Compounds and their uses

Abstract

The present disclosure features compounds useful for treating BAF complex-associated disorders.

Description

[Background technology]

[0001] The present invention relates to compounds useful for modulating BRG1 or BRM-associated factor (BAF) complexes. In particular, the present invention relates to compounds useful for treating disorders associated with BAF complex function.

[0002] Chromatin regulation is essential for gene expression, and ATP-dependent chromatin remodeling is the mechanism by which such gene expression occurs. The human switch / sucrose non-fermenting (SWI / SNF) chromatin remodeling complex, also known as the BAF complex, has two SWI2-like ATPases known as BRG1 (Brahma-related gene-1) and BRM (Brahma). The transcriptional activator BRG1, also known as the ATP-dependent chromatin remodeler SMARCA4, is encoded by the SMARCA4 gene on chromosome 19. BRG1 is overexpressed in some cancer tumors and is required for cancer cell proliferation. BRM, also known as the likely global transcriptional activator SNF2L2 and / or the ATP-dependent chromatin remodeler SMARCA2, is encoded by the SMARCA2 gene on chromosome 9, and has been shown to be essential for tumor cell proliferation in cells characterized by loss-of-function mutations in BRG1. Deactivation of BRG and / or BRM leads to downstream effects in cells, including cell cycle arrest and tumor suppression. Summary of the Invention

[0003] The present invention features compounds useful for modulating the BAF complex. In some embodiments, the compounds are useful for treating disorders associated with alterations in the BAF complex, such as disorders associated with alterations in one or both of the BRG1 and BRM proteins. The compounds of the present invention can be used alone or in combination with other pharmacologic active agents to treat such disorders.

[0004] In one aspect, the present invention provides a compound having the structure: [ka] During the ceremony, m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; X 1 is -S-, -SO-, -SO2-, or -S(O)(NH)-, X 2 But N or CR 8 and R 1 is hydrogen or optionally substituted C1-C6 alkyl; Each R 2 and each R 3 is independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; L 1 is an optionally substituted 9- or 10-membered bicyclic heterocyclyl or an optionally substituted 9- or 10-membered bicyclic heteroaryl; L 2 but absent or optionally replaced C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted 5-14 membered heteroaryl, or optionally substituted 4-14 membered heterocyclyl; R 4 is hydrogen, halo, optionally substituted C1-C6 alkyl, or optionally substituted C3-C 10 is cycloalkyl, R 5 is optionally substituted C-C alkyl, optionally substituted C-C heteroalkyl, or optionally substituted amino; R 6 is hydrogen, halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C3-C 10 cycloalkyl or R 5 and R 6 taken together with the atoms to which they are attached to form an optionally substituted 5- to 8-membered heterocyclyl; Each R 7 are independently selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, halo, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkyl C1-C6 alkyl, optionally substituted 5-14 membered heteroaryl, optionally substituted 4-14 membered heterocyclyl, -N(R 7A ) 2 or OR 7A And each R 7A are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclyl, or two geminal R 7A Groups, together with the atom to which they are attached, combine to form an optionally substituted 5- to 10-membered heteroaryl or an optionally substituted 4- to 10-membered heterocyclyl, or two geminal R 7 The groups combine with the atoms to which they are attached to form a carbonyl, R 8 is hydrogen, halo, optionally substituted C1-C6 alkyl, or optionally substituted C3-C 10 is cycloalkyl, R 9 is hydrogen or halo, or a pharma- ceutically acceptable salt thereof.

[0005] In some embodiments, the variables for the compound of formula I are as follows: m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; X 1 is -S-, -SO-, -SO2-, or -S(O)(NH)-, X 2But N or CR 8 and R 1 is hydrogen or optionally substituted C1-C6 alkyl; Each R 2 and each R 3 is independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; L 1 is an optionally substituted 9- or 10-membered bicyclic heterocyclyl or an optionally substituted 9- or 10-membered bicyclic heteroaryl; L 2 but absent or optionally replaced C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 4-10 membered heterocyclyl; R 4 is hydrogen, halo, optionally substituted C1-C6 alkyl, or optionally substituted C3-C 10 is cycloalkyl, R 5 is optionally substituted C-C alkyl, optionally substituted C-C heteroalkyl, or optionally substituted amino; R 6 is hydrogen, halo, cyano, optionally substituted C1-C6 alkyl, or optionally substituted C3-C 10 cycloalkyl or R 5 and R 6 taken together with the atoms to which they are attached to form an optionally substituted 5- to 8-membered heterocyclyl; Each R 7 are independently selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, halo, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, -N(R 7A )2, or -OR 7A And each R7A are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclyl, or two geminal R 7A groups, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 10-membered heteroaryl or an optionally substituted 4- to 10-membered heterocyclyl; R 8 is hydrogen, halo, optionally substituted C1-C6 alkyl, or optionally substituted C3-C 10 is cycloalkyl, R 9 is hydrogen, or a pharma- ceutically acceptable salt thereof.

[0006] In some embodiments, L 2 is absent or optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 4-10 membered heterocyclyl.

[0007] In some embodiments, each R 7 are independently selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, halo, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, -N(R 7A )2, or -OR 7A And each R 7A are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C10 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclyl, or two geminal R 7A The groups combine together with the atoms to which they are attached to form an optionally substituted 5- to 10-membered heteroaryl or an optionally substituted 4- to 10-membered heterocyclyl.

[0008] In some embodiments, R 5 and R 6 and the atoms to which they are attached combine together to form an optionally substituted 5-8 membered heterocyclyl. 5 and R 6 are combined together with the atoms to which they are attached to form an optionally substituted 7-membered heterocyclyl.

[0009] In some embodiments, R 5 is an optionally substituted C-C alkyl. In some embodiments, R 5 is an optionally substituted amino. In some embodiments, R 6 is an optionally substituted C-C alkyl. In some embodiments, R 6 is a halo.

[0010] In some embodiments, X 1 is SO2. In some embodiments, X 2 CR 8 It is.

[0011] In some embodiments, [ka] is a radical of the structure [ka] During the ceremony, Z is CH2, CO, or C(R X2 )2, Each R X1 is independently an optionally substituted C-C alkyl or halo, or two geminal R X1 The groups combine with the atoms to which they are attached to form a carbonyl, Each R X2 is independently H or optionally substituted C1-C6 alkyl; p is 0, 1, 2, 3, or 4.

[0012] In some embodiments, [ka] is a radical of the structure [ka] During the ceremony, Z is CH2, CO, or C(R X2 )2, Each R X1 is independently an optionally substituted C-C alkyl or halo, or two geminal R X1 The groups combine with the atoms to which they are attached to form a carbonyl, Each R X2 is independently H or optionally substituted C1-C6 alkyl; p is 0, 1, 2, 3, or 4.

[0013] In some embodiments, [ka] is a radical of the structure [ka] During the ceremony, Z is CH2, CO, or C(R X2 )2, Each R X1is independently an optionally substituted C-C alkyl or halo, or two geminal R X1 The groups combine with the atoms to which they are attached to form a carbonyl, Each R X2 is independently hydrogen or optionally substituted C1-C6 alkyl; p is 0, 1, 2, 3, or 4; q is 0 or 1.

[0014] In some embodiments, [ka] is a radical of the structure [ka] During the ceremony, Z is CH2, CO, or C(R X2 )2, Each R X1 is independently an optionally substituted C-C alkyl or halo, or two geminal R X1 The groups combine with the atoms to which they are attached to form a carbonyl, Each R X2 is independently hydrogen or optionally substituted C1-C6 alkyl; p is 0, 1, 2, 3, or 4.

[0015] In some embodiments, [ka] is a radical of the structure [ka] During the ceremony, [ka] is a single bond or a double bond, Each R X1is independently an optionally substituted C-C alkyl or halo, or two geminal R X1 The groups combine with the atoms to which they are attached to form a carbonyl, R X2 is hydrogen or optionally substituted C1-C6 alkyl; p is 0, 1, 2, 3, or 4.

[0016] In some embodiments, [ka] is a radical of the structure [ka] During the ceremony, Each R X1 is independently an optionally substituted C-C alkyl or halo, or two geminal R X1 The groups combine with the atoms to which they are attached to form a carbonyl, R X2 is hydrogen or optionally substituted C1-C6 alkyl; p is 0, 1, 2, 3, or 4.

[0017] In some embodiments, R 8 is hydrogen.

[0018] In some embodiments, R 8 is a halo.

[0019] In some embodiments, R 8 is an optionally substituted C3-C8 cycloalkyl.

[0020] In some embodiments, X 2 is N.

[0021] In some embodiments, [ka] is a radical of the structure [ka] During the ceremony, Z is CH2, CO, or C(R X2 )2, Each R X1 is independently an optionally substituted C-C alkyl or halo, or two geminal R X1 The groups combine with the atoms to which they are attached to form a carbonyl, Each R X2 is independently hydrogen or optionally substituted C1-C6 alkyl; p is 0, 1, 2, 3, or 4.

[0022] In some embodiments, [ka] is a radical of the structure [ka] During the ceremony, Each R X1 is independently an optionally substituted C-C alkyl or halo, or two geminal R X1 The groups, together with the atoms to which they are attached, combine to form a carbonyl or a C3-C8 cycloalkyl ring, or two adjacent R X1 the groups, taken together with the atoms to which they are attached, form a C3-C8 cycloalkyl ring; p is 0, 1, 2, 3, or 4; q is 0, 1, or 2.

[0023] In some embodiments, [ka] is a radical of the structure [ka] During the ceremony, Each R X1 is independently an optionally substituted C-C alkyl or halo, or two geminal R X1 The groups combine with the atoms to which they are attached to form a carbonyl, p is 0, 1, 2, 3, or 4.

[0024] In some embodiments, at least one R X1 is optionally substituted C1-C6 alkyl.

[0025] In some embodiments, -L 2 -(R 7 ) n is a radical of the structure

[0026] In some embodiments, at least one R X1 is a halo.

[0027] In some embodiments, at least two geminal R X1 The groups combine with the atom to which they are attached to form a carbonyl.

[0028] In some embodiments, L 1 is an optionally substituted 9 or 10 membered bicyclic heteroaryl.

[0029] In some embodiments, L 1 is [ka] During the ceremony, X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 each independently represents N or CR L1and Each R L1 is independently H, halo, or optionally substituted C1-C6 alkyl; A 1 But -(C(R 2 )(R 3 )) m - is a bond to A 2 But, L 2 is a bond to.

[0030] In some embodiments, L 1 is as follows: [ka]

[0031] In some embodiments, L 1 is as follows: [ka]

[0032] In some embodiments, L 1 is as follows: [ka]

[0033] In some embodiments, L 1 is as follows: [ka]

[0034] In some embodiments, L 1 is as follows: [ka]

[0035] In some embodiments, L 1 is [ka] During the ceremony, A 1 But -(C(R 2 )(R 3 )) m - is a bond to A 2 But, L 2 is a bond to.

[0036] In some embodiments, L 2 is an optionally substituted 5-10 membered heteroaryl.

[0037] In some embodiments, -L 2 -(R 7 ) n is a radical of the following structure: [ka] [ka]

[0038] In some embodiments, -L 2 -(R 7 ) n is a radical of the following structure: [ka] [ka]

[0039] In some embodiments, -L 2 -(R 7 ) n is a radical of the following structure: [ka]

[0040] In some embodiments, -L 2 -(R7 ) n is a radical of the following structure: [ka]

[0041] In some embodiments, -L 2 -(R 7 ) n is a radical of the following structure: [ka]

[0042] In some embodiments, -L 2 -(R 7 ) n is a radical of the following structure: [ka] In some embodiments, -L 2 -(R 7 ) n is a radical of the following structure: [ka] In some embodiments, -L 2 -(R 7 ) n is a radical of the following structure: [ka]

[0043] In some embodiments, -L 2 -(R 7 ) n is a radical of the following structure: [ka]

[0044] In some embodiments, -L 2 -(R 7 )n is a radical of the following structure: [ka]

[0045] In some embodiments, L 2 is an optionally substituted C6-C 10 It is aryl.

[0046] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0047] In some embodiments, R 7 is an optionally substituted C-C alkyl. In some embodiments, R 7 is an optionally substituted C-C heteroalkyl. In some embodiments, R 7 is an optionally substituted 4-10 membered heterocyclyl. In some embodiments, R 7 is an optionally substituted azetidinyl or an optionally substituted morpholinyl. In some embodiments, R 7 is an optionally substituted C3-C 10 In some embodiments, R 7 is optionally substituted cyclopropyl or optionally substituted cyclobutyl. In some embodiments, R 7 is -N(R 7A In some embodiments, R 7 is an optionally substituted N-azetidinyl or an optionally substituted N-morpholinyl. In some embodiments, two geminal R 7 The groups combine together with the atoms to which they are attached to form an optionally substituted 4-10 membered heterocyclyl. In some embodiments, at least one R 7 -OR 7A In some embodiments, R 7A is optionally replaced by C1-6 It is an alkyl.

[0048] In some embodiments, n is 0.

[0049] In some embodiments, at least one R 7are cyclopropyl, 2,2-difluorocyclopropyl, difluoromethoxy, 2,6-dimethylmorpholin-4-yl, N-azetidinyl, 3-fluorocyclobutyl, 2-methoxyethyl, ethoxy, methoxy, 2,2-difluoroethoxy, 2,2-difluoroethyl, trifluoromethyl, isopropyl, methyl, acetyl, fluoro, chloro, 1-methylpyrazol-3-yl, dimethylamino, N-methyl-N-(2-methoxyethyl)-amino, N-ethyl-N-(2-methoxyethyl)-amino, N-(2-propyl)-N-(2-methoxyethyl)-amino, 2-methoxyethylamino, 3-aza-8-oxa-bicyclo[4.3. 0]non-3-yl, 3-aza-7-oxa-bicyclo[4.3.0]non-3-yl, 1-fluorocyclobut-1-yl, 3-fluoropyrrolidin-1-yl, 3-methoxypyrrolidin-1-yl, oxetan-3-yl, N-methylindolin-4-yl, 2,2-difluoro-3-methylcycloprop-1-yl, 3-methoxyazetidin-1-yl, 3-methoxypiperidin-1-yl, 1,2-dimethyl-7-azaindol-4-yl, 1-methyl-7-azaindol-4-yl, 2,3-methylenedioxyphenyl, N-methyl-N-(3-oxetanyl)amino, 3-oxetanyloxy, 1,1-difluoro-5-azaspiro[2.3]Hex-5-yl, 1-fluoromethyl-cyclopropyl, N-(3-tetrahydrofuranyl)methylamino, N-indolinyl, N-1,4-oxazepanyl, 2-fluoro-2-propyl, 1,1-difluoro-2-propyl, 2,2-difluoro-1-methylcycloprop-1-yl, 1-methylcyclopropyl, 4,4-difluoropiperidin-1-yl, 2-methoxyethoxy, 3,3-difluorocyclobut-1-yl, N-methyl-N-1-methoxyprop-2-ylamino, 1-methoxyprop-2-ylamino, 1-methoxyethyl, 4-methylpiperazinyl, 3-methylmorpholinyl, 2,2-difluoropropoxy, 3- Methoxycyclobutyl, methylamino, 4-dimethylamino-3,3-difluoropiperidinyl, 4-methylamino-3,3-difluoropiperidinyl, 3,3-difluoropyrrololidinyl, N-methyl-N-3-methoxycyclobutylamino, 1-methylpyrazol-5-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl, cyclopropyloxy, 2,6-dimethylpyrid-4-yl, 2-methylpyrrololidinyl, 4-oxabicyclo[4.1.0]hept-1-yl, N-methyl-N-(2,6-dimethyltetrahydropyran-4-yl)amino, or N-methyl-N-3-methyloxetan-3-ylmethylamino.

[0050] In some embodiments, R 1 is hydrogen.

[0051] In another aspect, the present invention provides a compound selected from the group consisting of compounds 1-308 in Table 1A, and pharma- ceutically acceptable salts thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

[0052] In another aspect, the present invention provides a compound selected from the group consisting of compounds 309-856 in Table 1B, and pharma- ceutically acceptable salts thereof. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10]

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

Table 2-35

Table 2-36

Table 2-37

Table 2-38

Table 2-39

Table 2-40

Table 2-41

Table 2-42

Table 2-43

Table 2-44

Table 2-45

Table 2-46

Table 2-47

Table 2-48

Table 2-49

Table 2-50

Table 2-51

Table 2-52

Table 2-53

Table 2-54

Table 2-55

Table 2-56

Table 2-57

Table 2-58

Table 2-59

Table 2-60

Table 2-61

Table 2-62

Table 2-63

Table 2-64

Table 2-65

Table 2-66

Table 2-67

Table 2-68

Table 2-69

Table 2-70

Table 2-71

Table 2-72

Table 2-73

Table 2-74

Table 2-75

Table 2-76

Table 2-77

Table 2-78

[0053] In some embodiments, the compound is 50 and BRM IC 50 In some embodiments, the compound has a ratio of BRG1 IC 50 and BRM IC 50 In some embodiments, the compound has a ratio of BRG1 IC 50 and BRM IC 50 In some embodiments, the compound has a ratio of BRG1 IC 50 and BRM IC 50 In some embodiments, the compound has a ratio of BRG1 IC 50 and BRM IC 50 In some embodiments, the compound has a ratio of BRG1 IC 50 and BRM IC 50 In some embodiments, the compound has a ratio of BRG1 IC 50 and BRM IC 50 The ratio of

[0054] In another aspect, the invention features a pharmaceutical composition including any one of the above compounds and a pharma- ceutically acceptable excipient.

[0055] In another aspect, the invention features a method for decreasing activity of a BAF complex in a cell, comprising contacting the cell with an effective amount of any of the aforementioned compounds, or a pharmaceutical composition thereof.

[0056] In some embodiments, the cell is a cancer cell.

[0057] In another aspect, the invention features a method of treating a BAF complex-associated disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the aforementioned compounds, or a pharmaceutical composition thereof.

[0058] In some embodiments, the BAF complex-associated disorder is cancer.

[0059] In a further aspect, the invention features a method of inhibiting a BRM, the method including contacting a cell with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof, in some embodiments, the cell is a cancer cell.

[0060] In another aspect, the invention features a method of inhibiting BRG1, the method including contacting a cell with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell.

[0061] In a further aspect, the invention features a method of inhibiting BRM and BRG1, the method including contacting a cell with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof, in some embodiments, the cell is a cancer cell.

[0062] In another aspect, the invention features a method of treating a disorder associated with a loss-of-function mutation in BRG1 in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the aforementioned compounds, or a pharmaceutical composition thereof.

[0063] In some embodiments, the disorder associated with BRG1 loss-of-function mutation is cancer.In other embodiments, the subject is determined to have a BRG1 loss-of-function disorder, for example, is determined to have a BRG1 loss-of-function cancer (for example, the cancer is determined to comprise cancer cells with BRG1 loss-of-function).

[0064] In another aspect, the invention features a method of inducing apoptosis in a cell, comprising contacting the cell with an effective amount of any of the preceding compounds, or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell.

[0065] In a further aspect, the invention features a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the aforementioned compounds, or a pharmaceutical composition thereof.

[0066] In some embodiments of any of the aforementioned methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary site, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, CNS cancer, thymic tumor, adrenal cortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

[0067] In some embodiments of any of the aforementioned methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

[0068] In some embodiments of any of the foregoing methods, the cancer is a drug resistant cancer or has not responded to previous therapies (e.g., vemurafenib, dacarbazine, CTLA4 inhibitors, PD1 inhibitors, interferon therapy, BRAF inhibitors, MEK inhibitors, radiation therapy, temozolimide, irinotecan, CAR-T therapy, Herceptin, Perjeta, tamoxifen, Xeloda, docetaxol, platinum agents such as carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inhibitors, Alimta, Abraxane, Adriamycin®, gemcitabine, Avastin, Halaven, neratinib, PARP inhibitors, ARN810, mTOR inhibitors, topotecan, gemzar, VEGFR2 inhibitors, folate receptor antagonists, demcizumab, fosbretabulin, or PDL1 inhibitors).

[0069] In some embodiments of any of the aforementioned methods, the cancer has or has been determined to have a BRG1 mutation. In some embodiments of any of the aforementioned methods, the BRG1 mutation is homozygous. In some embodiments of any of the aforementioned methods, the cancer does not have or has been determined to have an epidermal growth factor receptor (EGFR) mutation. In some embodiments of any of the aforementioned methods, the cancer does not have or has been determined to have an anaplastic lymphoma kinase (ALK) driver mutation. In some embodiments of any of the aforementioned methods, the cancer has or has been determined to have a KRAS mutation. In some embodiments of any of the aforementioned methods, the BRG1 mutation is in the ATPase catalytic domain of the protein. In some embodiments of any of the aforementioned methods, the BRG1 mutation is a deletion at the C-terminus of BRG1.

[0070] In another aspect, the present disclosure provides a method of treating a disorder associated with BAF (e.g., cancer or viral infection) in a subject in need thereof, comprising contacting a cell with an effective amount of any of the aforementioned compounds or a pharma- ceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, the disorder is a retrovirus from the family Retroviridae, such as lentivirus (e.g., human immunodeficiency virus (HIV) and delta retrovirus (e.g., human T-cell leukemia virus type I (HTLV-I)), human T-cell leukemia virus type II (HTLV-II)), Hepadnaviridae (e.g., hepatitis B virus (HBV)), Flaviviridae (e.g., hepatitis C virus (HCV)), Adenoviridae (e.g., human adenovirus), Herpesviridae (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), human herpes virus type 6 (HHV-6), herpes virus K*, CMV, varicella zoster virus), Papillomaviridae (e.g., human papillomavirus (HPV, E1), Parvoviridae family (e.g., parvovirus B19), Polyomaviridae family (e.g., JC virus and BK virus), Paramyxoviridae family (e.g., measles virus), Togaviridae family (e.g., rubella virus). In some embodiments, the disorder is coffin schisis, neurofibromatosis (e.g., NF-1, NF-2, or schwannoma), or multiple meningiomas.

[0071] In another aspect, the disclosure provides a method for treating a viral infection in a subject in need thereof, comprising administering to the subject an effective amount of any of the aforementioned compounds, or a pharma- ceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, the viral infection is a viral infection, such as a retroviridae family, such as lentivirus (e.g., human immunodeficiency virus (HIV) and delta retrovirus (e.g., human T-cell leukemia virus type I (HTLV-I)), human T-cell leukemia virus type II (HTLV-II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., human adenovirus), Herpesviridae family (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), human herpes virus type 6 (HHV-6), herpes virus K*, CMV, varicella zoster virus), Papillomaviridae family (e.g., human papillomavirus (HPV), HPV E1), Parvoviridae (e.g. parvovirus B19), Polyomaviridae (e.g. JC virus and BK virus), Paramyxoviridae (e.g. measles virus), or Togaviridae (e.g. rubella virus).

[0072] In another aspect, the invention features a method of treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the aforementioned compounds, or a pharmaceutical composition thereof.

[0073] In another aspect, the invention features a method of reducing melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer tumor growth in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0074] In another aspect, the invention features a method of inhibiting metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject, comprising administering an effective amount of any of the preceding compounds or a pharmaceutical composition thereof.

[0075] In another aspect, the invention features a method of inhibiting metastatic colonization of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject, the method comprising administering an effective amount of any of the preceding compounds or a pharmaceutical composition thereof.

[0076] In another aspect, the invention features a method for reducing the level and / or activity of BRG1 and / or BRM in melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, blood cancer cells, or esophageal cancer cells, comprising contacting the cells with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0077] In some embodiments of any of the above aspects, the melanoma, prostate cancer, breast cancer, bone cancer, renal cell cancer, or blood cells are in the subject.

[0078] In some embodiments of any of the above aspects, an effective amount of a compound reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of a compound reduces the level and / or activity of BRG1 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of a compound reduces the level and / or activity of BRG1 by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0079] In some embodiments, an effective amount of a compound reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 ​​hours, 72 hours, or more) compared to a reference substance. In some embodiments, an effective amount of a compound that reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more) compared to a reference substance.

[0080] In some embodiments of any of the above aspects, an effective amount of a compound reduces the level and / or activity of a BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of a compound reduces the level and / or activity of a BRM by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference substance. In some embodiments, an effective amount of a compound reduces the level and / or activity of a BRM by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0081] In some embodiments, an effective amount of a compound reduces the level and / or activity of a BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 ​​hours, 72 hours, or more) compared to a reference substance. In some embodiments, an effective amount of a compound that reduces the level and / or activity of a BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more) compared to a reference substance.

[0082] In some embodiments, the subject has cancer. In some embodiments, the cancer expresses BRG1 and / or BRM protein and / or the cell or subject has been identified as expressing BRG1 and / or BRM. In some embodiments, the cancer expresses BRG1 protein and / or the cell or subject has been identified as expressing BRG1. In some embodiments, the cancer expresses BRM protein and / or the cell or subject has been identified as expressing BRM. In some embodiments, the cancer is melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a hematological cancer, e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia (e.g., T-cell acute lymphoblastic leukemia or B-cell acute lymphoblastic leukemia), diffuse large cell lymphoma, or non-Hodgkin's lymphoma. In some embodiments, the cancer is breast cancer (e.g., ER-positive breast cancer, ER-negative breast cancer, triple-positive breast cancer, or triple-negative breast cancer). In some embodiments, the cancer is bone cancer (e.g., Ewing's sarcoma). In some embodiments, the cancer is renal cell carcinoma (e.g., microphthalmia transcription factor (MITF) family translocation renal cell carcinoma (tRCC)). In some embodiments, the cancer is metastatic (e.g., the cancer has spread to the liver). The metastatic cancer may include cells that exhibit migratory cell migration and / or invasion, and / or may include cells that exhibit endothelial recruitment and / or angiogenesis. In other embodiments, the migratory cancer is a cell migration cancer. In yet other embodiments, the cell migration cancer is a non-metastatic cell migration cancer. The metastatic cancer may be a cancer that spreads via seeding the surfaces of the peritoneum, pleura, pericardium, or subarachnoid space. Alternatively, the metastatic cancer may be a cancer that spreads via the lymphatic system, or a cancer that spreads hematogenously. In some embodiments, the effective amount of the compound of the present invention is an amount that is effective to inhibit metastatic colonization of cancer to the liver.

[0083] In some embodiments, the cancer harbors a mutation in GNAQ. In some embodiments, the cancer harbors a mutation in GNA11. In some embodiments, the cancer harbors a mutation in PLCB4. In some embodiments, the cancer harbors a mutation in CYSLTR2. In some embodiments, the cancer harbors a mutation in BAP1. In some embodiments, the cancer harbors a mutation in SF3B1. In some embodiments, the cancer harbors a mutation in EIF1AX. In some embodiments, the cancer harbors a TFE3 translocation. In some embodiments, the cancer harbors a TFEB translocation. In some embodiments, the cancer harbors a MITF translocation. In some embodiments, the cancer harbors an EZH2 mutation. In some embodiments, the cancer harbors a SUZ12 mutation. In some embodiments, the cancer harbors an EED mutation.

