NanoBiT assay is shown in 293T cells co-transfected with SmBiT-H3.3 and LgBiT-GAS41-WT or W93A mutant as described in Example 7 after 24 hours of treatment.

[0173] Figure 4 shows the cellular activities of certain compounds as described in Example 8. A) Inhibition of cell proliferation of H1299 cells by Compound 221 and Compound 88. B) Inhibition of growth of A549 or A549-KO cells by Compound 221. C) Inhibition of growth of H1299 or H1993 cells by Compound 221. D) Relative mRNA levels of E2F2, FOXM1, and MCM6 in H1299 cells after 7 days of treatment with Compound 221.

[0174] definition

[0175] 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, some preferred methods, compositions, devices and materials are described herein. However, before describing the present materials and methods, it should be understood that the present invention is not limited to the specific molecules, compositions, methods or protocols described herein, as these can vary according to routine experimentation and optimization. It should also be understood that the terms used in this specification are for the purpose of describing only specific versions or embodiments and are not intended to limit the scope of the embodiments described herein.

[0176] 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 the invention belongs. However, in the event of a conflict, the present specification (including definitions) will prevail. Therefore, in the context of the embodiments described herein, the following definitions apply.

[0177] As used herein and in 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.

[0178] As used herein, the term "comprising" and its linguistic variations indicate the presence of the listed features, elements, method steps, etc., without excluding the presence of additional features, elements, method steps, etc. In contrast, the term "consisting of and its linguistic variations indicate the presence of the listed features, elements, method steps, etc., and excludes any unlisted features, elements, method steps, etc., except for typically associated impurities. The phrase "consisting essentially of" indicates the listed features, elements, method steps, etc. and any additional features, elements, method steps, etc. that do not materially affect the basic properties of the composition, system, or method. Many embodiments herein are described using open "comprising" language. Such embodiments encompass multiple closed "consisting of" and / or "consisting essentially of" embodiments that may alternatively be claimed or described using such language.

[0179] All chemical names of substituents should be interpreted according to IUPAC and / or modified nomenclature and with reference to the chemical structures depicted and / or described herein. For the compounds described herein, radicals and substituents thereof may be selected based on the permissible valences of the atoms and substituents, and such selections and substitutions result in stable compounds, e.g., compounds that do not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, and the like.

[0180] According to the convention used in the art, the group:

[0181]

[0182]

[0046] The structural formulae herein are used to depict a bond that serves as the point of attachment of a moiety or substituent to the core or backbone structure.

[0183] 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" generally refers to a subject who is being treated for a disease or disorder.

[0184] As used herein, the term "subject at risk of developing cancer" refers to a subject who has one or more risk factors for developing cancer. Risk factors may include, but are not limited to, gender, age, genetic predisposition, environmental exposure, history of infection and previous illness, lifestyle, etc.

[0185] 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 specific formulation or route of administration.

[0186] As used herein, the terms "administer" and "administer" refer to the act of administering 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 through the subarachnoid space of the brain or spinal cord (intrathecal), the eye (ocular), the mouth (oral), the skin (topical or transdermal), the nose (nasal), the lungs (inhalation), the oral mucosa (buccal), the ear, the rectum, the vagina, by injection (e.g., intravenous, subcutaneous, intratumoral, intraperitoneal, etc.), etc.

[0187] As used herein, the terms "co-administration" and "co-administering" refer to administering 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, the first agent / therapy is administered before the second agent / therapy. Those skilled in the art will appreciate that the formulations and / or routes of administration of the various agents or therapies used may vary. Those skilled in the art can easily determine the appropriate dose for co-administration. In some embodiments, when an agent or therapy is co-administered, the corresponding agent or therapy is administered at a lower dose than that suitable for administration alone. Therefore, in embodiments where the co-administration of an agent or therapy reduces the necessary dose of a potentially harmful (e.g., toxic) agent, and / or when the co-administration of two or more agents causes the subject to be sensitive to the beneficial effects of one agent by the co-administration of another agent, co-administration is particularly desirable.

[0188] As used herein, the term "pharmaceutical composition" refers to the combination of an active agent with an inert or active carrier, which renders the composition particularly suitable for therapeutic use in vitro, in vivo or ex vivo.

[0189] As used herein, the term "pharmaceutically acceptable" or "pharmacologically acceptable" refers to a composition that does not produce substantially adverse reactions, such as toxic, allergic, or immunological reactions, when administered to a subject.

[0190] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, including, but not limited to, phosphate-buffered saline solutions, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents, any and all solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintegrants (e.g., potato starch or sodium starch glycolate), and the like. The composition may also include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, e.g., Martin, Remington's Pharmaceutical Sciences, 15th edition, Mack Publ. Co., Easton, Pa. (1975), which is incorporated herein by reference in its entirety.

[0191] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt (e.g., acid salt or basic salt) 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, the "salt" of a compound of the present invention can be derived from an inorganic acid and an inorganic base or an organic acid and an organic base. 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, p-toluenesulfonic 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, although not pharmaceutically acceptable per se, can be used to prepare salts that are useful as intermediates in obtaining compounds of the present invention and pharmaceutically acceptable acid addition salts thereof.

[0192] Examples of bases include, but are not limited to, alkali metal (eg, sodium) hydroxides, alkaline earth metal (eg, magnesium) hydroxides, ammonia, and compounds of the formula NR4 + Compound (wherein each R is independently C 1-4 alkyl) and so on.

[0193] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, gluconate heptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmitate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and the like. Other examples of salts include pyruvate, ... + NH4 + and NR4 + (where each R is independently C 1-4 anions of the compounds of the present invention which are combined with alkyl groups) and the like.

[0194] For therapeutic use, salts of the compounds herein are considered pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also be useful, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0195] As used herein, the term "instructions for administering the compound to a subject" and grammatical equivalents thereof include instructions for using the compositions contained in the kit to treat a condition (e.g., providing dosing, route of administration, decision trees for the treating physician to link patient-specific characteristics to a therapeutic course of action).

[0196] "Amino" refers to a -NH2 moiety.

[0197] "Carbonyl" refers to a moiety of the formula -C(=O)-.

[0198] "Carboxy" or "carboxyl" refers to a -CO2H moiety.

[0199] "Cyano" refers to a -CN moiety.

[0200] "Hydroxy" or "hydroxyl" refers to an -OH moiety.

[0201] "Imino" refers to a =NH moiety. Unless stated otherwise specifically in the specification, an imino group is optionally substituted.

[0202] "Nitro" refers to the -NO2 moiety.

[0203] "Oxo" refers to the moiety =0.

[0204] "Thio" refers to the =S moiety.

[0205] "Acyl" refers to a 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 specifically stated otherwise in the specification, an acyl group is optionally substituted.

[0206] "Alkyl" refers to a group having 1 to 30 carbon atoms, for example 1 to 16 carbon atoms (C1-C 16 alkyl), 1 to 12 carbon atoms (C1-C 12 The alkyl group may be a straight or branched saturated hydrocarbon chain of 1 to 8 carbon atoms (C1-C8 alkyl), 1 to 6 carbon atoms (C1-C6 alkyl) or 1 to 4 carbon atoms (C1-C4 alkyl), for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 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, etc. Unless otherwise specifically stated in the specification, the alkyl group is optionally substituted.

[0207] "Alkenyl" refers to a straight or branched chain containing 2 to 30 carbon atoms, for example, 2 to 16 carbon atoms (C2-C 16 alkenyl), 2 to 12 carbon atoms (C2-C 12 The term "alkenyl" refers to a straight or branched hydrocarbon chain of 2 to 8 carbon atoms (C-C alkenyl), 2 to 8 carbon atoms (C-C alkenyl), 2 to 6 carbon atoms (C-C alkenyl) or 2 to 4 carbon atoms (C-C alkenyl), and contains at least one carbon-carbon double bond. Representative examples of alkenyl include but are not limited to vinyl, 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 otherwise specifically stated in the specification, alkenyl groups are optionally substituted.

[0208] "Alkynyl" refers to a group containing 2 to 30 carbon atoms, for example 2 to 16 carbon atoms (C2-C 16 Alkynyl), 2 to 12 carbon atoms (C2-C 12 Alkynyl refers to a straight or branched hydrocarbon chain of 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 contains at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl and hexynyl. Unless otherwise specifically stated in the specification, alkynyl groups are optionally substituted.

[0209] "Alkylene" refers to a group derived from a group having 1 to 30 carbon atoms (C1-C 30 Alkylene) is, for example, a divalent group of a straight or branched hydrocarbon 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-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH(CH3)CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH(CH3)CH2CH2-, -CH2CH(CH3)CH2CH2-, -CH2CH(CH3)CH2CH2-, -CH2CH(CH3)CH2CH2-, and -CH(CH3)CH2CH2CH2CH2-. Unless otherwise specifically stated in the specification, alkylene groups are optionally substituted.

[0210] "Alkoxy" refers to a moiety of the formula -OR, where R is an alkyl group as defined herein, for example, 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 otherwise specified in the specification, alkoxy groups are optionally substituted.

[0211] "Alkenyloxy" refers to a moiety of the formula -OR, wherein R is an alkenyl group as defined herein, for example, an alkenyl group containing 2 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkenyloxy group is optionally substituted.

[0212] "Alkynyloxy" refers to a moiety of the formula -OR, wherein R is an alkynyl group as defined herein, for example, an alkynyl group containing from 2 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkynyloxy group is optionally substituted.

[0213] "Alkylamino" refers to a moiety of the formula -NHR, wherein R is an alkyl group as defined herein. Unless stated otherwise specifically in the specification, an alkylamino or dialkylamino group is optionally substituted.

[0214] "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.

[0215] "Amide" or "amido" refers to a moiety having the formula -C(=O)NRR' or -NRC(=O)R', wherein 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 amido moiety is -C(=O)NRR', R and R' can optionally be taken together with the nitrogen to which they are attached to form a 4-, 5-, 6-, or 7-membered ring. Unless otherwise specified in the specification, an amido group is optionally substituted.

[0216] "Acylaminoalkyl" refers to an alkyl moiety as defined herein, wherein at least one hydrogen atom is replaced by an acylamino group as defined herein. Unless stated otherwise specifically in the specification, an acylaminoalkyl group is optionally substituted.

[0217] "Aminoalkyl" refers to an alkyl moiety as defined herein in which at least one hydrogen atom is replaced by an amino group as defined herein. The amino group can be substituted on a tertiary, secondary, or primary carbon. Unless otherwise specifically stated in the specification, an aminoalkyl group is optionally substituted.

[0218] "Aryl" refers to an aromatic carbocyclic ring system having a single ring (monocyclic) or multiple rings (bicyclic or tricyclic), including fused ring systems and zero heteroatoms. As used herein, an aryl group contains 6-20 carbon atoms (C6-C 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 otherwise specifically stated in the specification, the term "aryl" is intended to include optionally substituted aryl groups.

[0219] "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 in the specification, the term "arylalkyl" is intended to include groups that are optionally substituted on the aryl portion and / or the alkyl portion.

[0220] "Arylene" refers to a divalent aromatic radical (eg, phenylene). Unless otherwise specifically stated, an arylene group is optionally substituted.

[0221] "Aryloxy" refers to an -O-aryl moiety. Unless stated otherwise specifically in the specification, an aryloxy group is optionally substituted.

[0222] "Arylamino" refers to -NR a - aryl moiety, wherein R a is H or alkyl. Unless stated otherwise specifically in the specification, an arylamino group is optionally substituted.

[0223] "Cycloalkyl" refers to a saturated carbocyclic ring system containing three to ten carbon atoms in each ring. Cycloalkyl can be monocyclic, bicyclic, tricyclic, bridged, fused and / or spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl and bicyclo [5.2.0] nonyl. Unless otherwise specifically stated in the specification, the term "cycloalkyl" is intended to include optionally substituted cycloalkyl groups.

[0224] "Cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and preferably having 5-10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl. Unless otherwise specifically stated in the specification, the term "cycloalkenyl" is intended to include optionally substituted cycloalkenyl groups.

[0225] "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 that are optionally substituted on the cycloalkyl portion and / or the alkyl portion.

[0226] "Cycloalkylalkylamino" refers to a cycloalkylalkyl-NR a - part, where R a Is H or alkyl, and wherein the cycloalkylalkyl moiety is attached to the nitrogen via a carbon atom, wherein the nitrogen serves as a linker attaching the moiety to the rest of the molecule. Unless specifically stated otherwise in the specification, cycloalkylalkylamino is optionally substituted.

[0227] "Cycloalkylalkyloxy" refers to an -O-cycloalkylalkyl moiety, wherein the cycloalkylalkyl moiety is attached to an oxygen via a carbon atom, wherein the oxygen serves as a linker connecting the moiety to the rest of the molecule. Unless specifically stated otherwise in the specification, a cycloalkylalkyloxy group is optionally substituted.

[0228] "Cycloalkylamino" refers to -NR a -cycloalkyl moiety, wherein R a is H or alkyl. Unless stated otherwise specifically in the specification, a cycloalkylamino group is optionally substituted.

[0229] "Cycloalkyloxy" refers to an -O-cycloalkyl moiety. Unless stated otherwise specifically in the specification, a cycloalkyloxy group is optionally substituted.

[0230] "Dialkylamino" refers to a group of the formula -NRR ’ wherein R and R' are each independently an alkyl group as defined herein. Unless otherwise stated in the specification, an alkylamino or dialkylamino group is optionally substituted.

[0231] "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.

[0232] "Halo" or "halogen" refers to fluoro, chloro, bromo or iodo.

[0233] "Haloalkyl" refers to an alkyl group, as defined herein, substituted with one or more halogen atoms, as defined herein, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, -CH2CF3, -CH2CHF2, -CH2CH2F, -CHFCF3, -CHFCHF2, -CHFCH2F, -CHFCH3, -CF2CF3, -CF2CHF2, -CF2CH2F, -CF2CH3, -CH2CF2CH3, -CH2CHFCH3, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

[0234] "Haloalkoxy" means an alkoxy group, as defined herein, substituted with one or more halogen atoms, as defined herein.

[0235] 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).

[0236] " heteroalkyl " means such an alkyl group as defined herein, wherein one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by a heteroatom group, such as -NR-, -O-, -S-, -S(O)-, -S(O)2-, etc., wherein R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclic radical, each of which can be optionally substituted. For example, 1, 2 or 3 carbon atoms can be independently replaced by the same or different heteroatom groups. Examples of heteroalkyl groups include, but are not limited to -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3 and -CH2NRCH3, wherein R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl or heteroaryl, each of which can be optionally substituted. Heteroalkyl also includes groups in which the carbon atoms of the alkyl group are oxidized (i.e., -C(O)-).

[0237] " heteroalkylene " refers to such alkylene group as defined herein, wherein one or more (and any associated hydrogen atom) in the carbon atom are each independently replaced by a heteroatom group, such as -NR-, -O-, -S-, -S(O)-, -S(O)2-, etc., wherein R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclic radical, each of which can be optionally substituted. For example, 1, 2 or 3 carbon atoms can be independently replaced by the same or different heteroatom groups. Heteroalkylene also includes groups in which the carbon atoms of the alkyl are oxidized (i.e., -C(O)-). Examples of heteroalkylene groups include but are not limited to -CH2-O-CH2-, -CH2-S-CH2-, -CH2-NR-CH2-, -CH2-NH-C(O)-CH2-, etc., and polyethylene oxide chains, polypropylene oxide chains and polyethyleneimine chains.

[0238] "Heteroaryl" refers to an aromatic group having a single ring (monocyclic) or multiple rings (bicyclic or tricyclic) with one or more ring heteroatoms, the ring heteroatoms being independently selected from O, N and S. An aromatic monocyclic ring is a five-membered ring or a six-membered ring containing at least one heteroatom, the heteroatoms being independently selected from O, N and S (e.g., 1, 2, 3 or 4 heteroatoms, the heteroatoms being independently selected from O, N and S). A five-membered aromatic monocyclic ring has two double bonds, and a six-membered aromatic monocyclic ring has three double bonds. An example of a bicyclic heteroaryl group is a monocyclic heteroaryl ring fused to a monocyclic aryl group as defined herein or a monocyclic heteroaryl group as defined herein. An example of a tricyclic heteroaryl group is 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 groups 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, benzodioxazolyl, benzofuranyl, benzooxadiazolyl (benzooxadiazolyl), benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxadiazolyl (benzoxadiazolyl), benzoxazolyl, chromanyl, imidazopyridine, imidazothiazolyl, indazolyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, naphthyridinyl, purinyl, pyridoimidazolyl, quinazolinyl, quinolyl, quinoxalinyl, thiazolopyridyl, thiazolopyrimidinyl, thienopyrrolyl and thienothiphenyl. Representative examples of tricyclic heteroaryl include but are not limited to dibenzofuranyl and dibenzothienyl. The monocyclic heteroaryl, bicyclic heteroaryl, and tricyclic heteroaryl are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings.Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted.

[0239] "Heteroarylalkyl" refers to an alkyl group as defined herein wherein at least one hydrogen atom is replaced by a heteroaryl group as defined herein. Unless stated otherwise specifically in the specification, a heteroarylalkyl group is optionally substituted.

[0240] "Heteroarylalkylamino" refers to a heteroarylalkyl-NR a - part, where R a is H or alkyl. Unless stated otherwise specifically in the specification, heteroarylalkylamino is optionally substituted.

[0241] "Heteroarylalkyloxy" refers to a heteroarylalkyl-O- moiety. Unless stated otherwise specifically in the specification, a heteroarylalkyloxy group is optionally substituted.

[0242] "Heteroarylamino" refers to -NR a -heteroaryl moiety, wherein R a is H or alkyl. Unless stated otherwise specifically in the specification, heteroarylamino is optionally substituted.

[0243] "Heteroaryloxy" refers to an -O-heteroaryl moiety. Unless stated otherwise specifically in the specification, a heteroaryloxy group is optionally substituted.

[0244] "Heteroarylene" refers to a divalent heteroaryl group. Unless specifically stated otherwise, a heteroarylene group is optionally substituted.

[0245] "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. It refers to a monocyclic heterocycle, a bicyclic heterocycle or a tricyclic heterocycle. A monocyclic heterocycle is a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring, a seven-membered ring or an eight-membered ring containing at least one heteroatom independently selected from O, N and S. A three-membered ring or a four-membered ring contains zero or one double bond and one heteroatom selected from O, N and S. A five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from O, N and S. A six-membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from O, N and S. A seven-membered ring and an eight-membered ring 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, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolane, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazole The bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl group, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a spiroheterocyclic group, or a bridged monocyclic heterocycle ring system in which two non-adjacent atoms of the ring are connected by an alkylene bridge of 1, 2, 3 or 4 carbon atoms or an alkenylene bridge of two, three or four carbon atoms. Representative examples of bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyl, 2,3-dihydroisoquinolinyl, 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, isoindolyl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Examples of tricyclic heterocycles are bicyclic heterocycles fused to a phenyl group, or a bicyclic heterocycle fused to a monocyclic cycloalkyl group, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl group, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle wherein 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 two, three, or four carbon atoms.Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentadiene, hexahydro-2H-2,5-methanecyclopenta[b]furan, hexahydro-1H-1,4-methanecyclopenta[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 heterocycles, bicyclic heterocycles and tricyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained in the ring. Unless otherwise specifically stated in the specification, heterocyclyl groups are optionally substituted.