[0084] In some embodiments of any of the foregoing methods, the method further comprises administering to the subject an anti-cancer therapy or contacting the cell with an anti-cancer therapy, such as a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiation therapy, hyperthermia, or photocoagulation, or a combination thereof. In some embodiments, the anti-cancer therapy is a chemotherapeutic or cytotoxic agent, such as an antimetabolite, an antimitotic agent, an anti-tumor agent, an antibiotic, an asparagine-specific enzyme, a bisphosphonate, an anti-neoplastic agent, an alkylating agent, a DNA repair enzyme inhibitor, a histone deacetylase inhibitor, a corticosteroid, a demethylating agent, an immunomodulatory agent, a Janus-related kinase inhibitor, a phosphinositide 3-kinase inhibitor, a proteasome inhibitor, or a tyrosine kinase inhibitor, or a combination thereof.

[0085] In some embodiments of any of the foregoing methods, the compound of the present invention is used in combination with another anti-cancer therapy used to treat uveal melanoma, such as surgery, a MEK inhibitor, and / or a PKC inhibitor. For example, in some embodiments, the method further comprises performing surgery before, after, or simultaneously with administration of the compound of the present invention. In some embodiments, the method further comprises administering a MEK inhibitor and / or a PKC inhibitor before, after, or simultaneously with administration of the compound of the present invention.

[0086] In some embodiments, the anti-cancer therapy and the compound of the invention are administered within 28 days of each other, and each in an amount together effective to treat the subject.

[0087] In some embodiments, the subject or cancer has and / or has been identified as having a loss-of-function mutation in BRG1.

[0088] In some embodiments, the cancer is resistant to one or more chemotherapeutic or cytotoxic agents (e.g., the cancer has been determined to be resistant to a chemotherapeutic or cytotoxic agent (such as by genetic markers) or has been determined to be likely to be resistant to a chemotherapeutic or cytotoxic agent (such as a cancer that has failed to respond to a chemotherapeutic or cytotoxic agent)). In some embodiments, the cancer has failed to respond to one or more chemotherapeutic or cytotoxic agents. In some embodiments, the cancer is resistant to or has failed to respond to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, CTLA-4 inhibitors (e.g., ipilimumab), PD-1 inhibitors (e.g., nivolumab or pembrolizumab), PD-L1 inhibitors (e.g., atezolizumab, avelumab, or durvalumab), mitogen-activated protein kinase (MEK) inhibitors (e.g., selumetinib, binimetinib, or trametinib), and / or protein kinase C (PKC) inhibitors (e.g., sotrastaurin or IDE196).

[0089] In some embodiments, the cancer is resistant or has not responded to previously administered therapeutic agents used to treat uveal melanoma, such as MEK inhibitors or PKC inhibitors. For example, in some embodiments, the cancer is resistant or has not responded to mitogen-activated protein kinase (MEK) inhibitors (e.g., selumetinib, binimetinib, or tametinib) and / or protein kinase C (PKC) inhibitors (e.g., sotrastaurin or IDE196).

[0090] chemical terms The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0091] For any of the following chemical definitions, the number following the atomic symbol indicates the total number of atoms of that element present in a particular chemical moiety. As will be understood, other atoms such as H atoms or substituents as described herein may be present to satisfy the valence of the atom, if necessary. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used with groups defined herein, references to the number of carbon atoms include the divalent carbons in acetal and ketal groups, but do not include the carbonyl carbons in acyl, ester, carbonate, or carbamate groups. References to the number of oxygen, nitrogen, or sulfur atoms in heteroaryl groups include only those atoms that form part of the heterocyclic ring.

[0092] The term "acyl," as used herein, refers to an H or alkyl group, as defined herein, attached to the parent molecular group through a carbonyl group, and is exemplified by formyl (i.e., carboxaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups contain 1-6, 1-11, or 1-21 carbons.

[0093] As used herein, the term "alkenyl" refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, or 2 to 6 carbon atoms). Alkenyl can be, for example, monovalent or polyvalent. One of skill in the art will recognize the applicable number of valencies from the context.

[0094] As used herein, the term "alkyl" refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 3 carbon atoms). An alkyl can be, for example, monovalent or polyvalent. One of ordinary skill in the art will recognize the applicable number of valencies from the context.

[0095] As used herein, the term “amino” refers to —N(R N1 )2, and each R N1 are independently H, OH, NO2, N(R N2 )2, SO2OR N2 , SO2R N2 , SOR N2 , an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), heteroaryl, or heterocyclyl, and these enumerated R N1 Each of the groups may be optionally substituted or may have two R N1 together with the atom to which they are attached form a heterocyclyl or heteroaryl, and each R N2 is independently H, alkyl, or aryl. The amino group of the present invention can be an unsubstituted amino (i.e., -NH) or a substituted amino (i.e., -N(R N1 )2).

[0096] As used herein, the term "aryl" refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl. Aryl can be, for example, monovalent or polyvalent. One of ordinary skill in the art will recognize the number of valencies applicable from the context.

[0097] As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are 7-30 carbon (e.g., C1-C6 alkyl, C6 ... 10 Aryl, C1-C 10 Alkyl C6-C 10 Aryl or C1-C 20 Alkyl C6-C 10 aryl, 7-16 or 7-20 carbons. In some embodiments, alkyl and aryl can each be further substituted with 1, 2, 3, or 4 substituents as defined herein for each group.

[0098] As used herein, the term "azido" refers to a -N3 group.

[0099] As used herein, the term "bridged cyclyl" refers to a bridged polycyclic group of 5 to 20 carbons containing 1 to 3 bridges.

[0100] As used herein, the term "cyano" refers to a -CN group.

[0101] As used herein, the term "carbocyclyl" refers to a non-aromatic C-C ring formed by carbon atoms. 12 It refers to a monocyclic, bicyclic or tricyclic structure. The carbocyclyl structure includes a cycloalkyl group and an unsaturated carbocyclyl radical.

[0102] As used herein, the term "cycloalkyl" refers to a saturated non-aromatic mono- or polycarbocyclic radical of 3 to 10, preferably 3 to 6, carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. Cycloalkyls can be, for example, monovalent or polyvalent. One of skill in the art will recognize the applicable number of valencies from the context.

[0103] As used herein, the term "halo" means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0104] As used herein, the term "heteroalkyl" refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms are replaced with nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with one, two, three, or four substituents, as described herein for alkyl groups. An example of a heteroalkyl group is "alkoxy," which, as used herein, refers to alkyl-O- (e.g., methoxy and ethoxy). Heteroalkyl can be, for example, monovalent or polyvalent. One of ordinary skill in the art will recognize the number of valencies that are applicable from the context.

[0105] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic radical of 5-14 (e.g., 5-12 or 5-10) atoms having at least one aromatic ring and containing 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. In some embodiments, the heteroaryl is a C1-C9 heteroaryl (e.g., C2-C9 heteroaryl). One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl, thiazolyl, benzomorpholinyl, benzopiperidinyl, and indolinyl. The heteroaryl may be, for example, monovalent or polyvalent. One of ordinary skill in the art will recognize the number of valencies applicable from the context.

[0106] As used herein, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups include those having 7 to 30 carbons (e.g., C2-C9 heteroaryl C1-C6 alkyl, C2-C9 heteroaryl C1-C 10 Alkyl, or C2-C9 heteroaryl C1-C 20 In some embodiments, the alkyl and heteroaryl may each be further substituted with 1, 2, 3, or 4 substituents as defined herein for each group.

[0107] As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic radical having 3-14 (e.g., 4-12) atoms with at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S, and the ring is not aromatic. In some embodiments, the heterocyclyl is a C2-C9 heterocyclyl. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxanyl, aza-oxybicyclo[4.3.0]nonyl, and aza-oxybicyclo[4.4.0]decyl. A heterocyclyl may be, for example, monovalent or polyvalent. One of ordinary skill in the art will recognize the number of valencies applicable from the context.

[0108] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups include those having 7 to 30 carbons (e.g., C2-C9 heterocyclylC1-C6 alkyl, C2-C9 heterocyclylC1-C 10 Alkyl, or C2-C9 heterocyclyl C1-C 20 In some embodiments, the alkyl and heterocyclyl may each be further substituted with 1, 2, 3, or 4 substituents as defined herein for each group.

[0109] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with an --OH group.

[0110] As used herein, the term "hydroxyl" refers to an --OH group.

[0111] As used herein, the term "N-protecting group" refers to a group intended to protect an amino group against undesired reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 3rd Edition (John Wiley & Sons, New York, 1999).N-protecting groups include, but are not limited to, acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D,L, or D,L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl; benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-20 dimethoxybenzyl Oxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl 3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl Carbamate-forming groups such as aryl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups such as trimethylsilyl. Preferred N-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0112] As used herein, the term "nitro" refers to a -NO2 group.

[0113] As used herein, the term "thiol" refers to a --SH group.

[0114] Alkyl, heteroalkyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. If substituted, there will typically be 1-4 substituents present unless otherwise specified. Substituents include, for example, alkyl (e.g., unsubstituted and substituted, where the substituents are any of the groups described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkylamino), azido, cyano, nitro, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted, e.g., arylalkyl (e.g., substituted and unsubstituted benzyl)).

[0115] The compounds of the present invention may have one or more asymmetric carbon atoms and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, or mixtures of diastereomeric racemates. Optically active forms can be obtained, for example, by resolution of racemates, by asymmetric synthesis or asymmetric chromatography (chromatography using chiral adsorbents or eluents). That is, certain disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain asymmetrically substituted carbon atoms that function as chiral centers. Enantiomers refer to one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound may be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. Suitable techniques and / or methods for separating enantiomers of the compounds described herein from racemic mixtures can be readily determined by one of ordinary skill in the art. "Racemate" or "racemic mixture" refers to a compound containing two enantiomers, and such mixtures do not exhibit optical activity, i.e., they do not rotate the plane of polarized light. "Geometric isomer" refers to isomers that differ in the orientation of substituted atoms in relationship to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in the E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. "R", "S", "S*", "R*", "E", "Z", "cis", and "trans" refer to configurations relative to the core molecule. Certain disclosed compounds may exist in atropisomeric forms.Atropisomers are stereoisomers resulting from hindered rotation around a single bond, where the steric strain barrier to rotation is high enough to allow the isolation of the conformers. The compounds of the present invention can be prepared as individual isomers by isomer-specific synthesis or by resolution from an isomeric mixture. Traditional resolution techniques include forming a salt of the free base of each isomer of the isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming a salt of the acid form of each isomer of the isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each isomer of the isomeric pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving the isomeric mixture of either the starting material or the final product using a variety of well-known chromatographic methods. When the stereochemistry of a disclosed compound is named or shown by structure, the named or shown stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers. When a single enantiomer is named or shown by structure, the shown or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure. When a single diastereomer is named or shown by structure, the shown or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure. Percent optical purity is the weight of the enantiomer, or the ratio of the weight of the enantiomer to the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer to the weight of all diastereomers. When the stereochemistry of a disclosed compound is named or shown by structure, the named or shown stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction relative to the other stereoisomer.When a single enantiomer is named or shown by structure, the shown or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction. When a single diastereomer is named or shown by structure, the shown or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction. Percent purity by mole fraction is the ratio of moles of enantiomer, or moles of enantiomer and moles of its optical isomer. Similarly, percent purity by mole fraction is the ratio of moles of diastereomer, or moles of diastereomer and moles of its isomer. When a disclosed compound is named or shown by structure without showing stereochemistry and the compound has at least one chiral center, the name or structure should be understood to encompass any of the enantiomers of the compound free of the corresponding optical isomer, a racemic mixture of the compound, a mixture of the compound, or a mixture enriched in one enantiomer with respect to its corresponding optical isomer. When a disclosed compound is named or shown by structure without showing stereochemistry and the compound has more than one chiral center, the name or structure should be understood to encompass any of the diastereomers free of the other diastereomers, any of the diastereomers free of the other diastereomer pairs, mixtures of diastereomers, mixtures of diastereomer pairs, mixtures of diastereomers enriched in one diastereomer with respect to the other diastereomers, or mixtures of diastereomers enriched in one or more diastereomers with respect to the other diastereomers. The present invention encompasses all of these forms.

[0116] The compounds of the present disclosure also include all isotopes of atoms present in intermediate or final compounds. "Isotopes" refer to atoms with the same atomic number but different mass numbers resulting from different numbers of neutrons in the nucleus. For example, isotopes of hydrogen include tritium and deuterium.

[0117] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the invention include: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Isotopically labeled compounds (e.g., 3 H and 14 C) may be useful in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes can be useful for their ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) due to greater metabolic stability. In some embodiments, one or more hydrogen atoms are 2 H or 3 H or one or more carbon atoms are replaced by 13 C or 14 Replaced by C-enriched carbon. 15 O. 13 N, 11 C, and 18Positron-emitting isotopes such as F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by following procedures similar to those disclosed for the compounds of the present invention described herein, by substituting isotopically labeled reagents with non-isotopically labeled reagents.

[0118] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Methods and materials for use in this disclosure are described herein. Other suitable methods and materials known in the art may also be used. These materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, shall control.

[0119] definition In this application, unless otherwise clear from the context, (i) the term "a" may be understood to mean "at least one," (ii) the term "or" may be understood to mean "and / or," and (iii) the terms "including" and "including" may be understood to encompass the itemized elements or steps, whether presented by themselves or with one or more additional elements or steps.

[0120] As used herein, the terms "about" and "approximately" refer to values ​​within 10% above or below the stated value. For example, the term "about 5 nM" indicates a range of 4.5 to 5.5 nM.

[0121] As used herein, the term "administration" refers to administration of a composition (e.g., a compound or a preparation comprising a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) can be by any suitable route. For example, in some embodiments, administration can be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreous.

[0122] As used herein, the term "BAF complex" refers to the BRG1 or HBRM-associated factor complex in human cells.

[0123] As used herein, the term "BAF complex-associated disorder" refers to a disorder caused by or affected by the level of activity of the BAF complex.

[0124] As used herein, the term "loss-of-function mutation of BRG1" refers to a mutation in BRG1 that results in a protein with reduced activity (e.g., at least a 1% reduction in BRG1 activity, e.g., a 2%, 5%, 10%, 25%, 50%, or 100% reduction in BRG1 activity). Exemplary BRG1 loss-of-function mutations include, but are not limited to, homozygous BRG1 mutations and deletions at the C-terminus of BRG1.

[0125] As used herein, the term "BRG1 loss-of-function disorder" refers to a disorder (e.g., cancer) that exhibits a reduction in BRG1 activity (e.g., at least a 1% reduction in BRG1 activity, e.g., a 2%, 5%, 10%, 25%, 50%, or 100% reduction in BRG1 activity).

[0126] The term "cancer" refers to conditions caused by the proliferation of malignant cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

[0127] As used herein, "combination therapy" or "administered in combination" means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the dose and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents may be simultaneous or parallel, and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, the administration of the two or more agents or combined treatments is such that the reduction in symptoms, or other parameters associated with the disorder, is greater than that observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments may be partially additive, fully additive, or greater than additive (e.g., synergistic). The sequential or substantially simultaneous administration of each therapeutic agent may occur by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or by different routes, for example, a first therapeutic agent of the combination may be administered by intravenous injection, while a second therapeutic agent of the combination may be administered orally.

[0128] "Determining the level" of protein or RNA means detecting the protein or RNA, either directly or indirectly, by methods known in the art. "Directly determining" means performing a process to obtain a physical entity or value (e.g., performing an assay or test on a sample, or "analyzing a sample" as that term is defined herein). "Indirectly determining" refers to receiving a physical entity or value from another party or source (e.g., a third party laboratory that obtains the physical entity or value directly). Methods for measuring protein levels generally include, but are not limited to, Western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescence polarization, phosphorescence, immunohistochemistry, matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC) mass spectrometry, microcytometry, microscopy, fluorescence-activated cell sorting (FACS), and flow cytometry, as well as assays based on properties of the protein, including, but not limited to, enzymatic activity or interaction with other protein partners. Methods for measuring RNA levels are known in the art and include, but are not limited to, quantitative polymerase chain reaction (qPCR) and Northern blot analysis.

[0129] A "decreased level" or "increased level" of a protein or RNA refers to a decrease or increase, respectively, in protein or RNA levels compared to a reference substance (e.g., a decrease or increase of about 5%, 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%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500% or more). , a decrease or increase of about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or more than about 200%, a decrease or increase of about 0.01-fold, about 0.02-fold, about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold or less, or an increase of about 1.2-fold, about 1.4-fold, about 1.5-fold, about 1.8-fold, about 2.0-fold, about 3.0-fold, about 3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 100-fold, about 1000-fold or more. The level of protein may be expressed as mass / volume (e.g., g / dL, mg / mL, μg / mL, ng / mL) or as a percentage of the total protein in the sample.

[0130] "Reduce the activity of BAF complex" means to reduce the level of activity or downstream effect associated with BAF complex. A non-limiting example of reducing the activity of BAF complex is activation of Sox2. The activity level of BAF complex can be measured using any method known in the art, for example, the method described in Kadoch et al. Cell, 2013, 153, 71-85, which is incorporated herein by reference.

[0131] As used herein, the term "inhibiting BRM" refers to blocking or reducing the level or activity of the ATPase catalytic binding domain or bromodomain of a protein. BRM inhibition can be determined using methods known in the art, such as the BRM ATPase assay, the Nano DSF assay, or the BRM luciferase cellular assay.

[0132] As used herein, the term "LXS196," also known as IDE196, refers to a PKC inhibitor having the following structure: [ka] , or a pharma- ceutically acceptable salt thereof.

[0133] As used herein, the term "pharmaceutical composition" refers to a composition comprising a compound described herein, formulated with a pharmaceutically acceptable excipient and suitable for administration to a mammal, e.g., a human. Typically, a pharmaceutical composition is manufactured or sold by approval of a government regulatory agency as part of a therapeutic regimen for the treatment of a disease in a mammal. A pharmaceutical composition can be formulated, for example, for oral administration in a unit dosage form (e.g., tablet, capsule, caplet, gelcap, or syrup), for topical administration (e.g., as a cream, gel, lotion, or ointment), for intravenous administration (e.g., as a sterile solution free of particulate embolic material and in a solvent system suitable for intravenous use), or in any other pharmaceutically acceptable formulation.

[0134] As used herein, "pharmaceutical acceptable excipient" refers to any component of a compound described herein (e.g., a vehicle capable of suspending or dissolving an active compound) and having the properties of being substantially non-toxic and non-inflammatory in a patient. Excipients may include, for example, anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film-forming or coating agents, flavors, fragrances, glidants (glidants), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water of hydration.

[0135] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt of a compound, for example, any compound of formula I. The pharmaceutically acceptable salt of any of the compounds described herein may include salts that are suitable for use in contact with human and animal tissues without undue toxicity, irritation, or allergic reaction, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base group with a suitable organic acid.

[0136] The compounds of the present invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts, including inorganic or organic acids, or salts may be prepared from inorganic or organic bases when the compounds of the present invention are in acidic form. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases, as well as methods for preparing suitable salts, are well known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases.

[0137] "Reference material" refers to any useful reference material used to compare protein or RNA levels. A reference material can be any sample, standard, standard curve, or level used for comparison purposes. A reference material can be a normal reference sample or a reference standard or level. A "reference sample" can be, for example, a control, e.g., a predefined negative control value such as a "normal control," or a previous sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., cell or tissue) from a subject without a disease; a sample from a subject diagnosed with a disease but not yet treated with a compound of the invention; a sample from a subject being treated with a compound of the invention; or a sample of a known normal concentration of purified protein or RNA (e.g., any of those described herein). "Reference standard or level" refers to a value or numerical value derived from a reference sample. A "normal control value" is a predefined value indicative of a non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range ("between X and Y"), a high threshold ("below X"), or a low threshold ("above X"). A subject having a measurement within the normal control value of a particular biomarker is typically referred to as being "within the normal range" for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject without a disease or disorder (e.g., cancer); a subject being treated with a compound of the present invention. In a preferred embodiment, the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, stage of disease, and overall health. A standard curve of purified protein or RNA levels within the normal reference range, such as any of those described herein, can also be used as a reference.

[0138] As used herein, the term "subject" refers to any organism to which a composition according to the invention may be administered, for example, for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may be a human or animal seeking or in need of treatment, requesting treatment, undergoing treatment, will be undergoing treatment in the future, or being treated by a trained professional for a particular disease or condition.

[0139] As used herein, the terms "treat", "treated" or "treating" refer to a therapeutic treatment or any procedure, the purpose of which is to slow (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; attenuation of the severity of the condition, disorder, or disease; stabilization (i.e., not worsening) of the condition, disorder, or disease; delaying or slowing the onset of progression of the condition, disorder, or disease; improvement or remission (partial or complete) of the condition, disorder, or disease state; improvement of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or amelioration of the condition, disorder, or disease. Treatment includes eliciting a clinically significant response without an excessive level of side effects. Treatment also includes prolonging survival compared to the expected survival in the absence of treatment. The compounds of the invention can also be used to "prophylactically treat" or "prevent" disorders, for example, in subjects at increased risk of developing the disorder.

[0140] As used herein, the terms "variant" and "derivative" are used interchangeably and refer to naturally occurring, synthetic, and semi-synthetic analogs of the compounds, peptides, proteins, or other substances described herein. Variants or derivatives of the compounds, peptides, proteins, or other substances described herein may retain or improve the biological activity of the original material.

[0141] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will become apparent from the description and the claims. [Brief description of the drawings]

[0142] [Figure 1] 1 is a graph showing inhibition of cell proliferation of several cancer cell lines by a BRG1 / BRM inhibitor (Compound A). [Figure 2A] 1 is a graph showing inhibition of cell proliferation of uveal melanoma cell line 92-1 by a BRG1 / BRM inhibitor (Compound A), a MEK inhibitor (selumetinib), and a PKC inhibitor (LXS196). [Figure 2B] 1 is a graph showing inhibition of cell proliferation of the uveal melanoma cell line MP41 by a BRG1 / BRM inhibitor (Compound A), a MEK inhibitor (selumetinib), and a PKC inhibitor (LXS196). [Diagram 3] 1 is a graph showing inhibition of cell proliferation of several cancer cell lines by a BRG1 / BRM inhibitor (Compound B). [Figure 4] FIG. 1 is a graph showing the area under the curve (AUC) calculated from dose-response curves of cancer cell lines treated with BRG1 / BRM inhibitors. [Diagram 5] 1 is a graph showing inhibition of cell proliferation of uveal melanoma and non-small cell lung cancer cell lines by a BRG1 / BRM inhibitor (Compound B). [Figure 6A] 1 is a graph showing inhibition of cell proliferation of uveal melanoma cell line 92-1 by a BRG1 / BRM inhibitor (Compound B), a MEK inhibitor (selumetinib), and a PKC inhibitor (LXS196). [Figure 6B] 1 is a graph showing inhibition of cell proliferation of the uveal melanoma cell line MP41 by a BRG1 / BRM inhibitor (Compound B), a MEK inhibitor (selumetinib), and a PKC inhibitor (LXS196). [Figure 7A] 1 is a graph showing inhibition of cell proliferation of parental and PKC inhibitor-refractory uveal melanoma cell lines by a PKC inhibitor (LXS196). [Figure 7B] 1 is a graph showing inhibition of cell proliferation of parental and PKC inhibitor-refractory uveal melanoma cell lines by a BRG1 / BRM inhibitor (Compound B). [Figure 8A] 1 is a graph showing inhibition of tumor growth in mice implanted with uveal melanoma cell lines by a BRG1 / BRM inhibitor (Compound C). [Figure 8B] FIG. 1 shows the size of tumors from mice implanted with uveal melanoma cell lines and administered a BRG1 / BRM inhibitor (Compound C). [Figure 8C] 1 is a graph showing changes in body weight of mice transplanted with a uveal melanoma cell line and administered a BRG1 / BRM inhibitor (Compound C). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0143] The present disclosure features compounds useful for inhibiting BRM and optionally BRG1. These compounds may be used to modulate the activity of the BAF complex, for example, for the treatment of BAF-associated disorders (e.g., loss-of-function disorders of BRG1), such as cancer. Exemplary compounds described herein include compounds having a structure according to Formula I: [ka] During the ceremony, m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; X 1 is -S-, -SO-, -SO2-, or -S(O)(NH)-, X 2 But N or CR 8and R 1 is hydrogen or optionally substituted C1-C6 alkyl; Each R 2 and each R 3 is independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; L 1 is an optionally substituted 9- or 10-membered bicyclic heterocyclyl or an optionally substituted 9- or 10-membered bicyclic heteroaryl; L 2 but absent or optionally replaced C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted 5-14 membered heteroaryl, or optionally substituted 4-14 membered heterocyclyl; R 4 is hydrogen, halo, optionally substituted C1-C6 alkyl, or optionally substituted C3-C 10 is cycloalkyl, R 5 is optionally substituted C-C alkyl, optionally substituted C-C heteroalkyl, or optionally substituted amino; R 6 is hydrogen, halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C3-C 10 cycloalkyl or R 5 and R 6 taken together with the atoms to which they are attached to form an optionally substituted 5- to 8-membered heterocyclyl; Each R 7 are independently selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, halo, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10Cycloalkyl C1-C6 alkyl, optionally substituted 5-14 membered heteroaryl, optionally substituted 4-14 membered heterocyclyl, -N(R 7A ) 2 or OR 7A And each R 7A are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclyl, or two geminal R 7A Groups, together with the atom to which they are attached, combine to form an optionally substituted 5- to 10-membered heteroaryl or an optionally substituted 4- to 10-membered heterocyclyl, or two geminal R 7 The groups combine with the atoms to which they are attached to form a carbonyl, R 8 is hydrogen, halo, optionally substituted C1-C6 alkyl, or optionally substituted C3-C 10 is cycloalkyl, R 9 is hydrogen or halo, or a pharma- ceutically acceptable salt thereof.

[0144] In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, has the structure of any one of compounds 1-308 in Table 1A. In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, has the structure of any one of compounds 309-856 in Table 1B.

[0145] Other embodiments, and exemplary methods for the synthesis of the production of these compounds, are described herein.

[0146] Pharmaceutical Use The compounds described herein are useful in the methods of the invention and, without being bound by theory, are believed to exert their ability to modulate the level, status, and / or activity of the BAF complex, i.e., by inhibiting the activity of the BRG1 and / or BRM proteins within the mammalian BAF complex. BAF complex-associated disorders include, but are not limited to, disorders associated with loss-of-function mutations in BRG1.

[0147] One aspect of the invention relates to a method of treating a disorder associated with a loss-of-function mutation in BRG1, such as cancer (e.g., non-small cell lung cancer, colon cancer, bladder cancer, cancer of unknown primary site, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer) in a subject in need thereof. In some embodiments, the compound is administered in an amount and for a time effective to result in one or more (e.g., two or more, three or more, four or more) of: (a) a reduction in tumor size; (b) a reduction in tumor growth rate; (c) an increase in tumor cell death; (d) a reduction in tumor progression; (e) a reduction in the number of metastases; (f) a reduction in the rate of metastasis; (g) a reduction in tumor recurrence; (h) an increase in the subject's survival rate; (i) an increase in the subject's progression-free survival time.

[0148] Treating cancer can result in a reduction in tumor size or volume. For example, after treatment, the tumor size is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) relative to its size before treatment. The size of the tumor may be measured by any reproducible means of measurement. For example, the size of the tumor may be measured as the diameter of the tumor.

[0149] Treating cancer may further result in a reduction in the number of tumors. For example, after treatment, the number of tumors is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) relative to the number before treatment. The number of tumors may be measured by any reproducible means of measurement, for example, the number of tumors may be measured by counting tumors visible to the naked eye or at a particular magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).

[0150] Treatment of cancer may result in a decrease in the number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) compared to the number before treatment. The number of metastatic nodules may be measured by any reproducible measurement means. For example, the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a particular magnification (e.g., 2x, 10x, or 50x).

[0151] Treating cancer may result in an increase in the average survival time of a population of subjects treated according to the present invention compared to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). The increase in the average survival time of a population may be measured by any reproducible means. The increase in the average survival time of a population may be measured, for example, by calculating the average length of survival of a population after the start of treatment with a compound of the present invention. The increase in the average survival time of a population may also be measured, for example, by calculating the average length of survival of a population after the completion of the first round of treatment with a pharma- ceutically acceptable salt of a compound of the present invention.

[0152] Treating cancer may also result in a reduction in the mortality rate of a population of treated subjects compared to an untreated population. For example, the mortality rate is reduced by more than 2% (e.g., more than 5%, 10%, or 25%). The reduction in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating the average number of disease-related deaths per unit time for a population after the start of treatment with a pharma-ceutically acceptable salt of the present invention. The reduction in the mortality rate of a population may also be measured, for example, by calculating the average number of disease-related deaths per unit time for a population after the completion of the first round of treatment with a pharma-ceutically acceptable salt of the present invention.

[0153] Exemplary cancers that may be treated by the present invention include, but are not limited to, non-small cell lung cancer, small cell lung cancer, colon cancer, bladder cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, CNS cancer, thymic tumors, adrenal cortical carcinoma, appendix cancer, small intestine cancer, and penile cancer.

[0154] Combination preparations and their uses The compounds of the invention may be combined with one or more therapeutic agents. In particular, the therapeutic agents may be those that treat or prophylactically treat any of the cancers described herein.

[0155] Combination therapy The compounds of the present invention can be used alone or in combination with additional therapeutic agents, such as other drugs that treat cancer or related symptoms, or in combination with other types of treatments for treating cancer. In combination treatment, the dosage of one or more therapeutic compounds may be reduced from the standard dosage when administered alone. For example, dosage may be empirically determined from drug combinations and permutations, or estimated by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, the dosage of the compounds when combined should provide a therapeutic effect.

[0156] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other compound useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocorticotropic inhibitors, adrenocorticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents, such as thiotepa and cyclophosphamide; alkylsulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines, such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphate ... acid amides and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including the synthetic analogues KW-2189 and CBI-TMI); erutherobin; pancrustatin; sarcodictyin; spongistatins;nitrogen mustards, such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine hydrochloride oxide, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicins, especially calicheamicin gamma II and calicheamicin omega II (see, e.g., Agnew, Chem. Intl. Ed. Engl. 33:183-186 (1994); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicin; and neocarzinostatin chromophore and related enediyne antibiotic chromophores), antibiotics such as aclacinomycin, actinomycin, authramicin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, Adriamycin® (morpholino-doxorubicin, cyanomorpholino-doxorubicin doxorubicin, including 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, keramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;Pyrimidine analogues, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;Androgens, such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone;Antiadrenal agents, such as aminoglutethimide, mitotane, trilostane;Folic acid replacements, such as furoic acid;Aceglatone;Aldophosphamide glycosides;Aminolevulinic acid;Eniluracil;Amsacrine;Bestravcil;Bisantrene;Edatrexa acetate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidynin; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraelin; pentostatin; fenameth; pirarubicin; rosoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; schizophyllan; spirogermanium; tenuazonic acid; triazicon; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veraculin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids such as Taxol® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABraxane®, a chromophore-free albumin engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and Taxotere® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil;Gemzar® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitors RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; capecitabine; and pharma- ceutically acceptable salts, acids, or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail administered in combination with a first therapeutic agent described herein. Suitable dosing regimens for combination chemotherapy are known in the art and are described, for example, in Saltz et al. (1999) Proc ASCO 18:233a and Douillard et al. (2000) Lancet 355:1041-7.

[0157] In some embodiments, the second therapeutic agent is a therapeutic agent that is a biologic, such as a cytokine (e.g., an interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments, the biologic is an anti-VEGF agent, e.g., an anti-angiogenic agent, such as bevacizumab (Avastin®). In some embodiments, the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, fully human antibody, Fc fusion protein, or functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important to the cancer. Such medications include Rituxan (rituximab), Zenapax (daclizumab), Simulect (basiliximab), Synagis (palivizumab), Remicade (infliximab), Herceptin (trastuzumab), Mylotarg (gemtuzumab ozogamicin), Campath (alemtuzumab), Zevalin (ibritumomab tiuxetan), Humira (adalimumab), Xolair (omalizumab), Bexxar (tositumomab-I-131), Raptiva (efalizumab), Erbitux (cetuximab), Avastin (bevacizumab), Tysabri (natalizumab), Actemra (tosi Antibody-drug conjugates are also included.

[0158] The second agent may be a therapeutic agent that is a non-drug treatment, for example, the second therapeutic agent is radiation therapy, cryotherapy, thermotherapy, and / or surgical removal of tumor tissue.

[0159] The second agent may be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a ligand of the checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody such as ipilimumab / Yervoy or tremelimumab). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab / Opdivo®; pembrolizumab / Keytruda®; pidilizumab / CT-011). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS 936559). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2 / Ig fusion protein such as AMP 224). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligand, or combinations thereof.

[0160] In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately before, immediately after, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7, 1-14, 1-21, or 1-30 days before or after the second therapeutic agent.

[0161] Pharmaceutical Compositions The compounds of the invention are preferably formulated into pharmaceutical compositions for administration to mammals, preferably humans, in a biologically compatible form suitable for administration in vivo. Thus, in one aspect, the invention provides a pharmaceutical composition comprising a compound of the invention in admixture with a suitable diluent, carrier, or excipient.

[0162] The compounds of the present invention may be used in the form of free base, salt, solvate, and prodrug. All forms are within the scope of the present invention. According to the method of the present invention, as understood by those skilled in the art, the described compounds, or their salts, solvates, or prodrugs, may be administered to a patient in various forms depending on the selected route of administration. The compounds of the present invention may be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, by patch, pump, or transdermal administration, and the pharmaceutical composition is formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0163] The compounds of the present invention can be administered orally, for example, with an inert diluent or an assimilable edible carrier, or can be enclosed in hard or soft shell gelatin capsules, or can be compressed into tablets, or can be incorporated directly with dietary food. For oral therapeutic administration, the compounds of the present invention can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. The compounds of the present invention can also be administered parenterally. Solutions of the compounds of the present invention can be prepared in water suitably mixed with a surfactant. These preparations may contain a preservative to prevent the growth of microorganisms under ordinary conditions of storage and use. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003, 20th ed.) and The United States Pharmacopeia: The National Formulary, 1999 (USP 24 NF19). Suitable pharmaceutical forms for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be sufficiently fluid to be easily administered via a syringe. Compositions for nasal administration can be conveniently formulated as aerosols, drops, gels, and powders. Aerosol formulations typically contain a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent, and are usually provided in single or multiple doses in a sterile form in a sealed container that can take the form of a cartridge or refill for use with a spray device. Alternatively, the sealed container can be a single-dispensing device, such as a single-dose nasal inhaler or aerosol dispenser fitted with a metering valve, intended for disposal after use. When the dosage form includes an aerosol dispenser, it includes a propellant, which can be a compressed gas, such as compressed air, or an organic propellant. The aerosol dosage form can also take the form of a pump-atomizer.Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, in which the active ingredient is formulated with a carrier. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base. The compounds described herein may be administered intratumorally, for example, as an intratumoral injection. Intratumoral injection is a direct injection into the tumor vasculature, and is particularly contemplated for individual solid accessible tumors. Local, regional, or systemic administration may also be appropriate. The compounds described herein may be advantageously contacted by administering an injection or multiple injections to the tumor, for example, spaced approximately 1 cm apart. In the case of surgical intervention, the present invention may be used prior to surgery, such as to subject an inoperable tumor to resection. Continuous administration may also be applied where appropriate, for example, by implanting a catheter into the tumor or tumor vasculature.

[0164] The compounds of the invention, as described herein, may be administered to animals, e.g., humans, alone or in combination with pharma- ceutically acceptable carriers, the ratio of which will be determined by the solubility and chemical properties of the compound, the chosen route of administration, and standard pharmaceutical practice.

[0165] Dosage The dosage of the compound of the present invention and / or the composition comprising the compound of the present invention may vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of treatment and the type of concomitant treatment, if any; and the clearance rate of the compound in the treated animal. Those skilled in the art can determine the appropriate dosage based on the above factors. The compound of the present invention may be administered at a suitable dosage initially, and this amount may be adjusted as necessary depending on the clinical response. In general, satisfactory results can be obtained when the compound of the present invention is administered to humans at a daily dose of, for example, 0.05 mg to 3000 mg. When administered to humans at a daily dose between 0.05 mg and 3000 mg, the dosage range includes, for example, 10 to 1000 mg.

[0166] Alternatively, the patient's body weight can be used to calculate the dosage. For example, the dose of the compound or pharmaceutical composition thereof administered to the patient may be in the range of 0.1 to 100 mg / kg. EXAMPLES

[0167] Definitions used in the scheme below and elsewhere herein are as follows: [Table 3-1] [Table 3-2]

[0168] material Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere.

[0169] Table 1C lists compounds of the present invention that were prepared using the methods described herein. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5]

[0170] material Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere.

[0171] Example 1. Preparation of intermediates Intermediate 1. 2,3-Dihydro-5H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide [ka] Step 1: Preparation of methyl 4-bromo-2-mercaptobenzoate To a solution of methyl 4-bromo-2-fluoro-benzoate (100 g, 429.12 mmol) in DMF (1 L) was added sodium sulfide (33.49 g, 429.1 mmol, 18.0 mL) and the mixture was stirred at 30° C. for 16 h. After the mixture was poured into water (6000 mL), the pH was adjusted to about 3 with 2N HCl. The mixture was extracted with MTBE (3000 mL×2). The combined organic phase was washed with brine (3000 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give methyl 4-bromo-2-mercaptobenzoate (103 g, crude) as a yellow oil, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO_d6)δ=7.91(d,J=1.6 Hz,1H),7.83-7.81(m,1H),7.43-7.40(m,1H),5.58(br s,1H),3.83(s,3H)ppm

[0172] Step 2: Preparation of (4-bromo-2-mercaptophenyl)methanol To a mixture of methyl 4-bromo-2-mercaptobenzoate (103 g, 416.82 mmol) in THF (1000 mL) was added LiAlH4 (15.82 g, 416.82 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h. The mixture was poured into 1N HCl (2000 mL) and extracted with EtOAc (2000 mL x 2). The combined organic phase was washed with brine (2000 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give (4-bromo-2-mercaptophenyl)methanol (88 g, crude) as a yellow oil, which was used in the next step without further purification. 1H NMR(400 MHz,DMSO_d6)δ=7.59(s,1H),7.32(d,J=1.2 Hz,2H),5.56-5.36(m,2H),4.39(s,2H)ppm

[0173] Step 3: Preparation of (4-bromo-2-(vinylthio)phenyl)methanol and (4-bromo-2-((2-bromoethyl)thio)phenyl)methanol To a mixture of (4-bromo-2-mercaptophenyl)methanol (85 g, 387.95 mmol) in DMF (1700 mL) was added K2CO3 (160.9 g, 1.16 mol) and 1,2-dibromoethane (218.6 g, 1.16 mol, 87.8 mL) and the mixture was stirred at 25 °C for 1 h. Then the mixture was stirred at 70 °C for another 24 h. The reaction mixture was poured into saturated NH4Cl (10 L) and extracted with EA (3000 mL * 2). The combined organics were washed with brine (4000 mL × 2), dried over Na2SO4, filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (PE / EA = 50 / 1 to 5 / 1). The fractions were concentrated in vacuo to give (4-bromo-2-(vinylthio)phenyl)methanol (33.5 g, 136.66 mmol, 35% yield) and (4-bromo-2-((2-bromoethyl)thio)phenyl)methanol (10 g, 30.67 mmol, 8% yield) as a yellow oil. (4-Bromo-2-(vinylthio)phenyl)methanol: 1 H NMR(400 MHz,CDCl3)δ=7.55(s,1H),7.45(d,J=2 Hz,1H),7.43(d,J=2 Hz,1H),6.49-6.42(m,1H),5.45(d,J=9.6 Hz,1H),5.32(d,J=10.4 Hz,1H),4.73(s,2H)ppm. (4-bromo-2-((2-bromoethyl)thio)phenyl)methanol: 1H NMR(400 MHz, CDCl3)δ=7.46(s,1H),7.33(d,J=2 Hz,1H),7.09(d,J=2 Hz,1H),6.67(s,2H),3.41-3.38(m,2H),3.25-3.23(m,1H)ppm.

[0174] Step 4: Preparation of (4-bromo-2-(vinylsulfonyl)phenyl)methanol To a mixture of (4-bromo-2-(vinylthio)phenyl)methanol (35.5 g, 144.82 mmol) in MeOH (350 mL) and H2O (350 mL) was added Oxone® (133.54 g, 217.23 mmol) and the mixture was stirred at 25 °C for 2 h. Water (1500 mL) was added and the mixture was extracted with EtOAc (1500 mL x 2). The combined organic phase was washed with brine (1000 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give (4-bromo-2-vinylsulfonyl-phenyl)methanol as a yellow solid. (38.5 g, crude) was obtained, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO_d6)δ=7.98-7.95(m,2H),7.77-7.75(m,1H),7.22-7.15(m,1H),6.43-6.39(m,1H),6.31(d,J=10.0 Hz,1H),5.62-5.59(m,1H),4.75(d,J=5.2 Hz,2H)ppm

[0175] Step 5: Preparation of 8-bromo-2,3-dihydro-5H-benzo[e][1,4]oxathiepin 1,1-dioxide To a mixture of (4-bromo-2-vinylsulfonyl-phenyl)methanol (38.5 g, 138.9 mmol) in DMF (1000 mL) was added NaH (11.11 g, 277.84 mmol, 60% purity) at 0° C. under N2. The mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into saturated NH4Cl (2 L) and extracted with EA (2000 mL*2). The combined organic phase was washed with brine (2000 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, PE:EtOAc=50:1 to 5:1) and concentrated in vacuum to give 8-bromo-2,3-dihydro-5H-benzo[e][1,4]oxathiepin 1,1-dioxide (26.5 g, 95.62 mmol, 69% yield) as a white solid. 1 H NMR(400 MHz,DMSO_d6)δ=7.99(d,J=2.0 Hz,1H),7.92-7.90(m,1H),7.55(d,J=8.0 Hz,1H),4.88(s,2H),4.20-4.17(m,2H),3.68-3.66(m,2H)ppm

[0176] Step 6: Preparation of 2,3-dihydro-5H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide (Intermediate 1) To a mixture of 8-bromo-2,3-dihydro-5H-benzo[e][1,4]oxathiepin 1,1-dioxide (8.8 g, 31.75 mmol) in DMSO (90 mL) and H2O (9 mL) was added 1,3-bis(bicyclohexylphosphino)propane bis(tetrafluoroborate) (3.89 g, 6.35 mmol), K2CO3 (6.58 g, 47.63 mmol), and Pd(OAc)2 (712.90 mg, 3.18 mmol). The mixture was purged with CO three times and then stirred at 100 °C under CO (15 psi) for 4 h. Water (3000 mL) was added and the mixture was extracted with EtOAc (500 mL x 2) before discarding the organic phase. The aqueous layer was adjusted to pH ∼3 with 1N HCl. The mixture was then extracted with EA (500 mL * 5). The combined organic phase was washed with brine (2000 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude material was washed with MTBE (20 mL*2), then filtered and the filter cake was evaporated to dryness to give 2,3-dihydro-5H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide (15 g, 61.92 mmol, 65% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.43(s,1H),8.20-8.18(m,1H),7.72-7.70(m,1H),4.96(s,2H),4.23-4.20(m,2H),3.67-3.66(m,2H)ppm.

[0177] Intermediate 2. 3,5-Dihydro-2H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid 1,1-dioxide [ka] Step 1: Preparation of methyl 5-bromo-3-mercaptopicolinate To a solution of methyl 5-bromo-3-fluoro-pyridine-2-carboxylate (1 g, 4.27 mmol) in DMF (10 mL) was added Na2S (333.49 mg, 4.27 mmol). The mixture was stirred at 25 °C for 2 h. Three of the same batches were combined and purified together. The mixture was diluted with water (50 mL) and adjusted to pH = 5 with 1N aqueous HCl. The mixture was extracted with EA (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4 and concentrated to give methyl 5-bromo-3-mercaptopicolinate (3.3 g, crude) as a brown oil. LCMS (ESI) m / z: [M+H] + =247.8 / 249.8

[0178] Step 2: Preparation of (5-bromo-3-mercaptopyridin-2-yl)methanol To a solution of methyl 5-bromo-3-mercaptopicolinate (3.3 g, 13.30 mmol) in THF (33 mL) was added LiAlH4 (504.8 mg, 13.30 mmol) at 0° C. The mixture was stirred at 25° C. for 2 h. The mixture was diluted with water (100 mL) and adjusted to pH=6 with 1N aqueous HCl. Then the mixture was extracted with EA (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give (5-bromo-3-mercaptopyridin-2-yl)methanol (1.66 g, 7.54 mmol) as a brown oil. LCMS(ESI)m / z:[M+H] + =219.8 / 221.8.

[0179] Step 3: Preparation of (5-bromo-3-(vinylthio)pyridin-2-yl)methanol To a solution of (5-bromo-3-mercaptopyridin-2-yl)methanol (1.66 g, 7.54 mmol) in DMF (15 mL) was added K2CO3 (3.13 g, 22.63 mmol) and 1,2-dibromoethane (7.08 g, 37.71 mmol, 2.85 mL). The mixture was stirred at 60 °C for 12 h. The mixture was diluted with water (100 mL) and extracted with EA (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0 to 100% ethyl acetate / petroleum ether). The eluent was concentrated to give (5-bromo-3-(vinylthio)pyridin-2-yl)methanol (600 mg, 2.44 mmol, 32% yield) as a brown oil. LCMS(ESI)m / z:[M+H] + =245.9 / 247.9. 1 HNMR(400 MHz,DMSO-d6)δ=8.53(d,J=2.0 Hz,1H),7.92(d,J=2.0 Hz,1H),6.81-6.74(m,1H),5.64-5.51(m,2H),5.32-5.29(m,1H),4.54(d,J=6.0 Hz,2H)ppm.

[0180] Step 4: Preparation of (5-bromo-3-(vinylsulfinyl)pyridin-2-yl)methanol To a solution of (5-bromo-3-(vinylthio)pyridin-2-yl)methanol (600 mg, 2.44 mmol) in MeOH (6 mL) was slowly added Oxone® (824.27 mg, 1.34 mmol) in water (6 mL) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was quenched with saturated aqueous Na2SO3 (30 mL) and extracted with EA (30 mL×2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0 to 100% ethyl acetate / petroleum ether). The eluent was concentrated to give (5-bromo-3-(vinylsulfinyl)pyridin-2-yl)methanol (500 mg, 1.91 mmol, 78.25% yield) as a colorless oil. 1 HNMR(400 MHz,DMSO-d6)δ=8.74(d,J=2.4 Hz,1H),8.17(d,J=2.0 Hz,1H),7.18-7.12(m,1H),6.09-6.02(m,2H),5.95(d,J=9.6 Hz,1H),4.85-4.78(m,1H),4.73-4.66(m,1H)ppm.

[0181] Step 5: Preparation of 8-bromo-3,5-dihydro-2H-[1,4]oxathiepino[6,5-b]pyridine 1-oxide To a solution of (5-bromo-3-(vinylsulfinyl)pyridin-2-yl)methanol (500 mg, 1.91 mmol) in DMF (5 mL) was added NaH (152.59 mg, 3.81 mmol, 60% purity) at 0° C. The mixture was stirred at 0° C. for 2 h. The mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EA (30 mL×2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0 to 10% ethyl acetate / petroleum ether). The eluate was concentrated to give 8-bromo-3,5-dihydro-2H-[1,4]oxathiepino[6,5-b]pyridine 1-oxide (350 mg, 1.34 mmol, 70% yield) as a colorless oil. 1 HNMR(400 MHz,DMSO-d6)δ=8.75(d,J=2.4 Hz,1H),8.19(d,J=2.0 Hz,1H),4.91-4.74(m,2H),4.43-4.34(m,1H),4.21-4.18(m,1H),3.65-3.56(m,1H),3.49-3.44(m,1H)ppm.

[0182] Step 6: Preparation of 3,5-dihydro-2H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid 1-oxide To a solution of 8-bromo-3,5-dihydro-2H-[1,4]oxathiepino[6,5-b]pyridine 1-oxide (350 mg, 1.34 mmol) in DMSO (4 mL) and water (120.27 mg, 6.68 mmol, 120.27 uL) was added 1,3-bis(bicyclohexylphosphino)propane bis(tetrafluoroborate) (81.75 mg, 133.52 μmol), K2CO3 (276.82 mg, 2.00 mmol), and Pd(OAc)2 (29.98 mg, 133.52 μmol). The mixture was degassed and purged with CO three times. The mixture was stirred at 100 °C under CO (15 psi) atmosphere for 12 h. The mixture was filtered and washed with DMSO (2 mL) and water (2 mL). The filtrate was then adjusted to pH=6 with 1N HCl aqueous solution. The filtrate was purified by reverse-phase HPLC (0.1% FA condition). The eluate was concentrated to remove ACN and lyophilized to give 3,5-dihydro-2H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid 1-oxide (70 mg, 0.262 mmol, 20% yield) as a white solid. LCMS(ESI)m / z:[M+H] + =227.9. 1 HNMR(400 MHz,DMSO-d6)δ=9.03(d,J=2.0 Hz,1H),8.51(d,J=2.0 Hz,1H),5.01-4.88(m,2H),4.43-4.41(m,1H),4.18-4.15(m,1H),3.63-3.62(m,2H),3.52-3.48(m,2H)ppm.

[0183] Step 7: Preparation of 3,5-dihydro-2H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid 1,1-dioxide (intermediate 2) To a solution of 3,5-dihydro-2H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid 1-oxide (70 mg, 0.309 mmol) in MeOH (0.7 mL) was added Oxone® (284.07 mg, 462.07 μmol) in water (0.7 mL) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was filtered. The filter cake was washed with MeOH (5 mL). The filtrate was then quenched with saturated Na2SO3 solution. The solution was then purified by reverse phase HPLC (0.1% FA condition). The eluate was concentrated to remove ACN and lyophilized to give 3,5-dihydro-2H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid 1,1-dioxide (36 mg, 136.16 μmol, 44% yield) as a white solid. LCMS(ESI)m / z:[M+H] + =243.9.

[0184] Intermediate 3. 3,4-Dihydro-2H-benzo[b][1,4]oxathiepin-7-carboxylic acid 5,5-dioxide [ka] Step 1: Preparation of 3-chlorosulfonyl-4-hydroxy-benzoic acid To a solution of HSO3Cl (31 mL) was added dropwise 4-hydroxybenzoic acid (5.5 g, 39.82 mmol). The mixture was stirred at 20° C. for 16 h. To the reaction mixture was slowly added dropwise ice water (300 mL). The mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give a residue. The crude product was triturated with PE (30 mL) at 20° C. for 30 min to give 3-chlorosulfonyl-4-hydroxy-benzoic acid (4.5 g, 13.72 mmol, 74% yield) as a white solid. 1 HNMR(400 MHz,DMSO-d6)δ=8.09-8.06(m,1H),7.82-7.75(m,1H),6.89-6.81(m,1H)ppm.

[0185] Step 2: Preparation of 4-hydroxy-3-mercaptobenzoic acid To a solution of 3-chlorosulfonyl-4-hydroxy-benzoic acid (1 g, 4.23 mmol) in toluene (20 mL) was added PPh3 (3.88 g, 14.79 mmol) in portions. The mixture was stirred at 90 °C for 2 h. 10% NaOH solution (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL x 3). The aqueous phase was adjusted to pH 2 with 1N HCl. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 4-hydroxy-3-mercaptobenzoic acid (0.62 g, 3.64 mmol, 86.21% yield) as a yellow oil. 1 H NMR(400 MHz,DMSO-d6)δ=12.34(s,1H),7.89-7.83(m,1H),7.61-7.52(m,1H),6.90-6.83(m,1H),5.01(s,1H)ppm.

[0186] Step 3: Preparation of methyl 4-hydroxy-3-mercaptobenzoate To a solution of 4-hydroxy-3-mercaptobenzoic acid (0.6 g, 3.53 mmol) in MeOH (5 mL) was added H2SO4 (352.84 mg, 3.53 mmol, 191.76 uL, 98% purity) dropwise. The mixture was stirred at 70°C for 40 h. Water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo to give 4-hydroxy-3-mercaptobenzoic acid (0.6 g, crude) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ=11.30(s,1H),8.07-8.01(m,1H),7.77-7.71(m,1H),6.99-6.95(m,1H),3.80-3.78(m,3H)ppm.