[0246] "Heterocyclylalkyl" refers to an alkyl group as defined herein, wherein 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.

[0247] "Heterocyclylalkylamino" refers to a heterocyclylalkyl-NR a - part, where R a Is H or alkyl, and wherein the heterocyclylalkyl moiety is attached to the nitrogen via a carbon atom, wherein the nitrogen serves as a linker attaching the moiety to the rest of the molecule. Unless otherwise specifically stated in the specification, heterocyclylalkylamino is optionally substituted.

[0248] "Heterocyclylalkyloxy" refers to an -O-heterocyclylalkyl moiety, wherein the heterocyclylalkyl moiety is attached to an oxygen via a carbon atom, wherein the oxygen serves as a linker connecting the moiety to the rest of the molecule. Unless specifically stated otherwise in the specification, a heterocyclylalkyloxy group is optionally substituted.

[0249] "Heterocyclylamino" refers to -NR a -heterocyclyl moiety, wherein R a Is H or alkyl, and wherein the heterocyclyl moiety is attached to the nitrogen via a carbon atom, wherein the nitrogen serves as a linker attaching the moiety to the rest of the molecule. Unless otherwise specifically stated in the specification, heterocyclylamino is optionally substituted.

[0250] "Heterocyclyloxy" refers to an -O-heterocyclyl moiety, wherein the heterocyclyl moiety is attached to an oxygen via a carbon atom, wherein the oxygen serves as a linker connecting the moiety to the rest of the molecule. Unless specifically stated otherwise in the specification, a heterocyclyloxy group is optionally substituted.

[0251] "Hydroxyalkyl" refers to an alkyl group containing at least one hydroxy substituent. The -OH substituent can be on a primary, secondary, or tertiary carbon. Unless otherwise specified in the specification, a hydroxyalkyl group is optionally substituted.

[0252] "Sulfonamido" refers to a moiety of the formula -SO2NRR', wherein 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 taken together with the nitrogen to which they are attached to form a 4-, 5-, 6-, or 7-membered ring. Unless otherwise specifically stated in the specification, a sulfonamido group is optionally substituted.

[0253] "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 stated otherwise specifically in the specification, a sulfonamidoalkyl group is optionally substituted.

[0254] "Thioalkyl" refers to a moiety of the formula -SR, wherein R is an alkyl moiety as defined herein containing from one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group is optionally substituted.

[0255] "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 can be optionally substituted.

[0256] "Thioureaalkyl" refers to an alkyl group, as defined herein, in which at least one hydrogen atom is replaced with a thiourea group, as defined herein. Unless stated otherwise specifically in the specification, a thioureaalkyl group is optionally substituted.

[0257] "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 can be optionally substituted.

[0258] "Ureaalkyl" refers to an alkyl group, as defined herein, in which at least one hydrogen atom is replaced with a urea group, as defined herein. Unless stated otherwise specifically in the specification, a ureaalkyl group is optionally substituted.

[0259] As used herein, the term "substituted" means that at least one hydrogen atom is replaced by a group as described above (e.g., amino, carboxyl, hydroxyl, imino, acyl, alkyl, alkoxy, alkylamino, alkylaminoalkyl, acylamino, aminoalkyl, aminocarbonyl, aryl, arylalkyl, arylalkylamino, arylalkyloxy, arylamino, aryloxy, carboxylalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkyl, cycloalkylamino, cycloalkylalkyloxy, cycloalkylamino, cycloalkyloxy, halide, alkyl, haloalkyl, heteroatom, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylamino, heteroarylalkyloxy, heteroarylamino, heteroaryloxy, heterobicycloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkylamino, heterocyclylalkyloxy, heterocyclylamino, heterocyclyloxy, hydroxyalkyl, thioalkyl, alkylene, alkylenecarbonyl, alkenylene, alkenylcarbonyl, arylene, heteroalkylene, heteroalkylenecarbonyl, heteroarylene, heteroarylenecarbonyl, heterocyclylalkylene, and In some embodiments, the present invention provides an alkylene group (e.g., an alkylthio group, an alkylthio group, an alkylsulfone group, an alkylsulfone group, a sulfonyl group, an alkylsulfonyl group, an alkylsulfonyl group, an alkylsulfoxide ... "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a carbon atom or heteroatom through a higher order bond (e.g., a double bond or a triple bond), such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. "Substituted" includes any of the above groups in which one or more hydrogen atoms are replaced by: -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 、-ORg 、-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 , where R g and R h and / or heteroarylalkyl. "Substituted" also refers to any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, carbonyl, carboxyl, cyano, hydroxyl, imino, nitro, oxo, thio, acyl, alkyl, alkoxy, alkylamino, alkylaminoalkyl, amide, aminoalkyl, aminocarbonyl, aryl, arylalkyl, arylalkylamino, arylalkyloxy, arylamino, aryloxy, bicycloalkyl, carboxylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylamino, cycloalkyloxy, halo, haloalkyl, heteroatom, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylamino, heteroarylalkyloxy, heteroarylamino , heteroaryloxy, heterobicycloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkylamino, heterocyclylalkyloxy, heterocyclylamino, heterocyclyloxy, hydroxyalkyl, N-heteroaryl, N-heterocyclyl, thioalkyl, alkylene, alkylenecarbonyl, alkenylene, alkenylcarbonyl, arylene, heteroalkylene, heteroalkylenecarbonyl, heteroarylene, heteroarylenecarbonyl, heterocyclylalkyleneheterocyclylalkylenecarbonyl, methylene, trimethylsilyl, dialkylphosphine oxide, -OR, -SR, -OC(O)-R, -N(R)2, -C(O)R, -C(O)OR, -C(O)N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)S(O) t R (where t is 1 or 2), -S(O) t OR (where t is 1 or 2), -S(O) tN(R)2 (wherein t is 1 or 2), -PO(R)2, or -PO(OR)2 groups, wherein each R is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl groups. In addition, each of the above substituents is optionally substituted with one or more of the above substituents.

[0260] As used herein, the term "optionally substituted" means that the referenced group (eg, alkyl, cycloalkyl, etc.) may or may not be substituted with one or more substituents. DETAILED DESCRIPTION

[0261] Provided herein are small molecules that bind to GAS41 and inhibit GAS41 activity, and methods of using the small molecules to treat cancer.

[0262] Proteins that recognize post-transcriptional modifications in histones play a key 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 shown that the YEATS domain binds to chromatin by recognizing histones with acetylated or crotonylated lysine side chains.

[0263] Previous studies have reported the molecular details of GAS41 YEATS-mediated histone acetyl or crotonyl lysine recognition events (Cho et al. ACS Chem. Biol. 13, 2739-2746 (2018)). GAS41 YEATS demonstrates site-specific recognition of acetylated and crotonylated histone H3 peptides, although with a moderate moderate μM affinity (supra). Structural analysis shows that the acylated lysine binds to the GAS41 YEATS domain in the channel, which can constitute a site targeted by small molecule inhibitors. It has been shown that the compounds disclosed herein are low and sub-μM GAS41 YEATS domain inhibitors. GAS41 is a dimer in cells and can recognize diacylated histone peptides with enhanced affinity through a divalent binding mode. Therefore, some compounds disclosed herein are dimeric GAS41 inhibitors that show enhanced efficacy and activity in non-small cell lung cancer (NSCLC) cells.

[0264] In some embodiments, the compounds described herein can be used to treat or prevent cancer (e.g., brain cancer, sarcoma, colorectal cancer, lung cancer, or gastric cancer) and / or alleviate symptoms associated with cancer. In some embodiments, provided herein are pharmaceutical compositions comprising compounds described herein and / or within the scope herein. In some embodiments, pharmaceutical compositions comprising compounds described herein and / or within the scope herein are administered to a subject to treat cancer (e.g., brain cancer, sarcoma, colorectal cancer, lung cancer, or gastric cancer).

[0265] Provided herein are compounds of formula (I):

[0266]

[0267] or a pharmaceutically acceptable salt thereof, wherein:

[0268] R 1 is selected from the group consisting of heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxyl, acyl, amido, cyano, sulfonyl, and hydrogen;

[0269] X is -C(O)-, -C(S)-, -CH2- or -SO2-, or is absent;

[0270] Y is -NR a -or-O-;

[0271] R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl and aminoalkyl, or R a Together with the nitrogen atom to which it is attached, it forms 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;

[0272] Z does not exist or is -CR b R c -;

[0273] R b and R c are each independently selected from hydrogen and alkyl;

[0274] A is a five-membered heteroaryl group;

[0275] Q is a four-membered heterocyclic group, a five-membered heterocyclic group, or a six-membered heterocyclic group;

[0276] R 2 is selected from hydrogen, halo, alkyl, amino and hydroxy;

[0277] R 3Selected from hydrogen, halogen, -OR d 、-NR e R f , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl and groups of the formula:

[0278]

[0279] 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, 4, or 5; and R g and R h each independently selected from the group consisting of 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, carboxyl, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl;

[0280] or R 2 and R 3 Together with the one or more carbon atoms to which they are attached, they 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; and

[0281] R d 、R e and R f each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl;

[0282] wherein 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,

[0283] The prerequisite is that when Z is -CR b R c -, R 1 Not a cycloalkyl group.

[0284] In some embodiments, provided herein are compounds of Formula (I):

[0285]

[0286] or a pharmaceutically acceptable salt thereof, wherein:

[0287] R 1 is selected from the group consisting of heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxyl, acyl, amido, cyano, sulfonyl, and hydrogen;

[0288] X is -C(O)-, -C(S)-, -CH2- or -SO2-, or is absent;

[0289] Y is -NR a -or-O-;

[0290] R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl and aminoalkyl, or R a Together with the nitrogen atom to which it is attached, it forms a fused ring with A;

[0291] Z does not exist or is -CR b R c -;

[0292] R b and R c are each independently selected from hydrogen and alkyl;

[0293] A is a five-membered heteroaryl group;

[0294] Q is a four-membered heterocyclic group, a five-membered heterocyclic group, or a six-membered heterocyclic group;

[0295] R 2 is selected from hydrogen, halo, alkyl, amino and hydroxy;

[0296] R 3 Selected from hydrogen, halogen, -OR d 、-NR e R f , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl and groups of the formula:

[0297]

[0298] 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, 4, or 5; and R g and R heach independently selected from the group consisting of 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, carboxyl, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl;

[0299] or R 2 and R 3 Together with the one or more carbon atoms to which they are attached, they 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; and

[0300] R d 、R e and R f each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl;

[0301] wherein 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,

[0302] The prerequisite is that when Z is -CR b R c -, R 1 Not a cycloalkyl group.

[0303] In some embodiments, R 1 is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, and alkyl. 1 is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl and C1-C6 alkyl. In some embodiments, R 1 is selected from heterocyclyl, aryl, arylalkyl, heteroarylalkyl and C1-C6 alkyl. 1 is selected from heterocyclyl (e.g., 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., wherein 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, R1 is a monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S. In some embodiments, R 1 is a monocyclic heterocyclic group having 1 or 2 nitrogen atoms. 1 Is pyrrolidinyl. R 1 Can 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 methylene. In some embodiments, R 1 is unsubstituted. In some embodiments, R 1 is an unsubstituted pyrrolidinyl group.

[0304] In some embodiments, R 1 Selected from:

[0305]

[0306]

[0307] In some embodiments, R 1 yes:

[0308]

[0309] 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)-.

[0310] 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 In some embodiments, Y is -NR a -, and R a In some embodiments, Y is O. In some embodiments, Y is -NR a -, where R a Together with the nitrogen atom to which it is attached, it forms a fused ring with A (eg, a five-membered ring or a six-membered ring fused to Ring A). In some embodiments, Y is -NRa -, where R a Together with the nitrogen atom to which it is attached, it forms the 1 Fused fused rings (eg, bicyclic ring systems such as 1,7-diazaspiro[4.4]nonane ring systems), said rings being optionally substituted (eg, with oxo groups).

[0311] In some embodiments, Z is absent or is selected from -CH2-, -CH(CH3)-, and -C(CH3)2-. In some embodiments, Z is absent or is -CH2-. In some embodiments, Z is absent.

[0312] In some embodiments, A is a five-membered heteroaryl group having 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, A is a five-membered heteroaryl group having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, A is a five-membered heteroaryl group 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 following formula:

[0313]

[0314] 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:

[0315]

[0316] In some embodiments, Q is a four-membered heterocyclic radical, a five-membered heterocyclic radical or a six-membered heterocyclic radical with a nitrogen atom (i.e., the nitrogen atom shown in formula (I)), wherein the heterocyclic radical 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.

[0317] In some embodiments, R 2 is selected from hydrogen, halo, amino and hydroxy. 2 is selected from hydrogen, halo and hydroxy. 2 It's hydrogen.

[0318] In some embodiments, R 3 Selected from hydrogen, -OR d 、-NR e R f , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl and groups of the formula:

[0319]

[0320] where 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; B is a 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 Each is 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, carboxyl, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkylalkyl.

[0321] In some embodiments, R 3 Selected from 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.

[0322] In some embodiments, R 3 Selected from 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 heteroaryl or a bicyclic heteroaryl having 1 or 2 heteroatoms independently selected from N, S and O, and wherein each heterocyclyl is independently a monocyclic heterocyclyl or a bicyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, S and O.

[0323] In some embodiments, R 3 is a group of the formula:

[0324]

[0325] In some embodiments, R 3 is a group of the formula:

[0326]

[0327] wherein B is a 5-membered monocyclic heteroaryl group 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; R g is a C1-C6 alkyl group; and each R h 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 groups having 1 or 2 nitrogen atoms. In some embodiments, C is selected from phenyl and pyridyl.

[0328] In some embodiments, at least one R h It has the formula -(CH2) r C(O)NR i R j or -(CH2) s NR k C(O)R m an acylamino or acylaminoalkyl group, wherein:

[0329] r and s are each independently selected from 0, 1 and 2;

[0330] R i and R k are each independently selected from hydrogen and C1-C6 alkyl;

[0331] R j is selected from the group consisting of C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, heterocyclyl, heterocyclyl-C1-C6-alkyl, cycloalkyl and cycloalkyl-C1-C6-alkyl;

[0332] R mis selected from the group consisting of 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;

[0333] wherein each alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-C6-alkyl, C1-C6-alkoxy, hydroxy, amino and oxo.

[0334] In some embodiments, R 2 and R 3 Together with the carbon atom or carbon atoms to which they are attached, they form a ring selected from aryl, heteroaryl, cycloalkyl, and heterocycle, wherein any of these rings may 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).

[0335] In some embodiments, R 2 and R 3 are substituted on adjacent carbon atoms of ring Q and, together with the carbon atoms to which they are attached, form a benzene ring fused to ring Q, wherein the benzene ring is optionally substituted. In some embodiments, the benzene ring is unsubstituted.

[0336] In some embodiments, R 2 and R 3 are substituted on the same carbon atom of ring Q and together with the carbon atom to which they are attached form a spiro ring which is optionally substituted. 2 and R 3 In some embodiments, spirocyclic ring is substituted with a substituent selected from -OR' and heteroaryl, wherein R' is selected from C1-C6 alkyl, aryl and heteroaryl.In some embodiments, spirocyclic ring is substituted with a substituent selected from -OR', wherein R' is selected from methyl, phenyl and 1 or 2 heteroatomic monocyclic 5 yuan or 6 yuan heteroaryl (for example, pyridyl) with 1 or 2 heteroatomic monocyclic 5 yuan or 6 yuan heteroaryl (for example, pyridyl) with 1 or 2 heteroatomic monocyclic 5 yuan or 6 yuan heteroaryl (for example, pyridyl) with 1 or 2 N and S independently selected.In some embodiments, spirocyclic ring is substituted with a substituent selected from -OR' and heteroaryl.

[0337] In some embodiments, R 2 and R3 are substituted on the same carbon atom of ring Q and, together with the carbon atom to which they are attached, form an alkenyl group (eg, a methylene group or a substituted form thereof).

[0338] In some embodiments, the group Having a formula selected from the following:

[0339]

[0340] where R x 、R y and R z are each independently selected from -OR v , aryl and heteroaryl substituents, wherein R v is selected from C1-C6 alkyl, aryl and heteroaryl. x 、R y and R z Independently selected from -OR v , phenyl, and monocyclic 5-membered or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N and S (eg, pyridyl or thiazolyl), wherein R v is selected from C1-C6 alkyl (e.g., methyl), aryl (e.g., phenyl), and monocyclic 5-membered or 6-membered heteroaryl (e.g., pyridyl or thiazolyl) having 1 or 2 heteroatoms independently selected from N and S. x is aryl (eg, phenyl). In some embodiments, R y Select from -OR v and monocyclic 5-membered or 6-membered heteroaryl groups (eg, 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 monocyclic 5-membered or 6-membered heteroaryl (e.g., pyridyl or thiazolyl) having 1 or 2 heteroatoms independently selected from N and S. z is a monocyclic 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently selected from N and S, such as a monocyclic 6-membered heteroaryl group (eg, pyridyl).

[0341] In some embodiments, the group Has the following formula:

[0342]

[0343] Among them, B, J, C, R g 、R h , m and n are as defined herein.

[0344] In some embodiments, the group Has the following formula:

[0345]

[0346] where R h and n are as defined herein. For example, in some embodiments, n is 0, 1, 2, or 3; and each R h R is independently selected from the group consisting of C1-C6 alkyl, halo, halo-C1-C6-alkyl, amino, amino-C1-C6-alkyl, hydroxy, hydroxy-C1-C6-alkyl, C1-C6 alkoxy, amido, amido-C1-C6-alkyl, acyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, heterocyclyl, heterocyclyl-C1-C6-alkyl, cycloalkyl, and cycloalkyl-C1-C6-alkyl. In some embodiments, at least one R h Formula: -(CH2) r C(O)NR i R j or -(CH2) s NR k C(O)R m ,in:

[0347] r and s are each independently selected from 0, 1 and 2;

[0348] R i and R k are each independently selected from hydrogen and C1-C6 alkyl;

[0349] R j is selected from the group consisting of C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, heterocyclyl, heterocyclyl-C1-C6-alkyl, cycloalkyl and cycloalkyl-C1-C6-alkyl;

[0350] R m is selected from the group consisting of 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;

[0351] wherein each alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-C6-alkyl, C1-C6-alkoxy, hydroxy, amino and oxo.