[0187] Step 4: Preparation of methyl 3,4-dihydro-2H-benzo[b][1,4]oxathiepin-7-carboxylate To a solution of methyl 4-hydroxy-3-mercaptobenzoate (0.1 g, 542.85 μmol, 1 equiv) in DMF (5 mL) was added Cs2CO3 (884.36 mg, 2.71 mmol) and 1,3-dibromopropane (109.6 mg, 0.543 mmol, 55 uL) was added dropwise. The mixture was stirred at 20° C. for 2 h. Water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=1:1) and the eluent was concentrated in vacuo to give methyl 3,4-dihydro-2H-benzo[b][1,4]oxathiepin-7-carboxylate (65 mg, 0.274 mmol, 51% yield) as a yellow oil. LCMS(ESI)m / z:[M+H] += 225.1. 1 H NMR(400 MHz, CDCl3)δ=8.09-8.02(m,1H),7.83-7.74(m,1H),7.03-6.94(m,1H),4.4 5-4.34(m,2H),3.93-3.84(m,3H),3.10-2.98(m,2H),2.34-2.22(m,2H)ppm.

[0188] Step 5: Preparation of methyl 3,4-dihydro-2H-benzo[b][1,4]oxathiepin-7-carboxylate 5,5-dioxide To a mixture of methyl 3,4-dihydro-2H-1,5-benzoxathiepin-7-carboxylate (60 mg, 267.53 μmol) in MeOH (5 mL) and H2O (5 mL), Oxone® (493.40 mg, 802.58 μmol) was added and the mixture was stirred at 20° C. for 16 h. Saturated Na2SO3 (30 mL) was added to quench the reaction. The mixture was extracted with DCM (30 mL×5). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give methyl 3,4-dihydro-2H-benzo[b][1,4]oxathiepin-7-carboxylate 5,5-dioxide (66 mg, 0.257 mmol, 96% yield) as a yellow oil. 1 H NMR(400 MHz, CDCl3)δ=8.73-8.60(m,1H),8.32-8.16(m,1H),7.26-7.23(m,1H),4.4 3-4.30(m,2H),3.97-3.91(m,3H),3.48-3.36(m,2H),2.53-2.41(m,2H)ppm.

[0189] Step 6: Preparation of 3,4-dihydro-2H-benzo[b][1,4]oxathiepin-7-carboxylic acid 5,5-dioxide (intermediate 3) To a mixture of 3,4-dihydro-2H-benzo[b][1,4]oxathiepin-7-carboxylic acid methyl 5,5-dioxide (65 mg, 0.254 mmol) in MeOH (3 mL) and HO (3 mL), NaOH (30.44 mg, 0.761 mmol) was added dropwise, and the mixture was stirred at 20 °C for 2 h. The reaction was concentrated in vacuo to give a residue. The residue was partitioned between EA (10 mL) and 1N NaOH solution (10 mL). The aqueous layer was adjusted to pH 1 with 1N HCl solution and extracted with EA (10 mL x 3). The combined organic phase was concentrated in vacuo to give 3,4-dihydro-2H-benzo[b][1,4]oxathiepin-7-carboxylic acid 5,5-dioxide (60 mg, 0.248 mmol, 98% yield) as a yellow solid. LCMS(ESI)m / z:[M+Na] += 265.2. 1 H NMR(400 MHz,DMSO-d6)δ=8.42-8.30(m,1H),8.21-8.10(m,1H),7.41-7.29(m,1H),4.34-4.22(m,2H),2.31-2.22(m,2H),1.81-1.71(m,2H)ppm.

[0190] Intermediate 4. 6-Chloro-2,3-dihydro-5H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide [ka] Step 1: Preparation of methyl 4-bromo-2-chloro-6-fluorobenzoate To a solution of 4-bromo-2-chloro-6-fluorobenzoic acid (10 g, 39.46 mmol) in MeOH (90 mL) was slowly added concentrated H2SO4 (18.4 g, 187.60 mmol, 10 mL), and the mixture was then stirred at 70 °C for 8 h. The mixture was concentrated in vacuo to remove some MeOH, then poured into saturated NaHCO3 (200 mL), and then extracted with EA (200 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated in vacuo to give methyl 4-bromo-2-chloro-6-fluorobenzoate (9.2 g, crude) as a colorless oil, which was used directly in the next step. 1 H NMR(400 MHz,DMSO-d6)δ=7.87-7.76(m,2H),3.91(s,3H)ppm.

[0191] Step 2: Preparation of methyl 4-bromo-2-chloro-6-mercaptobenzoate To a solution of methyl 4-bromo-2-chloro-6-fluorobenzoate (7.2 g, 26.92 mmol) in DMF (72 mL) was added Na2S (2.10 g, 26.92 mmol), and the mixture was stirred at 25 °C for 2 h. After diluting the mixture with water (300 mL), the resulting mixture was acidified to pH 3 with 1N HCl solution and extracted with EA (200 mL x 2). The combined organic layers were washed with brine (250 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl 4-bromo-2-chloro-6-mercaptobenzoate (7 g, crude) as a yellow oil, which was used directly in the next step.

[0192] Step 3: Preparation of (4-bromo-2-chloro-6-mercaptophenyl)methanol To a mixture of methyl 4-bromo-2-chloro-6-mercaptobenzoate (9 g, 31.97 mmol) in THF (90 mL) was added LiAlH4 (1.33 g, 35.16 mmol) at 0 °C, and then the mixture was stirred at 0 °C for 1 h. The mixture was poured into HCl (1N, 200 mL) and then extracted with EA (250 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated in vacuo to give (4-bromo-2-chloro-6-mercaptophenyl)methanol (5.8 g, crude) as a colorless oil.

[0193] Step 4: Preparation of (4-bromo-2-chloro-6-(vinylthio)phenyl)methanol To a mixture of (4-bromo-2-chloro-6-mercaptophenyl)methanol (5.7 g, 22.48 mmol) in DMF (110 mL) was added K2CO3 (9.32 g, 67.44 mmol) and 1,2-dibromoethane (21.12 g, 112.41 mmol, 8.5 mL), and the mixture was then stirred at 25 °C for 12 h. The mixture was poured into water (200 mL) and extracted with EA (100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE / EA = 10 / 1 to 1:1, SiO2) and the eluent was evaporated to give (4-bromo-2-chloro-6-(vinylthio)phenyl)methanol (2.7 g, 9.66 mmol, 43% yield) as a colorless oil. 1 H NMR(400 MHz,DMSO-d6)δ=7.65(d,J=2.0 Hz,1H),7.42(d,J=2.0 Hz,1H),6.78-6.71(m,1H),5.61-5.52(m,2H),5.25-5.23(m,1H),4.62(d,J=5.2 Hz,2H)ppm

[0194] Step 5: Preparation of methyl 3-chloro-4-(hydroxymethyl)-5-(vinylthio)benzoate To a mixture of (4-bromo-2-chloro-6-(vinylthio)phenyl)methanol (1000 mg, 3.58 mmol) in MeOH (20 mL) and TEA (10 mL), Pd(OAc)2 (80.30 mg, 357.68 μmol) and XPhos (341 mg, 0.715 mmol) were added, the mixture was degassed and degassed three times with CO (15 psi), then the mixture was stirred under CO (15 psi) atmosphere at 70 °C for 8 h. The mixture was diluted with water (20 mL), extracted with EA (15 mL × 3), and the combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 5 / 1). The fractions were concentrated in vacuo to give 3-chloro-4-(hydroxymethyl)-5-(vinylthio)benzoic acid (650 mg, 2.36 mmol, 66% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ=7.83(d,J=1.6 Hz,1H),7.80(d,J=1.6 Hz,1H),6.74-6.67(m,1H),5.62-5.51(m,2H),5.36-5.33(m,1H),4.70(d,J=5.2 Hz,2H),3.87(s,3H)ppm

[0195] Step 6: Preparation of methyl 3-chloro-4-(hydroxymethyl)-5-(vinylsulfonyl)benzoate To a mixture of methyl 3-chloro-4-(hydroxymethyl)-5-(vinylthio)benzoate (500 mg, 1.93 mmol) in HO (5 mL) and MeOH (5 mL) was added Oxone® (3.56 g, 5.80 mmol) and the mixture was stirred at 25° C. for 1 h. After the mixture was diluted with water (200 mL), it was extracted with EA (250 mL×2) and the combined organic solution was washed with saturated NaSO (150 mL×2) and brine (100 mL), dried over NaSO, filtered and concentrated under reduced pressure to give methyl 3-chloro-4-(hydroxymethyl)-5-vinylsulfonyl-benzoate (560 mg, crude) as a yellow oil. LCMS(ESI)m / z:[M+H] +=273.0 1 H NMR(400 MHz,DMSO-d6)δ=8.42(d,J=1.6 Hz,1H),8.27(d,J=1.6 Hz,1H),7.34-7.27(m,1H),6.47-6.31(m,2H),5.52-5.49(m,2H),4.98(d,J=5.2 Hz,2H),3.91(s,3H)ppm.

[0196] Step 7: Preparation of 6-chloro-2,3-dihydro-5H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide (Intermediate 4) To a mixture of 3-chloro-4-(hydroxymethyl)-5-vinylsulfonyl-methyl-benzoate (560 mg, 1.93 mmol) in THF (18 mL), NaH (154.09 mg, 3.85 mmol, 60% purity) was added at 0° C., and the mixture was stirred at 0° C. for 1 h. The mixture was diluted with water (10 mL) and MeOH (5 mL), and then stirred at 25° C. for 15 min. The resulting mixture was diluted with water (100 mL) and acidified to pH 2 with HCl (1N), and the resulting solution was extracted with EA (150 mL×2), and the combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 6-chloro-2,3-dihydro-5H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide (300 mg, crude) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ=13.91-13.84(m,1H),8.38(d,J=1.6 Hz,1H),8.22(d,J=1.6 Hz,1H),5.19(s,2H),4.23-4.21(m,2H),3.79-3.77-3.74(m,2H)ppm.

[0197] Intermediate 5: 6-Fluoro-2,3-dihydro-5H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide [ka] Step 1: Preparation of methyl 4-bromo-2-fluoro-6-((4-methoxybenzyl)thio)benzoate To a mixture of methyl 4-bromo-2,6-difluoro-benzoate (5 g, 19.92 mmol) and (4-methoxyphenyl)methanethiol (3.07 g, 19.92 mmol, 2.77 mL) in DMF (50 mL) was added Cs2CO3 (12.98 g, 39.84 mmol) and the mixture was stirred at 60° C. for 2 h. The mixture was diluted with water (400 mL) and extracted with EA (200 mL×3), and the combined organic layers were washed with brine (200 mL×2), then dried over Na2SO4, filtered and concentrated in vacuo to give methyl 4-bromo-2-fluoro-6-((4-methoxybenzyl)thio)benzoate (9 g, crude) as a yellow oil, which was used directly in the next step. 1 H NMR(400 MHz,DMSO-d6)δ=7.54-7.51(m,2H),7.29-7.26(m,2H),6.90-6.87(m,2H),4.29(s,2H),3.83(s,3H),3.73-3.72(m,3H)ppm.

[0198] Step 2: Preparation of methyl 4-bromo-2-fluoro-6-mercaptobenzoate A mixture of methyl 4-bromo-2-fluoro-6-((4-methoxybenzyl)thio)benzoate (9 g, 23.36 mmol) in TFA (138.60 g, 1.22 mol, 90 mL) was stirred at 60° C. for 2 h. The mixture was evaporated and then neutralized to pH 7 with saturated NaHCO3. The mixture was then extracted with EA (200 mL). The organic layer was separated and dried over anhydrous Na2SO4. The organic phase was concentrated in vacuo to give methyl 4-bromo-2-fluoro-6-mercaptobenzoate (6 g, crude) as a yellow oil, which was used directly in the next step. 1 H NMR(400 MHz,DMSO-d6)δ=7.77-7.61(m,2H),3.93(s,3H)ppm.

[0199] Step 3: Preparation of (4-bromo-2-fluoro-6-mercaptophenyl)methanol To a mixture of methyl 4-bromo-2-fluoro-6-mercaptobenzoate (3.4 g, 12.83 mmol) in THF (34 mL) was added LiAlH4 (535.5 mg, 14.11 mmol) and the mixture was stirred at 0° C. for 1 h. The mixture was quenched with 1N HCl (100 mL) and extracted with EA (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give (4-bromo-2-fluoro-6-mercaptophenyl)methanol (3 g, crude) as a yellow oil, which was used directly in the next step. 1 H NMR(400 MHz,DMSO-d6)δ=7.51(s,1H),7.32-7.24(m,1H),4.45(d,J=1.2 Hz,2H)

[0200] Step 4: Preparation of (4-bromo-2-fluoro-6-(vinylthio)phenyl)methanol To a mixture of (4-bromo-2-fluoro-6-mercaptophenyl)methanol (3 g, 12.65 mmol), K2CO3 (5.25 g, 37.96 mmol) in DMF (60 mL) was added 1,2-dibromoethane (11.89 g, 63.27 mmol), and the mixture was stirred at 25 °C for 15 h. The mixture was poured into water (200 mL) and extracted with EA (100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE / EA=10 / 1, SiO2) and the eluent was evaporated to give (4-bromo-2-fluoro-6-(vinylthio)phenyl)methanol (1.6 g, 6.08 mmol, 48% yield) as a colorless oil. 1 H NMR(400 MHz,DMSO-d6)δ=7.47-7.44(m,1H),7.30-7.29(m,1H),6.77-6.70(m,1H),5.59-5.52(m,2H),5.22-5.20(m,1H),4.51-4.46(m,2H)ppm

[0201] Step 5: Preparation of (4-bromo-2-fluoro-6-(vinylsulfinyl)phenyl)methanol To a mixture of (4-bromo-2-fluoro-6-(vinylthio)phenyl)methanol (800 mg, 3.04 mmol) in DCM (12 mL) was added m-CPBA (678.98 mg, 3.34 mmol, 85% purity) at 0° C., and the mixture was stirred at 25° C. for 1 h. The reaction mixture was quenched by adding saturated aqueous Na2SO3 (20 mL) at 0° C., then diluted with H2O (20 mL) and extracted with EA (100 mL×3). The combined organic layers were washed with 100 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=20 / 1 to 1 / 1). The fractions were concentrated in vacuo to give (4-bromo-2-fluoro-6-(vinylsulfinyl)phenyl)methanol (690 mg, 2.47 mmol, 81% yield) as a yellow solid. LCMS(ESI)m / z:[ 79 BrM+H] + =278.9 1 H NMR(400 MHz,DMSO-d6)δ=7.74-7.71(m,1H),7.61-7.60(m,1H),7.12-7.06(m,1H),6. 05-5.92(m,2H),5.85-5.82(m,1H),4.75-4.71(m,1H),4.63-4.58(m,1H)ppm

[0202] Step 6: Preparation of 8-bromo-6-fluoro-2,3-dihydro-5H-benzo[e][1,4]oxathiepin 1-oxide To a mixture of (4-bromo-2-fluoro-6-(vinylsulfinyl)phenyl)methanol (650 mg, 2.33 mmol) in DMF (40 mL) was added NaH (186.3 mg, 4.66 mmol, 60% purity) at 0 °C, and the mixture was stirred at 0 °C for 1 h. The reaction solution was quenched with 50 mL of saturated aqueous NH4Cl and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (60 mL × 3), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1), and the eluent was concentrated in vacuo to give 8-bromo-6-fluoro-2,3-dihydro-5H-benzo[e][1,4]oxathiepin 1-oxide (350 mg, 1.25 mmol, 54% yield) as a white solid. 1 H NMR(400 MHz, CDCl3)δ=7.79(m,1H),7.38-7.35(m,1H),5.13(d,J=14.4 Hz,1H),4.49-4.34(m,3H),3.47-3.41(m,1H),3.26-3.21(m,1H)ppm.

[0203] Step 7: Preparation of 6-fluoro-2,3-dihydro-5H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1-oxide To a mixture of 8-bromo-6-fluoro-2,3-dihydro-5H-benzo[e][1,4]oxathiepin 1-oxide (320 mg, 1.15 mmol), Pd(OAc)2 (12.87 mg, 57.32 μmol), and bicyclohexyl(3-bicyclohexylphosphaniumylpropyl)phosphonium; ditetrafluoroborate (70.19 mg, 114.64 μmol) in DMSO (4 mL) and H2O (0.2 mL), K2CO3 (475.33 mg, 3.44 mmol) was added, and the mixture was stirred at 100 °C under CO (15 psi) for 4 h. The mixture was diluted with water (50 mL) and extracted with EA (30 mL × 3). The aqueous layer was acidified to pH = 3 with HCl solution (2 M) and extracted with EA (100 mL × 2). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 6-fluoro-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1-oxide (210 mg, crude) as a white solid, which was used directly in the next step. LCMS(ESI)m / z:[M+H] + =244.9

[0204] Step 8: Preparation of 6-fluoro-2,3-dihydro-5H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide (Intermediate 5) To a mixture of 6-fluoro-2,3-dihydro-5H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1-oxide (210.00 mg, 859.81 μmol) in MeOH (4 mL) and HO (4 mL), Oxone® (634.30 mg, 1.03 mmol) was added and the mixture was stirred at 25° C. for 2 h. The mixture was diluted with water (50 mL) and then extracted with EA (30 mL×3), and the combined organic layers were washed with brine (40 mL×2), dried over Na2SO4, filtered, and concentrated in vacuo to give 6-fluoro-2,3-dihydro-5H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide (220 mg, crude) as a white solid, which was used directly in the next step.

[0205] Intermediates 6 and 7. (R)-2-Methyl-2,3-dihydro-5H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide and (S)-2-Methyl-2,3-dihydro-5H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide [ka] Step 1: Preparation of 8-bromo-2-methyl-3,5-dihydro-2H-benzo[e][1,4]oxathiepin 1,1-dioxide To a solution of 8-bromo-2,3-dihydro-5H-benzo[e][1,4]oxathiepin 1,1-dioxide (380 mg, 1.37 mmol, 641.03 uL) in DMF (5 mL) was added NaH (65.82 mg, 1.65 mmol, 60% purity) at 0° C. The mixture was stirred at 0° C. for 0.5 h. Then, MeI (233.55 mg, 1.65 mmol, 102.43 uL) was added slowly at 0° C. The mixture was stirred at 25° C. for 1.5 h. The mixture was diluted with saturated NH4Cl solution (30 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give a residue. The residue was purified by reverse phase HPLC (0.1% FA condition). The eluate was concentrated to remove MeCN and lyophilized to give 8-bromo-2-methyl-3,5-dihydro-2H-benzo[e][1,4]oxathiepin 1,1-dioxide (100 mg, 309.11 μmol, 23% yield) as a white solid. LCMS(ESI)m / z:[M+H] + =291.0 / 292.9 1 HNMR(400 MHz,DMSO-d6)δ=7.99(d,J=2.0 Hz,1H),7.95-7.92(m,1H),7.56(d,J=8.0 Hz,1H),4.87(s,2H),4.27-4.23(m,1H),4.00-3.95(m,1H),3.71-3.62(m,1H),1.14(d,J=7.2 Hz,3H)ppm.

[0206] Step 2: Preparation of 2-methyl-3,5-dihydro-2H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide To a solution of 8-bromo-2-methyl-3,5-dihydro-2H-benzo[e][1,4]oxathiepin 1,1-dioxide (100 mg, 343.45 μmol) in DMSO (1 mL) and HO (30.95 mg, 1.72 mmol, 31 μL) was added 1,3-bis(bicyclohexylphosphino)propane bis(tetrafluoroborate) (21.03 mg, 34.35 μmol), KCO (71.20 mg, 515.18 μmol), and Pd(OAc) (7.71 mg, 34.35 μmol). The flask was degassed and purged with CO three times. The mixture was stirred at 100 °C under CO (15 psi) atmosphere for 4 h. The mixture was filtered and washed with EA (2 mL) and water (2 mL). The mixture was then diluted with water (5 mL) and extracted with EA (5 mL×2). The combined organic layers were discarded. The aqueous phase was adjusted to pH=6 with 1N HCl aq. The aqueous phase was then extracted with EA (5 mL×2). The combined organic layers were washed with brine (5 mL×2), dried over anhydrous Na2SO4, and concentrated to give 2-methyl-3,5-dihydro-2H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide (80 mg, 0.290 mol, 85% yield) as a white solid. LCMS(ESI)m / z:[M+H] + =256.9. 1 HNMR(400 MHz,DMSO-d6)δ=8.44(d,J=1.6 Hz,1H),8.22-8.19(m,1H),7.72(d,J=8.0 Hz,1H),4.95(s,2H),4.29-4.25(m,1H),4.03-3.98(m,1H),3.72-3.60(m,1H),1.14(d,J=6.8 Hz,3H)ppm.

[0207] Step 3: Preparation of (R)-2-methyl-3,5-dihydro-2H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide (Intermediate 6) and (S)-2-methyl-3,5-dihydro-2H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide (Intermediate 7) Racemic 2-methyl-3,5-dihydro-2H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide was separated by SFC (column: Daicel ChiralPak IG (250×30 mm, 10 um); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 30% to 30%, 3.0; 85 min). The eluate was concentrated to remove most of the solvent and adjusted to pH=6 with FA. The mixture was then extracted with DCM (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give (R)-2-methyl-3,5-dihydro-2H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide (35 mg, 0.136 mmol, 44% yield) as a white solid and (S)-2-methyl-3,5-dihydro-2H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide (40 mg, 0.156 mmol, 50.00% yield) as a white solid. Stereochemistry arbitrarily assigned. (R)-2-Methyl-3,5-dihydro-2H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide (Intermediate 6): LCMS(ESI)m / z:[M+Na] + =279.1. Chiral SFC:IG-3_5CM_MEOH(DEA)_5_40_3ML_T35.M;Rt=1.729 minutes. (S)-2-Methyl-3,5-dihydro-2H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide (Intermediate 7): LCMS(ESI)m / z:[M+Na] + =279.1. Chiral SFC:IG-3_5CM_MEOH(DEA)_5_40_3ML_T35.M;Rt=1.897 min.

[0208] Intermediate 8. 6,7,8,9-Tetrahydrothiepino[3,2-b]pyridine-3-carboxylic acid 5,5-dioxide [ka] Step 1: Preparation of 2-bromo-5-chloro-pyridine-3-thiol To a mixture of 2-bromo-5-chloro-3-fluoro-pyridine (1.3 g, 6.18 mmol, 1 equiv) in DMF (20 mL) was added Na2S (482.14 mg, 6.18 mmol, 259.22 μL) in one portion at 25 °C under N2. The mixture was stirred at 25 °C for 12 h. The mixture was poured into (100 mL). The mixture was adjusted to pH = 3 by adding aqueous HCl (2 M). The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (50 mL x 1), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 2-bromo-5-chloro-pyridine-3-thiol (1.2 g, 5.35 mmol, 86.52% yield) as a yellow solid. LCMS(ESI)m / z:[ 79 BrM+H] + =225.8. 1 H NMR(400 MHz,DMSO-d6)δ=8.33-8.23(m,1H),8.17-8.08(m,1H)ppm.

[0209] Step 2: Preparation of 2-bromo-3-(but-3-en-1-ylthio)-5-chloropyridine To a mixture of 2-bromo-5-chloro-pyridine-3-thiol (1.2 g, 5.35 mmol) and but-3-en-1-ol (385.41 mg, 5.35 mmol, 459.91 μL) in THF (10 mL), PPh3 (2.10 g, 8.02 mmol) was added dropwise at 0 °C under N2, followed by DEAD (1.40 g, 8.02 mmol, 1.46 mL). The mixture was stirred at 25 °C for 12 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (30 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1). The eluate was concentrated to give 2-bromo-3-(but-3-en-1-ylthio)-5-chloropyridine (1.2 g, 4.31 mmol, 81% yield) as a yellow oil. LCMS(ESI)m / z:[ 79 BrM+H] + =277.9. 1 H NMR(400 MHz, CDCl3)δ=8.05-7.99(m,1H),7.34-7.28(m,1H),5.88-5.73(m,1H),5.16-5.01(m,2H),2.99-2.86(m,2H),2.48-2.35(m,2H)ppm.

[0210] Step 3: Preparation of 3-(but-3-en-1-ylthio)-5-chloro-2-vinylpyridine A mixture of 2-bromo-3-(but-3-en-1-ylthio)-5-chloropyridine (860 mg, 3.09 mmol), potassium vinyltrifluoroborate (1.24 g, 9.26 mmol), Pd(dtbpf)Cl2 (201.19 mg, 308.69 μmol), and K3PO4 (1.97 g, 9.26 mmol) in dioxane (12 mL) and H2O (3 mL) was stirred at 80 °C under N2 for 1 h. The mixture was poured into H2O (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE-PE / EA = 20 / 1). The eluate was concentrated under reduced pressure to obtain 3-(but-3-en-1-ylthio)-5-chloro-2-vinylpyridine (510 mg, 2.26 mmol, yield 73%) as a yellow oil. LCMS(ESI)m / z:[M+H] + =226.0. 1 H NMR(400 MHz, CDCl3)δ=8.36(d,J=2.4 Hz,1H),7.60(d,J=2.4 Hz,1H),7.26-7.19(m,1H),6.41-6.36(m,1H),5.89-5.81(m,1H),5.57-5 .53(m,1H),5.20-5.07(m,2H),2.97-2.93(m,2H),2.44-2.36(m,2H)ppm.

[0211] Step 4: Preparation of 3-chloro-6,7-dihydrothiepino[3,2-b]pyridine A mixture of 3-(but-3-en-1-ylthio)-5-chloro-2-vinylpyridine (250 mg, 1.11 mmol) and benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-ruthenium;tricyclohexylphosphane (Grubbs II) (94.0 mg, 0.111 mol) in DCM (12 mL) was stirred at 25° C. under N2 for 16 h. The solution was concentrated in vacuo. The residue was purified by silica gel chromatography (PE-PE / EA=20 / 1). The eluate was concentrated in vacuo to give 3-chloro-6,7-dihydrothiepino[3,2-b]pyridine (110 mg, 556.44 μmol, 50% yield) as a yellow oil. LCMS(ESI)m / z:[M+H] + =198.0. 1 H NMR(400 MHz,CDCl3)δ=8.40(d,J=2.0 Hz,1H),7.71(d,J=1.6 Hz,1H),6.81-6.71(m,1H),6.32-6.26(m,1H),3.10-3.05(m,2H),2.88-2.81(m,2H)

[0212] Step 5: Preparation of 6,7-dihydrothiepino[3,2-b]pyridine-3-carboxylic acid A mixture of 3-chloro-6,7-dihydrothiepino[3,2-b]pyridine (50 mg, 0.253 mol), K2CO3 (52.44 mg, 0.379 mol), Pd(OAc)2 (2.84 mg, 12.65 μmol), 1,3-bis(bicyclohexylphosphino)propane bis(tetrafluoroborate) (15.49 mg, 25.29 μmol), and H2O (100 μL) in DMSO (1 mL) was stirred at 100 °C under CO (15 psi) for 4 h. The mixture was poured into H2O (10 mL) and extracted with EA (10 mL × 2). The organic phase was discarded. The aqueous phase was acidified with HCl (1 M) to pH = 3 and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (10 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 6,7-dihydrothiepino[3,2-b]pyridine-3-carboxylic acid (28 mg, 135.10 μmol, 53.4% ​​yield) as a white solid. LCMS(ESI)m / z:[M+H] + =207.9. 1 H NMR(400 MHz, CDCl3)δ=8.36(d,J=2.4 Hz,1H),7.60(d,J=2.4 Hz,1H),7.26-7.19(m,1H),6.41-6.36(m,1H),5.89-5.81(m,1H),5.57-5 .53(m,1H),5.20-5.07(m,2H),2.97-2.93(m,2H),2.44-2.36(m,2H)ppm.

[0213] Step 6: Preparation of 6,7,8,9-tetrahydrothiepino[3,2-b]pyridine-3-carboxylic acid To a mixture of 6,7-dihydrothiepino[3,2-b]pyridine-3-carboxylic acid (28 mg, 135.10 μmol) in MeOH (5 mL) was added Pd / C (wet, 50 mg, 10% purity) at 25° C. The mixture was purged with H2 three times and stirred under H2 (15 psi) at 25° C. for 30 min. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 6,7,8,9-tetrahydrothiepino[3,2-b]pyridine-3-carboxylic acid (23 mg, 109.91 μmol, 81.2% yield) as a white solid. LCMS(ESI)m / z:[M+H] + =210.0. 1 H NMR(400 MHz,DMSO-d6)δ=8.81(d,J=2.0 Hz,1H),8.20(d,J=2.0 Hz,1H),3.23-3.17(m,2H),2.88-2.78(m,2H),2.11-1.96(m,2H),1.76-1.62(m,2H)ppm.

[0214] Step 7: Preparation of 5,5-dioxo-6,7,8,9-tetrahydrothiepino[3,2-b]pyridine-3-carboxylic acid (Intermediate 8) To a mixture of 6,7,8,9-tetrahydrothiepino[3,2-b]pyridine-3-carboxylic acid (23 mg, 109.91 μmol) in MeOH (1 mL) and HO (1 mL) was added Oxone® (67.57 mg, 109.9 μmol) at 25° C. The mixture was stirred at 25° C. for 4 h. The mixture was quenched with saturated Na2SO3 (20 mL), acidified to pH=2 with HCl (1 M) and extracted with EA (20 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 5,5-dioxo-6,7,8,9-tetrahydrothiepino[3,2-b]pyridine-3-carboxylic acid (18 mg, 74.61 μmol, 68% yield) as a white solid. LCMS(ESI)m / z:[M+H] + =241.9. 1 H NMR(400 MHz,DMSO-d6)δ=9.14(d,J=2.0 Hz,1H),8.55(d,J=2.1 Hz,1H),3.53-3.51(m,2H),3.17(br d,J=5.2 Hz,2H),2.19-2.13(m,2H),1.82(br d,J=3.2 Hz,2H)ppm.

[0215] Intermediate 9: 4,5-Dihydro-2H-benzo[d][1,3]oxathiepin-8-carboxylic acid 1,1-dioxide [ka] Step 1: Preparation of (6-bromobenzo[b]thiophen-2-yl)boronic acid To a mixture of 6-bromobenzo[b]thiophene (8 g, 37.54 mmol) in THF (80 mL) was added LDA (2 M, 22.53 mL) dropwise at −70° C. under N2. The mixture was stirred at −70° C. for 1 h. Then, to the mixture was added triisopropyl borate (8.47 g, 45.05 mmol, 10.36 mL) at −70° C. and the mixture was stirred for 1 h. To the mixture was added H2SO4 (7.36 g, 75.08 mmol, 4.00 mL) at −70° C. and the mixture was stirred at 25° C. for 1 h. The mixture was poured into water (300 mL) and extracted with ethyl acetate (200 mL×2). The combined organic phase was washed with brine (200 mL×1), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was triturated with PE / MTBE=10 / 1 (50 mL). The suspension was filtered. The filter cake was dried under pump to give (6-bromobenzo[b]thiophen-2-yl)boronic acid (7.3 g, 28.41 mmol, 76% yield) as a pale yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.58-8.53(m,2H),8.28-8.24(m,1H),7.96-7.93(m,1H),7.88-7.84(m,1H),7.54-7.46(m,1H)ppm.

[0216] Step 2: Preparation of 6-bromobenzo[b]thiophen-2(3H)-one To a mixture of (6-bromobenzo[b]thiophen-2-yl)boronic acid (6.5 g, 25.30 mmol) in EtOH (78 mL) was added H2O2 (38.35 g, 338.24 mmol, 32.50 mL) dropwise at 25 °C under N2. The mixture was stirred at 25 °C for 1 h. The mixture was filtered. The filter cake was washed with H2O (50 mL) and dried in vacuum to give 6-bromobenzo[b]thiophen-2(3H)-one (4.2 g, 18.33 mmol, 72% yield) as a brown solid. LCMS(ESI)m / z:[M+H] + =214.8,216.9. 1 H NMR(400 MHz, CDCl3)δ=7.53-7.47(m,1H),7.38-7.32(m,1H),7.16(d,J=8.0 Hz,1H),4.06-3.84(m,2H)ppm.

[0217] Step 3: Preparation of 2-(4-bromo-2-mercaptophenyl)ethan-1-ol To a mixture of 6-bromobenzo[b]thiophen-2(3H)-one (4.2 g, 18.33 mmol) in EtOH (67 mL) was added NaBH4 (3.47 g, 91.67 mmol) portionwise at 25 °C under N2. The mixture was stirred at 80 °C for 30 min. The mixture was cooled to 25 °C. Aqueous HCl (1 M) was slowly added to the mixture to adjust pH = 2. The mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1). The eluate was concentrated to give 2-(4-bromo-2-mercaptophenyl)ethan-1-ol (3.6 g, 15.44 mmol, 84% yield) as a yellow oil. 1 H NMR(400 MHz,DMSO-d6)δ=7.61(d,J=2.0 Hz,1H),7.24-7.22(m,1H),7.13(d,J=8.2 Hz,1H),5.58(s,1H),4.97-4.49(m,1H),3.59-3.57(m,2H),2.71-2.69(m,2H).

[0218] Step 4: Preparation of 8-bromo-4,5-dihydrobenzo[d][1,3]oxathiepin To a mixture of 2-(4-bromo-2-mercaptophenyl)ethan-1-ol (500 mg, 2.14 mmol) in DMF (50 mL) was added NaH (257.37 mg, 6.43 mmol) portionwise at 0 °C under N2. The mixture was stirred at 25 °C for 30 min. Then, to the mixture was added chloro(iodo)methane (416.13 mg, 2.36 mmol, 171 μL) in DMF (1 mL) dropwise at 0 °C under N2. The mixture was stirred at 25 °C for 1.5 h. The mixture was poured into saturated NH4Cl (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1). The eluate was concentrated to give 8-bromo-4,5-dihydrobenzo[d][1,3]oxathiepine (50 mg, 0.189 mmol, 9% yield) as a yellow oil. LCMS(ESI)m / z:[M+H] + =246.2,248.0. 1 H NMR(400 MHz,DMSO-d6)δ=7.67-7.60(m,1H),7.47-7.38(m,1H),7.31-7.22(m,1H),5.00-4.86(m,2H),3.81-3.67(m,2H),3.12-3.09(m,2H)ppm.

[0219] Step 5: Preparation of 4,5-dihydrobenzo[d][1,3]oxathiepin-8-carboxylic acid A solution of 8-bromo-4,5-dihydrobenzo[d][1,3]oxathiepin (50 mg, 203.97 μmol), Pd(OAc)2 (4.58 mg, 20.40 μmol), 1,3-bis(bicyclohexylphosphino)propane bis(tetrafluoroborate) (24.98 mg, 40.79 μmol), and K2CO3 (56.38 mg, 0.408 mmol) in DMSO (2 mL) and H2O (0.2 mL) was degassed under vacuum and purged with CO several times. The mixture was stirred at 100 °C under CO (15 psi) for 2 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL × 2). The organic layer was discarded. Aqueous HCl solution (1 M) was added to the aqueous phase to adjust pH = 3. The mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 4,5-dihydrobenzo[d][1,3]oxathiepin-8-carboxylic acid (40 mg, 190.25 μmol, 93% yield) as a yellow solid. LCMS(ESI)m / z:[M+H] + =211.1.

[0220] Step 6: Preparation of 4,5-dihydro-2H-benzo[d][1,3]oxathiepin-8-carboxylic acid 1,1-dioxide (Intermediate 9) To a mixture of 4,5-dihydrobenzo[d][1,3]oxathiepin-8-carboxylic acid (20 mg, 95.13 μmol) in DCM (1 mL) was added mCPBA (48.28 mg, 237.81 μmol, 85% purity) portionwise under N2 at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was filtered and the filtrate was concentrated. The residue was directly purified by reversed phase column (FA). The eluate was concentrated to remove MeCN. The aqueous phase was lyophilized to give 4,5-dihydrobenzo[d][1,3]oxathiepin-8-carboxylic acid 1,1-dioxide (20 mg, 82.56 μmol, 86.79% yield) as a white solid. LCMS(ESI)m / z:[M+H2O] + =260.0. 1H NMR(400 MHz,DMSO-d6)δ=8.38(d,J=1.6 Hz,1H),8.16-8.14(m,1H),7.62(d,J=7.8 Hz,1H),4.99(s,2H),4.01-4.00(m,2H),3.42(s,2H)ppm.

[0221] Intermediate 10: 4,5-Dihydro-2H-benzo[d][1,3]oxathiepin-8-carboxylic acid 1,1-dioxide [ka] Step 1: Preparation of 4-bromo-2-[(4-methoxyphenyl)methylsulfanyl]benzonitrile To a solution of 4-bromo-2-fluoro-benzonitrile (10 g, 50.00 mmol) and (4-methoxyphenyl)methanethiol (7.71 g, 50.00 mmol) in DMF (100 mL) was added Cs2CO3 (16.29 g, 50.00 mmol) and the mixture was stirred at 60° C. for 2 h. The reaction mixture was poured into water (1000 mL), the solution was extracted with EA (1000 mL×3), and the combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated to give 4-bromo-2-[(4-methoxyphenyl)methylsulfanyl]benzonitrile (13 g, crude) as a white solid.

[0222] Step 2: Preparation of [4-bromo-2-[(4-methoxyphenyl)methylsulfanyl]phenyl]methanamine To a solution of 4-bromo-2-[(4-methoxyphenyl)methylsulfanyl]benzonitrile (13 g, 38.90 mmol) in THF (150 mL) was added LiAlH4 (1.62 g, 42.78 mmol) under N2 at 0° C. and the mixture was stirred at 0° C. for 1 h. The mixture was poured into water (1.62 g) and 15% NaOH solution (2.5 mL), the solution was poured into EA (500 mL), the solution was filtered and the filtrate was concentrated to give [4-bromo-2-[(4-methoxyphenyl)methylsulfanyl]phenyl]methanamine (13 g, crude) as a yellow oil. 1H NMR(400 MHz,DMSO-d6)δ=7.48-7.47(m,1H),7.21-7.20(m,1H),7.19-7.18(m,3H),6.85-6.82(m,2H),4.08(s,2H),3.80-3.79(m,5H)ppm

[0223] Step 3: Preparation of [2-[[2-(aminomethyl)-5-bromo-phenyl]disulfanyl]-4-bromo-phenyl]methanamine A mixture of [4-bromo-2-[(4-methoxyphenyl)methylsulfanyl]phenyl]methanamine (13 g, 38.43 mmol) in TFA (130 mL) was stirred at 60° C. for 16 h. The reaction mixture was concentrated to give a residue. The residue was purified by reverse-phase HPLC (0.1% FA condition). The solution was lyophilized to give aminomethyl)-5-bromo-phenyl]disulfanyl]-4-bromo-phenyl]methanamine (3.5 g, 7.20 mmol, 19% yield) as a white solid. LCMS(ESI)m / z:[ 79 BrM+H] += 434.8 1H NMR(400 MHz,DMSO-d6)δ=8.35(br s,3H),7.55(s,2H),7.50-7.37(m,1H),4.05(s,2H)ppm

[0224] Step 4: Preparation of 8-bromo-4,5-dihydro-1,4-benzothiazepin-3-one To a solution of aminomethyl)-5-bromo-phenyl]disulfanyl]-4-bromo-phenyl]methanamine (1 g, 2.30 mmol) in THF (15 mL) was added NaBH4 (261.37 mg, 6.91 mmol) and the mixture was stirred at 30° C. for 2 h. Then, to the solution was added TEA (11.52 mmol, 1.60 mL), 2-chloroacetyl chloride (312.13 mg, 2.76 mmol) and the mixture was stirred at 30° C. for 3 h. The reaction mixture was poured into water (100 mL) and extracted with EA (100 mL×3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1 to 0:1), and the solution was concentrated to give 8-bromo-4,5-dihydro-1,4-benzothiazepin-3-one (300 mg, 871.29 μmol, 38% yield) as a white solid. LCMS(ESI)m / z:[ 79 BrM+H] += 260.0 1H NMR(400 MHz,DMSO-d6)δ=7.37(d,J=2.0 Hz,1H),7.24-7.22(m,1H),7.07(d,J=8.0 Hz,1H),4.45(s,2H),3.89(s,2H)ppm

[0225] Step 5: Preparation of 3-oxo-4,5-dihydro-1,4-benzothiazepine-8-carboxylic acid (Intermediate 10) To a solution of 8-bromo-4,5-dihydro-1,4-benzothiazepin-3-one (280 mg, 1.08 mmol) in DMSO (5 mL) was added bicyclohexyl(3-bicyclohexylphosphaniumylpropyl)phosphonium;ditetrafluoroborate (66.41 mg, 108.47 μmol), K2CO3 (224.88 mg, 1.63 mmol), Pd(OAc)2 (24.35 mg, 108.47 μmol), and H2O (3.91 mg, 216.94 μmol) and the mixture was stirred at 100 °C under CO (15 psi) for 2 h. The reaction mixture was filtered, the solution was extracted with MTBE (10 mL), and the organic layer was discarded. The aqueous phase was then adjusted to pH = 2 with 1N HCl, the solution was extracted with EA (50 mL × 5), and the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give 3-oxo-4,5-dihydro-1,4-benzothiazepine-8-carboxylic acid (120 mg, 0.487 mmol, 45% yield) as a white solid. LCMS(ESI)m / z:[M+H] += 224.1 1 H NMR(400 MHz,DMSO-d6)δ=13.09-13.06(m,1H),8.18(t,J=6.4 Hz,1H),7.64(d,J=1.6 Hz,1H),7.60-7.57(m,1H),7.29(d,J=8.0 Hz,1H),4.45(d,J=6.4 Hz,2H),3.91(s,2H)ppm

[0226] Step 6: Preparation of 1,1,3-trioxo-4,5-dihydro-1λ6,4-benzothiazepine-8-carboxylic acid To a solution of 3-oxo-4,5-dihydro-1,4-benzothiazepine-8-carboxylic acid (50 mg, 223.97 μmol) in MeOH (0.5 mL) and HO (0.5 mL) was added Oxone (275.37 mg, 447.93 μmol) and the mixture was stirred for 2 h at 30° C. The reaction mixture was poured into MeOH (5 mL), the solution was filtered, and the filtrate was concentrated to give 1,1,3-trioxo-4,5-dihydro-1λ6,4-benzothiazepine-8-carboxylic acid (57 mg, 223.31 μmol, 99.71% yield) as a white solid.

[0227] Intermediate 11. 4-(2-Methoxyethyl)-3-methylsulfonyl-benzoic acid [ka] Step 1: Preparation of 2-(4-chloro-2-methylsulfanyl-phenyl)acetic acid A mixture of 2-(2-bromo-4-chlorophenyl)acetic acid (1 g, 4.01 mmol), CuI (763.36 mg, 4.01 mmol), and DABCO (899.20 mg, 8.02 mmol, 881.57 uL) in DMSO (10 mL) was stirred at 145 °C under N2 for 12 h. The reaction mixture was diluted with 1N HCl (300 mL) and filtered. The filtrate was extracted with DCM (300 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The eluate was concentrated to give 2-(4-chloro-2-methylsulfanyl-phenyl)acetic acid (1.5 g, crude) as a yellow solid, which was used directly in the next step.

[0228] Step 2: Preparation of 2-(4-chloro-2-methylsulfonyl-phenyl)acetic acid To a solution of 2-(4-chloro-2-methylsulfanyl-phenyl)acetic acid (500 mg, 2.31 mmol) in MeOH (3 mL) and HO (3 mL) was added oxone (4.26 g, 6.92 mmol) in HO (3 mL) at 0° C. The mixture was stirred at 25° C. for 12 h. The reaction mixture was diluted with saturated NaSO (100 mL) and stirred for 10 min, then extracted with DCM (100 mL×3). The organic layer was dried over anhydrous NaSO, filtered and concentrated to give a residue. The residue was purified by reverse phase (0.1% FA). The eluate was concentrated to give 2-(4-chloro-2-methylsulfonyl-phenyl)acetic acid (200 mg, 0.804 mol, 35% yield) as a white solid. LCMS(ESI)m / z:[M+H] + =248.9. 1 H NMR(400 MHz,DMSO-d6)δ=12.62-12.54(m,1H),7.91(d,J=2.0 Hz,1H),7.78-7.76(m,1H),7.55(d,J=8.0 Hz,1H),4.05(s,2H),3.26(s,3H)ppm.

[0229] Step 3: Preparation of 2-(4-chloro-2-methylsulfonyl-phenyl)ethanol To a solution of 2-(4-chloro-2-methylsulfonyl-phenyl)acetic acid (200 mg, 804.24 μmol) in THF (4 mL), BH3-Me2 S A mixture of (10M, 402.12uL) was added at 0°C. The mixture was stirred at 25°C for 2h. The reaction mixture was diluted with 1N HCl (10mL) and extracted with DCM (10mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by reverse phase (0.1% FA). The eluate was concentrated to give 2-(4-chloro-2-methylsulfonyl-phenyl)ethanol (180mg, 766.94μmol, 96% yield) as a colorless oil. LCMS(ESI)m / z:[M+H] + =235.0. 1H NMR(400 MHz, CDCl3)δ=8.06(d,J=2.4 Hz,1H),7.58-7.55(m,1H),7.42(d,J=8.0 Hz,1H),3.97-3.94(m,2H),3.28-3.25(m,2H),3.15(s,3H)ppm.

[0230] Step 4: Preparation of 4-chloro-1-(2-methoxyethyl)-2-methylsulfonyl-benzene To a solution of 2-(4-chloro-2-methylsulfonyl-phenyl)ethanol (80 mg, 0.341 mmol) in DCM (1 mL) was added Ag2O (236.97 mg, 1.02 mmol) and MeI (241.91 mg, 1.70 mmol, 106 uL). The mixture was stirred at 30 °C for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give a residue which was purified by reverse phase (0.1% FA). The eluate was concentrated to give 4-chloro-1-(2-methoxyethyl)-2-methylsulfonyl-benzene (60 mg, 0.241 mmol, 71% yield) as a yellow solid. LCMS(ESI)m / z:[M+H] + =248.9. 1 H NMR(400 MHz, CDCl3)δ=8.06(d,J=2.4 Hz,1H),7.55-7.52(m,1H),7.42(d,J=8.4 Hz,1H),3.70-3.67(m,2H),3.33-3.29(m,5H),3.15(s,3H)ppm.

[0231] Step 5: Preparation of 4-(2-methoxyethyl)-3-methylsulfonyl-benzoic acid (Intermediate 11) A mixture of 4-chloro-1-(2-methoxyethyl)-2-methylsulfonyl-benzene (60 mg, 0.241 mmol), K2CO3 (50.0 mg, 0.362 mmol), bicyclohexyl(3-bicyclohexylphosphaniumylpropyl)phosphonium; ditetrafluoroborate (14.77 mg, 24.12 μmol), and Pd(OAc)2 (2.71 mg, 12.06 μmol) in DMSO (1 mL) and H2O (0.2 mL) was degassed and purged with CO three times. The mixture was stirred at 100 °C under CO (15 psi) atmosphere for 3 h. The reaction mixture was diluted with MeOH (10 mL) and filtered. The filtrate was concentrated to give a residue. The residue was purified by reverse phase (0.1% FA). The eluate was concentrated to remove ACN and lyophilized to give 4-(2-methoxyethyl)-3-methylsulfonyl-benzoic acid (50 mg, 0.194 mmol, 80% yield) as a white solid. LCMS(ESI)m / z:[M+H] + =259.0. 1 H NMR(400 MHz,CDCl3)δ=8.78(d,J=1.6 Hz,1H),8.28-8.26(m,1H),7.61(d,J=8.4 Hz,1H),3.77-3.74(m,2H),3.45-3.42(m,2H),3.33(s,3H),3.19(s,3H)ppm.

[0232] Intermediate 12. 4-(2-Methoxyethyl)-3-methylsulfonyl-benzoic acid [ka] Step 1: Preparation of methyl 3-[allyl(tert-butoxycarbonyl)sulfamoyl]-4-vinyl-benzoate To a solution of methyl 3-(arylsulfamoyl)-4-vinyl-benzoate (1.2 g, 4.27 mmol) (prepared according to the method of FG-A4366) and DMAP (52.11 mg, 426.55 μmol) in DCM (20 mL) was added TEA (863.24 mg, 8.53 mmol, 1.19 mL) and Boc2O (1.86 g, 8.53 mmol, 1.96 mL) at 0° C. The mixture was stirred at 20° C. for 2 h. It was poured into water (60 mL) and extracted with DCM (40 mL×3). The combined organic layer was washed with brine (40 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a gradient of 0 to 50% ethyl acetate / petroleum ether at 50 mL / min). Fractions were concentrated in vacuo to give methyl 3-[allyl(tert-butoxycarbonyl)sulfamoyl]-4-vinyl-benzoate (1.5 g, 3.93 mmol, 92% yield) as a yellow oil. 1 H NMR(400 MHz,DMSO-d6)δ=8.50(d,J=2.0 Hz,1H),8.34-8.15(m,1H),7.92(d,J=8.4 Hz,1H),7.23-7.00(m,1H),6.01-5.86(m,2H),5.75-5.61(m,1H),5.39-5.14(m,2H),4.38(d,J=4.8 Hz,2H),3.91(s,3H),1.13(s,9H)ppm.

[0233] Step 2: Preparation of 8-methylbenzo[f][1,2]thiazepine-2,8(3H)-dicarboxylic acid 2-(tert-butyl) 1,1-dioxide A mixture of methyl 3-[allyl(tert-butoxycarbonyl)sulfamoyl]-4-vinyl-benzoate (1.5 g, 3.93 mmol) and benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-ruthenium;tricyclohexylphosphane (333.85 mg, 393.24 μmol) in DCM (80 mL) was degassed and purged with N2 three times. The mixture was stirred at 25° C. under N2 atmosphere for 2 h. It was concentrated to remove DCM. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a gradient of 0 to 50% ethyl acetate / petroleum ether at 50 mL / min). The fractions were concentrated in vacuo to give 8-methylbenzo[f][1,2]thiazepine-2,8(3H)-dicarboxylic acid 2-(tert-butyl) 1,1-dioxide (1.1 g, 2.77 mmol, 70% yield) as a yellow solid. LCMS(ESI)m / z:[Br 79 M+H] += 298.0 1 H NMR(400 MHz,DMSO-d6)δ=8.43(d,J=1.6 Hz,1H),8.32-8.17(m,1H),7.82(d,J=8.0 Hz,1H),6.75(d,J=12.8 Hz,1H),6.39-6.18(m,1H),4.95-4.57(m,2H),3.92(s,3H),1.11(s,9H)ppm.

[0234] Step 3: Preparation of 4,5-dihydrobenzo[f][1,2]thiazepine-2,8(3H)-dicarboxylic acid 2-(tert-butyl) 8-methyl 1,1-dioxide A mixture of benzo[f][1,2]thiazepine-2,8(3H)-dicarboxylic acid 2-(tert-butyl) 8-methyl 1,1-dioxide (500 mg, 1.41 mmol), Pd / C (50 mg, 10% purity) in MeOH (10 mL) was degassed and purged with H three times. The mixture was stirred at 20° C. under H atmosphere for 16 h. It was filtered and concentrated to give 4,5-dihydrobenzo[f][1,2]thiazepine-2,8(3H)-dicarboxylic acid 2-(tert-butyl) 8-methyl 1,1-dioxide (4.1 g, 12.27 mmol, 96% yield) as a yellow oil. LCMS(ESI)m / z:[Br 79 M+H] += 300.0 1 H NMR(400 MHz,DMSO-d6)δ=8.37(d,J=2.0 Hz,1H),8.23-8.11(m,1H),7.66(d,J=8.0 Hz,1H),4.17-4.06(m,2H),3.90(s,3H),3.32-3.14(m,2H),1.90-1.53(m,2H),1.22(s,9H)ppm.

[0235] Step 4: Preparation of 2-tert-butoxycarbonyl-1,1-dioxo-4,5-dihydro-3H-1λ6,2-benzothiazepine-8-carboxylic acid To a solution of 4,5-dihydrobenzo[f][1,2]thiazepine-2,8(3H)-dicarboxylic acid 2-(tert-butyl)8-methyl 1,1-dioxide (250 mg, 0.703 mmol) in THF (2.5 mL) and HO (2.5 mL) was added LiOH.HO (118.06 mg, 2.81 mmol). The mixture was stirred at 25 °C for 2 h. It was adjusted to pH = 5 with aqueous HCl (1 M) and extracted with EA (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered and concentrated to give 2-tert-butoxycarbonyl-1,1-dioxo-4,5-dihydro-3H-1λ6,2-benzothiazepine-8-carboxylic acid (190 mg, 0.473 mmol, 67% yield) as a white solid. LCMS(ESI)m / z:[M+H] +=285.9

[0236] Step 5: Preparation of 1,1-dioxo-2,3,4,5-tetrahydro-1λ6,2-benzothiazepine-8-carboxylic acid (Intermediate 12) A mixture of 2-tert-butoxycarbonyl-1,1-dioxo-4,5-dihydro-3H-1λ6,2-benzothiazepine-8-carboxylic acid (180 mg, 0.527 mmol) in HCl / dioxane (4 M, 3 mL) was stirred for 2 h at 25° C. It was concentrated to remove dioxane to give 1,1-dioxo-2,3,4,5-tetrahydro-1λ6,2-benzothiazepine-8-carboxylic acid (130 mg, 0.468 mmol, 89% yield, HCl) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.31(d,J=1.6 Hz,1H),8.05-8.00(m,1H),7.57-7.52(m,2H),3.66(br s,2H),3.22(br d,J=3.2 Hz,2H),1.91-1.77(m,1H),1.70(br s,2H)ppm.