[0352] In some embodiments, the group Selected from:

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362] In some embodiments, the compound of formula (I) is a compound of formula (Ia):

[0363]

[0364] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 3 has any of the meanings disclosed herein.

[0365] In some embodiments, the compound of formula (I) is a compound of formula (Ib):

[0366]

[0367] or a pharmaceutically acceptable salt thereof, wherein B, J, C, R g 、R h , m and n have any of the meanings disclosed herein.

[0368] In some embodiments, the compound of formula (I) is a compound of formula (Ic):

[0369]

[0370] or a pharmaceutically acceptable salt thereof, wherein R h and c have any of the meanings disclosed herein.

[0371] Herein, when reference is made to a compound of Formula (I) (e.g., reference is made to 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).

[0372] In some embodiments, the compound is selected from the compounds shown in Table 1 herein, or a pharmaceutically acceptable salt thereof.

[0373] Also disclosed herein are compounds of formula (IIa):

[0374]

[0375] or a pharmaceutically acceptable salt thereof, wherein:

[0376] R 1 and R 1’ each independently selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxyl, acyl, amido, cyano, sulfonyl, and hydrogen;

[0377] X and X' are each independently absent or selected from -C(O)-, -C(S)-, -CH2- and -SO2-;

[0378] Y and Y' are each independently -NR a -or-O-;

[0379] R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl and aminoalkyl, or R a Together with the nitrogen atom to which it is attached, it forms 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;

[0380] Z and Z' are each independently absent or -CR b R c -;

[0381] R b and R c are each independently selected from hydrogen and alkyl;

[0382] A and A' are each independently a five-membered heteroaromatic ring;

[0383] Q and Q' are each independently a four-membered heterocycle, a five-membered heterocycle or a six-membered heterocycle;

[0384] R 2 and R 2 ' are each independently selected from hydrogen, halo, alkyl, amino and hydroxy;

[0385] R 3 and R 3 ' are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyclyl and a group of the formula:

[0386]

[0387] 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 each independently selected from the group consisting of 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, carboxyl, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl;

[0388] R d 、R e and R f are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; and

[0389] L is the connector;

[0390] wherein 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.

[0391] In some embodiments, disclosed herein are compounds of formula (IIa):

[0392]

[0393] or a pharmaceutically acceptable salt thereof, wherein:

[0394] R 1 and R 1’ each independently selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxyl, acyl, amido, cyano, sulfonyl, and hydrogen;

[0395] X and X' are each independently absent or selected from -C(O)-, -C(S)-, -CH2- and -SO2-;

[0396] Y and Y' are each independently -NR a -or-O-;

[0397] R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl and aminoalkyl, or R a Together with the nitrogen atom to which it is attached, it forms a fused ring with A

[0398] Z and Z' are each independently absent or -CR b R c -;

[0399] R b and R c are each independently selected from hydrogen and alkyl;

[0400] A and A' are each independently a five-membered heteroaromatic ring;

[0401] Q and Q' are each independently a four-membered heterocycle, a five-membered heterocycle or a six-membered heterocycle;

[0402] R 2 and R 2 ' are each independently selected from hydrogen, halo, alkyl, amino and hydroxy;

[0403] R 3 and R 3 ' are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyclyl and a group of the formula:

[0404]

[0405] 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 each independently selected from the group consisting of 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, carboxyl, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl;

[0406] R d 、R e and R f are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; and

[0407] L is the connector;

[0408] wherein 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.

[0409] In some embodiments, R 1 and R 1 ' is the same, R 2 and R 2 ' is the same, R 3 and R 3 ' are 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.

[0410] In some embodiments, R 1 and R 1 ' is an optionally substituted heterocyclyl. In some embodiments, R 1 and R 1 ' is an optionally substituted monocyclic 4- to 6-membered heterocyclic group having 1 or 2 nitrogen atoms. In some embodiments, R 1 and R 1 ' are each an optionally substituted 4-membered or 5-membered monocyclic heterocyclyl, such as a 4-membered or 5-membered heterocyclyl having 1 nitrogen atom. In some embodiments, R 1 and R 1 ' is optionally substituted pyrrolidine. In some embodiments, R 1 and R 1 ' is an unsubstituted pyrrolidine.

[0411] In some embodiments, X and X' are -C(O)-.

[0412] In some embodiments, Y and Y' are -NR a -, and R a In some embodiments, Y and Y' are -NR a -, and R a In some embodiments, Y and Y' are -NR a -, and R a It's hydrogen.

[0413] In some embodiments, Z and Z' are each absent.

[0414] In some embodiments, A and A' are each a five-membered monocyclic heteroaryl group 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.

[0415] In some embodiments, Q and Q' are each a four-membered, five-membered, or six-membered heterocyclic radical having a 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.

[0416] In some embodiments, R 2 and R 2 'It's hydrogen.

[0417] In some embodiments, R 3 and R 3' A group selected from aryl, heteroaryl and the following formula:

[0418]

[0419] In some embodiments, R 3 and R 3' Each is a group of the formula:

[0420]

[0421] wherein B is a 5-membered monocyclic heteroaryl group 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; R g is C1-C6 alkyl; n is 0, 1 or 2; and each R h R is independently selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, amino, amino-C1-C6-alkyl, amido-C1-C6-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 Formula: -(CH2) r C(O)NR i R j or -(CH2) s NR k C(O)R m ,in:

[0422] r and s are each independently selected from 0, 1 and 2;

[0423] R i and R k are each independently selected from hydrogen and C1-C6 alkyl;

[0424] Rj is selected from the group consisting of C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, heterocyclyl, heterocyclyl-C1-C6-alkyl, cycloalkyl and cycloalkyl-C1-C6-alkyl;

[0425] R m is selected from the group consisting of 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;

[0426] wherein each alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-C6-alkyl, C1-C6-alkoxy, hydroxy, amino and oxo.

[0427] In some embodiments, L is a linker comprising one or more groups independently selected from methylene (-CH2-), vinylene (-CH=CH-), acetylene (-C≡C-), ether (-O-), amine (-NH-), alkylamine (-NR-, wherein R is an optionally substituted C1-C6 alkyl group), amide (-C(O)NH-), ester (-C(O)O-), carbamate (-OC(O)NH-), sulfonamide (-S(O)2NH-), phenylene (-C6H4-), heteroarylene, heterocyclylene, and any combination thereof.

[0428] In some embodiments, L is selected from:

[0429]

[0430]

[0431] 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; X 1 and X 2 are each independently O or -NR x , where R x is hydrogen or optionally substituted alkyl; and Y 1 and Z 1 are each independently selected from -CH2-, -NH- and -O-.

[0432] In some embodiments, the compound is selected from the compounds shown in Table 2 herein, or a pharmaceutically acceptable salt thereof.

[0433] Also disclosed herein are compounds of formula (IIb)

[0434]

[0435] or a pharmaceutically acceptable salt thereof, wherein:

[0436] R 1 and R 1' each independently selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, and alkynyl;

[0437] X and X' are each independently absent or selected from -C(O)-, -C(S)-, -CH2- and -SO2-;

[0438] Y and Y' are each independently selected from -NR a -or-O-;

[0439] R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl and aminoalkyl, or R a Together with the nitrogen atom to which it is attached, it forms a fused ring with A;

[0440] Z and Z' are each independently absent or -CR b R c -;

[0441] R b and R c are each independently selected from hydrogen and alkyl;

[0442] A and A' are each independently a five-membered heteroaromatic ring;

[0443] Q and Q' are each independently a four-membered heterocyclic group, a five-membered heterocyclic group or a six-membered heterocyclic group;

[0444] R 2 and R 2 ' are each independently selected from hydrogen, halo, alkyl, amino and hydroxy;

[0445] R 3 and R 3 ' are each independently selected from hydrogen, halogen, -OR d 、-NR e R f , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, and groups of the formula:

[0446]

[0447] 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 each independently selected from the group consisting of 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, carboxyl, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl;

[0448] or R 2 and R 3 Together with the one or more carbon atoms to which they are attached, they 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, they form an alkenyl group;

[0449] R d 、R e and R f are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; and

[0450] L is the connector;

[0451] wherein 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.

[0452] In some embodiments, R 1 and R 1 ' is the same, R 2 and R 2 ' is the same, R 3 and R 3 ' are 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.

[0453] In some embodiments, R 1 and R 1 ' is an optionally substituted heterocyclyl. In some embodiments, R1 and R 1 ' is an optionally substituted monocyclic 4- to 6-membered heterocyclic group having 1 or 2 nitrogen atoms. In some embodiments, R 1 and R 1 ' are each an optionally substituted 4-membered or 5-membered monocyclic heterocyclyl, such as a 4-membered or 5-membered heterocyclyl having 1 nitrogen atom. In some embodiments, R 1 and R 1 ' is optionally substituted pyrrolidine. In some embodiments, R 1 and R 1 ' is an unsubstituted pyrrolidine.

[0454] In some embodiments, X and X' are -C(O)-.

[0455] In some embodiments, Y and Y' are -NR a -, and R a In some embodiments, Y and Y' are -NR a -, and R a In some embodiments, Y and Y' are -NR a -, and R a It's hydrogen.

[0456] In some embodiments, Z and Z' are each absent.

[0457] In some embodiments, A and A' are each a five-membered monocyclic heteroaryl group 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.

[0458] In some embodiments, Q and Q' are each a four-membered, five-membered, or six-membered heterocyclic radical having a 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.

[0459] In some embodiments, R 2 and R 2 'It's hydrogen.

[0460] In some embodiments, R 3 and R 3' A group selected from aryl, heteroaryl and the following formula:

[0461]

[0462] In some embodiments, R 3’ and R 3’ is selected from monocyclic heteroaryl and bicyclic heteroaryl groups having 1, 2 or 3 heteroatoms independently selected from N and S.

[0463] In some embodiments, R 3 and R 3' Each is a group of the formula:

[0464]

[0465] wherein B is a 5-membered monocyclic heteroaryl group 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; R g is C1-C6 alkyl; n is 0, 1 or 2; and each R h R is independently selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, amino, amino-C1-C6-alkyl, amido-C1-C6-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 Formula: -(CH2) r C(O)NR i R j or -(CH2) s NR k C(O)R m ,in:

[0466] r and s are each independently selected from 0, 1 and 2;

[0467] R i and R k are each independently selected from hydrogen and C1-C6 alkyl;

[0468] R j is selected from the group consisting of C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, heterocyclyl, heterocyclyl-C1-C6-alkyl, cycloalkyl and cycloalkyl-C1-C6-alkyl;

[0469] R m is selected from the group consisting of 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;

[0470] wherein each alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-C6-alkyl, C1-C6-alkoxy, hydroxy, amino and oxo.

[0471] In some embodiments, L is a linker comprising one or more groups independently selected from methylene (-CH2-), vinylene (-CH=CH-), acetylene (-C≡C-), ether (-O-), amine (-NH-), alkylamine (-NR-, wherein R is an optionally substituted C1-C6 alkyl group), amide (-C(O)NH-), ester (-C(O)O-), carbamate (-OC(O)NH-), sulfonamide (-S(O)2NH-), phenylene (-C6H4-), heteroarylene, heterocyclylene, and any combination thereof.

[0472] In some embodiments, L is selected from:

[0473]

[0474]

[0475] 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; X 1 and X 2 are each independently O or -NR x , where R x is hydrogen or optionally substituted alkyl; and Y 1 and Z 1 are each independently selected from -CH2-, -NH- and -O-.

[0476] In some embodiments, the compound is selected from the compounds shown in Table 2 herein, or a pharmaceutically acceptable salt thereof.

[0477] Also disclosed herein are compounds of formula (IIc)

[0478]

[0479] or a pharmaceutically acceptable salt thereof, wherein:

[0480] R 1is selected from the group consisting of heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxyl, acyl, amido, cyano, sulfonyl, and hydrogen;

[0481] R 1' is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, and alkynyl;

[0482] X and X' are each independently absent or selected from -C(O)-, -C(S)-, -CH2- and -SO2-;

[0483] Y and Y' are each independently selected from -NR a -or-O-;

[0484] R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl and aminoalkyl, or R a Together with the nitrogen atom to which it is attached, it forms 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;

[0485] Z and Z' are each independently absent or -CR b R c -;

[0486] R b and R c are each independently selected from hydrogen and alkyl;

[0487] A and A' are each independently a five-membered heteroaromatic ring;

[0488] Q and Q' are each independently a four-membered heterocycle, a five-membered heterocycle or a six-membered heterocycle;

[0489] R 2 and R 2 ' are each independently selected from hydrogen, halo, alkyl, amino and hydroxy;

[0490] R 3 A group selected from aryl, heteroaryl, heterocyclic and the following formula:

[0491]

[0492] 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 heach independently selected from the group consisting of 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, carboxyl, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl;

[0493] R 3 'Selected from hydrogen, halogen, -OR d’ 、-NR e’ R f’ , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, and groups of the formula:

[0494]

[0495] 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’ each independently selected from the group consisting of 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, carboxyl, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl;

[0496] R d’ 、R e’ and R f’ are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; and

[0497] L is the connector;

[0498] wherein 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.

[0499] Also disclosed herein are compounds of formula (IIc)

[0500]

[0501] or a pharmaceutically acceptable salt thereof, wherein:

[0502] R 1 is selected from the group consisting of heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkyl, halogen, haloalkyl, carboxyl, acyl, amido, cyano, sulfonyl, and hydrogen;

[0503] R 1' is selected from heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, and alkynyl;

[0504] X and X' are each independently absent or selected from -C(O)-, -C(S)-, -CH2- and -SO2-;

[0505] Y and Y' are each independently selected from -NR a -or-O-;

[0506] R a is selected from hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, hydroxyalkyl and aminoalkyl, or R a Together with the nitrogen atom to which it is attached, it forms a fused ring with A;

[0507] Z and Z' are each independently absent or -CR b R c -;

[0508] R b and R c are each independently selected from hydrogen and alkyl;

[0509] A and A' are each independently a five-membered heteroaromatic ring;

[0510] Q and Q' are each independently a four-membered heterocycle, a five-membered heterocycle or a six-membered heterocycle;

[0511] R 2 and R 2 ' are each independently selected from hydrogen, halo, alkyl, amino and hydroxy;

[0512] R 3 A group selected from aryl, heteroaryl, heterocyclic and the following formula:

[0513]

[0514] 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 Rh each independently selected from the group consisting of 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, carboxyl, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl;

[0515] R 3 'Selected from hydrogen, halogen, -OR d’ 、-NR e’ R f’ , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, and groups of the formula:

[0516]

[0517] 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’ each independently selected from the group consisting of 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, carboxyl, nitro, oxo, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkylalkyl;

[0518] R d’ 、R e’ and R f’ are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroaryl; and

[0519] L is the connector;

[0520] wherein 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.

[0521] In some embodiments, R 1 and R 1 ' is the same, R 2 and R2 ' is the same, R 3 and R 3 ' are 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.

[0522] In some embodiments, R 1 and R 1 ' is an optionally substituted heterocyclyl. In some embodiments, R 1 and R 1 ' is an optionally substituted monocyclic 4- to 6-membered heterocyclic group having 1 or 2 nitrogen atoms. In some embodiments, R 1 and R 1 ' is each an optionally substituted 4-membered or 5-membered monocyclic heterocyclyl, such as a 4-membered or 5-membered heterocyclyl having 1 nitrogen atom. In some embodiments, R 1 and R 1 ' is optionally substituted pyrrolidine. In some embodiments, R 1 and R 1 ' is an unsubstituted pyrrolidine.

[0523] In some embodiments, X and X' are -C(O)-.

[0524] 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 In some embodiments, Y and Y' are -NR a -, and R a It's hydrogen.

[0525] In some embodiments, Z and Z' are each absent.

[0526] In some embodiments, A and A' are each a five-membered monocyclic heteroaryl group 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.

[0527] In some embodiments, Q and Q' are each a four-membered, five-membered, or six-membered heterocyclic radical having a 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.

[0528] In some embodiments, R 2 and R 2 'It's hydrogen.

[0529] In some embodiments, R 3 A group selected from aryl, heteroaryl and the following formula:

[0530]

[0531] In some embodiments, R 3 is a group of the formula:

[0532]

[0533] wherein B is a 5-membered monocyclic heteroaryl group 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; R g is C1-C6 alkyl; n is 0, 1 or 2; and each R h In some embodiments, B is selected from the group consisting of C1-C6 alkyl, halo, C1-C6 haloalkyl, amino, amino-C1-C6-alkyl, amido-C1-C6-alkyl, and heterocyclyl. In some embodiments, B is selected from the group consisting of thiazole and thiophene. In some embodiments, B is thiazole. In some embodiments, C is selected from the group consisting of aryl and monocyclic heteroaryl. In some embodiments, C is selected from the group consisting of phenyl and pyridyl. In some embodiments, C is phenyl.

[0534] In some embodiments, R 3' A group selected from hydrogen, aryl, heteroaryl and the following formula:

[0535]

[0536] In some embodiments, R 3’ is selected from monocyclic heteroaryl and bicyclic heteroaryl groups having 1, 2 or 3 heteroatoms independently selected from N and S.

[0537] In some embodiments, R 3’ is a group of the formula:

[0538]

[0539] wherein B' is a 5-membered monocyclic heteroaryl group 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; R g’ is C1-C6 alkyl; n' is 0, 1 or 2; and each R h’R is independently selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, amino, amino-C1-C6-alkyl, amido-C1-C6-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 Formula: -(CH2) r C(O)NR i R j or -(CH2) s NR k C(O)R m ,in:

[0540] r and s are each independently selected from 0, 1 and 2;

[0541] R i and R k are each independently selected from hydrogen and C1-C6 alkyl;

[0542] R j is selected from the group consisting of C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, heterocyclyl, heterocyclyl-C1-C6-alkyl, cycloalkyl and cycloalkyl-C1-C6-alkyl;

[0543] R m is selected from the group consisting of 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;

[0544] wherein each alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-C6-alkyl, C1-C6-alkoxy, hydroxy, amino and oxo.

[0545] In some embodiments, L is a linker comprising one or more groups independently selected from methylene (-CH2-), vinylene (-CH=CH-), acetylene (-C≡C-), ether (-O-), amine (-NH-), alkylamine (-NR-, wherein R is an optionally substituted C1-C6 alkyl group), amide (-C(O)NH-), ester (-C(O)O-), carbamate (-OC(O)NH-), sulfonamide (-S(O)2NH-), phenylene (-C6H4-), heteroarylene, heterocyclylene, and any combination thereof.

[0546] In some embodiments, L is selected from:

[0547]

[0548]

[0549] 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; X 1 and X 2 are each independently O or -NR x , where R x is hydrogen or optionally substituted alkyl; and Y 1 and Z 1 are each independently selected from -CH2-, -NH- and -O-.