[0237] Intermediate 13. 2-Methyl-1,1-dioxo-4,5-dihydro-3H-1λ6,2-benzothiazepine-8-carboxylic acid [ka] Step 1: Preparation of 4-bromo-3-chlorosulfonyl-benzoic acid A mixture of 4-bromobenzoic acid (10 g, 49.75 mmol) in HSO3Cl (86.95 g, 0.746 mol, 49.7 mL) was stirred at 100° C. for 16 h. The reaction was stirred at 120° C. for an additional 16 h. It was poured into ice water (400 mL). A precipitate formed and the mixture was filtered. The filter cake was dried in vacuum to give 4-bromo-3-chlorosulfonyl-benzoic acid (11 g, 36.72 mmol, 73% yield) as a grey solid. LCMS(ESI)m / z:[Br 79 M+H] += 300.0 1H NMR(400 MHz,DMSO-d6)δ=13.96(br s,1H),8.46(d,J=1.6 Hz,1H),7.79-7.60(m,2H)ppm.

[0238] Step 2: Preparation of methyl 4-bromo-3-chlorosulfonyl-benzoate A mixture of 4-Bromo-3-chlorosulfonyl-benzoic acid (11 g, 36.72 mmol) in SOCl2 (43.69 g, 367.25 mmol, 26.64 mL) was stirred at 80° C. for 2 h. Then the mixture was concentrated to remove SOCl2. MeOH (11 mL) was added. The mixture was stirred at 20° C. for 0.5 h. It was poured into water (600 mL) and extracted with EA (300 mL×3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated to give methyl 4-bromo-3-chlorosulfonyl-benzoate (10 g, crude) as a yellow solid. LCMS(ESI)m / z:[Br 79 M+H] += 314.8 1 H NMR(400 MHz,DMSO-d6)δ=9.31(br s,2H),8.71-8.31(m,1H),7.89-7.62(m,2H),3.86(s,3H).

[0239] Step 3: Preparation of methyl 3-(arylsulfamoyl)-4-bromo-benzoate To a solution of methyl 4-bromo-3-chlorosulfonyl-benzoate (4 g, 12.76 mmol) and prop-2-en-1-amine (1.31 g, 14.03 mmol, 1.73 mL, HCl) in DCM (40 mL) was added DIEA (6.60 g, 51.03 mmol, 8.89 mL) at 0° C. The mixture was then stirred at 25° C. for 2 h. It was poured into water (100 mL) and extracted with DCM (60 mL×3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, elution with a gradient of 0 to 50% ethyl acetate / petroleum ether at 100 mL / min). The fractions were concentrated in vacuo to give methyl 3-(arylsulfamoyl)-4-bromo-benzoate (4.1 g, 12.27 mmol, 96% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.51-8.42(m,1H),8.29(br s,1H),8.01(d,J=0.8 Hz,2H),5.77-5.52(m,1H),5.17-5.06(m,1H),5.03-4.93(m,1H),3.89(s,3H),3.57(br d,J=4.8 Hz,2H)ppm.

[0240] Step 4: Preparation of methyl 3-(arylsulfamoyl)-4-vinyl-benzoate A mixture of methyl 3-(arylsulfamoyl)-4-bromo-benzoate (3.1 g, 9.28 mmol), potassium; trifluoro(vinyl)borane (6.21 g, 46.38 mmol), ditert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (604.6 mg, 0.928 mmol), and K3PO4 (5.91 g, 27.8 mmol) in dioxane (30 mL) and H2O (6 mL) was degassed and purged with N2 three times. The mixture was stirred at 60 °C under N2 atmosphere for 16 h. It was poured into water (100 mL) and extracted with EA (60 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a gradient of 0 to 50% ethyl acetate / petroleum ether at 80 mL / min). Fractions were concentrated in vacuo to give methyl 3-(arylsulfamoyl)-4-vinyl-benzoate (1.5 g, 5.33 mmol, 57% yield) as a white solid. LCMS(ESI)m / z:[M+H] += 282.1 1 H NMR(400 MHz,CDCl3)δ=8.62(d,J=1.6 Hz,1H),8.29-8.11(m,1H),7.69(d,J=8.0 Hz,1H),7.62-7.47(m,1H),5.92-5.77(m,1H),5.73-5.53(m,2H),5.22-4.97(m,2H),4.84-4.57(m,1H),3.69-3.41(m,2H)ppm.

[0241] Step 5: Preparation of methyl 3-[allyl(methyl)sulfamoyl]-4-vinyl-benzoate To a solution of methyl 3-(arylsulfamoyl)-4-vinyl-benzoate (200 mg, 0.711 mmol) and K2CO3 (196.5 mg, 1.42 mmol) in DMF (2 mL) was added MeI (201.81 mg, 1.42 mmol, 88.5 μL). The mixture was stirred at 20 °C for 3 h. It was poured into water (60 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (20 mL) and then dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, gradient elution of 0 to 50% ethyl acetate / petroleum ether at 50 mL / min). The fractions were concentrated in vacuo to give methyl 3-[allyl(methyl)sulfamoyl]-4-vinyl-benzoate (190 mg, 0.643 mmol, 90% yield) as a yellow oil. LCMS(ESI)m / z:[M+H] += 296.0 1 H NMR(400 MHz,CDCl3)δ=8.56(d,J=1.6 Hz,1H),8.26-8.09(m,1H),7.73(d,J=8.4 Hz,1H),7.67-7.53(m,1H),5.88-5.77(m,1H),5.76-5.64(m,1H),5.59-5.50(m,1H),5.27-5.16(m,2H),3.96(s,3H),3.75(d,J=6.4 Hz,2H),2.75(s,3H)ppm.

[0242] Step 6: Preparation of methyl 2-methyl-1,1-dioxo-3H-1λ6,2-benzothiazepine-8-carboxylate A mixture of methyl 3-[allyl(methyl)sulfamoyl]-4-vinyl-benzoate (190 mg, 0.643 mmol) and benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-ruthenium;tricyclohexylphosphane (54.61 mg, 64.33 μmol) in DCM (10 mL) was degassed and purged with N2 three times. The mixture was stirred at 25° C. under N2 atmosphere for 2 h. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with a gradient of approximately 50% ethyl acetate / petroleum ether at 30 mL / min). The fractions were concentrated in vacuo to give methyl 2-methyl-1,1-dioxo-3H-1λ6,2-benzothiazepine-8-carboxylate (130 mg, 0.486 mmol, 76% yield) as a white solid. LCMS(ESI)m / z:[M+H] += 268.0 1 H NMR(400 MHz,DMSO-d6)δ=8.38(d,J=2.0 Hz,1H),8.26-8.10(m,1H),7.78(d,J=8.4 Hz,1H),6.72(br d,J=13.2 z,1H),6.31-5.96(m,1H),4.45-4.17(m,2H),3.90(s,3H),2.55(s,3H)ppm.

[0243] Step 7: Preparation of methyl 2-methyl-1,1-dioxo-4,5-dihydro-3H-1λ6,2-benzothiazepine-8-carboxylic acid A mixture of methyl 2-methyl-1,1-dioxo-3H-1λ6,2-benzothiazepine-8-carboxylate (130 mg, 0.486 mmol), Pd / C (13 mg, 10% purity) in MeOH (4 mL) was degassed and purged with H2 three times. The mixture was then stirred at 20° C. under H2 atmosphere for 2 h. It was filtered and concentrated to give methyl 2-methyl-1,1-dioxo-4,5-dihydro-3H-1λ6,2-benzothiazepine-8-carboxylate (110 mg, 0.408 mmol, 84% yield) as a white solid. LCMS(ESI)m / z:[M+H]+= 270.0 1 H NMR(400 MHz,CDCl3)δ=8.56(d,J=2.0 Hz,1H),8.17-8.03(m,1H),7.38(d,J=7.6 Hz,1H),3.95(s,3H),3.92-3.59(m,2H),3.45-3.23(m,2H),2.65(s,3H),1.91-1.80(m,3H)ppm.

[0244] Step 8: Preparation of 2-methyl-1,1-dioxo-4,5-dihydro-3H-1λ6,2-benzothiazepine-8-carboxylic acid (Intermediate 13) To a solution of methyl 2-methyl-1,1-dioxo-4,5-dihydro-3H-1λ6,2-benzothiazepine-8-carboxylate (110 mg, 0.408 mmol) in THF (1 mL) and HO (1 mL) was added LiOH.HO (68.56 mg, 1.63 mmol). The mixture was stirred at 25 °C for 2 h. It was adjusted to PH = 5 with aqueous HCl (1 M) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine (20 mL), then dried over Na2SO4, filtered and concentrated to give 2-methyl-1,1-dioxo-4,5-dihydro-3H-1λ6,2-benzothiazepine-8-carboxylic acid (80 mg, 0.313 mmol, 77% yield) as a white solid. LCMS(ESI)m / z:[M+H] += 519.2 1 H NMR(400 MHz,DMSO-d6)δ=8.27(d,J=1.6 Hz,1H),8.14-8.01(m,1H),7.59(d,J=8.0 Hz,1H),3.75-3.55(m,2H),3.23(br s,3H),2.55(s,3H),1.83-1.71(m,2H)ppm.

[0245] Intermediate 14. 4-(Difluoromethyl)-3-(methylsulfonyl)benzoic acid [ka] Step 1: Preparation of methyl 3-bromo-4-(difluoromethyl)benzoate To a solution of methyl 3-bromo-4-formylbenzoate (300 mg, 1.23 mmol) in DCM (3 mL) was added DAST (596.87 mg, 3.70 mmol, 489.24 uL). The mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with saturated NaHCO3 (20 mL) and extracted with DCM (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1). The eluate was concentrated to give methyl 3-bromo-4-(difluoromethyl)benzoate (190 mg, 716.84 μmol, 58% yield) as a yellow oil. 1 H NMR(400 MHz, CDCl3)δ=8.28(s,1H),8.09(d,J=8.0 Hz,1H),7.75(d,J=8.0Hz,1H),7.06-6.79(m,1H),3.96(s,3H)ppm.

[0246] Step 2: Preparation of 3-bromo-4-(difluoromethyl)benzoic acid To a solution of methyl 3-bromo-4-(difluoromethyl)benzoate (90 mg, 339.56 μmol) in THF / MeOH / H2O=2 / 1 / 1 (1 mL) was added NaOH (27.16 mg, 679.11 μmol). The mixture was stirred at 30° C. for 2 h. The reaction mixture was diluted with 1N HCl (10 mL) and extracted with DCM (10 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give 3-bromo-4-(difluoromethyl)benzoic acid (70 mg, 278.86 μmol, 82% yield) as a yellow oil, which was used directly in the next step.

[0247] Step 3: Preparation of 4-(difluoromethyl)-3-methylsulfanyl-benzoic acid A mixture of 3-bromo-4-(difluoromethyl)benzoic acid (50 mg, 0.199 mmol), DABCO (44.68 mg, 0.398 mmol, 44 uL), and CuI (37.93 mg, 0.199 mmol) in DMSO (0.5 mL) was stirred at 145° C. for 12 h. 1N HCl was added to the mixture to adjust pH=5. The mixture was filtered. The filtrate was concentrated to give a residue. The residue was purified by reverse phase (0.1% FA). The eluate was concentrated to give 4-(difluoromethyl)-3-methylsulfanyl-benzoic acid (30 mg, 0.137 mmol, 69% yield) as a yellow solid. LCMS(ESI)m / z:[M+H] + =218.9 1 H NMR(400 MHz, CDCl3)δ=8.10(s,1H),8.02(d,J=8.4 Hz,1H),7.75(d,J=8.0 Hz,1H),7.15-6.87(m,1H),2.58(s,3H)ppm.

[0248] Step 4: Preparation of 4-(difluoromethyl)-3-methylsulfonyl-benzoic acid (Intermediate 14) To a solution of 4-(difluoromethyl)-3-methylsulfanyl-benzoic acid (30 mg, 137.48 μmol) in MeOH (0.5 mL) was added a mixture of Oxone (169.03 mg, 274.95 μmol) in H2O (0.5 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by reverse phase (0.1% FA). The eluate was concentrated to give 4-(difluoromethyl)-3-(methylsulfonyl)benzoic acid (20 mg, 79.9 μmol, 58% yield) as a white solid. LCMS(ESI)m / z:[M+H] + =250.9.

[0249] Intermediate 15. 6-Methyl-5-(methylsulfonyl)nicotinic acid [ka] Step 1: Preparation of 6-methyl-5-(methylthio)nicotinic acid To a solution of methyl 5-fluoro-6-methyl-pyridine-3-carboxylate (300 mg, 1.77 mmol) in DMF (2 mL) was added thiomethoxide (320.30 mg, 1.95 mmol). The mixture was stirred at 100° C. for 16 h. The reaction mixture was quenched with HCl (1M) (40 mL) and extracted with EA / MeOH=15 / 1 (40 mL×5). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase HPLC (0.1% FA condition). The solution was concentrated under reduced pressure to remove MeCN, and then lyophilized to give 6-methyl-5-(methylthio)nicotinic acid (200 mg, 1.09 mmol, 62% yield) as a yellow solid. LCMS(ESI)m / z:[M+H] + =183.9. 1 H NMR(400 MHz,DMSO-d6)δ=14.14-12.40(m,1H),8.69(d,J=1.6 Hz,1H),7.94(d,J=2.0 Hz,1H),2.55(s,3H),2.50(s,3H)ppm.

[0250] Step 2: Preparation of 6-methyl-5-(methylsulfonyl)nicotinic acid (intermediate 15) To a solution of 6-methyl-5-(methylthio)nicotinic acid (30 mg, 163.73 μmol) in MeOH (1 mL) was added Oxone® (150.98 mg, 0.246 mmol) and HO (1 mL). The mixture was stirred at 25° C. for 16 h. The reaction mixture was dissolved in DMSO (5 mL) and then filtered to obtain a filtrate. The filtrate was purified by reverse phase HPLC (0.1% FA condition). The solution was concentrated under reduced pressure to remove MeCN, and then freeze-dried to obtain 6-methyl-5-(methylsulfonyl)nicotinic acid (15 mg, 67.8 μmol, 41% yield) as a white solid. LCMS(ESI)m / z:[M+H] + =216.1. 1H NMR(400 MHz,DMSO-d6)δ=15.43-11.63(m,1H),9.17(d,J=2.0 Hz,1H),8.61(d,J=2.0 Hz,1H),3.36(s,3H),2.90(s,3H)ppm.

[0251] Intermediate 16. 3-Chloro-4-methyl-5-methylsulfonyl-benzoic acid [ka] Step 1: Preparation of 3-chloro-5-chlorosulfonyl-4-methylbenzoic acid A mixture of 3-chloro-4-methylbenzoic acid (1 g, 5.86 mmol) in chlorosulfonic acid (10.25 g, 87.93 mmol, 5.85 mL) was stirred at 120° C. for 12 h. The reaction mixture was added with HO (20 mL) at 0° C. A white solid precipitated from the mixture. The solid was collected by filtration and dried under vacuum to give 3-chloro-5-chlorosulfonyl-4-methylbenzoic acid (1.2 g, 4.46 mmol, 76% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.30(d,J=2.0 Hz,1H),7.85(d,J=2.0 Hz,1H),2.63(s,3H)ppm.

[0252] Step 2: Preparation of 3-chloro-4-methyl-5-methylsulfonyl-benzoic acid (Intermediate 16) To a solution of Na2SO3 (140.51 mg, 1.11 mmol) and NaHCO3 (280.97 mg, 3.34 mmol, 130.08 uL) in H2O (1.2 mL) was added 3-chloro-5-chlorosulfonyl-4-methylbenzoic acid (300 mg, 1.11 mmol) at 80 °C. The mixture was stirred at 80 °C for 1 h. Then, 2-bromoacetic acid (309.8 mg, 2.23 mmol, 161 μL) and NaOH (89.19 mg, 2.23 mmol) were added and the mixture was stirred at 110 °C for 12 h. The reaction mixture was diluted with H2O (10 mL) and then 1N HCl was added to adjust the pH = 3. A white solid precipitated from the mixture. The solid was collected by filtration and dried in vacuo to give 3-chloro-4-methyl-5-methylsulfonyl-benzoic acid (120 mg, 0.483 mmol, 43% yield) as a white solid. LCMS(ESI)m / z:[M+H] + =248.9 1 H NMR(400 MHz,DMSO-d6)δ=8.41(d,J=1.6 Hz,1H),8.21(d,J=1.6 Hz,1H),3.32(s,3H),2.74(s,3H)ppm.

[0253] Intermediate 17. 4-Chloro-3-fluoro-5-methylsulfonyl-benzoic acid [ka] Step 1: Preparation of 4-chloro-3-fluoro-5-methylsulfanyl-benzoic acid A mixture of methyl 3-bromo-4-chloro-5-fluoro-benzoate (200 mg, 747.72 μmol), CuI (142.40 mg, 747.72 μmol), and DABCO (167.8 mg, 1.50 mmol, 164 μL) in DMSO (2 mL) was stirred at 145° C. under N2 for 12 h. The reaction mixture was filtered. The filtrate was purified by reverse-phase HPLC (0.1% FA condition). The desired fraction was lyophilized to give 4-chloro-3-fluoro-5-methylsulfanyl-benzoic acid (90 mg, 0.371 mmol, 50% yield) as a white solid. LCMS(ESI)m / z:[M+H]+ =220.9. 1 H NMR(400 MHz,DMSO-d6)δ=7.66-7.56(m,2H),2.59(s,3H)ppm.

[0254] Step 2: Preparation of 4-chloro-3-fluoro-5-methylsulfonyl-benzoic acid (Intermediate 17) To a solution of 4-chloro-3-fluoro-5-methylsulfanyl-benzoic acid (90 mg, 0.408 mmol) in H2O (1 mL) and MeOH (2 mL) was added Oxone® (501.5 mg, 0.816 mmol). The reaction was stirred at 20 °C under N2 for 12 h. To the mixture was added saturated aqueous Na2SO3 (5 mL). The mixture was extracted with EA (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give 4-chloro-3-fluoro-5-methylsulfonyl-benzoic acid (40 mg, 0.158 mmol, 39% yield) as a white solid. LCMS(ESI)m / z:[M+H] + =252.9. 1 H NMR(400 MHz,DMSO-d6)δ=8.35(s,1H),8.21-8.19(m,1H),3.45(s,3H)ppm.

[0255] Intermediate 18. tert-Butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate [ka] Step 1. Preparation of 2-bromo-5-iodo-pyridin-4-amine NIS (93.6 g, 416 mmol) was added to a solution of 2-bromopyridin-4-amine (60 g, 347 mmol) in MeCN (1.5 L) at 80° C. The reaction mixture was stirred at 80° C. for 36 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with saturated Na2SO3 (1.5 L) and extracted with EA (1.5 L×2). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EA=20:3) and concentrated under reduced pressure to give 2-bromo-5-iodo-pyridin-4-amine (65 g, 217 mmol) as a light yellow solid. 1 H NMR(400 MHz, CDCl3)δ=8.31(s,1H),6.79(s,1H),4.75(br s,2H)ppm.

[0256] Step 2. Preparation of ethyl-3-(4-amino-6-bromo-3-pyridyl)prop-2-enoate Ethyl prop-2-enoate (45.1 mL, 415 mmol), Et3N (43.3 mL, 311 mmol), Pd(OAc)2 (2.3 g, 10.4 mmol), and tris-o-tolylphosphane (6.3 g, 20.7 mmol) were added to a solution of 2-bromo-5-iodo-pyridin-4-amine (62 g, 207 mmol) in DMF (620 mL). The mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water (4 L) and extracted with EA (2 L x 2). The combined organic layers were washed with brine (2 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EA=20:3) and concentrated under reduced pressure to give ethyl-3-(4-amino-6-bromo-3-pyridyl)prop-2-enoate (50 g, 170 mmol) as a pale yellow solid. LCMS(ESI)m / z:[79BrM+H]+=271.1. 1H NMR(400 MHz,DMSO-d6)δ=8.23(s,1H),7.73(d,J=16.0 Hz,1H),6.90-6.67(m,3H),6.52(d,J=16.0 Hz,1H),4.18(d,J=7.2 Hz,2H),1.25(d,J=7.2 Hz,3H)ppm.

[0257] Step 3. Preparation of 7-bromo-1,6-naphthyridin-2(1H)-one Sodium thiomethoxide (24.2 mL, 380 mmol) was added to a solution of ethyl-3-(4-amino-6-bromo-3-pyridyl)prop-2-enoate (40 g, 148 mmol) in EtOH (200 mL). The reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with water (400 mL) and then neutralized to pH=7.0 with 1N HCl. The solid was filtered and the filter cake was washed with water (50 mL). The filter cake was concentrated under reduced pressure to give 7-bromo-1,6-naphthyridin-2(1H)-one (22 g, 96.8 mmol) as an off-white solid. LCMS(ESI)m / z:[79BrM+H]+=224.9. 1 H NMR(400 MHz,DMSO-d6)δ=12.08(br s,1H),8.65(s,1H),7.99(d,J=9.6 Hz,1H),7.36(s,1H),6.62(d,J=9.6 Hz,1H)ppm.

[0258] Step 4. Preparation of 2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile Zinc dust (406.80 mg, 6.22 mmol) was dissolved in 7-bromo-1,6-naphthyridin-2(1H)-one (7 g, 31.1 mmol), Zn(CN)2 (3.95 mL, 62.2 mmol), and Pd(dppf)Cl2 in DMA (140 mL). .A solution of CH2Cl2 (5.08 g, 6.22 mmol) was added to the solution. After the reaction mixture was degassed and purged with N2 three times, the mixture was stirred at 120 °C for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with DCM / isopropanol (v / v=3:1) (150 mL x 2). The combined organic layers were filtered, washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, PE / EA=1:1) and concentrated in vacuo to give 2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile (3 g, 17.5 mmol) as an off-white solid. 1 H NMR(400 MHz,DMSO-d6)δ=12.37(br s,1H),8.97(s,1H),8.09(d,J=9.6 Hz,1H),7.67(s,1H),6.77(d,J=9.6 Hz,1H)ppm.

[0259] Step 5. Preparation of 2-chloro-1,6-naphthyridine-7-carbonitrile A mixture of 2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile (3.0 g, 17.5 mmol) and POCl3 (30 mL, 323 mmol) was stirred at 80 °C for 2 h. The reaction mixture was poured into H2O (2 L) and adjusted to pH = 7 with NaHCO3. The solution was extracted with EA (1.5 L x 2) and the combined organic layers were washed with brine (2 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-chloro-1,6-naphthyridine-7-carbonitrile (1.1 g, 5.76 mmol) as a brown solid. LCMS(ESI) m / z:[M+H]+=190.1. 1 H NMR(400 MHz,DMSO-d6)δ=9.58(d,J=0.8 Hz,1H),8.79(d,J=0.8 Hz,1H),8.69(s,1H),8.00(d,J=8.8 Hz,1H)ppm.

[0260] Step 6. Preparation of (2-chloro-1,6-naphthyridin-7-yl)methanamine To a solution of 2-chloro-1,6-naphthyridine-7-carbonitrile (25 g, 131.86 mmol) in DCM (1000 mL) was added DIBAL-H (1 M, 329.64 mL, 2.5 equiv) dropwise under N2 at -70 °C. The reaction mixture was stirred at -70 °C for 2 h. The reaction mixture was quenched with water (500 mL) and saturated potassium sodium tartrate (1500 mL) and stirred for an additional 30 min. The mixture was extracted with DCM:MeOH = 10:1 (6000 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give (2-chloro-1,6-naphthyridine-7-yl)methanamine (51 g, crude) as a brown solid, which was used directly in the next step. LCMS(ESI)m / z:[ 35 ClM+H] += 194.2

[0261] Step 7: Preparation of tert-butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate (Intermediate 18) To a solution of (2-chloro-1,6-naphthyridin-7-yl)methanamine (51 g, 263.4 mmol) in DCM (1500 mL) was added (Boc)2O (172.45 g, 790.16 mmol) and DIEA (102.12 g, 790.16 mmol). The mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with water (1500 mL) and then filtered. The filtrate was extracted with DCM (1000 mL×3). The combined organic layers were washed with brine (1500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1 to 1 / 3), and the eluate was concentrated under reduced pressure to give tert-butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate (21 g, 64.34 mmol, yield 24%) as a pale yellow solid. LCMS(ESI) m / z:[M+H]+=293.9. 1H NMR(400 MHz,DMSO-d6)δ=9.37(s,1H),8.62(d,J=8.4 Hz,1H),7.71(d,J=8.4 Hz,1H),7.58-7.53(m,2H),4.39(d,J=6.4 Hz,2H),4.20-4.25(m,2H),1.41(s,9H)ppm.

[0262] Intermediate 19: [2-[6-(2,2-difluorocyclopropyl)-2-pyridyl]-1,6-naphthyridin-7-yl]methanamine [ka] Step 1: Preparation of 2-bromo-6-(2,2-difluorocyclopropyl)pyridine To a mixture of 2-bromo-6-ethenylpyridine (500 mg, 2.72 mmol) and NaI (81.45 mg, 0.543 mmol) in THF (4 mL) was added a solution of TMSCF3 (1.55 g, 10.87 mmol) in THF (1 mL) at 70 °C under N2 over 1 h. The mixture was stirred at 70 °C under N2 for 1 h. The residue was purified by silica gel chromatography (PE-PE / EA=50 / 1). The eluate was concentrated under reduced pressure to give 2-bromo-6-(2,2-difluorocyclopropyl)pyridine (570 mg, 2.44 mmol, 90% yield) as a yellow oil. LCMS(ESI)m / z:[M+H] += 233.9. 1 H NMR(400 MHz, CDCl3)δ=7.52-7.48(m,1H),7.39-7.37(m,1H),7.19(d,J=7.6 Hz,1H),2.95-2.84(m,1H),2.21-2.12(m,1H),1.89-1.83(m,1H)ppm.

[0263] Step 2: Preparation of [6-(2,2-difluorocyclopropyl)-2-pyridyl]-trimethylstannane A mixture of 2-bromo-6-(2,2-difluorocyclopropyl)pyridine (100 mg, 427.28 μmol), hexamethylditin (279.97 mg, 854.55 μmol, 177.20 uL), and Pd(PPh3)4 (49.37 mg, 42.73 μmol) in dioxane (2 mL) was stirred at 100° C. under N2 for 2 h. The mixture was filtered and concentrated in vacuo to give [6-(2,2-difluorocyclopropyl)-2-pyridyl]-trimethylstannane (170 mg, crude) as a brown oil. LCMS(ESI)m / z:[M+H] += 320.1.

[0264] Step 3: Preparation of tert-butyl N-[[2-[6-(2,2-difluorocyclopropyl)-2-pyridyl]-1,6-naphthyridin-7-yl]methyl]carbamate A mixture of tert-butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate (50 mg, 170.21 μmol), [6-(2,2-difluorocyclopropyl)-2-pyridyl]-trimethylstannane (163 mg, 0.511 mmol), and Pd(PPh3)2Cl2 (11.95 mg, 17.02 μmol) in dioxane (1 mL) was stirred at 100 °C under N2 for 16 h. The mixture was poured into saturated KF (10 mL) and stirred at 20 °C for 30 min. The mixture was extracted with EA (10 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE / EA = 10 / 1-EA). The eluate was concentrated under reduced pressure to give tert-butyl N-[[2-[6-(2,2-difluorocyclopropyl)-2-pyridyl]-1,6-naphthyridin-7-yl]methyl]carbamate (30 mg, 72.74 μmol, yield 43%) as a yellow solid. LCMS(ESI)m / z:[M+H] += 413.3.

[0265] Step 4: Preparation of [2-[6-(2,2-difluorocyclopropyl)-2-pyridyl]-1,6-naphthyridin-7-yl]methanamine (Intermediate 19) To a mixture of tert-butyl N-[[2-[6-(2,2-difluorocyclopropyl)-2-pyridyl]-1,6-naphthyridin-7-yl]methyl]carbamate (30 mg, 72.74 μmol) in DCM (1 mL) was added TFA (462 mg, 4.05 mmol, 0.3 mL) at 0° C. The mixture was stirred at 30° C. for 1 h. The mixture was concentrated under reduced pressure to give [2-[6-(2,2-difluorocyclopropyl)-2-pyridyl]-1,6-naphthyridin-7-yl]methanamine (31 mg, 72.71 μmol, 100% yield, TFA salt) as a yellow solid. LCMS(ESI)m / z:[M+H] += 313.2.

[0266] Intermediate 20. (2-(2-(2,2-difluorocyclopropyl)pyrimidin-4-yl)-1,6-naphthyridin-7-yl)methanamine mate [ka] Step 1: Preparation of 2,2-difluorocyclopropanecarboximidamide To a mixture of NH4Cl (6.88 g, 128.59 mmol) in toluene (50 mL) was added a solution of Al(CH3)3 (2 M, 64.29 mL) at 0 °C. The mixture was then stirred at 25 °C for 1 h. To the solution was added methyl 2,2-difluorocyclopropanecarboxylate (3.5 g, 25.72 mmol) at 0 °C, and then the solution was stirred at 80 °C for 12 h. A heavy white solid formed. The reaction mixture was cooled to 0 °C. MeOH (50 mL) was added and then stirred for 10 min. The mixture was filtered. The filtrate was concentrated in vacuo to give 2,2-difluorocyclopropanecarboximidamide (3 g, crude) as a white solid, which was used directly.

[0267] Step 2: Preparation of 2-(2,2-difluorocyclopropyl)pyrimidin-4-ol To a mixture of 2,2-difluorocyclopropanecarboximidamide (3.00 g, 24.97 mmol) in EtOH (40 mL) was added K2CO3 (6.90 g, 49.94 mmol) in one portion at 25 °C under N2. After the mixture was stirred at 25 °C for 10 min, (E)-ethyl 3-ethoxyacrylate (1.2 g, 8.32 mmol, 1.20 mL) was added at 25 °C. The mixture was stirred at 75 °C for 6 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The mixture was purified by silica gel chromatography (DCM / MeOH=20 / 1). The eluate was concentrated to give 2-(2,2-difluorocyclopropyl)pyrimidin-4-ol (500 mg, 2.90 mmol, 35% yield) as a white solid. LCMS(ESI)m / z:[M+H] + =173.2. 1 H NMR(400 MHz, CDCl3)δ=8.04-7.95(m,1H),6.43-6.35(m,1H),2.84-2.69(m,1H),2.51-2.39(m,1H),2.00-1.88(m,1H)ppm.

[0268] Step 3: Preparation of 4-chloro-2-(2,2-difluorocyclopropyl)pyrimidine To a mixture of 2-(2,2-difluorocyclopropyl)pyrimidin-4-ol (350 mg, 2.03 mmol) and DMF (14.9 mg, 0.203 mmol, 15.6 uL) in DCM (6 mL) was added oxalyl chloride (516 mg, 4.07 mmol, 356 μL) in one portion at 0° C. under N2. The mixture was stirred at 25° C. for 20 min. The mixture was added to saturated NaHCO3 (50 mL) at 0° C. The aqueous phase was extracted with DCM (50 mL×2). The combined organic phase was washed with brine (50 mL×1), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EA=10 / 1). The eluate was concentrated to give 4-chloro-2-(2,2-difluorocyclopropyl)pyrimidine (150 mg, 0.787 mmol, 39% yield) as a pale yellow oil. LCMS(ESI)m / z:[M+H] +=190.9,192.9.

[0269] Step 4: Preparation of 2-(2,2-difluorocyclopropyl)-4-(tributylstannyl)pyrimidine To a mixture of 4-chloro-2-(2,2-difluorocyclopropyl)pyrimidine (100 mg, 0.525 mmol) and trimethyl(trimethylstannyl)stannane (343.8 mg, 1.05 mmol, 218 μL) in dioxane (2 mL) was added Pd(PPh3)4 (60.63 mg, 52.47 μmol) in one portion at 25 °C under N2. The mixture was stirred at 100 °C for 2 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 2-(2,2-difluorocyclopropyl)-4-(tributylstannyl)pyrimidine (150 mg, crude) as a yellow oil. LCMS(ESI)m / z:[M+H] + =320.9.

[0270] Step 5: Preparation of tert-butyl ((2-(2-(2,2-difluorocyclopropyl)pyrimidin-4-yl)-1,6-naphthyridin-7-yl)methyl)carbamate To a mixture of 2-(2,2-difluorocyclopropyl)-4-(tributylstannyl)pyrimidine (147 mg, 0.460 mmol) and tert-butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate (90 mg, 0.306 mmol) in dioxane (2 mL) was added Pd(PPh3)2Cl2 (21.51 mg, 30.64 μmol) in one portion at 25 °C under N2. The mixture was stirred at 100 °C for 12 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL x 1), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (PE / EA = 3 / 1). The eluate was concentrated to give tert-butyl ((2-(2-(2,2-difluorocyclopropyl)pyrimidin-4-yl)-1,6-naphthyridin-7-yl)methyl)carbamate (90 mg, 0.218 mmol, 71% yield) as a yellow solid. LCMS(ESI)m / z:[M+H] + =414.0. 1 H NMR(400 MHz,DMSO-d6)δ=9.50-9.43(m,1H),9.08-9.01(m,1H),8.84-8.78(m,1H),8.73-8.67(m,1H),8.50-8.44(m,1H),7. 86-7.80(m,1H),7.72-7.60(m,1H),4.51-4.42(m,2H),2.30-2.13(m,1H),1.52-1.41(m,9H),1.41-1.21(m,2H)ppm.

[0271] Step 6: Preparation of (2-(2-(2,2-difluorocyclopropyl)pyrimidin-4-yl)-1,6-naphthyridin-7-yl)methanamine mate To a mixture of tert-butyl ((2-(2-(2,2-difluorocyclopropyl)pyrimidin-4-yl)-1,6-naphthyridin-7-yl)methyl)carbamate (90 mg, 0.218 mmol) in DCM (1 mL) was added TFA (770.0 mg, 6.75 mmol, 500 μL) in one portion at 25 °C under N2. The mixture was stirred at 25 °C for 30 min. The mixture was poured into ice water (20 mL) and extracted with ethyl acetate (20 mL x 1). The organic phase was discarded. The aqueous phase was adjusted to pH = 8 with saturated NaHCO3. The aqueous phase was then extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (10 mL*1), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give (2-(2-(2,2-difluorocyclopropyl)pyrimidin-4-yl)-1,6-naphthyridin-7-yl)methanamine mate (70 mg, crude) as a light yellow solid, which was used directly without further purification.

[0272] Intermediate 21. [2-[6-(2,2-difluoro-1-methyl-cyclopropyl)-2-pyridyl]-1,6-naphthyridin-7-yl]methanamine [ka] Step 1: Preparation of 2-bromo-6-(2,2-difluoro-1-methyl-cyclopropyl)pyridine To a mixture of 2-bromo-6-isopropenyl-pyridine (100 mg, 504.90 μmol) and NaI (15.14 mg, 100.98 μmol) in THF (0.8 mL) was added TMSCF3 (287.19 mg, 2.02 mmol) dropwise over 30 min at 70 °C under N2. The mixture was stirred at 70 °C under N2 for 30 min. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE-PE / EA=20 / 1). The eluent was concentrated under reduced pressure to give 2-bromo-6-(2,2-difluoro-1-methyl-cyclopropyl)pyridine (125 mg, 0.504 mmol, 100% yield) as a yellow oil. LCMS(ESI)m / z:[M+H] += 247.9. 1H NMR(400 MHz, CDCl3)δ=7.56-7.50(m,1H),7.40-7.37(m,1H),7.30(d,J=7.6 Hz,1H),2.28-2.21(m,1H),1.63-1.59(m,3H),1.48-1.41(m,1H)ppm.

[0273] Step 2: Preparation of [6-(2,2-difluoro-1-methylcyclopropyl)-2-pyridyl]-trimethyl-stannane A mixture of 2-bromo-6-(2,2-difluoro-1-methyl-cyclopropyl)pyridine (100 mg, 403.12 μmol), hexamethylditin (264.15 mg, 0.806 mmol, 167 μL), and Pd(PPh3)4 (46.58 mg, 40.31 μmol) in dioxane (2 mL) was stirred at 100° C. under N2 for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give [6-(2,2-difluoro-1-methylcyclopropyl)-2-pyridyl]-trimethyl-stannane (210 mg, crude) as a dark brown oil. LCMS(ESI)m / z:[M+H] += 334.0.

[0274] Step 3: Preparation of tert-butyl N-[[2-[6-(2,2-difluoro-1-methyl-cyclopropyl)-2-pyridyl]-1,6-naphthyridin-7-yl]methyl]carbamate A mixture of tert-butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate (60 mg, 0.204 mmol), [6-(2,2-difluoro-1-methylcyclopropyl)-2-pyridyl]-trimethyl-stannane (203.4 mg, 0.613 mmol), and Pd(PPh3)2Cl2 (14.34 mg, 20.43 μmol) in dioxane (1 mL) was stirred at 100° C. for 16 h under N2. The mixture was poured into saturated KF (10 mL) and stirred at 20° C. for 30 min. The mixture was extracted with EA (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE / EA=10 / 1-EA). The eluate was concentrated under reduced pressure to give tert-butyl N-[[2-[6-(2,2-difluoro-1-methyl-cyclopropyl)-2-pyridyl]-1,6-naphthyridin-7-yl]methyl]carbamate (42 mg, 98.49 μmol, 48% yield) as a yellow solid. LCMS(ESI)m / z:[M+H] += 427.0.

[0275] Step 4: Preparation of [2-[6-(2,2-difluoro-1-methyl-cyclopropyl)-2-pyridyl]-1,6-naphthyridin-7-yl]methanamine (Intermediate 21) To a solution of tert-butyl N-[[2-[6-(2,2-difluoro-1-methyl-cyclopropyl)-2-pyridyl]-1,6-naphthyridin-7-yl]methyl]carbamate (42 mg, 98.49 μmol) in DCM (1 mL) was added TFA (462.0 mg, 4.05 mmol, 0.3 mL) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to give [2-[6-(2,2-difluoro-1-methyl-cyclopropyl)-2-pyridyl]-1,6-naphthyridin-7-yl]methanamine (43 mg, 97.65 μmol, 99% yield, TFA salt) as a yellow solid. LCMS(ESI)m / z:[M+H] += 327.0.

[0276] Intermediate 22. 1-Imino-1-oxo-3,5-dihydro-2H-4,1λ6-benzoxathiepin-8-carboxylic acid [ka] Step 1: Preparation of N-(8-bromo-1-oxo-3,5-dihydro-2H-4,1λ6-benzoxathiepin-1-ylidene)-2,2,2-trifluoro-acetamide A mixture of 8 8-bromo-3,5-dihydro-2H-4,1λ4-benzoxathiepin 1-oxide (50 mg, 191.47 μmol), 2,2,2-trifluoroacetamide (64.93 mg, 574.42 μmol), [acetoxy(phenyl)-λ3-iodanyl]acetate (129.51 mg, 402.09 μmol), and MgO (46.30 mg, 1.15 mmol) in DCM (3 mL) was stirred for 5 min at 25° C. Rhodium(II) diacetate (8.46 mg, 19.15 μmol) was then added to the mixture and the mixture was stirred at 25° C. under N2 for 16 h. The reaction mixture was diluted with MeOH (3 mL) to give N-(8-bromo-1-oxo-3,5-dihydro-2H-4,1λ6-benzoxathiepin-1-ylidene)-2,2,2-trifluoro-acetamide (71 mg, 190.78 μmol, 100% yield) as a yellow liquid, which was used directly in the next step. LCMS(ESI)m / z=[M+H] += 373.2.

[0277] Step 2: Preparation of 8-bromo-1-imino-3,5-dihydro-2H-4,1λ6-benzoxathiepin 1-oxide To a mixture of N-(8-bromo-1-oxo-3,5-dihydro-2H-4,1λ6-benzoxathiepin-1-ylidene)-2,2,2-trifluoro-acetamide (70 mg, 188.09 μmol) in MeOH (3 mL) was added K2CO3 (181.97 mg, 1.32 mmol) and the mixture was stirred at 25° C. for 4 h. The mixture was diluted with water (10 mL) and filtered to remove the precipitate. The filtrate was separated and the aqueous layer was extracted with DCM (10 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE:EtOAc = 20:1 to 1:1) to give 8-bromo-1-imino-3,5-dihydro-2H-4,1λ6-benzoxathiepin 1-oxide (40 mg, 137.65 μmol, 73% yield) as a white solid. LCMS(ESI)m / z=[M+H] += 277.2. 1 H NMR(400 MHz,DMSO_d6)δ=8.07(d,J=2.0 Hz,1H),7.81-7.79(m,1H),7.46(d,J=8.0 Hz,1H),4.99-4.81(m,3H),4.21-4.13(m,2H),3.42-3.39(m,2H)ppm

[0278] Step 3: Preparation of 1-imino-1-oxo-3,5-dihydro-2H-4,1λ6-benzoxathiepin-8-carboxylic acid To a mixture of 8-bromo-1-imino-3,5-dihydro-2H-4,1λ6-benzoxathiepin 1-oxide (40 mg, 144.85 μmol) and diacetoxypalladium (3.25 mg, 14.48 μmol) in DMSO (3 mL) and H2O (0.3 mL) was added K2CO3 (30.03 mg, 217.27 μmol) and bicyclohexyl(3-bicyclohexylphosphaniumylpropyl)phosphonium; ditetrafluoroborate (17.74 mg, 28.97 μmol). The mixture was degassed and purged with CO three times, then stirred at 100 °C under CO atmosphere (15 psi) for 4 h. The mixture was poured into water (50 mL), extracted with EA (20.0 mL × 2), and the combined organics were discarded. The aqueous solution was adjusted to pH 5 with HCl (1M) and then extracted with DCM (20.0 mL*3). The combined organic phase was washed with brine (50.0 mL*2), dried over Na2SO4, filtered, and the filtrate was evaporated to dryness to give 1-imino-1-oxo-3,5-dihydro-2H-4,1λ6-benzoxathiepin-8-carboxylic acid (34 mg, crude) as a yellow solid.

[0279] Example 2. N-[[2-[6-(azetidin-1-yl)-2-pyridyl]-1,6-naphthyridin-7-yl]methyl]-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiepin-8-carboxamide [ka] Step 1. Preparation of [6-(azetidin-1-yl)-2-pyridyl]-trimethyl-stannane To a solution of 2-(azetidin-1-yl)-6-bromo-pyridine (150 mg, 703.98 μmol) in dioxane (3 mL) was added hexamethylditin (461.28 mg, 1.41 mmol) and Pd(PPh3)4 (81.35 mg, 70.40 μmol). The mixture was purged with N2 three times and then stirred at 100 °C under N2 atmosphere for 2 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EA (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give [6-(azetidin-1-yl)-2-pyridyl]-trimethyl-stannane (209 mg, crude) as a brown oil, which was used in the next step without further purification. LCMS (ESI) m / z: [M+H] + =299.3.

[0280] Step 2. Preparation of tert-butyl N-[[2-[6-(azetidin-1-yl)-2-pyridyl]-1,6-naphthyridin-7-yl]methyl]carbamate To a solution of tert-butyl N-[(2-chloro-1,6-naphthyridin-7-yl)methyl]carbamate (100 mg, 340.43 μmol) in dioxane (2 mL) was added [6-(azetidin-1-yl)-2-pyridyl]-trimethyl-stannane (202.2 mg, 680.7 μmol μmol) and Pd(PPh3)2Cl2 (23.9 mg, 34.04 μmol). The mixture was purged with N2 three times and then stirred at 100 °C under N2 atmosphere for 12 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10:1-1:1) to give tert-butyl N-((2-(6-(azetidin-1-yl)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)carbamate (70 mg, 173.45 μmol, 51% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + =392.4. 1H NMR(400 MHz,CDCl3)δ=9.22(s,1H),8.68(d,J=8.8 Hz,1H),8.33(d,J=8.4 Hz,1H),7.98(d,J=7.2 Hz,1H),7.93(s,1H),7.72-7.61(m,1H),6.43(d,J=8.4 Hz,1H),4.68(d,J=4.8 Hz,2H),4.18-4.14(m,4H),2.18(s,2H),1.50(s,9H)ppm.

[0281] Step 3. Preparation of [2-[6-(azetidin-1-yl)-2-pyridyl]-1,6-naphthyridin-7-yl]methanamine To a solution of tert-butyl N-((2-(6-(azetidin-1-yl)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)carbamate (70 mg, 178.82 μmol) in DCM (3 mL) was added TFA (1 mL) at 0° C. The mixture was stirred at 25° C. for 2 h. The reaction mixture was poured into saturated aqueous NaHCO3 (30 mL) and extracted with EA (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give [2-[6-(azetidin-1-yl)-2-pyridyl]-1,6-naphthyridin-7-yl]methanamine (60 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS(ESI)m / z:[M+H] + =292.4.

[0282] Step 4. Preparation of N-[[2-[6-(azetidin-1-yl)-2-pyridyl]-1,6-naphthyridin-7-yl]methyl]-1,1-dioxo-3,5-dihydro-2H-4,16-benzoxathiepin-8-carboxamide (1) To a solution of 1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiepin-8-carboxylic acid (24.94 mg, 102.97 μmol) in DCM (1 mL) was added EDCI (21.38 mg, 111.55 μmol), HOBt (15.07 mg, 111.55 μmol), and DIEA (33.27 mg, 257.42 μmol). Then, [2-[6-(azetidin-1-yl)-2-pyridyl]-1,6-naphthyridin-7-yl]methanamine (25 mg, 85.81 μmol) was added. The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EA (30 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by preparative TLC (SiO2, DCM:MeOH=15:1) to give the crude product. The crude product was then further purified by preparative HPLC (0.1% FA additive). The eluent was concentrated under reduced pressure to remove MeCN, and the residue was lyophilized to give N-[[2-[6-(azetidin-1-yl)-2-pyridyl]-1,6-naphthyridin-7-yl]methyl]-1,1-dioxo-3,5-dihydro-2H-4,16-benzoxathiepin-8-carboxamide (10.21 mg, 19.21 μmol, 22% yield) as a yellow solid. LCMS(ESI)m / z=[M+H] += 261.9. 1 H NMR(400 MHz,CD3OD)δ=9.33(s,1H),8.69-8.63(m,2H),8.62-8.57(m,1H),8.39(s,1H),8.24(d,J=2.0 Hz,1H),7.98(s,1H),7.87(d,J=7.2 Hz,1H),7.73-7.65(m,2H),6.54(d,J=7.6 Hz,1H),5.07(s,2H),4.95(s,2H),4.39-4.34(m,2H),4.17-4.15(m,4H),3.58-3.53(m,2H),2.53-2.40(m,2H)ppm.

[0283] The following examples in Table 2 were prepared using standard chemical manipulations and procedures similar to those used in the preparation of Example 2. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6]

[0284] Example 3. N-[[2-[6-(azetidin-1-yl)-2-pyridyl]-1,6-naphthyridin-7-yl]methyl]-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiepin-8-carboxamide [ka] Step 1. Preparation of (6-fluoro-2-pyridyl)-trimethyl-stannane To a mixture of 2-bromo-6-fluoro-pyridine (500 mg, 2.84 mmol) in dioxane (5 mL) was added trimethyl(trimethylstannyl)stannane (2.79 g, 8.52 mmol) and Pd(PPh3)4 (328.31 mg, 284.11 μmol). The mixture was purged with N2 for 1 min and then stirred at 100° C. for 2 h. Water (20 mL) was added to the mixture and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to give (6-fluoro-2-pyridyl)-trimethyl-stannane (730 mg, crude) as a brown oil. LCMS(ESI)m / z=[M+H] +=261.9.

[0285] Step 2. Preparation of tert-butyl N-[[2-(6-fluoro-2-pyridyl)-1,6-naphthyridin-7-yl]methyl]carbamate To a mixture of tert-butyl N-[(2-chloro-1,6-naphthyridin-7-yl)methyl]carbamate (300 mg, 1.02 mmol) and (6-fluoro-2-pyridyl)-trimethyl-stannane (530.85 mg, 2.04 mmol) in dioxane (6 mL) was added Pd(PPh3)2Cl2 (71.68 mg, 102.13 μmol) and the mixture was purged with N2 for 1 min. The resulting mixture was stirred at 110° C. for 16 h. The reaction mixture was then poured into saturated KF (30 mL), stirred for 30 min, and the mixture was extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The reaction mixture was purified by column chromatography (SiO2, PE:EtOAc = 20:1 to 1:1) to give tert-butyl N-[[2-(6-fluoro-2-pyridyl)-1,6-naphthyridin-7-yl]methyl]carbamate (230 mg, 649.03 μmol, yield 64%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =355.1. 1 H NMR(400 MHz,CDCl3)δ=9.26(s,1H),8.63-8.58(m,2H),8.41-8.39(m,1H),8.04-7.98(m,1H),7.94(s,1H),7.09-7.06(m,1H),5.49(br s,1H),4.69(br d,J=5.2 Hz,2H),1.50(s,9H)ppm.

[0286] Step 3. Preparation of [2-(6-fluoro-2-pyridyl)-1,6-naphthyridin-7-yl]methanamine A mixture of tert-butyl N-[[2-(6-fluoro-2-pyridyl)-1,6-naphthyridin-7-yl]methyl]carbamate (220 mg, 620.81 μmol) in HCl / dioxane (2 mL) was stirred at 25° C. for 1 h. The mixture was evaporated to dryness and the residue was triturated with MTBE (20 mL×2). The mixture was filtered and the filter cake was evaporated to dryness to give [2-(6-fluoro-2-pyridyl)-1,6-naphthyridin-7-yl]methanamine (180 mg, crude, HCl) as a yellow oil. LCMS(ESI)m / z:[M+H] + =255.1.

[0287] Step 4. Preparation of N-[[2-(6-fluoro-2-pyridyl)-1,6-naphthyridin-7-yl]methyl]-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiepin-8-carboxamide To a mixture of [2-(6-fluoro-2-pyridyl)-1,6-naphthyridin-7-yl]methanamine (180 mg, 619.15 μmol) and 1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiepin-8-carboxylic acid (180 mg, 0.743 mmol) in DCM (2 mL) was added DIEA (320.08 mg, 2.48 mmol), EDCI (178 mg, 0.928 mmol), and HOBt (125.49 mg, 928.72 μmol). The mixture was stirred at 25° C. for 1 h. The mixture was poured into water (20 mL) and extracted with EA (10.0 mL×3). The combined organics were washed with brine (20.0 mL), dried over Na2SO4, filtered, and the filtrate was evaporated to dryness. The residue was purified by preparative HPLC (0.1% FA condition), and the eluate was concentrated in vacuo to remove MeCN. The residue was lyophilized to give N-[[2-(6-fluoro-2-pyridyl)-1,6-naphthyridin-7-yl]methyl]-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiepin-8-carboxamide (253 mg, 0.528 mmol, 85% yield) as a white solid. LCMS(ESI)m / z:[M+H] + =479.0. 1 H NMR(400 MHz,DMSO-d6)δ=9.66-9.61(m,1H),9.45(d,J=0.8 Hz,1H),8.75-8.72(m,1H),8.54-8.49(m,3H),8.26-8.26(m,1H),8.25-8.17(m,1H),7.84(s,1H),7.73(d,J=8.0 Hz,1H),7.39-7.36(m,1H),4.97(s,2H),4.83(d,J=5.6 Hz,2H),4.23-4.21(m,2H),3.68-3.66(m,2H)ppm.

[0288] Step 5. Preparation of N-[[2-[6-[(2R)-2-methylmorpholin-4-yl]-2-pyridyl]-1,6-naphthyridin-7-yl]methyl]-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiepin-8-carboxamide (37) To a mixture of N-[[2-(6-fluoro-2-pyridyl)-1,6-naphthyridin-7-yl]methyl]-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiepin-8-carboxamide (20 mg, 0.0418 mmol) and (2R)-2-methylmorpholine; hydrochloride (17.26 mg, 125.39 μmol) in DMSO (1 mL) was added DIEA (27.0 mg, 0.209 mmol). The mixture was stirred at 120° C. for 16 h. Then the mixture was poured into saturated NaHCO3 (20 mL) and extracted with EA (10.0 mL×3). The combined organics were washed with brine (20.0 mL), dried over Na2SO4, filtered and the filtrate was evaporated to dryness. The residue was purified by preparative HPLC (column: Shim-pack C18 150*25*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 38% to 58%, 10 min), and the eluent was concentrated in vacuum to remove MeCN. The residue was lyophilized to give N-[[2-[6-[(2R)-2-methylmorpholin-4-yl]-2-pyridyl]-1,6-naphthyridin-7-yl]methyl]-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiepin-8-carboxamide (15.89mg, 26.24μmol, yield 63%, FA) as a yellow solid. LCMS(ESI)m / z:[M+H] + =560.3. 1 H NMR(400 MHz,DMSO-d6)δ=9.65-9.62(m,1H),9.40(s,1H),8.68-8.61(m,2H),8.54(d,J=2.0 Hz,1H),8.46(s,1H),8.28-8.25(m,1H),7.92(d,J=7.2 Hz,1H),7.81(s,1H),7.77-7.73(m,2H),7.03(d,J=8.4 Hz,1H),4.98(s,2H),4.82(d,J=5.6 Hz,2H),4.30-4.22(m,4H),3.99-3.96(m,1H),3.70-3.58(m,4H),2.94-2.87(m,1H),2.62-2.56(m,1H),1.22(d,J=6.0 Hz,3H)ppm.