[0550] Compounds can be synthesized in a variety of ways. For example, compounds of formula (I) can be synthesized as shown in Schemes 1 and 2. Generally, compounds can be synthesized by coupling appropriate amines with acids 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 hexafluorophosphate 3-oxide, DIPEA is N,N-diisopropylethylamine, DCM is dichloromethane, and Mt is a metal selected from Li, Na, K, etc.)

[0551] Solution 1

[0552]

[0553] Option 2

[0554]

[0555] Compound and intermediate can be separated and purified by the method well known to those skilled in the art of organic synthesis.Examples of conventional methods for separating and purifying compounds can include, but are not limited to, chromatography on a solid support (such as silica gel, aluminum oxide or alkylsilane group-derivatized silica), by recrystallization at high or low temperatures and optionally pre-treated with activated carbon, thin layer chromatography, distillation at different pressures, vacuum sublimation and grinding, as described in, for example, "Vogel's Textbook of Practical Organic Chemistry" 5th edition (1989), compiled by Furniss, Hannaford, Smith and Tatchell, pub.Longman Scientific & Technical, Essex CM20 2JE, England.

[0556] The reaction conditions and the reaction times of each individual step can vary according to the substituent present in the specific reactant used and the reactant used.Specific procedures are provided in the examples section.Reaction can be post-processed in a conventional manner, for example, by removing the solvent from residue and further purified according to methods generally known in the art, such as, but not limited to, crystallization, distillation, extraction, grinding and chromatography.Unless otherwise indicated, starting material and reagent are commercially available, or can be prepared from commercially available materials using the method described in the chemical literature by those skilled in the art.Starting material, if not commercially available, can be prepared by a program selected from standard organic chemistry techniques, similar to the technology of the synthesis of known structurally similar compounds or similar to the technology of the program described in the scheme or synthesis example section described above.

[0557] Routine experiments, including appropriate manipulation of reaction conditions, reagents and synthetic route sequences, protection of any chemical functional groups incompatible with the reaction conditions, and the deprotection performed at appropriate points in the reaction sequence of the method are all included in the scope of the present disclosure. Suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples thereof can be found in P.G. Wuts and T.W. Greene, in Greene's book titled Protective Groups in Organic Synthesis (4th edition), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. The synthesis of compounds of the present disclosure can be accomplished by methods similar to those described in the synthetic schemes described above and the specific embodiments described below.

[0558] In some cases, the compounds described herein exist as diastereomers, enantiomers or other stereoisomeric forms. The compounds provided herein include all diastereomers, enantiomers and stereoisomeric forms and their appropriate mixtures. The separation of stereoisomers can be carried out by chromatography or by forming diastereomers and by recrystallization or chromatography separation or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, which is incorporated herein by reference for the present disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0559] In some embodiments, compounds may exist as tautomers.All tautomers are included within the formulae described herein.

[0560] Unless otherwise indicated, divalent variables or groups described herein can be linked in the orientation in which they are depicted, or they can be linked in the reverse orientation.

[0561] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also referred to as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Likewise, active metabolites of these compounds having the same type of activity are also included within the scope of this disclosure. In addition, the compounds described herein may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds provided herein are also considered to be disclosed herein.

[0562] 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 cases, they can be more easily administered than the parent drug. For example, they can be bioavailable via oral administration, whereas the parent drug cannot. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. Examples (but not limited to) of prodrugs are compounds described herein that are administered as esters ("prodrugs") to facilitate transport across cell membranes, where water solubility is detrimental to mobility, but once inside the cell, where water solubility is beneficial, the ester is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug might be a short peptide (polyamino acid) bonded to an acid group, where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized to the biologically, pharmaceutically, or therapeutically active form of the compound through one or more steps or processes.

[0563] To create a prodrug, a pharmaceutically active compound is modified so that the active compound will be regenerated upon in vivo administration. Prodrugs can be designed to alter the metabolic stability or transport characteristics of a drug, mask side effects or toxicity, improve the flavor of a drug, or alter other characteristics or properties of a drug. In some embodiments, once a pharmaceutically active compound is identified, a prodrug of that compound can be designed using knowledge of pharmacodynamic processes and drug metabolism in vivo. (See, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pp. 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pp. 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, 5097-5116, 2003; Aesop Cho, “Recent Advances in Oral Prodrug Discovery”, Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006).

[0564] The compounds described herein can be labeled with an isotope (e.g., with a radioisotope) or by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, photoactivatable or chemiluminescent labels, affinity labels (e.g., biotin), and the like.

[0565] The compounds and salts described herein include isotopically labeled compounds. Generally speaking, isotopically labeled compounds are identical to those compounds recited in the various formulas and structures provided herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the 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, into which radioactive isotopes such as 3 H and 14 C, are useful in drug and / or substrate tissue distribution assays. In addition, isotopes such as deuterium (i.e., 2 H) substitutions may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0566] In further or additional embodiments, the compounds described herein, when administered to an organism in need thereof, are metabolized to produce a metabolite, which is then used to produce a desired effect, including a desired therapeutic effect.

[0567] The compounds described herein can form and / or be used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, which are formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, or an organic acid, such as, for example, 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]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic 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 when the acidic protons present in the compounds of the present invention are replaced by metal ions such as alkali metal ions (e.g., lithium, sodium, potassium), alkaline earth ions (e.g., magnesium or calcium), or aluminum ions. In some cases, the compounds described herein can be coordinated with an organic base such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, trishydroxymethylaminomethane, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein can form salts with amino acids such as, but not limited to, arginine, lysine, etc. Acceptable inorganic bases for forming salts with compounds comprising acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0568] It should be understood that the pharmaceutically acceptable salts mentioned include solvent addition forms or their crystalline forms, particularly solvates or polymorphs. Solvates contain stoichiometric and non-stoichiometric amounts of solvents and can be formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. 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, for the purposes of the compounds and methods provided herein, solvated forms are considered to be equivalent to unsolvated forms.

[0569] In some embodiments, the compounds described herein are in various forms, including but not limited to amorphous forms, milled forms, and nanoparticle forms. In addition, the compounds described herein include crystalline forms, also referred to as polymorphs. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, melting points, densities, hardnesses, crystal shapes, optical properties, stability, and solubility. Various factors such as recrystallization solvents, crystallization rates, and storage temperatures can cause a single crystalline form to predominate.

[0570] Screening and characterization of pharmaceutically acceptable salts, polymorphs and / or solvates can be accomplished using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods analyze thermochemical degradation or thermophysical processes, including but not limited to polymorphic transitions, and such methods are used to analyze the relationship between polymorphic forms, determine weight loss, discover glass transition temperatures, or for excipient compatibility studies. 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 and powder diffractometers and synchrotron radiation sources. The various spectroscopic techniques used include but are not limited to Raman, FTIR, UV-VIS, and NMR (liquid and solid). 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 with EDX (in gas or water vapor environments), IR microscopy, and Raman microscopy.

[0571] Pharmaceutical composition

[0572] 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 can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that aid in processing the active compound into a pharmaceutically acceptable preparation. Appropriate formulations depend on the chosen route of administration. Additional details regarding suitable excipients for the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (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 Edition (Lippincott Williams & Wilkins 1999), incorporated herein by reference for such disclosure.

[0573] 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 carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients). Pharmaceutical compositions facilitate administration of the compound to a subject. In practicing the treatments or methods of use provided herein, a therapeutically effective amount of a compound as described herein is administered in the form of a pharmaceutical composition to a subject suffering from a disease, condition or illness (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 efficacy of the compound used, and other factors. The compound or a pharmaceutically acceptable salt thereof can be used alone or in combination with one or more therapeutic agents that are components of a mixture (e.g., in combination therapy).

[0574] The pharmaceutical formulations described herein can be administered to a subject by a variety of routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. In addition, 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, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, fast-dissolve formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, lozenges, and capsules.

[0575] Compounds and / or compositions can be applied in a local rather than systemic manner, for example, by injecting the compound usually in a long-lasting formulation or a sustained-release formulation directly into an organ or tissue. Such long-acting formulations can be applied by transplanting (for example, subcutaneously or intramuscularly) or by intramuscular injection. In addition, drugs can be applied in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. Liposomes are selectively absorbed by the targeted organ. In addition, drugs can be provided in a quick-release formulation form, in an extended-release formulation form, or in an intermediate-release formulation form.

[0576] Pharmaceutical compositions containing the compounds described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.

[0577] In certain embodiments, the compositions provided herein may further comprise one or more preservatives to inhibit microbial activity. Suitable preservatives include quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0578] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more of the compounds disclosed herein (e.g., compounds of formula (I), (IIa), (IIb) or (IIc)), or a pharmaceutically acceptable salt thereof, optionally grinding the resulting mixture, and processing the mixture of particles after adding suitable adjuvants if necessary 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, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or other fillers such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, a disintegrant such as cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (such as sodium alginate) may be added.

[0579] The lozenge cores have a suitable coating. For this reason, concentrated sugar solutions can be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or lozenge coatings for use in identifying or characterizing different combinations of active compound dosages.

[0580] Pharmaceutical preparations that can be used orally include push-in capsules made of gelatin and soft sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Push-in 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 can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, a stabilizer can be added.

[0581] In some embodiments, the solid dosage forms disclosed herein can be in the form of tablets (including suspension tablets, fast-dissolving tablets, bite-disintegrating tablets, rapidly disintegrating tablets, effervescent tablets, or capsules), pills, powders (including sterile packaged powders, loose powders, or effervescent powders), capsules (including soft capsules or hard capsules, such as capsules made of animal-derived gelatin or plant-derived HPMC, or "spray capsules"), solid dispersions, solid solutions, bioerodible dosage forms, multi-particulate dosage forms, pellets, granules, or aerosols. In other embodiments, the pharmaceutical preparation is in powder form. In other embodiments, the pharmaceutical preparation is in tablet form, including but not limited to fast-dissolving tablets. In addition, the pharmaceutical preparations of the compounds described herein can be administered as a single capsule or multiple capsules. In some embodiments, the pharmaceutical preparation is administered in two, three, or four capsules or tablets.

[0582] 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. When these bulk blend compositions are referred to as homogeneous, it is meant that the particles of the compound are evenly dispersed throughout the composition so that the composition can be subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. Individual unit doses may also include a film coating that disintegrates upon oral ingestion or upon contact with a diluent. These formulations can be manufactured by conventional pharmaceutical techniques.

[0583] The pharmaceutical solid 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 additives, such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, or one or more combinations thereof. In yet other aspects, a film coating is provided around the formulation of the 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 the compound described herein are coated. In another embodiment, some or all of the particles of the compound described herein are microencapsulated. In yet another embodiment, the particles of the compound described herein are not microencapsulated and are not coated.

[0584] Suitable carriers for 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.

[0585] Suitable fillers 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.

[0586] In order to release the compound from the solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage form is compressed with a binder. Disintegrants help break up the dosage form matrix by swelling or capillary action when water is absorbed into the dosage form. Disintegrants suitable for use in the solid dosage forms described herein include, but are not limited to, natural starches (such as corn starch or potato starch), pregelatinized starches (such as National 1551 or ), or sodium starch glycolate (such as or ), cellulose (such as wood products), methyl crystalline cellulose (e.g., PH101, PH102, PH105, P100, Ming and ), methylcellulose, cross-linked carboxymethylcellulose, or cross-linked cellulose (such as cross-linked carboxymethylcellulose sodium Cross-linked carboxymethyl cellulose or cross-linked croscarmellose), cross-linked starch (such as sodium starch glycolate), cross-linked polymer (such as crospovidone, cross-linked polyvinyl pyrrolidone), alginates (such as alginic acid or alginates such as sodium alginate), clays (such as HV (magnesium aluminum silicate), gums (such as agar, guar gum, locust bean gum, karaya gum, pectin, or tragacanth gum), sodium starch glycolate, bentonite, natural sponges, surfactants, resins (such as cation exchange resins), citrus pulp, sodium lauryl sulfate, combinations of sodium lauryl sulfate and starch, and the like.

[0587] Binders impart cohesiveness to solid oral dosage form formulations: for powder-filled capsule formulations, they help form a fill that can be filled into soft or hard shell capsules; for tablet formulations, they ensure that the tablet remains intact after compression and help ensure blending uniformity prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethyl cellulose, methyl cellulose (e.g., ), hydroxypropyl methylcellulose (e.g., Hydroxypropyl methylcellulose USP Pharmacoat-603, Hydroxypropyl methylcellulose acetate stearate (Aqoate HS-LF and HS), Hydroxyethyl cellulose, Hydroxypropyl cellulose (e.g., ), ethyl cellulose (e.g., ) and microcrystalline cellulose (e.g., ), microcrystalline glucose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonite, gelatin, polyvinyl pyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth gum, dextrin, sugars (such as sucrose (e.g., ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., ), lactose), natural or synthetic gums such as gum arabic, gum tragacanth, gum ghatti, esabol husk mucilage, starch, polyvinyl pyrrolidone (e.g., CL, CL, XL-10 and K-12), larch arabinogalactan, Polyethylene glycol, wax, sodium alginate, etc.

[0588] Generally speaking, the binder level used in powder-filled gelatin capsule formulations is 20%-70%. The level of binder used in tablet formulations varies, whether it is direct compression, wet granulation, roller compaction, or the use of other excipients (such as fillers) that can themselves act as a suitable binder. In some embodiments, the formulation designer determines the binder level of the formulation, but it is common to use binder levels as high as 70% in tablet formulations.

[0589] Lubricants or glidants suitable 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 salts and alkaline earth metal salts (such as aluminum salts, calcium salts, magnesium salts, zinc salts), stearic acid, sodium stearate, magnesium stearate, zinc stearate, waxes, Boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxy polyethylene glycol (such as Carbowax TM , PEG 4000, PEG 5000, PEG 6000), propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium lauryl sulfate or sodium lauryl sulfate, etc.

[0590] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and glucose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like.

[0591] Suitable wetting agents 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 ), sodium oleate, sodium lauryl sulfate, magnesium stearate, docusate sodium, triacetin, vitamin E TPGS, etc.

[0592] 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, e.g. (BASF), etc.

[0593] Suspending agents suitable for use in the solid dosage forms described herein include, but are not limited to, polyvinyl pyrrolidone (e.g., polyvinyl pyrrolidone K12, polyvinyl pyrrolidone K17, polyvinyl pyrrolidone K25, or polyvinyl pyrrolidone K30), polyethylene glycol (e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 5400 to about 7000), vinyl pyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethyl cellulose, Methylcellulose, hydroxypropyl methylcellulose, polysorbate 80, hydroxyethylcellulose, sodium alginate, gums (e.g., gum tragacanth and gum acacia, guar gum, xanthan gum, including xanthan gum), sugars, celluloses (e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose), polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0594] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0595] There is considerable overlap between the additives used in the solid dosage forms described herein. Therefore, the additives listed above should be considered merely exemplary, and not limiting, of the types of additives that may be included in the solid dosage forms of the pharmaceutical compositions described herein.

[0596] In other embodiments, one or more layers of pharmaceutical preparation are plasticized. Illustratively, plasticizers are typically high boiling point solids or liquids. Suitable plasticizers can be added in an amount 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, polyethylene glycol, glycerol, acetylated glyceride, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearyl alcohol, stearate and castor oil.

[0597] Compressed tablets are solid dosage forms prepared by compacting a large blend of the formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth will contain one or more flavorings. In other embodiments, compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, film coatings aid in patient compliance (e.g., coating or sugar coating). Film coating, including Typically, it comprises from about 1% to about 3% of the tablet weight.In other embodiments, the compressed tablets contain one or more excipients.

[0598] In some embodiments, the preparation of the present invention can be placed in a plurality of capsules. For example, a large amount of blends of the compound preparation described above can be placed in a capsule to prepare the capsule. In some embodiments, the preparation (non-aqueous suspension and solution) is placed in a soft gelatin capsule. In other embodiments, the preparation is placed in a standard gelatin capsule or a non-gelatin capsule such as a capsule comprising HPMC. In other embodiments, the preparation is placed in a spray capsule, wherein the capsule can be swallowed whole or the capsule can be opened and before eating, content is sprayed on food. In some embodiments, the therapeutic dose is divided into multiple (for example, two, three or four) capsules. In some embodiments, the whole dosage of the preparation is delivered in capsule form.

[0599] 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, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates 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, thereby releasing the formulation into the gastrointestinal fluids.

[0600] In another aspect, the dosage form can include a microencapsulated formulation. In some embodiments, one or more other compatible materials are present in the microencapsulated material. Exemplary materials include, but are not limited to, pH regulators, erosion accelerators, defoamers, antioxidants, flavorings, and carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0601] Materials useful for microencapsulation as described herein include materials that are compatible with the compounds described herein and that sufficiently isolate the compound from other incompatible excipients.

[0602] In yet other embodiments, effervescent powders are also prepared according to the present disclosure. Effervescent salts are used to disperse pharmaceuticals in water for oral administration. Effervescent salts are granules or coarse powders containing the drug in a dry mixture, typically consisting of sodium bicarbonate, citric acid, and / or tartaric acid. When such salts are added to water, the acid and base react to release carbon dioxide gas, thereby causing "effervescence." Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid, and / or tartaric acid. Any acid-base combination that releases carbon dioxide can be used to replace the combination of sodium bicarbonate, citric acid, and tartaric acid, as long as the ingredients are suitable for pharmaceutical use and produce a pH of about 6.0 or higher.

[0603] In other embodiments, the preparations described herein are solid dispersions. The method for producing such solid dispersions includes, but is not limited to, for example, U.S. Patent Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269 and U.S. Patent Publication No. 2004 / 0013734. In other embodiments, the preparations described herein are solid solutions. Solid solutions incorporate substances with active agents and other excipients, and heating the mixture like this causes the drug to dissolve, and then cooling the resulting composition to provide a solid blend, which can be further formulated or directly added to a capsule or compressed into a tablet. The method for producing such solid solutions includes, but is not limited to, for example, U.S. Patent Nos. 4,151,273, 5,281,420 and 6,083,518.

[0604] In some embodiments, a pharmaceutical formulation 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 agent or suspending agent is provided for oral administration to a subject. The formulation can be a powder and / or granules for suspension, and when mixed with water, a substantially uniform suspension is obtained.

[0605] Liquid formulations for oral administration can be aqueous suspensions selected from the group consisting of, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd ed., pp. 754-757 (2002).

[0606] As defined in USP Pharmacists'Pharmacopeia (2005 edition, Chapter 905), aqueous suspensions and dispersions as herein described can maintain a homogeneous state for at least 4 hours. Homogeneity should be determined by a sampling method consistent with determining the homogeneity of the entire composition. In one embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by continuing a physical agitation less than 1 minute. In another embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by continuing a physical agitation less than 45 seconds. In yet another embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by continuing a physical agitation less than 30 seconds. In yet another embodiment, stirring is not required to maintain a homogeneous aqueous dispersion.

[0607] The pharmaceutical compositions described herein can include sweeteners such as, but not limited to, arabic syrup, acesulfame potassium, alitame, anise, apple, aspartame, banana, Bavarian cream, berries, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, marshmallow, cocoa, cola, cool cherry, cool citrus, cyclamate, cyclamate, glucose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhizate, glycyrrhiza (licorice) syrup, grapes, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizate Maltol, Mannitol, Maple, Hollyhock, Menthol, Mint Cream, Mixed Berry, Nobiletin DC, Neotame, Orange, Pear, Peach, Mint, Mint Cream, powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, tartin, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, candied fruit, 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.

[0608] In some embodiments, the pharmaceutical formulations described herein can be self-emulsifying drug delivery systems (SEDDS). An emulsion is a dispersion of an immiscible phase in another phase, typically in the form of droplets. Typically, an emulsion is produced by intense mechanical dispersion. SEDDS is different from emulsions or microemulsions and can spontaneously form an emulsion when added to excess water without any external mechanical dispersion or stirring. The advantage of SEDDS is that it only requires gentle mixing to disperse the droplets throughout the solution. In addition, water or aqueous phase can be added before administration to ensure the stability of unstable or hydrophobic active ingredients. Therefore, SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDS can improve the bioavailability of hydrophobic active ingredients. Methods for producing self-emulsifying dosage forms include, but are not limited to, for example, U.S. Patent Nos. 5,858,401, 6,667,048, and 6,960,563.

[0609] There is overlap between the above-mentioned additives used in the aqueous dispersions or suspensions described herein, as a given additive is often classified differently by different practitioners in the art, or is often used for any of several different functions. Therefore, the additives listed above should be considered merely exemplary, and not limiting, of the types of additives that may be included in the formulations described herein.

[0610] Potential excipients for intranasal formulations include, for example, U.S. Patent Nos. 4,476,116, 5,116,817, and 6,391,452. Solutions are prepared in saline using benzyl alcohol or other suitable preservatives, fluorocarbons, and / or other solubilizers or dispersants. See, for example, Ansel, HC et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Edition (1995). Preferably, these compositions and formulations are prepared with suitable non-toxic pharmaceutically acceptable ingredients. The choice of a suitable carrier depends largely on the exact nature of the desired nasal dosage form, such as a solution, suspension, ointment, or gel. In addition to the active ingredient, nasal dosage forms typically contain a large amount of water. Small amounts of other ingredients, such as pH adjusters, emulsifiers or dispersants, preservatives, surfactants, gelling agents or buffers, and other stabilizers and solubilizers, may also be present. Preferably, the nasal dosage form should be isotonic with nasal secretions.

[0611] For inhalation administration, compound as herein described can be in aerosol, fine mist or powder form. Pharmaceutical composition as herein described uses suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, conveniently delivers in aerosol spray form from pressurized package or sprayer. In the case of pressurized aerosol, dosage unit can be determined by providing valve to deliver metered amount. Capsules and cartridges such as (only as an example) gelatin for inhaler or insufflator can be formulated as powder mixture containing compound as herein described and suitable powder base (such as lactose or starch).

[0612] Buccal formulations comprising the compounds described herein can be administered using a variety of formulations, including but not limited to U.S. Patent Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136. In addition, the buccal dosage forms described herein may also comprise a bioerodible (hydrolyzable) polymer carrier, which is also used to adhere the dosage form to the buccal mucosa. The buccal dosage form is prepared to gradually erode over a predetermined time period, wherein delivery of the compound is provided substantially throughout. Buccal drug delivery avoids the disadvantages encountered with oral drug administration, such as slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract, and / or first-pass inactivation in the liver. With respect to the bioerodible (hydrolyzable) polymer carrier, virtually any such carrier may be used, as long as the desired drug release profile is not compromised and the carrier is compatible with the compounds described herein and any other components that may be present in the buccal dosage unit. Typically, the polymer carrier comprises a hydrophilic (water-soluble and water-swellable) polymer that adheres to the wet surface of the buccal mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and copolymers, such as those known as "carbomers" ( Available from BF Goodrich, is one such polymer. Other components may also be incorporated into the buccal dosage forms described herein, including, but not limited to, disintegrants, diluents, binders, lubricants, flavorings, colorants, preservatives, and the like. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in conventional manner.

[0613] The transdermal formulations described herein can be administered using a variety of devices, including, but not limited to, U.S. Patent 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, 4 ,031,894, 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.

[0614] 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 compound disclosed herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc)), or a formulation of a pharmaceutically acceptable salt thereof; (2) a penetration enhancer; and (3) an aqueous adjuvant. In addition, the transdermal formulations may comprise additional components such as, but not limited to, gelling agents, creams, and ointment bases. In some embodiments, the transdermal formulations may also comprise a woven or non-woven backing material to enhance absorption and prevent the transdermal formulation from falling off the skin. In other embodiments, the transdermal formulations described herein may be maintained in a saturated or supersaturated state to facilitate diffusion into the skin.

[0615] Preparations suitable for transdermal administration of compounds described herein can adopt transdermal delivery devices and transdermal delivery patches, and can be lipophilic emulsions or buffered aqueous solutions, dissolved and / or dispersed in polymers or adhesives. Such patches can be constructed for continuous, pulsed or on-demand drug delivery. In addition, transdermal delivery of compounds described herein can be achieved by iontophoresis patches and the like. In addition, transdermal patches can provide controlled delivery of compounds described herein. The absorption rate can be slowed down by using a rate-controlling membrane or by trapping the compound in a polymer matrix or gel. On the contrary, absorption enhancers can be used to increase absorption. Absorption enhancers or carriers can include absorbable pharmaceutically acceptable solvents to help pass through the skin. For example, a transdermal device is in the form of a bandage, including a backing element, a reservoir containing the compound and optionally a carrier, optionally a rate-controlling barrier to deliver the compound to the host's skin at a controlled and predetermined rate over an extended period of time, and means for fixing the device to the skin.

[0616] The preparation that is suitable for intramuscular, subcutaneous or intravenous injection can include physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and the sterile powder that is used for reconstructing into sterile injection solution or dispersion.The example of suitable aqueous and non-aqueous carrier, diluent, solvent or vehicle includes water, ethanol, polyol (propylene glycol, polyethylene glycol, glycerol, Cremophor etc.), their suitable mixture, vegetable oil (such as olive oil) and injection organic ester (such as ethyl oleate).For example, can by the use of coating (such as lecithin), by maintaining required particle size (in the case of dispersion) and by using surfactant to maintain suitable fluidity.The preparation that is suitable for subcutaneous injection can also contain additives, such as preservative, wetting agent, emulsifying agent and distributing agent.Can ensure to prevent the growth of microorganism by multiple antibacterial agent and antifungal agent (such as parahydroxybenzoate, chlorobutanol, phenol, sorbic acid etc.).Also desirable, include isotonic agent, such as sugar, sodium chloride etc. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0617] For intravenous injection, the compounds described herein can be formulated in an aqueous solution, preferably in a physiologically compatible buffer (such as Hanks' solution, Ringer's solution, or physiological saline buffer). For transmucosal administration, penetrants suitable for the barrier to be permeated are used in the formulation. Such penetrants are generally recognized in the art. For other parenteral injections, appropriate formulations may include aqueous solutions or non-aqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally recognized in the art.

[0618] Parenteral injection can involve bolus injection or continuous infusion. Injectable preparations can be presented in unit doses, for example, in ampoules or in multidose containers, and are preservative-added. The pharmaceutical compositions described herein can be in a form suitable for parenteral injection, such as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain preparatons, such as suspending agents, stabilizers, and / or dispersants. Pharmaceutical preparations for parenteral administration include aqueous solutions of the active compound in a water-soluble form. In addition, suspensions of the active compound can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils (such as sesame oil) or synthetic fatty acid esters (such as ethyl oleate or triglycerides) or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension can also contain a suitable stabilizer, or an agent that increases the solubility of the compound to allow the preparation of a highly concentrated solution. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) before use.

[0619] In certain embodiments, delivery systems of the pharmaceutical compound can be employed, such as liposomes and emulsions. In certain embodiments, the compositions provided herein further comprise 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.

[0620] In some embodiments, the compounds described herein can be administered topically and are formulated into a variety of topically administrable compositions such as solutions, suspensions, lotions, gels, pastes, sticks, balms, creams, or ointments. Such pharmaceutical compounds may contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.

[0621] The compounds described herein may also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, etc. In suppository forms of the compositions, a low melting wax such as, but not limited to, a mixture of fatty acid glycerols, optionally in combination with cocoa butter, is first melted.

[0622] Typically, the agents disclosed herein, such as compounds (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 development of symptoms of a disease or condition (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 condition. The dosage required to achieve an effective amount can vary depending on the agent, formulation, disease or condition, and the individual to whom the agent is administered.

[0623] Determination of an effective amount can also involve in vitro assays in which varying doses of the drug are administered to cultured cells and the concentration of the drug effective to ameliorate some or all of the symptoms is determined to calculate the concentration required in vivo. An effective amount can also be based on in vivo animal studies.

[0624] The agent can be administered before, simultaneously with, or after the onset of symptoms of the disease or condition. In some embodiments, the agent is administered to a subject with a family history of the disease or condition, or a subject with a phenotype that may indicate a predisposition to the disease or condition, or a subject with a genotype that predisposes the subject to the disease or condition.

[0625] 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 required and the area to be treated. Administration can be topical (including ophthalmic and mucous membranes, including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional carriers; aqueous, powder or oily bases; thickeners; etc. may be necessary or desired. Compositions and formulations for oral administration include powders or granules, suspensions or solutions in aqueous or non-aqueous media, capsules, sachets or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids or adhesives may be desired. Compositions and preparations for parenteral, intrathecal or intraventricular administration may include sterile aqueous solutions, which may also contain buffers, diluents and other suitable additives, such as but not limited to penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. Medications and / or therapeutic compositions of the present invention include but are not limited to solutions, emulsions and liposome-containing preparations. These compositions may be produced by a variety of components including but not limited to preformed liquids, self-emulsifying solids and self-emulsifying semisolids.

[0626] Pharmaceutical and / or therapeutic formulations that can be conveniently presented in unit dosage form can be prepared according to conventional techniques well known in the pharmaceutical / nutraceutical industry. Such techniques include the step of combining the active ingredient with one or more pharmaceutical carriers or one or more excipients. Typically, the formulation is prepared by uniformly and intimately combining the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then shaping the product as desired. The compositions of the present invention can be formulated into any of a number of possible dosage forms, such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present invention can also be formulated into suspensions in aqueous, non-aqueous, oil-based, or mixed media. The suspension may also contain substances that increase the viscosity of the suspension, including, for example, sodium carboxymethylcellulose, sorbitol, and / or dextran. The suspension may also contain a stabilizer. In one embodiment of the present invention, the pharmaceutical composition can be formulated and used as a foam. Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies, and liposomes. Although essentially similar, these formulations differ in their components and the consistency of the final product.

[0627] The pharmaceutical compositions described herein can be in unit dosage form suitable for single administration of precise dosages. In a unit dosage form, the formulation is divided into unit doses containing an appropriate amount of one or more compounds. A unit dose can be a packaged form containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, a multi-dose reclosable container can be used, in which case a preservative is typically included in the composition. By way of example only, formulations for parenteral injection can be in unit dosage form, including but not limited to ampoules, or in multi-dose containers, with the addition of a preservative.

[0628] The dosage and administration regimen are adjusted by a clinician or other technician in the field of pharmacology according to well-known pharmacology and treatment considerations, including but not limited to the desired level of therapeutic effect and the actual level of the therapeutic effect that can be obtained. Generally, it is recommended to follow the pharmacological principles of well-known chemotherapeutic agent administration (for example, it is generally recommended that the dose be changed by no more than 50% at a time, and no more than every 3-4 drug half-lives). For compositions with relatively few or no dose-related toxicity considerations and requiring maximum efficacy, it is not uncommon to exceed the average required dose. This method of administration is generally referred to as a "maximum dose" strategy. In certain embodiments, the compound is 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 compound described herein is co-administered with another agent (for example, as a sensitizer), the effective amount can be less than the effective amount when the agent is used alone. Administration can be once a day or multiple times a day, for one day or several consecutive days.

[0629] Use / treatment methods

[0630] 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). These methods include methods of inhibiting GAS41 and methods of treating diseases such as cancer.

[0631] In certain embodiments, the present disclosure provides a method for inhibiting GAS41 activity in a sample, 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 or ex vivo sample (e.g., a sample comprising cells, tissues, or organs).

[0632] In some embodiments, the present disclosure provides a method of inhibiting GAS41 activity by contacting GAS41 with an effective amount of a compound as 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), for example, by contacting a cell, tissue or organ expressing GAS41 with a compound or a salt thereof. In some embodiments, the present disclosure provides a method of inhibiting GAS41 activity in a subject (including but not limited to rodents and mammals, such as humans) by administering an effective amount of a compound as 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) to the subject. In some embodiments, the percentage of inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.

[0633] In some embodiments, the present disclosure provides a method for 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 present disclosure provides a method for inhibiting GAS41 activity in a tissue, the method being performed 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 the activity of GAS41 in the tissue. In some embodiments, the present disclosure provides a method for inhibiting GAS41 activity in an organism (e.g., a mammal, a human, etc.), the method being performed 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 the activity of GAS41 in the organism.

[0634] Inhibition of GAS41 activity can be assessed and demonstrated by a variety of methods known in the art. Non-limiting examples include measuring (a) a direct decrease in GAS41 activity; (b) a decrease in cell proliferation and / or cell viability; (c) an increase in cell differentiation; (d) a decrease in the level of downstream targets of GAS41 activity; and (e) a decrease in tumor volume and / or tumor volume growth rate. One or more of the above can be determined using kits and commercially available assays.

[0635] The present disclosure also provides a method for treating cancer in a subject in need thereof (e.g., a subject suffering from cancer), the method comprising administering a compound or pharmaceutical composition as 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) to the subject. In certain embodiments, the cancer is associated with GAS41 expression (e.g., abnormal expression, overexpression, etc.) and / or activity. In certain embodiments, the cancer is brain cancer (e.g., astrocytoma or glioblastoma), sarcoma, colorectal cancer, lung cancer (e.g., non-small cell lung cancer), or gastric cancer.

[0636] In certain embodiments, the present disclosure provides a method of treating cancer in a subject, wherein the method comprises 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).

[0637] Determining whether a tumor or cancer expresses (e.g., overexpression, abnormal expression, etc.) GAS41 can be performed by evaluating the nucleotide sequence encoding GAS41 or by evaluating the amino acid sequence of GAS41. Methods for detecting GAS41 nucleotide sequences are well known to those skilled 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, mutant 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 well known to those skilled in the art. These methods include, but are not limited to, using specific binding agents (e.g., antibodies) for GAS41, protein electrophoresis, Western blotting, and direct peptide sequencing for detection.

[0638] Methods for determining whether a tumor or cancer expresses (e.g., overexpresses, aberrantly expresses, etc.) GAS41 or is mediated by GAS41 activity can use various samples. In some embodiments, the sample is obtained from a subject suffering from 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.

[0639] 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 relate to the treatment of cancers such as acute myeloid leukemia, juvenile cancers, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., 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 lymphoma, carcinoid tumor, chondrosarcoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, heart tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), ), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancers, endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancers, fibrous histiocytoma of bone, biliary bladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, glioblastoma, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumors, Pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, leiomyosarcoma, lip and oral cancer, liposarcoma, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, occult primary metastatic squamous neck cancer, midline tract cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasms, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, myxofibrosarcoma, nasal and sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral In some embodiments, the method is directed to treating a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin, e.g., psoriasis, restenosis, or benign prostatic hyperplasia (BPH), oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal sinus and nasal cavity 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, gastric cancer (stomach cancer), small cell lung cancer, small intestine cancer, soft tissue sarcoma, synovial sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumors, uncommon childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virally induced cancers. In some embodiments, the method is directed to treating a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin, e.g., psoriasis, restenosis, or prostate, e.g., benign prostatic hyperplasia (BPH).In some embodiments, the methods relate to the treatment of brain cancer (eg, astrocytoma or glioblastoma), sarcoma, colorectal cancer, lung cancer (eg, non-small cell lung cancer), or gastric cancer.

[0640] Subjects that can be treated with the compounds of the present disclosure according to the methods of the present disclosure include, for example, subjects who have been diagnosed with acute myeloid leukemia, juvenile cancers, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., 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, heart tumor, chronic lymphocytic leukemia (CLL), and other diseases. ), chronic myeloid leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, biliary bladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, glioblastoma, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma sarcoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, leiomyosarcoma, lip and oral cancer, liposarcoma, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, occult primary metastatic squamous neck cancer, midline tract cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasms, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, myxofibrosarcoma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer In some embodiments, the method is directed to treating a non-cancerous hyperproliferative disorder such as a benign hyperplasia of the skin, e.g., psoriasis, restenosis, or benign prostatic hyperplasia (BPH).In some embodiments, the subject has been diagnosed with brain cancer (eg, astrocytoma or glioblastoma), sarcoma, colorectal cancer, lung cancer (eg, non-small cell lung cancer), or gastric cancer.

[0641] Compositions containing the compounds or salts described herein can be administered for prophylactic and / or therapeutic treatment. In therapeutic administration, the compound or composition is 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. The effective amount for this use will depend on the severity and course of the disease, previous therapy, the patient's health, weight, and response to medication, and the judgment of the treating physician.

[0642] In prophylactic applications, a composition containing a compound described herein or a salt thereof is administered to a patient suspected of having, or otherwise at risk for, a particular disease, condition, or illness. This amount is defined as a "prophylactically effective amount or dose." In this use, the precise amount also depends on the patient's health, weight, and the like. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, condition, or illness, previous therapy, the patient's health status and response to drugs, and the judgment of the treating physician.

[0643] In cases where the patient's condition does not improve, administration of the compound is administered chronically (ie, for an extended period of time, including throughout the patient's life) at the discretion of the physician to ameliorate or otherwise control or limit the symptoms of the patient's disease.

[0644] If the patient's condition does improve, the compound may be continued at the clinician's discretion; alternatively, the dose of the drug being administered may be temporarily reduced or suspended for a period of time (i.e., a "drug holiday"). The length of a drug holiday can vary between 2 days and 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 a drug holiday can 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%.

[0645] Once the patient's disease improves, a maintenance dose is administered if necessary. Subsequently, the dosage or frequency of administration or both can be reduced to a level that maintains the disease, condition, or disease improvement, depending on the symptoms. However, the patient may need to undergo intermittent treatment for a long time upon any recurrence of symptoms.

[0646] The amount of the given agent corresponding to this amount will vary according to a variety of factors, such as specific compounds, diseases and their severity, the identity of the subject or host in need of treatment (e.g., body weight), but can still be determined in an art-recognized manner according to the specific circumstances surrounding the case, including, for example, the specific agent administered, the route of administration, the disorder to be treated, and the subject or host to be treated. However, in general, the dosage for adult treatment is typically in the range of about 0.02 to about 5000 mg per day, in some embodiments, about 1 to about 1500 mg per day. The desired dosage can be conveniently administered in single or divided doses simultaneously (or over a short period of time) or at appropriate intervals, for example, two, three, four or more divided doses per day.

[0647] Toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to LD 50 (a dose lethal to 50% of the population) and ED 50 The ratio of the doses of toxic effect to therapeutic effect is the therapeutic index, which can be expressed as LD 50 and ED 50 Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage of such compounds is preferably within the range that includes the ED with minimal toxicity. 50 The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0648] Combination therapy

[0649] Provided herein are methods for combination therapy in which agents known to modulate other pathways or other components of the same pathway, or even overlapping groups of target enzymes, are used 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 compounds of the present disclosure with a chemotherapeutic agent, a targeted agent, a therapeutic antibody, and / or radiation therapy to provide a synergistic or additive therapeutic effect.

[0650] In general, the compounds and compositions described herein, and in embodiments employing combination therapy, other agents need not be administered in the same pharmaceutical composition and may have to be administered by different routes due to different physical and chemical characteristics. Where possible, it is within the knowledge of the clinician to determine the mode of administration and the feasibility of administration in the same pharmaceutical composition. The initial administration can be carried out according to established protocols recognized in the art, and the clinician can then modify the dosage, mode of administration, and time of administration based on the observed effects.

[0651] In some 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 one of the side effects experienced by a patient while receiving a compound described herein (e.g., a compound of Formula (I), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt thereof) is nausea, then administering an anti-nausea agent in combination with the initial therapeutic agent may be appropriate. Alternatively, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administering an adjuvant (i.e., the adjuvant may have minimal therapeutic benefit by itself, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the beneficial effect experienced by the patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a treatment regimen) that also has a therapeutic beneficial effect. In any case, regardless of the disease, condition, or disorder being treated, the overall beneficial effect experienced by the patient may be simply the sum of the two therapeutic agents, or the patient may experience a synergistic beneficial effect.

[0652] The specific choice of compound used will depend on the diagnosis and judgment of the patient's illness and the appropriate treatment regimen. Depending on the nature of the disease, condition or illness, the patient's illness and the actual choice of compound used, the compounds can be administered simultaneously (e.g., simultaneously, substantially simultaneously or within the same treatment regimen) or sequentially. The determination of the order of administration, as well as the number of repetitions of each therapeutic agent administered during the treatment regimen, is entirely within the knowledge of the clinician after evaluating the disease being treated and the patient's condition.

[0653] When drugs are used in combination therapy, the therapeutically effective dose can vary. Methods for experimentally determining the therapeutically effective dose of drugs and other agents used in combination therapy regimens are described in the literature. For example, the use of metronomic dosing, i.e., providing more frequent, lower doses to minimize toxic side effects, has been widely described in the literature. Combination therapy also includes cyclical treatments that are started and stopped at different times to assist in the clinical management of patients.

[0654] For the combination therapies described herein, the dosage of the co-administered compounds will, of course, vary depending on the type of combination drug used, the specific drug used, the disease being treated, and the like. In addition, when co-administered with one or more biologically active agents, the compounds provided herein can be administered simultaneously or sequentially with the one or more biologically active agents. If administered sequentially, the attending physician will determine the appropriate order for administering the protein and one or more biologically active agents in combination.

[0655] In any 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), can be administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents can be provided in a single unified form or in multiple forms (by way of example only, as a single pill or as two separate pills). One of the therapeutic agents can be given in multiple doses, or both can be given in multiple doses. If not administered simultaneously, the time schedule between multiple doses can range from greater than zero weeks to less than four weeks. In addition, the combination methods, compositions, and formulations are not limited to the use of only two agents; the use of multiple therapeutic combinations is also contemplated.

[0656] It should be understood that the dosage regimen for treating, preventing, or ameliorating one or more conditions sought to be alleviated may be modified based on a variety of factors. These factors include the condition or illness suffered by the subject, as well as the subject's age, weight, sex, diet, and medical condition. Therefore, the dosage regimen actually employed may vary widely and may deviate from the dosage regimens described herein.

[0657] The medicaments constituting the combination therapy disclosed herein can be a combined dosage form or a separate dosage form for substantially simultaneous administration. The medicaments constituting the combination therapy can also be administered sequentially, wherein any therapeutic compound is administered by a scheme requiring two-step administration. The two-step administration scheme can require sequential administration of the active agent or interval administration of the active agent alone. The time period between multiple administration steps can be in the range of several minutes to several hours, depending on the properties of each medicament, such as the efficacy, solubility, bioavailability, plasma half-life and kinetic characteristics of the medicament. The diurnal variation of the target molecule concentration can also determine the optimal dose interval.

[0658] In addition, the compounds described herein can also be used in combination with procedures that can provide additional or synergistic beneficial effects to the patient. By way of example only, it is expected that patients will find therapeutic and / or prophylactic benefits in the methods described herein, wherein pharmaceutical compositions of the compounds disclosed herein and / or combinations with other therapeutics are combined with genetic testing to determine whether the individual is a carrier of a mutant gene known to be associated with certain diseases or conditions.

[0659] The compounds and combination therapies described herein can be administered before, during, or after the onset of the disease, and the schedule for administering the compositions containing the compounds can vary. Thus, for example, the compounds can be used as prophylactics and can be continuously administered to subjects with a tendency to develop an illness or disease to prevent the onset of the disease. The compounds and compositions can be administered to the subject as soon as possible during or after the onset of symptoms. Administration of the compound 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. The initial administration can be performed by any feasible route, such as intravenous injection, push injection, infusion for about 5 minutes to about 5 hours, pills, capsules, transdermal patches, buccal delivery, etc., or a combination thereof. Preferably, the compound is administered as quickly as possible after the onset of the disease is detected or suspected, and the duration of treatment for the disease is continued for a period of time, such as 1 day to about 3 months. The length of treatment can be different for each subject, and the length can be determined using known standards. For example, the compound or a formulation containing the compound can be administered for at least 2 weeks, preferably about 1 month to about 5 years.

[0660] The compounds and pharmaceutical compositions disclosed herein can be co-administered with one or more chemotherapeutic agents. Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds herein. In some embodiments, the chemotherapeutic agent is selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, protein-protein interaction inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.

[0661] Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as (imatinib mesylate), (bortezomib), Casodex (bicalutamide), (gefitinib) and adriamycin and a large number of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXANT™); alkyl sulfonates such as busulfan, endosulfan and piposulfan; aziridines such as phenodopa, carboquinone, metodepa and urodopa; ethyleneimines and methylmelamines including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trishydroxymethylmelamine; nitrogen mustards such as chlorambucil, chlornaphthyl, cholephosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, new nitrogen mustard, phenylephrine, chloramphenicol, chlorambucil, chlorambucil, chlorambucil, cholestyramide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, new nitrogen mustard, phenylephrine, chlorambucil, chlorambucil, chlorambucil, chlorambucil, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, new nitrogen mustard, phenylephrine, chlorambucil, chlorambucil, chlorambucil, estramustine ... Nisostamide, uracil mustard; nitrosoureas such as carmustine, chlorozocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclarubicin, dactinomycin, anthramycin, azaserine, bleomycin, actinomycin C, calicheamicin, carbicin, carminomycin, carmomycin, Constar™, chromomycin, actinomycin D, daunorubicin, detoxib, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, mariamycin, mitomycin, mycophenolic acid, nogamycin, olivemycin, pembrolizumab antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as dimethylformamide, methotrexate, pteroyltriglutamate, trimesate; purine analogs such as fludarabine, 6-mercaptopurine, thiopurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, deoxyfluridine, enocitabine, floxuridine, and androgens such as dimethyltestosterone. ketone, drostanolone propionate, epithioandrostol, mepitentan, testosterone lactone; antiadreners such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; aceglucuronolide; aldophosphamide; aminolevulinic acid; amsacrine; belabuxix; bisantrene; edatrexate; diffoamine; descarboxycolchicine; diacrazone; elfoimide; hydroxypicrazole acetate; glycidyl ether; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguatone; mitoxantrone; mopidamole; nitrile; pentostatin; methamidine; pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK.RTM.; Razoxane; Cetirizine; Spirogermanium; Alternaria tenuisporic acid; Triimidoquinone; 2,2',2"-trichlorotriethylamine; Ethyl carbamate; Vindesine; Dacarbazine; Mannomustine; Dibromomannitol; Mitonolactone; Propirazine bromide; Garcitosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Taxanes, for example, paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); Retinoic acid; Esperamycin; Capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing. Suitable chemotherapeutic cell conditioning agents also include antihormonal agents that act to modulate or inhibit the effects of hormones on tumors, such as antiestrogens, including, for example, tamoxifen, (Nolvadex. TM ), raloxifene, aromatase-inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, troxifene, ketoxifen, LY 117018, onapristone, and toremifene (Faloxone); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprorelin, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; norvanolone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). Where necessary, the compounds of the pharmaceutical composition of the present invention may be used in combination with commonly prescribed anticancer drugs, such as ABVD, AVICINE, abavoizumab, acridinium carboxamide, adelimumab, 17-N-allylamino-17-demethoxygeldanamycin, Alpharadin, avosidic acid, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, aminopyridinium chloride, anthracenedione, anti-CD22 immunotoxin, anti-malignant tumor traditional Chinese medicine, anti-tumor traditional Chinese medicine, apiquatone, atimod, azathioprine, belotecan, bendamustine, BIBW 2992, bilicada, brostatin, bryostatin, buthionine sulfate imine, CBV (chemotherapy), calyculin, cell cycle nonspecific antineoplastic agent, dichloroacetic acid, scutellarin, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exitecan, exixuline, mylosporin, forodesine, fosfosfosterol, ICE chemotherapy regimen, IT-101, imik, imiquimod, indolecarbazole, ilofofen, laniqueda, lalotaxel, lenalidomide, lucanthone, lertotecan, mafosfamide, mitozolamide, nafoxidine, nedaplatin, olaparib, votataxel, PAC-1, papaya, pixantrone, proteasome inhibitors, phaeocytocin, resiquimod, rubitecan, SN-38, salinosporamide A, sacitabine, Stanford V, swainsonine, talaporfin, tareqada, tegafur-uracil, temozolomide, tesetaxel, triplatinium tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uracil, uracil, valerian, vinflunine, ZD6126, or zosucada.

[0662] The embodiments herein also relate to methods for inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal 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 radiotherapy. Techniques for administering radiotherapy are known in the art, and these techniques can be used in the combination therapies described herein. Administration of the compound of the present invention in this combination therapy can be determined as described herein.

[0663] Radiotherapy can be applied by the combination of one or more of several methods, including but not limited to external beam therapy, internal radiotherapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and permanent or temporary genomic brachytherapy. As used herein, term "brachytherapy" refers to the radiotherapy delivered by the spatially confined radioactive material inserted into or near a tumor or other proliferative tissue disease site. The term is intended to include but is not limited to being exposed to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32 and Lu). Suitable radioactive sources used as cell conditioning agents of the present invention include solid and liquid. As non-limiting examples, radioactive sources can be radionuclides, such as I-125, I-131, Yb-169, Ir-192 solid sources, I-125 solid sources or other radionuclides of emission photons, beta particles, gamma radiation or other therapeutic rays. The radioactive material may also be a fluid made from a solution of any one or more radionuclides, such as a solution of I-125 or I-131, or the radioactive fluid may be produced using a slurry of a suitable fluid containing small solid particles of radionuclides, such as Au-198, Y-90. Additionally, one or more radionuclides may be contained in a gel or radioactive microspheres.

[0664] The compounds or pharmaceutical compositions herein are also used in combination with an amount of one or more substances selected from anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors.

[0665] Anti-angiogenic 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 combination with the compounds of the present disclosure and the pharmaceutical compositions described herein. Anti-angiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib and bevacizumab. Examples of useful COX-II inhibitors include CELEBREX®, CELEBREX®, and CELEBREX®. TM(Alecoxib), valdecoxib and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are disclosed in WO 96 / 33172 (published on October 24, 1996), WO 96 / 27583 (published on March 7, 1996), European Patent Application No. 97304971.1 (filed on July 8, 1997), European Patent Application No. 99308617.2 (filed on October 29, 1999), WO 98 / 07697 (published on February 26, 1998), WO 98 / 03516 (published on January 29, 1998), WO 98 / 34918 (published on August 13, 1998), WO 98 / 34915 (published on August 13, 1998), WO 98 / 33768 (published on August 6, 1998), WO 98 / 30566 (published on July 16, 1998), European Patent Publication 606,046 (published on July 13, 1994), European Patent Publication 931,788 (published on July 28, 1999), WO 90 / 05719 (published on May 31, 1990), WO 99 / 52910 (published on October 21, 1999), WO 99 / 52889 (published on October 21, 1999), WO 99 / 29667 (published June 17, 1999), PCT International Application No. PCT / IB98 / 01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), UK Patent Application No. 9912961.1 (filed June 3, 1999), U.S. Provisional 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 entirety. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no inhibition of MMP-1 activity. More preferred are those that selectively inhibit MMP-2 and / or AMP-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-II, MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, and RS 13-0830.

[0666] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil TM), bafilomycin A1, 5-amino-4-imidazolecarboxamide ribonucleoside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatase, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine ribonucleoside, and vinblastine. In addition, antisense or siRNA that inhibits protein expression, including but not limited to ATG5 (associated with autophagy), can also be used.

[0667] In some embodiments, the compounds described herein are formulated or administered with a liquid or solid tissue barrier (also known as a lubricant). Examples of tissue barriers include, but are not limited to, polysaccharides, glycans, seprafilm, interceed, and hyaluronic acid.

[0668] In some embodiments, drugs administered in combination with the compounds described herein include any suitable drug effectively delivered by inhalation, such as analgesics, such as codeine, dihydromorphine, ergotamine, fentanyl, or morphine; angina preparations, such as diltiazem; antiallergics, such as cromoglycate, ketotifen, or nedocromil; anti-infectives, such as cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines, or pentamidine; antihistamines, such as pyrimethamine; anti-inflammatory drugs, such as beclomethasone, flunisolide, budesonide, tipronan, triamcinolone acetonide, or fluticasone; antitussives, such as noscapine; bronchodilators, such as ephedrine, epinephrine, fenoterol, formosan, or fentanyl; diuretics such as amiloride; anticholinergics such as ipratropium, atropine, or oxytropine; hormones such as cortisone, hydrocortisone, or prednisolone; xanthines such as aminophylline, theophylline choline, theophylline lysine, or theophylline; and therapeutic proteins and peptides such as insulin or glucagon. It will be clear to those skilled in the art that, where appropriate, the drug is used in salt form (e.g., as an alkali metal salt or an amine salt or as an acid addition salt) or as an ester (e.g., a lower alkyl ester) or as a solvate (e.g., a hydrate) to optimize the activity and / or stability of the drug.

[0669] Other exemplary therapeutic agents that can be used in combination therapy include, but are not limited to, the agents described above, radiation therapy, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid drugs, estrogens and progestins, androgens, adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and action of adrenocortical hormones, insulin, oral hypoglycemic agents and endocrine pancreatic pharmacology, drugs that affect calcification and bone turnover: calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitamins such as water-soluble vitamins, B complex vitamins, ascorbic acid, fat-soluble vitamins, vitamins A, K and E, growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterase agents; agents that act at the neuromuscular junction and / or autonomic ganglia; catecholamines, sympathomimetics and adrenergic receptor agonists or antagonists; and 5-hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists.

[0670] Other suitable therapeutic agents for co-administration with the compounds herein also include agents for pain and inflammation such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances produced by biotransformation of selective hydrolysis products of membranes, phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory drugs, antipyretic analgesics, drugs that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of inducible cyclooxygenase, selective inhibitors of inducible cyclooxygenase-2, endotoxins, paracrine hormones, somatostatin, gastrin, cytokines that mediate the interaction of humoral and cellular immune responses, lipid-derived endocrine hormones, eicosanoids, beta-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers, and leukotriene inhibitors.

[0671] Additional therapeutic agents contemplated for co-administration with the compounds and compositions herein include diuretics, vasopressins, agents that affect renal conservation of water, rennet, angiotensin, agents useful for treating myocardial ischemia, antihypertensive agents, angiotensin converting enzyme inhibitors, beta-adrenergic receptor antagonists, agents for treating hypercholesterolemia, and agents for treating dyslipidemia.

[0672] Other therapeutic agents contemplated for co-administration with the compounds and compositions herein include drugs for controlling gastric acidity, drugs for treating peptic ulcers, drugs for treating gastroesophageal reflux disease, prokinetics, antiemetics, drugs for irritable bowel syndrome, drugs for diarrhea, drugs for constipation, drugs for inflammatory bowel disease, drugs for biliary tract disease, drugs for pancreatic disease, therapeutic agents for treating protozoal infections, drugs for treating malaria, amebiasis, giardiasis, trichomoniasis, trypanosomiasis and / or leishmaniasis, and / or drugs for chemotherapy of helminthiasis. Other therapeutic agents include antimicrobials, sulfonamides, trimethoprim-sulfamethoxazole quinolones, and urinary tract infection medications, penicillins, cephalosporins and other medications, beta-lactam antibiotics, drugs including aminoglycosides, protein synthesis inhibitors, drugs used in chemotherapy for tuberculosis, Mycobacterium avium complex, and leprosy, antifungals, antivirals including non-retroviral and antiretroviral agents.

[0673] Examples of therapeutic antibodies that can be combined with the compounds herein 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.

[0674] In addition, the methods herein contemplate therapeutic agents for immunomodulation, such as immunomodulators, immunosuppressants, tolerogens, and immunostimulants. Additionally, therapeutic agents acting on blood and blood-forming organs, hematopoietic agents, growth factors, minerals and vitamins, anticoagulants, thrombin and antiplatelet drugs.

[0675] Other therapeutic agents that can be combined with the compounds herein can be found in Goodman and Gilman's "The Pharmacological Basis of Therapeutics," Tenth Edition, Hardman, Limbird and Gilman, eds., or the Physician's Desk Reference, both of which are incorporated herein by reference in their entirety.

[0676] In some embodiments, the compounds described herein are co-administered with another therapeutic agent that is effective in treating brain cancer (such as glioblastoma or astrocytoma). In some embodiments, the another therapeutic agent can be bevacizumab, carmustine (e.g., carmustine wafers), cisplatin, everolimus, lomustine, procarbazine, temozolomide, vincristine, or any combination thereof (e.g., a combination of procarbazine hydrochloride, lomustine, and vincristine sulfate).

[0677] In some embodiments, the compounds described herein are co-administered 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., liposomal doxorubicin hydrochloride), 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.

[0678] In some embodiments, the compounds described herein are co-administered 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, tipicava, trifluridine, aflibercept, or any combination thereof.

[0679] In some embodiments, the compounds described herein are co-administered with one or more therapeutic agents approved for the treatment of lung cancer (such as non-small cell lung cancer). In these embodiments, another 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, naximol, nivolumab, osimertinib, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, selpatinib, trametinib, vinorelbine, or any combination thereof.

[0680] In some embodiments, the compounds described herein are co-administered 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, trifluorouracil, tipiracil, trastuzumab, or any combination thereof.

[0681] In some embodiments, the compounds described herein are co-administered with one or more alkylating agents (e.g., for the treatment of cancer) selected from, for example, nitrogen mustard nitrogen oxide, cyclophosphamide, ifosfamide, thiotepa, ranimustine, nimustine, temozolomide, altretamine, apiquatone, brotalicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, mafosfamide, bendamustine, dibromodulcitol, cisplatin, carboplatin, epplatin, lobaplatin, nedaplatin, oxaliplatin, and satraplatin.

[0682] In some embodiments, the compounds described herein are co-administered with one or more antimetabolites (e.g., for the treatment of cancer) selected from, for example, methotrexate, 6-mercaptopurine ribonucleoside, mercaptopurine, 5-fluorouracil, tegafur, deoxyfluridine, carmofur, cytarabine, cytarabine octadecyl phosphate, escitabine, gemcitabine, fludarabine, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, melphalan, nelarabine, nolatrexed, octadecyl phosphate, pemetrexed disodium, pentostatin, piritrexol, raltitrexed, triamcinolone, trimetrexate, vidarabine, vincristine, and vinorelbine;

[0683] In some embodiments, the compounds described herein are co-administered with one or more hormonal therapeutics (e.g., for the treatment of cancer) selected from, for example, exemestane, leuprolide, anastrozole, docecalciferol, fadrozole, formestane, abiraterone acetate, finasteride, aplid, tamoxifen citrate, fulvestrant, trestad, toremifene, raloxifene, lasofoxifene, letrozole, sagopilone, ixabepilone, epothilone B, vinblastine, vinflunine, docetaxel, and paclitaxel;

[0684] In some embodiments, the compounds described herein are co-administered with one or more cytotoxic topoisomerase inhibitors (e.g., for the treatment of cancer) selected from, for example, aclarubicin, doxorubicin, amofetil, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflutecan, irinotecan, topotecan, etokaline, epirubicin, etoposide, exitecan, gimatecan, rutotecan, mitoxantrone, pirbicin, pixantrone, rubitecan, sobuzoxane, taflutoposide, and the like.

[0685] In some embodiments, the compounds described herein are co-administered 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 alanine, cilengitide, combriotin, DAST, endostatin, fenretinide, halofuginone, pazopanib, ranibizumab, remastat, remuva, relimumab, sorafenib, vatalanib, squalamine, sunitinib, telatinib, thalidomide, uretin, and vitacin.

[0686] In some embodiments, the compounds described herein are co-administered with one or more antibodies (e.g., for treating cancer) selected from, for example, trastuzumab, cetuximab, bevacizumab, rituximab, tesitumumab, ipilimumab, lumiliximab, catumaxomab, atacicept, oregol, and alemtuzumab.

[0687] In some embodiments, the compounds described herein are co-administered (e.g., for the treatment of cancer) with one or more VEGF inhibitors selected from, for example, sorafenib, DAST, bevacizumab, sunitinib, cediranib, axitinib, aflibercept, telatinib, brivanib alanine, vatalanib, pazopanib, and ranibizumab.

[0688] In some embodiments, the compounds described herein are co-administered with one or more EGFR inhibitors (e.g., for treating cancer) selected from, for example, cetuximab, panitumumab, vicitinib, gefitinib, erlotinib, and zacitinib.

[0689] In some embodiments, the compounds described herein are co-administered with one or more HER2 inhibitors (e.g., for treating cancer), selected from, for example, lapatinib, trastuzumab, and pertuzumab; CDK inhibitors selected from roscovitide and flavopiridol;

[0690] In some embodiments, the compounds described herein are co-administered (eg, for the treatment of cancer) with one or more proteasome inhibitors selected from, for example, bortezomib and carfilzomib.

[0691] In some embodiments, the compounds described herein are co-administered (eg, for the treatment of cancer) with one or more serine / threonine kinase inhibitors selected from, for example, MEK inhibitors and Raf inhibitors, such as sorafenib.

[0692] In some embodiments, the compounds described herein are co-administered 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, teratinib, imatinib mesylate, brivapenib alanine, pazopanib, ranibizumab, vatananib, cetuximab, panitumumab, vicitinib, gefitinib, erlotinib, lapatinib, trastuzumab, and pertuzumab.

[0693] In some embodiments, the compounds described herein are co-administered with one or more androgen receptor antagonists (e.g., for the treatment of cancer) selected from, for example, nandrolone decanoate, fluoxymesterone, amylase, prostaglandins, androstine, bicalutamide, flutamide, apoproterone acetate, apoflutamide, chlormadinone acetate, cyproterone acetate, tybee, cyproterone acetate, and nilutamide.

[0694] In some embodiments, the compounds described herein are co-administered (eg, for the treatment of cancer) with one or more aromatase inhibitors selected from, for example, anastrozole, letrozole, testolactone, exemestane, aminoglutethimide, and formestane.

[0695] In some embodiments, the compounds described herein are co-administered with one or more other anticancer agents, including, for example, alitretinoin, ampligen, atrasentan bexarotene, bortezomib, bosentan, calcitriol, sulin, fotemustine, ibandronic acid, miltefosine, mitoxantrone, 1-asparaginase, procarbazine, dacarbazine, hydroxyurea, pegaspargase, pentostatin, tazarotene, velcade, gallium nitrate, canfosamide, daripascin and tretinoin. In a preferred embodiment, the compounds of the present disclosure can be used in combination with chemotherapy (e.g., cytotoxic agents), antihormones and / or targeted therapies, such as other kinase inhibitors, mTOR inhibitors and angiogenesis inhibitors.

[0696] In embodiments where the compounds and pharmaceutical compositions herein are used to treat or prevent non-cancer diseases and / or conditions, the compounds and pharmaceutical compositions herein may be co-administered with therapeutic agents and / or therapies known in the art to be suitable for treating such diseases and / or conditions.

[0697] Reagent test kit

[0698] Also provided are kits and articles of manufacture comprising a compound or pharmaceutical composition 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). In some embodiments, such kits include a carrier, packaging, or container that is partitioned to receive one or more containers, such as vials, tubes, and the like, each of which includes one of the individual elements for use in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are made of various materials, such as glass or plastic.

[0699] The articles provided herein contain packaging materials. The 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 materials suitable for selected formulations and the predetermined mode of administration and treatment. For example, in some embodiments, one or more containers include 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 disclosed herein. The container optionally has a sterile access port (for example, the container is an intravenous infusion bag or a vial with a stopper that can be pierced by a hypodermic needle). Such kits optionally include a compound having an identifying description or label or instructions related to its use in the methods described herein.

[0700] For example, a kit typically includes one or more additional containers, each container having one or more different materials (such as reagents, optionally in concentrated form, and / or devices) that are desired from a commercial and user perspective for using the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; carriers, packaging, container, vial and / or test tube labels, listing the contents and / or instructions for use, and package inserts with instructions for use. A set of instructions is typically also included. The label is optionally located on or associated with the container. For example, when letters, numbers, or other characters forming the label are attached, molded, or etched into the container itself, the label is on the container, and when the label is present in a reservoir or carrier in which the container is stored, as a package insert, the label is associated with the container. In addition, the label is used to indicate that the contents are for a specific therapeutic application. In addition, the label indicates the direction of use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is present in a package or dispenser device containing one or more unit dosage forms containing the compounds provided herein. For example, the package contains metal or plastic foil, such as a blister pack. Alternatively, the packaging or dispenser device is accompanied by instructions for administration. Alternatively, the packaging or dispenser is accompanied by a notice associated with the container in a format prescribed by a governmental agency regulating the manufacture, use, or sale of drugs, which notice reflects the form of the drug approved by that agency for human or veterinary administration. For example, such a notice is a prescription drug label approved by the U.S. Food and Drug Administration, or an approved product insert. In some embodiments, a composition containing a compound provided herein formulated in a compatible pharmaceutical carrier is prepared, placed in a suitable container, and labeled for treatment of a specified condition.

[0701] Example

[0702] Abbreviations used in the following examples include: 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 hexafluorophosphate 3-oxide; MeOH is methanol; RPH refers to reverse phase chromatography; RT is room temperature; TFA is trifluoroacetic acid.

[0703] General synthetic methods

[0704] General Procedure A: To a screw cap 10 dr vial was added carboxylic acid (1.1 eq), DIPEA (2 eq, 3 eq in the case of amine hydrochloride), HATU (1.2 eq) and anhydrous DCM (5 ml). The mixture was stirred at room temperature for 15 minutes, then the corresponding amine or its hydrochloride (1.2 eq) was added, the vial was sealed and the reaction mixture was heated at 45 ° C overnight. After cooling to room temperature, the mixture was diluted with DCM (20 mL) and washed sequentially with water, saturated aqueous NaHCO 3 solution and brine. The organic phase was dried over Na 2 SO 4, concentrated in vacuo and purified by silica gel column chromatography (DCM: EtOAc or DCM: MeOH) and then (if necessary) by RPH chromatography (10-100% gradient of MeOH in water) to give the title compound.

[0705] General Procedure B: To a solution of the corresponding methyl ester (1 mmol, 1 eq) in MeOH (2 mL / mmol) was added 1 M LiOH solution (2 eq) and the mixture was stirred at room temperature for 4 h (for proline esters) or overnight (for aromatic esters). The mixture was concentrated in vacuo and the crude product was diluted with water (5 mL) and acidified to pH 4 with 1 M HCl. The resulting mixture was extracted with EtOAc (3*10 mL) and the combined organics were washed with brine (3*10 mL), dried over Na2SO4 and concentrated to give the product, which was used directly in the next step without further purification or purified by silica gel column chromatography.

[0706] General Procedure C: To a degassed suspension of zinc powder (217 mg, 3.338 mmol, 1.8 eq) in DMA (2 mL) in a screw cap vial was added trimethylsilyl chloride (67.3 μL, 57.6 mg, 0.53 mmol, 0.3 eq) and 1,2-dibromoethane (45.9 μL, 99.6 mg, 0.53 mmol, 0.3 eq) dropwise and the resulting mixture was stirred at room temperature under Ar for 15 min. To this mixture was then added neat tert-butyl 3-iodoazetidine-1-carboxylate (753 mg, 2.661 mmol, 1.4 eq) 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 eq) and cuprous iodide (30 mg, 0.157 mmol, 0.08 mmol) were added to a degassed solution of the corresponding hexa(aryl) bromide (1.862 mmol, 1 eq) in DMA (1 mL). After stirring for 30 minutes, the zinc suspension was added to the dissolved suspension of hexa(aryl) bromide, PdCl2(dppf)*DCM and cuprous iodide, and the reaction mixture was stirred at 80 ° C for 2 hours under argon. The resulting mixture was cooled to room temperature, diluted with EtOAc and filtered through a celite pad, which was washed with EtOAc. The collected organics were washed with a mixture of saturated ammonium chloride solution 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 flash chromatography on silica gel (0-100% ethyl acetate in hexanes), with the correspondingly selected fractions combined in LC-MS, concentrated and used in the next step without further purification.

[0707] General Procedure D: To a solution of the Boc-protected substituted azetidine (1 mmol) in 3 mL of 1,4-dioxane was added 4 M HCl in 1,4-dioxane (3 mL) dropwise, and the mixture was stirred at room temperature overnight. After this time, all volatiles were removed under reduced pressure, the residue was triturated with anhydrous 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.

[0708] General Procedure E: To a degassed suspension of boronic acid or boronic acid pinacol ester (1.3 eq., 0.65 mmol), bromide (1 eq., 0.5 mmol), NaHCO 3 (3 eq., 1.5 mmol) in a mixture of 1,4-dioxane:water=10:1 PdCl 2 (dppf) * DCM (0.025 mmol) was added in one portion. The resulting suspension was degassed once more, refilled with Ar, and stirred at 80° C. under argon overnight. The resulting mixture was cooled to room temperature, diluted with EtOAc and filtered through a pad of celite, which was washed with EtOAc. The collected organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% ethyl acetate in hexane, then 0-20% methanol in dichloromethane), the corresponding selected fractions were combined in LC-MS, concentrated, and the residue was redissolved in DCM (5 mL). To this mixture was added TFA (30 equivalents) 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 obtained residue was purified by silica gel column chromatography (0-100% hexane / EtOAc to DCM / MeOH) followed by RPH (0-100% MeOH / water) to give the title compound as an off-white solid.

[0709] General procedure F:Amine (1 equivalent), DIPEA (2 equivalents) and anhydrous DCM (5ml) are added to a screw cap 10dr bottle. The mixture is stirred at 0°C for 15 minutes, then the corresponding acid chloride is added, the bottle is sealed and the reaction mixture is stirred at room temperature overnight. After cooling to room temperature, the mixture is diluted with DCM (20mL), and washed with water, saturated NaHCO3 aqueous solution and brine in sequence. The organic phase is dried over sodium sulfate, concentrated in a vacuum and the residue is redissolved in DCM (2mL) at 0°C and TFA (30 equivalents) is added dropwise, and the mixture is stirred at 0°C for 60 minutes. The mixture is concentrated in a vacuum, and the crude product is ground with 7N ammonia in methanol and concentrated again. The residue obtained is purified by silica gel column chromatography (0-100% hexane / EtOAc to DCM / MeOH) followed by RPH (0-100% MeOH / water) to obtain the title compound as a pale solid.

[0710] General Procedure G: The Boc protected compound was dissolved in DCM (2 mL) at 0°C and TFA (30 eq) was added dropwise. The mixture was stirred at 0°C for 60 minutes. It was then concentrated in vacuo, the crude product was triturated with 7N ammonia in methanol and concentrated again. The obtained residue was purified by silica gel column chromatography (0-100% hexane / EtOAc to DCM / MeOH) followed by RPH (0-100% MeOH / water) to give the title compound as an off-white solid.

[0711] Example 1

[0712] Compound Synthesis – Monomers

[0713] Compound 14: N-((5-(Pyrrolidine-1-carbonyl)thiophen-2-yl)methyl)azetidine-3-carboxamide

[0714]

[0715] Compound 14 (10 mg, 72%) was synthesized according to General Procedure A using (5-aminothiophen-2-yl)(pyrrolidin-1-yl)methanone and 1-Bo c-azetidine-3-carboxylic acid and General Procedure G to give compound 14 as an off-white solid (10 mg, 72%). 1 H NMR (600MHz, CD3OD): δ7.46(d,J=3.8Hz,1H),7.00(d,J=3.8Hz,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 (125MHz, CD3OD): δ174.9,163.6,148.3,139.1,131.4,127.1,118.1,68.1,50.3,49.6,39.0,27.6,24.9.HR-MS(ESI):[M+H + ]Calculated value 294.1271, measured value 294.1270.

[0716] Compound 37: N-(5-(Pyrrolidine-1-carbonyl)thiophen-2-yl)azetidine-2-carboxamide

[0717]

[0718] Compound 20 (13 mg, 79%) was synthesized according to General Procedure A using (5-aminothiophen-2-yl)(pyrrolidin-1-yl)methanone and (rac)-1-Boc-azetidine-2-carboxylic acid and General Procedure G to give compound 20 as an off-white solid (13 mg, 79%). 1H NMR (600MHz, CD3OD): δ7.44(d,J=4.2Hz,1H),6.79(d,J=4.2Hz,1H),4.46(dd,J=9.1,7.1Hz,1H),3.82(s,2H),3.69(q,J=7.9Hz ,1H),3.61(s,2H),3.49(td,J=8.5,5.1Hz,1H),2.70(ddt,J=8.9,6.2,4.4Hz,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.

[0719] Compound 44: (S)-N-(5-(Pyrrolidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide

[0720]

[0721] The title compound was synthesized from the corresponding amine and N-Boc-L-proline according to General Procedure A and General Procedure G to give an off-white solid (18 mg, 83%). 1 H NMR MeO D(600MHz): δ7.44(d,J=4.2Hz,1H),6.78(d,J=4.2Hz,1H),3.89-3.77(m,3H),3.60(s,2H),3.06(dt,J=10.5,6.5Hz,1H),2 .97(dt,J=10.5,6.5Hz,1H),2.19(dt,J=12.7,6.8Hz,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, found: 294.1275

[0722] Compound 85. (S)-N-(5-(3-(thiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide

[0723]

[0724] Step 1. (S)-tert-Butyl 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 obtained residue was purified by silica gel column chromatography (0-100% DCM / EtOAc) to give the title compound (182 mg, 73%) as a semisolid. 1 H NMR DMS O- 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 value 355.1322, found value 355.1336.

[0725] Step 2. (S)-5-(1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxamido)thiophene-2-carboxylic acid. Synthesized from (S)-tert-butyl 2-((5-(methoxycarbonyl)thiophen-2-yl)carbamoyl)pyrrolidine-1-carboxylate according to General Procedure B. The obtained residue was purified by silica gel column chromatography (0-100% DCM / EtOAc) to give the title compound (120 mg, 93%) as a semisolid. 1 HNMR DMSO- d6 (600 MHz) (mixture of rotamers 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, selectively overlapped with HDO), 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 (150MHz)(Based on 1 H NMR, mixture of rotamers (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, found value 341.1179.

[0726] Step 3. (S)-N-(5-(3-(thiazol-2-yl)azetidine-1-carbonyl)thiophene-2-yl)pyrrolidine-2-carboxamide (Compound 85). Synthesized from (S)-5-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)thiophene-2-carboxylic acid and 2-(azetidine-3-yl)thiazole dihydrochloride according to general procedure A. The obtained residue was used in the next step without further purification. To a solution of the residue from the previous step in DCM (2 mL) was added TFA (0.5 mL) dropwise at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. After all volatiles were removed under reduced pressure, the residue was triturated with 7N ammonia in methanol, concentrated and purified by silica gel column chromatography (0-100% DCM / MeOH + 0.5% ammonia (v / v)) to give the title compound (9 mg, 75%) as an off-white solid. 1 H NMR MeOD(600MHz)δ:7.80(d,J=3.3Hz,1H),7.56(d,J=3.3Hz,1H),7.40(d,J=4.2Hz,1H ),6.80(d,J=4.2Hz,1H),4.96(s,1H),4.67(s,2H),4.41(m,2H),3.83(dd,J=8.7,5 .9Hz,1H),3.05(dt,J=10.5,6.5Hz,1H),2.97(dt,J=10.5,6.5Hz,1H),2.20(td,J= 15.6,12.7,7.3Hz,1H),1.88(td,J=15.6,12.7,7.3Hz,1H),1.80(p,J=6.9Hz,2H); 13 C 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 by HSQC spectrum), 56.8 (azetidine CH2, identified by HSQC spectrum), 48.1, 33.3, 32.0, 27.0. HR-ESI-MS: C 16 H 19 N4O2S2[M+H] + m / z calculated value 363.0944, found value 363.0952.

[0727] Compound 90. ((S)-N-(5-(3-(5-phenylthiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide

[0728]

[0729] Step 1. 2-(Azetidin-3-yl)-5-phenylthiazole hydrochloride. Synthesized according to general procedures C and D to give 2-(azetidin-3-yl)-5-phenylthiazole hydrochloride (70 mg, 15%) as an off-white solid. 1 H NMR(600MHz,DMSO-d6)δ9.51(s,1H),9.22(s,1H),8.24(s,1H),7.70–7.63(m,2H),7.46(t,J =7.7Hz,2H),7.41–7.34(m,1H),4.50(p,J=8.3Hz,1H),4.38–4.28(m,2H),4.26–4.18(m,2H). 13 CNMR (150MHz, DM SO-d6): δ166.6,139.4,138.5,130.6,129.3,128.5,126.4,50.6,33.5.MS(m / z)[M+H + ]:Calculated value 217, measured value 217.

[0730] (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-carboxamido)thiophene-2-carboxylic acid and 2-(azetidin-3-yl)-5-phenylthiazole hydrochloride and General Procedure G to give Compound 90 (8 mg, 79%) as an off-white solid. 1 H NMR(600MHz,CD3OD)δ7.91(s,1H),7.55(d,J=9.6Hz,1H),7.41–7.37(m,3H),7.33( t,J=7.4Hz,1H),6.75(d,J=4.2Hz,1H),4.94(s,1H),4.81(s,2H),4.48(s,2H),4.3 3(tt,J=8.8,5.8Hz,1H),3.86–3.80(m,1H),3.07(dt,J=11.1,6.5Hz,1H),3.04–2. 96(m,1H),2.28–2.16(m,1H),1.92(dq,J=12.9,6.6Hz,1H),1.81(p,J=6.9Hz,2H). HR-MS(ESI):[M+H + ]Calculated value 439.1257, measured value 439.1259.

[0731] Compound 123. (S)-N-(5-(3-(5-(4-(Acetylaminomethyl)phenyl)thiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide.

[0732]

[0733] Compound 123 (8 mg, 86%) was synthesized 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 directly via General Procedure E using the Boc-intermediate) and acetyl chloride to give compound 123 as an off-white solid (8 mg, 86%). 1 H NMR(600MHz, CD3OD+30%DMSO-d6)δ8.07(s,1H),7.64–7.58(m,2H),7.39–7.33(m, 3H),6.84(d,J=4.2Hz,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=8.8,5.9Hz,1H),3.02(dtd,J=17.1,10.5,6.7Hz,2H),2.1 9(dq,J=12.6,7.5Hz,1H),1.96(s,3H),1.93–1.84(m,1H),1.78(p,J=7.0Hz,2H). 13 C NMR(150MH z, CD3OD+30%DMSO-d6): δ173.2,172.2,170.7,165.0,146.0,141.1,140.6,139.5,131.1,130.0,1 29.5,128.0,127.8,113.8,61.5,60.0,56.3,48.0,43.5,33.6,31.7,26.8,23.1.HR-MS(ESI):[M+H + ]Calculated value 510.1628, measured value 510.1628.

[0734] Compound 125. (S)-N-(5-(3-(5-(4-(aminomethyl)phenyl)thiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)pyrrolidine-2-carboxamide

[0735]

[0736] Step 1.3- (5- bromothiazol-2-yl) azetidine -1- tert-butyl formate. The corresponding Bo c- intermediate is synthesized according to general procedure C and can be used in the next step without further purification. To a solution of tert-butyl 3- (thiazol-2-yl) azetidine -1- formate (1 g, 4.17 mmol, 1 equivalent) in 20 mL of anhydrous DMF NBS (890 mg, 5 mmol, 1.2 equivalents) was added portionwise at room temperature. The mixture was stirred at room temperature for 12 hours, poured onto ice and extracted with EtOAc (3 * 50 mL). The collected organic matter was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-60% ethyl acetate in hexane) to obtain tert-butyl 3- (5- bromothiazol-2-yl) azetidine -1- formate (665 mg, 50%) as a clear oil. 1 H NMR (600MHz, CDCl3) δ7.62 (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 (150MHz, CDCl3): δ172.3,156.3,144.1,108.6,80.1,55.5,32.4,28.5.MS(m / z)[M+H + ]:Calculated value 262,264, measured value 262,264.

[0737] Step 2. (S)-tert-Butyl 2-((5-(3-(5-bromothiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)carbamoyl)pyrrolidine-1-carboxylate. (S)-tert-Butyl 2-((5-(3-(5-bromothiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)carbamoyl)pyrrolidine-1-carboxylate (58 mg, 57%) was synthesized as an off-white solid according to General Procedure A using (S)-5-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)thiophene-2-carboxylic acid and 3-(5-bromothiazol-2-yl)azetidin-1-ium trifluoroacetate (obtained by treating a solution of tert-butyl 3-(5-bromothiazol-2-yl)azetidine-1-carboxylate in DCM with TFA (30 equiv) at 0°C, stirring at 0°C for 60 min and removing all volatiles in vacuo. The residue obtained was used for HATU-assisted coupling reaction without further purification. 1H NMR (600 MHz, CDCl3, compound 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.

[0738] 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 (S)-tert-butyl 2-((5-(3-(5-bromothiazol-2-yl)azetidine-1-carbonyl)thiophen-2-yl)carbamoyl)pyrrolidine-1-carboxylate and (4-aminomethylphenyl)borate hydrochloride. The resulting Boc-analog was further redissolved in DCM (2 mL) at 0°C and treated with TFA (0.5 mL). The mixture was stirred at 0°C for 30 minutes. After this time, all volatiles were removed under reduced pressure and the residue was triturated with 7N ammonia in methanol, concentrated and purified by silica gel column chromatography (0-100% DCM / MeOH + 0.5% ammonia (v / v)) to give the title compound (8 mg, 53%) as an off-white solid. 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 in the presence of water, provided in HSQC at 59.8, 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 (150MHz, CD3OD): δ171.5,166.7,165.3,145.4,140.3,139.9,134.7,133.1,131.0,130 .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.

[0739] Other compounds

[0740] Additional compounds were synthesized using appropriate starting materials according to similar procedures. The compound structures and HR-MS data are shown in Table 1.

[0741] Table 1. Exemplary compounds

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785] Example 2

[0786] Compound Synthesis-Dimer

[0787] 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)

[0788]

[0789] 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).

[0790]

[0791] At 0 ° C, to a suspension of NaH (60% dispersion in mineral oil, 400 mg, 0.01 mol) in anhydrous DMF (10 mL) was added dropwise a solution of 2-methyl (2S, 4R) -4-hydroxypyrrolidine -1,2- dicarboxylic acid 1- (tert-butyl) ester (2.45 g, 0.01 mol). The mixture was stirred at 0 ° C for 30 minutes, and then 1,6-diiodohexane (1.54 g, 750 μL, 4.55 mmol) was added. The temperature was slowly raised to room temperature, the reaction mixture was stirred for 16 hours, and then treated with a saturated NH4Cl aqueous solution. 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 (EtOAc gradient in hexanes from 10% to 100%) to afford the target compound, 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 value 573.3382, found value 573.3356.

[0792] Step 2. (2'S,4R,4'R)-4,4'-(Hexane-1,6-diylbis(oxy))bis(1-(tert-butyloxycarbonyl)-L-proline).

[0793]

[0794] 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%). 1 H 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). 13C 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, 6 9.9,59.5,59.1,58.9,58.7,53.5,53.2,53.2,52.7,52.7,37.5,37.5,36.8,36.8,36.8,36.7,35. 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 value 545.3069, found value 545.3075.

[0795] Step 3. 5,5'-(((2S,2'S,4R,4'R)-4,4'-(hexane-1,6-diylbis(oxy))bis(1-(tert-butyloxycarbonyl)pyrrolidine-4,2-diyl-2-carbonyl))bis(azanediyl))bis(thiophene-2-carboxylic acid)

[0796]

[0797] Synthesized according to General Procedure A from (2'S,4R,4'R)-4,4'-(hexane-1,6-diylbis(oxy))bis(1-(tert-butyloxycarbonyl)-L-proline) and methyl 5-amino-2-thiophenecarboxylate. The crude product was directly hydrolyzed (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% over 2 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). 13C 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] + The calculated m / z value was 795.2939 and the found value was 795.2948.

[0798] 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)

[0799] Synthesized 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 according to General Procedure A. The obtained residue was used in the next step without further purification. To a solution of the residue from the previous step in DCM (2 mL) was added TFA (0.5 mL) dropwise at 0°C, and the mixture was stirred at 0°C for 30 minutes. After removing all volatiles under reduced pressure, the residue was triturated with 7N 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 as a free base, which was redissolved in 1 mL of DCM and treated with 200 uL of TFA at 0° C. After stirring for 10 minutes, the mixture was concentrated under reduced pressure, the residue was redissolved in MeOH and passed through a pad of Amberlite IRA402 Cl, and the resulting solution was reconcentrated to give the title compound as a dihydrochloride salt (23 mg, 52% over 2 steps). 1H NMR (600MHz, methanol-d4) δ7.80(d,J=3.3Hz,2H),7.56(d,J=3.3Hz,2H),7.38(d,J=4.2Hz,2H), 6.84(d,J=4.2Hz,2H),4.97(s,2H),4.76-4.56(br.s.,4H),4.53(dd,J=10.4,7.4Hz,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 .4Hz,2H),2.11(ddd,J=14.2,10.4,4.3Hz,2H),1.63(t,J=6.9Hz,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 is azetidine CH2, identified by HSQC spectrum), 56.7 (azetidine CH2, identified by HSQC spectrum), 52.8, 49.8, 37.0, 33.3, 30.8, 27.1. HR-ESI-MS: C 38 H 47 N8O6S4[M+H] + The calculated m / z value was 839.2496, and the found value was 839.2498.

[0800] Other compounds

[0801] Similar procedures were used to synthesize additional dimer compounds using appropriate starting materials. The compound structures and HR-MS data are shown in Table 2.

[0802] Table 2. Exemplary compounds

[0803]

[0804]

[0805]

[0806]

[0807] Example 3

[0808] Fluorescence polarization assay

[0809] A fluorescence polarization anisotropy (FP) assay has been developed that employs a dicrotonylated histone H3-derived peptide conjugated to a fluorophore (FAM-H3K23crK27cr) that binds to H3 with submicromolar affinity (K D =0.9 μM) binds to the GAS41 YEATS domain fused to GST. A 5'6-fluorescein (FAM)-labeled dicrotonylated histone H3 peptide probe H3K23crK27cr has been synthesized for competition experiments in which 1 μM GST-GAS41 (1-148) and a competitor (e.g., a compound of the present disclosure) are incubated together 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. 25 nM FAM-H3K23crK27cr peptide is added and the plate is incubated for another hour, and then fluorescence polarization data of 525 nM is measured on a Pherastar plate reader (BMG Labtech).

[0810] The assay was validated by testing competition with H3K27ac peptides, and the IC 50 =243 μM, which is consistent with the relatively weak affinity of the monoacetylated peptide (Cho 2018). In this assay, compound 134 ((5-(tert-butyl)thiophen-2-yl)(pyrrolidin-1-yl)methanone) showed comparable activity to H3K27ac, with an IC 50 =210μM.

[0811] The IC values ​​of selected compounds of the present disclosure were determined using fluorescence polarization assays with GAS41-YEATS and FAM-H3K23crK27cr. 50 Table 3 shows the biological activities of selected compounds in Table 1 in fluorescence polarization assay (IC values ​​for GAS41YEATS inhibition). 50 The compound numbers correspond to the numbers and structures provided in Table 1.

[0812] Table 3

[0813]

[0814] Example 4

[0815] AlphaScreen assay

[0816] AlphaScreen competition assay was also developed using full-length GAS41 and biotinylated, dicrotonylated H3 peptide (biotin-H3K23crK27cr) tagged with His6. For full-length protein competition experiments, 100nM MOCR-his6-Gas41 protein was incubated with 100x competitor in 96-well 1 / 2 area AlphaPlate in 50mM HEPES pH 7.5, 100mM NaCl, 1mM TCEP, 0.05% BSA, 0.01% Tween-20 at 1% DMSO for 1 hour. Adding H3K23crK27cr-biotin to a final concentration of 25nM was incubated for 1 hour. Adding nickel chelate receptor AlphaScreen beads to a final concentration of 10 μg / mL was incubated for 1 hour. Streptavidin donor AlphaScreen beads were added to a final concentration of 10 μg / mL and incubated for 2 hours. The alpha signal was measured on a Pherastar plate reader. We found that for the compound (5-(tert-butyl)thiophen-2-yl)(pyrrolidin-1-yl)methanone (compound 134 in Table 1), the IC 50 =73 μM, for H3K27ac, IC 50 =24μM.

[0817] Table 4 shows the biological activities of selected compounds from Table 2 in the AlphaScreen assay (IC 50 The compound numbers correspond to the numbers and structures provided in Table 2.

[0818] Table 4.

[0819]

[0820] Example 5

[0821] Crystal structure

[0822] exist The crystal structure of the complex of compound 85 and GAS41YEATS was determined at a resolution of Figure 1 Compound 85 binds in the channel that constitutes the acetyl-lysine recognition site (Cho 2018) and is composed of the side chains of H43, H71, S73, Y74, W93, and F96 and the main chain of G92, G94, and E95 ( Figure 1 ).

[0823] Example 6

[0824] Dimeric compounds induce dimerization of the GAS41 YEATS domain

[0825] The AlphaScreen assay based on the GAS41YEATS domain structure of the Avi tag of the His tag and biotin tag has been developed. For dimerization experiments, 500nM his6-Gas41 (13-158) and 250nM avi-Gas41-YEATS were incubated for 30 minutes in 50mM HEPES pH 7.5, 100mM NaCl, 1mM TCEP, 0.05% BSA, 0.01% Tween-20 in a 96-well 1 / 2 area AlphaPlate. Compounds 221 and 223 were added to a final concentration of 250nM at 1% DMSO. Adding nickel chelate receptor AlphaScreen beads to a final concentration of 10 μg / mL and incubating for 1 hour. Adding streptavidin donor AlphaScreen beads to a final concentration of 10 μg / mL and incubating for 2 hours. For competition experiments with the dimeric complex, 500 nM his-Gas41 (13-158) and 250 nM avi-Gas41-YEATS were incubated for 30 minutes in assay buffer containing 250 nM dimer inhibitor before adding the monomeric competitor. AlphaScreen beads were added as in the previous experiment. Alpha signals were measured on a Pherastar plate reader.

[0826] Titration of his6-Gas41(13-158) and avi-Gas41-YEATS with compound 223 or 221 resulted in an increase in the luminescence signal reflecting the formation of the dimeric complex ( Figure 2A The signal was further reduced at the highest compound concentration, indicating that the YEATS domain was saturated by independent inhibitor molecules (Hook effect). 15 Binding of the N-labeled GAS41 YEATS domain was also compared by NMR; only the dimeric compound 223, but not the monomeric compound 85, induced a very significant signal broadening, indicating the formation of a larger dimeric complex ( Figure 2B , C).

[0827] Example 7

[0828] Inhibition of intracellular GAS41 interactions

[0829] The NanoBiT assay (Promega Corporation, Madison, WI) has been developed to detect the inhibition of protein-protein interactions in HEK293T cells by compounds. 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 plated into 6-well plates (DMEM containing 10% FBS) and incubated for 5 hours. LgBiT-GAS41 and SmBiT-H3.3 plasmids were co-transfected using FuGENE HD for 42 hours. 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. After adding Nano-Glo live cell reagent to each well, luminescence was immediately measured using a PHERAstar FS instrument.

[0830] Co-expression of the two proteins produced a strong luciferase signal, reflecting the interaction of GAS41 with acetylated H3.3 in cells. Introducing the point mutation W93A in LgBit GAS41 to eliminate histone recognition (Hsu 2018) greatly reduced the luminescence signal and validated the NanoBit assay. Subsequently, the activity of the dimeric compound 221 was tested in the NanoBit assay, and a dose-dependent inhibition of the luminescence signal was found, with an estimated IC 50 =6μM( Figure 3 Importantly, treatment with compound 221 did not reduce the signal of the W93A GAS41 mutant, further supporting the specific activity ( Figure 3 ).

[0831] Example 8

[0832] Activity in NSCLS cells

[0833] To investigate the cellular activity of GAS41 inhibitors, H1299 cells were treated with monomeric compound 88 and dimeric compound 221 for 4 days. Only dimeric compound 221 induced GI 50 Dose-dependent growth inhibition of ∼3 μM ( Figure 4A To determine whether growth inhibition depends on the presence of GAS41, we developed A549 GAS41 knockout cells using the CRISPR / CAS9 system. We found that GAS41-KO was viable but grew more slowly than parental A549 cells, with approximately 70% reduction in growth at day 14 ( Figure 4B Treatment with compound 221 at a concentration of 12 μM partially inhibited the growth of A549 cells by approximately 40%, but had no effect on GAS41-KO cells ( Figure 4B ), which validated specific growth inhibition. We then evaluated the effect of compound 221 on the growth of two NSCLC cell lines with GAS41 amplification, H1299 and H1933. Treatment with compound 221 reduced GI 50 ~6 μM growth of both cell lines ( Figure 4C This effect correlates well with the activity of compound 221 in the NanoBit assay ( Figure 3 To further validate the on-target activity of compound 221, we tested the expression of GAS41 target genes in H1299 (Hsu 2018). Treatment with compound 221 resulted in a statistically significant decrease in the expression of E2F2, FOXM1, and MCM6 ( Figure 4D In conclusion, the dimer inhibitor compound 221 reduced the binding of GAS41 to acetylated H3.3 in cells and induced on-target growth inhibition in NSCLC cell lines.

Claims

1. A compound selected from the following and a pharmaceutically acceptable salt thereof:

2. A compound selected from the following and a pharmaceutically acceptable salt thereof:

3. A pharmaceutical composition comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is formulated for oral administration.

5. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is formulated for parenteral administration.

6. Compounds or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier in the preparation of a medicament for reducing cancer cell proliferation, wherein the cancer cells are non-small cell lung cancer cells.

7. Compounds or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier in the preparation of a medicament for treating cancer, wherein the cancer is non-small cell lung cancer.

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