[0289] The following examples in Table 3 were prepared using standard chemical manipulations and procedures similar to those used in the preparation of Example 3. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4]

[0290] Example 4. N-((2-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-1,6-naphthyridin-7-yl)methyl)-3,5-dihydro-2H-benzo[e][1,4]oxathiepin-8-carboxamide 1,1-dioxide [ka] Step 1: Preparation of 4-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine Pd(dppf)Cl2 (32.1 mg, 0.0448 mmol) and AcOK (129 mg, 1.32 mmol) were added to a solution of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (134 mg, 0.526 mmol) and 8-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (100 mg, 0.438 mmol) in dioxane (2 mL). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (125 mg, crude) as a brown oil. LCMS(ESI)m / z:[M+H]+=276.1

[0291] Step 2: Preparation of tert-butyl ((2-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-1,6-naphthyridin-7-yl)methyl)carbamate A mixture of tert-butyl N-[(2-chloro-1,6-naphthyridin-7-yl)methyl]carbamate (100 mg, 0.340 mmol), 4-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (122 mg, 0.443 mmol), K3PO4 (217 mg, 1.02 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (22.2 mg, 0.340 mmol) in dioxane (1 mL) and HO (0.3 mL) was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with HO (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase HPLC (0.1% FA additive). The fractions were concentrated under reduced pressure to remove MeCN, then extracted with EA (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (100 mg, 0.205 mmol) as a yellow solid. LCMS (ESI) m / z: [M+H]+ = 407.3. 1 H NMR(400 MHz,DMSO-d6)δ=9.30(s,1H),8.48(d,J=8.8 Hz,1H),7.98(d,J=8.4 Hz,1H),7.69(s,1H),7.63-7.58(m,1H),7.04-7.02(m,1H),6.94-6.90(m,1H),6.87-6.81(m,1H),4.43(d,J=5.6 Hz,2H),4.35-4.27(m,2H),3.34-3.33(m,2H),2.91(s,3H),1.43(s,9H)ppm.

[0292] Step 3: Preparation of (2-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-1,6-naphthyridin-7-yl)methanamine hydrochloride HCl / dioxane (4N, 750 uL) was added to a solution of tert-butyl ((2-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-1,6-naphthyridin-7-yl)methyl)carbamate (90 mg, 0.221 mmol) in dioxane (1 mL). The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was washed with MTBE (5 mL×2), filtered and dried in vacuum to give the title compound (70 mg, 0.204 mmol) as a brown solid. LCMS (ESI) m / z: [M+H]+=307.2.

[0293] Step 4: Preparation of N-((2-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-1,6-naphthyridin-7-yl)methyl)-3,5-dihydro-2H-benzo[e][1,4]oxathiepin-8-carboxamide 1,1-dioxide (58) EDCI (25.2 mg, 0.131 mol), HOBt (17.7 mg, 0.131 mmol), DIEA (76.2 uL, 0.438 mmol), and (2-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-1,6-naphthyridin-7-yl)methanamine hydrochloride (30 mg, 0.0875 mmol) were added to a solution of 2,3-dihydro-5H-benzo[e][1,4]oxathiepin-8-carboxylic acid 1,1-dioxide (25.4 mg, 0.105 mmol) in DCM (0.5 mL). The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (5 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (0.1% FA condition). The solution was concentrated under reduced pressure to remove MeCN and lyophilized to give the title compound (14.2 mg, 0.0257 mmol) as a yellow solid. LCMS (ESI) m / z: [M+H]+=531.2. 1H NMR(400 MHz,CD3OD)δ=9.30(s,1H),8.64-8.59(m,1H),8.48(d,J=8.8 Hz,1H),8.22-8.20(m,1H),8.00(d,J=8.4 Hz,1H),7.93(s,1H),7.63(d,J=7.6 Hz,1H),7.01-6.92(m,2H),6.88-6.83(m,1H),5.04(s,2H),4.92(s,2H),4.35-4.31(m,4H),3.53-3.50(m,2H),3.34(d,J=4.4 Hz,2H),2.97-2.92(m,3H)ppm.

[0294] The following examples in Table 4A were prepared using standard chemical manipulations and procedures similar to those used to prepare Example 4. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4]

[0295] The following examples in Table 4B were prepared using standard chemical manipulations and procedures similar to those used above. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5]

Table 8-6

Table 8-7

Table 8-8

Table 8-9

Table 8-10

Table 8-11

Table 8-12

Table 8-13

Table 8-14

Table 8-15

Table 8-16

Table 8-17

Table 8-18

Table 8-19

Table 8-20

Table 8-21

Table 8-22

Table 8-23

Table 8-24

Table 8-25

Table 8-26

Table 8-27

Table 8-28

Table 8-29

Table 8-30

Table 8-31

Table 8-32

Table 8-33

Table 8-34

Table 8-35

Table 8-36

Table 8-37

Table 8-38

Table 8-39

Table 8-40

Table 8-41

Table 8-42

Table 8-43

Table 8-44

Table 8-45

Table 8-46

Table 8-47

Table 8-48

Table 8-49

Table 8-50

Table 8-51

Table 8-52

Table 8-53

Table 8-54

Table 8-55

Table 8-56

Table 8-57

Table 8-58

Table 8-59

Table 8-60

Table 8-61

Table 8-62

Table 8-63

Table 8-64

Table 8-65

Table 8-66

Table 8-67

Table 8-68

Table 8-69

Table 8-70

Table 8-71

Table 8-72

Table 8-73

[0296] Example 5. Assay of ATPase catalytic activity of BRM and BRG-1 The ATPase catalytic activity of BRM or BRG-1 was measured by an in vitro biochemical assay using ADP-Glo™ (Promega, V9102). Once the reaction is complete, the ADP-Glo™ kinase assay is performed in two steps. The first step is to deplete any ATP that is not consumed during the reaction. The second step is to convert the reaction product, ADP, to ATP, which is used to generate luminescence by luciferase and detected by a luminescence reader such as Envision.

[0297] The assay reaction mixture (10 μL) contained 30 nM BRM or BRG-1, 20 nM salmon sperm DNA (Invitrogen, UltraPure™ Salmon Sperm DNA Solution, Catalog No. 15632011), and 400 μM ATP in ATPase assay buffer, which consists of 20 mM Tris (pH 8), 20 mM MgCl2, 50 mM NaCl, 0.1% Tween-20, and 1 mM fresh DTT (Pierce™ DTT (dithiothreitol), Catalog No. 20290). The reaction was initiated by adding 2.5 μL of ATPase solution to 2.5 μL of ATP / DNA solution on a low volume white Proxiplate-384 plus plate (PerkinElmer, Catalog No. 6008280) and incubated for 1 hour at room temperature. Next, 5 μL of ADP-Glo™ reagent provided in the kit is added, and the reaction is incubated at room temperature for 40 minutes. Next, 10 μL of kinase detection reagent provided in the kit is added to convert ADP to ATP, and the reaction is incubated at room temperature for 60 minutes. Finally, luminescence measurements are collected with a plate-reading luminometer such as Envision.

[0298] BRM and BRG-1 were synthesized from the High Five insect cell line with a purity of >90%. IC from the ATPase catalytic activity assay described herein 50 The data are shown below in Tables 5A and 5B. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7] [Table 10-8]

[0299] Example 6. Synthesis of Compound A BRG1 / BRM inhibitor compound A has the following structure: [ka]

[0300] Compound A was synthesized as shown in Scheme 1 below. [ka] Scheme 1. Synthesis of Compound A

[0301] The ATPase catalytic activity of BRM or BRG-1 in the presence of Compound A was measured by an in vitro biochemical assay using ADP-Glo™ (Promega, V9102) as described above. Compound A had an IC of 10.4 nM for BRM and 19.3 nM for BRG1 in the assay. 50 It was found to have the following structure:

[0302] Example 7. Effect of BRG1 / BRM ATPase inhibition on proliferation of uveal melanoma and hematological cancer cell lines Procedure: Uveal melanoma cell lines (92-1, MP41, MP38, MP46), prostate cancer cell line (LNCAP), lung cancer cell line (NCI-H1299), and immortalized embryonic kidney line (HEK293T) were seeded into 96-well plates containing growth medium (see Table 6). Compound A, a BRG1 / BRM ATPase inhibitor, was dissolved in DMSO and added to the cells at the time of seeding in a concentration gradient of 0-10 micromolar. Cells were incubated at 37 degrees Celsius for 3 days. After 3 days of treatment, media was removed from the cells and 30 μL of TrypLE (Gibco) was added to the cells for 10 minutes. Cells were detached from the plate and resuspended by adding 170 microliters of growth medium. Cells from the two DMSO-treated control wells were counted and the initial number of cells seeded at the start of the experiment were re-seeded into fresh compound-containing plates for an additional 4 days at 37 degrees Celsius. On day 7, cells were harvested as described above. On days 3 and 7, relative cell proliferation was measured by adding Cell-titer glo (Promega) and measuring luminescence with an Envision plate reader (Perkin Elmer). The concentration of compound at which proliferation of each cell line was inhibited by 50% (GI 50) was calculated using Graphpad Prism and is plotted below. The above method was performed for multiple myeloma cell lines (OPM2, MM1S, LP1), ALL cell lines (TALL1, JURKAT, RS411), DLBCL cell lines (SUDHL6, SUDHL4, DB, WSUDCL2, PFEIFFER), AML cell line (OCIAML5), MDS cell line (SKM1), ovarian cancer cell lines (OV7, TYKNU), esophageal cancer cell line (KYSE150), rhabdoid tumor cell lines (RD, G402, G401, HS729, A204), liver cancer cell lines (HLF, HLE, PLCRPF5), and lung cancer cell lines (SW1573, NCIH2444) with the following modifications: cells were seeded in 96-well plates, and the next day, compound A, a BRG1 / BRM ATPase inhibitor, was dissolved in DMSO and added to the cells in a concentration gradient of 0 to 10 micromolar. At the time of cell splitting on days 3 and 7, cells were split into new 96-well plates and new compounds were added 4 hours after reseeding.

[0303] Table 6 lists the test cell lines and growth media used. [Table 11]

[0304] Results: As shown in Figure 1, uveal melanoma and hematological cancer cell lines were more sensitive to BRG1 / BRM inhibition than other cell lines tested. Inhibition of uveal melanoma and hematological cancer cell lines was maintained through day 7.

[0305] Example 8. Comparison of BRG1 / BRM inhibitors with clinical PKC and MEK inhibitors in uveal melanoma cell lines Procedure: Uveal melanoma cell lines, 92-1 or MP41, were seeded in 96-well plates in the presence of growth medium (see Table 5). BAF ATPase inhibitor (Compound A), PKC inhibitor (LXS196; MedChemExpress), or MEK inhibitor (Selumetinib; Selleck Chemicals) were dissolved in DMSO and added to the cells at the time of seeding in a concentration gradient of 0-10 micromolar. Cells were incubated at 37 degrees Celsius for 3 days. After 3 days of treatment, cell proliferation was measured with a Cell-titer glow (Promega) and luminescence was read on an Envision plate reader (Perkin Elmer).

[0306] Results: As shown in Figures 2A and 2B, Compound A exhibited comparable inhibition of uveal melanoma cell proliferation as clinical PKC inhibitors and clinical MEK inhibitors. Furthermore, Compound A was found to have a faster onset of inhibition than clinical PKC inhibitors and clinical MEK inhibitors.

[0307] Example 9. Synthesis of Compound B The BRG1 / BRM inhibitor compound B has the following structure: [ka]

[0308] Compound B was synthesized as shown in Scheme 2 below. [ka] Scheme 2. Synthesis of Compound B Preparation of (S)-1-(methylsulfonyl)-N-(4-(methylthio)-1-oxo-1-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-)yl)amino)butan-2-yl)-1H-pyrrole-3-carboxamide (compound B) [ka] To a mixture of (2S)-2-amino-4-methylsulfanyl-N-[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]butanamide (2 g, 4.75 mmol, HCl salt) and 1-methylsulfonylpyrrole-3-carboxylic acid (898.81 mg, 4.75 mmol) in DMF (20 mL) was added EDCI (1.37 g, 7.13 mmol), HOBt (962.92 mg, 7.13 mmol), and DIEA (2.46 g, 19.00 mmol, 3.31 mL) and the mixture was stirred at 25° C. for 3 h. The mixture was poured into HO (100 mL) and the precipitate was collected by filtration. The solid was triturated in MeOH (20 mL) and the precipitate was collected by filtration. After dissolving the solid in DMSO (10 mL), the mixture was poured into MeOH (50 mL) and the precipitate formed was collected by filtration and lyophilized to give compound B (2.05 g, 3.66 mmol, 77.01% yield) as a white solid. LCMS (ESI) m / z [M+H] + =555.9. 1 H NMR(400 MHz,DMSO)δ 12.49(s,1H),8.68-8.66(m,2H),8.46(d,J=7.2 Hz,1H),8.31-8.30(m,1H),8.02-8.00(m,1H),7.94-7.96(m,1H),7.83( s,1H),7.73-7.74(m,3H),7.61-7.57(m,1H),7.31-7.29(m,1H),6.79-6 .77(m,1H),4.74-4.69(m,1H),3.57(s,3H),2.67-2.53(m,2H),2.13-2.01(m,5H).SFC:AS-3-MeOH(DEA)-40-3mL-35T.lcm,t=0.932min,ee%=100%.

[0309] Example 10. Effect of BRG1 / BRM ATPase inhibition on proliferation of uveal melanoma, hematological cancer, prostate cancer, breast cancer, and Ewing's sarcoma cell lines Procedure: All cell lines listed above in Example 7 were also tested with Compound B as described above. In addition, the following cell lines were also tested as follows: Briefly, Ewing's sarcoma cell lines (CADOES1, RDES, SKES1), retinoblastoma cell line (WERIRB1), ALL cell line (REH), AML cell line (KASUMI1), prostate cancer cell lines (PC3, DU145, 22RV1), melanoma cell lines (SH4, SKMEL28, WM115, COLO829, SKMEL3, A375), breast cancer cell lines (MDAMB415, CAMA1, MCF7, BT474, HCC14), and HER2 cell lines (HER2, ... The above method was performed for the following cell lines: B-ALL cell line (SUPB15), CML cell line (K562, MEG01), Burkitt's lymphoma cell line (RAMOS2G64C10, DAUDI), mantle cell lymphoma cell line (JEKO1, REC1), bladder cancer cell line (HT1197), and lung cancer cell line (SBC5), with the following modifications: cells were seeded in 96-well plates, and the next day, BRG1 / BRM ATPase inhibitor compound B was dissolved in DMSO and added to the cells in a concentration gradient of 0 to 10 micromolar. At the time of cell splitting on days 3 and 7, cells were split into new 96-well plates, and new compound was added 4 hours after reseeding.

[0310] Table 7 lists the test cell lines and growth media used. [Table 12]

[0311] Results: As shown in Figure 3, uveal melanoma, hematological cancer, prostate cancer, breast cancer, and Ewing's sarcoma cell lines were more sensitive to BRG1 / BRM inhibition than the other cell lines tested. Inhibition of uveal melanoma, hematological cancer, prostate cancer, breast cancer, and Ewing's sarcoma cell lines was maintained through day 7.

[0312] Example 11. Effect of BRG1 / BRM ATPase inhibition on the proliferation of uveal melanoma and blood cancer cell lines Procedure: Pooled cell viability assays were performed using PRISM (simultaneous profiling of relative inhibition in mixtures) as previously described ("High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines", Yu et al, Nature Biotechnology 34, 419-423, 2016) with the following modifications. Cell lines were obtained from the Cancer Cell Line Encyclopedia (CCLE) collection and adapted to phenol red-free RPMI-1640 medium supplemented with 10% heat-inactivated fetal bovine serum (FBS) in order to apply the unique infection and pooling protocol to this large list of cell lines. A lentiviral spin-infection protocol was performed to introduce the 24-nucleotide barcode into each cell line, with an estimated multiplicity of infection (MOI) of 1 for all cell lines, using blasticidin as a selection marker. Then, over 750 stably barcoded PRISM cancer cell lines were pooled together into pools of 25 according to their doubling times. For screening runs, instead of seeding a pool of 25 cell lines in each well as previously described (Yu et al.), a pool of all adherent or all suspension cell lines was seeded together using T25 flasks (100,000 cells / flask) or 6-well plates (50,000 cells / well), respectively. Cells were treated with either DMSO or compounds in triplicate with 8-point, 3-fold dose responses starting at a top concentration of 10 μM. As a control for assay robustness, cells were treated in parallel with two previously validated compounds, the pan-Raf inhibitor AZ-628, and the proteasome inhibitor bortezomib, using top concentrations of 2.5 μM and 0.039 μM, respectively.

[0313] After 3 days of treatment with compounds, cells were lysed, genomic DNA was extracted, and barcodes were amplified by PCR and detected using next generation sequencing. Cell viability was determined by comparing the counts of cell line-specific barcodes in treated samples with those in DMSO and day 0 controls. Dose-response curves were fitted for each cell line and the corresponding area under the curve (AUC) was calculated and compared to the median AUC of all cell lines (Figure 4). Cell lines with AUC below the median were considered the most sensitive.

[0314] Example 12. Effect of BRG1 / BRM ATPase inhibitors on the proliferation of uveal melanoma cell lines Procedure: Uveal melanoma cell lines (92-1, MP41, MP38, MP46) and non-small cell lung cancer cells (NCI-H1299) were seeded in 96-well plates containing growth medium (see Table 6). Compound 67, a BRG1 / BRM ATPase inhibitor, was dissolved in DMSO and added to the cells at the time of seeding in a concentration gradient of 0 to 10 micromolar. Cells were incubated at 37°C for 3 days. After 3 days of treatment, cell proliferation was measured with a Cell-titer glow (Promega) and luminescence was read on an Envision plate reader (Perkin Elmer).

[0315] Results: As shown in Figure 5, compound B produced potent growth inhibition in uveal melanoma cell lines.

[0316] Example 13. Comparison of BRG1 / BRM inhibitors with clinical PKC and MEK inhibitors in uveal melanoma cell lines Procedure: Uveal melanoma cell lines, 92-1 or MP41, were seeded in 96-well plates in the presence of growth medium (see Table 6). BAF ATPase inhibitor (Compound B), PKC inhibitor (LXS196; MedChemExpress), and MEK inhibitor (Selumetinib; Selleck Chemicals) were dissolved in DMSO and added to cells at the time of seeding in a concentration gradient of 0-10 micromolar. Cells were incubated at 37°C for 3 days. After 3 days of treatment, cell proliferation was measured with a Cell-titer glow (Promega) and luminescence was read on an Envision plate reader (Perkin Elmer).

[0317] Results: As shown in Figures 6A and 6B, Compound B showed a stronger effect on inhibiting the proliferation of uveal melanoma cells than clinical PKC inhibitors and clinical MEK inhibitors. Furthermore, it was found that Compound B initiated proliferation inhibition more quickly than clinical PKC inhibitors and clinical MEK inhibitors.

[0318] Example 14. BRG1 / BRM ATPase inhibitors are effective in inhibiting the proliferation of PKC inhibitor-resistant cells. Procedure: MP41 uveal melanoma cells were made resistant to a PKC inhibitor (LXS196, MedChemExpress) by long-term culture in growth medium containing increasing concentrations of the compound up to 1 μM (see Table 6). After 3 months, the sensitivity of parental MP41 cells and PKC inhibitor (PKCi)-resistant cells to the PKC inhibitor (LXS196) or the BRG1 / BRM ATPase inhibitor (Compound B) was tested in a 7-day growth inhibition assay as described above in Example 9.

[0319] Results: Although PKCi-resistant cells could tolerate growth at higher concentrations of LXS196 than the parental MP41 cell line (Figure 7A), the BRG1 / BRM ATPase inhibitor (compound B) still resulted in strong growth inhibition of both the PKCi-resistant and parental cell lines (Figure 7B). The PKCi-resistant cells were more sensitive to compound B than the parental MP41 cells (Figure 7B).

[0320] Example 15. Synthesis of Compound C [ka] Step 1. Preparation of 6-fluoropyridine-2-carbonyl chloride (intermediate B) [ka] To a cooled (0° C.) solution of 6-fluoropyridine-2-carboxylic acid (50.00 g, 354.36 mmol) in dichloromethane (500 mL) and N,N-dimethylformamide (0.26 mL, 3.54 mmol) was added oxalyl chloride (155.10 mL, 1.77 mol). After all the oxalyl chloride was added, the reaction mixture was allowed to warm to room temperature and stirred for an additional 0.5 h. The mixture was concentrated in vacuo to give intermediate B (56.50 g) as a white solid, which was used in the next step without further purification.

[0321] Step 2. Preparation of 2-chloro-1-(6-fluoro-2-pyridyl)ethenone (intermediate C) [ka] To a cooled (0° C.) mixture of intermediate B (56.00 g, 351.00 mmol) in 1,4-dioxane (800 mL) was added dropwise a solution of 2 M trimethylsilyldiazomethane in hexane (351 mL). The resulting reaction mixture was stirred at 25° C. for 10 h. The reaction mixture was then quenched with a solution of 4 M HCl in 1,4-dioxane (500 mL). After stirring for 2 h, the reaction solution was concentrated in vacuo to give an oil. The residue was diluted with saturated aqueous NaHCO3 (500 mL) and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine (300 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to give intermediate C (35.50 g) as a white solid, which was used directly in the next step. LCMS (ESI) m / z: [M+H] += 173.8.

[0322] Step 3. Preparation of 4-(6-fluoro-2-pyridyl)thiazol-2-amine (Intermediate E) [ka] To a solution of intermediate C (35.50 g, 204.53 mmol) and thiourea (14.01 g, 184.07 mmol) in a mixture of MeOH (250 mL) and H2O (250 mL) was added NaF (3.56 g, 84.82 mmol) at room temperature. After stirring for 0.5 h, the reaction mixture was partially concentrated in vacuum to remove MeOH and the resulting solution was acidified to pH ∼3 with 2M aqueous HCl. After 15 min, the solution was extracted with ethyl acetate (200 mL x 3), the organic layer was discarded, the aqueous phase was alkalized with NaHCO3 (500 mL) and stirred for 30 min, then extracted with ethyl acetate (325 mL * 3), the combined organic layers were washed with brine (225 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with petroleum ether (300 mL), stirred at 25 °C for 10 min and filtered. The resulting solid was dried in vacuum to give intermediate E (28.00 g, 143.43 mmol, yield 70.13%, purity 100%) as a white solid. LCMS (ESI) m / z: [M+H] += 195.8.; 1 H NMR(400 MHz,DMSO-d6)δ 8.00-7.96(m,1H),7.72(d,J=7.2 Hz,1H),7.24(s,1H),7.16(s,2H),7.02(d,J=8.0 Hz,1H).

[0323] Step 4. Preparation of tert-butyl N-[2-[[4-(6-fluoro-2-pyridyl)thiazol-2-yl]amino]-2-oxo-ethyl]carbamate (Intermediate G) [ka] To a solution of N-Boc-glycine (5.92 g, 33.81 mmol), HATU (12.86 g, 33.81 mmol), and DIEA (15.89 g, 122.94 mmol, 21.41 mL) in dichloromethane (100 mL) was added intermediate E (6.00 g, 30.74 mmol). After stirring for 2 h, the reaction mixture was concentrated, then diluted with water (100 mL) and extracted with ethyl acetate (60 mL×4). The combined organic layers were washed with brine (100 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with a 1:1 mixture of petroleum ether and MeOH (40 mL). After stirring at 25° C. for 20 min, the suspension was filtered, and the filter cake was washed with MTBE (20 mL) and dried in vacuum to give intermediate G (7.7 g, 21.63 mmol, 70.4% yield, 99.0% purity) as a white solid. LCMS (ESI) m / z: [M+H] + =353.1.

[0324] Step 5. Preparation of 2-((4-(6-fluoropyridin-2-yl)thiazol-2-yl)amino)-2-oxoethan-1-aminium chloride (Intermediate H) [ka] A solution of intermediate G (5.40 g, 15.32 mmol) in 4M HCl in 1,4-dioxane (35 mL) was stirred at 25° C. for 1.5 h. The mixture was concentrated in vacuo to give intermediate H (4.42 g) as a white solid, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] += 252.9.

[0325] Step 6. Preparation of 1-tert-butyl-N-[2-[[4-(6-fluoro-2-pyridyl)thiazol-2-yl]amino]-2-oxo-ethyl]pyrrole-3-carboxamide (Intermediate J) [ka] To a solution of intermediate H (3.00 g, 10.39 mmol), 1-tert-butylpyrrole-3-carboxylic acid (1.74 g, 10.39 mmol), and DIEA (6.71 g, 51.95 mmol, 9.05 mL) in dichloromethane (40 mL) were added HOBt (1.68 g, 12.47 mmol) and EDCI (2.39 g, 12.47 mmol) successively. After stirring for 4 h, the mixture was concentrated in vacuo. The residue was diluted with water (250 mL) and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine (300 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting solid was triturated with a 1:1 mixture of MTBE / ethyl acetate (400 mL) and after 30 min, the suspension was filtered. The solid was washed with MTBE (85 mL×3) and then dried in vacuum to obtain intermediate J (3.10 g, 7.64 mmol, yield 73.6%, purity 99.0%) as a white solid. LCMS(ESI)m / z:[M+H] += 402.3. 1 H NMR(400 MHz,DMSO-d6)δ 12.40(s,1H),8.18-8.15(m,1H),8.09-8.08(m,1H),7.87-7.83(m,2H),7.52(s,1H),7.11(d,J=8.0 Hz,1H),6.97(m,1H),6.47(s,1H),4.10(d,J=5.6 Hz,2H),1.49(s,9H).

[0326] Step 7. Preparation of 1-(tert-butyl)-N-(2-((4-(6-(cis-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound C) [ka] To a solution of intermediate J (0.100 g, 0.249 mmol) in DMSO (1 mL), DIEA (0.130 mL, 0.747 mmol) and cis-2,6-dimethylmorpholine (0.057 g, 0.498 mmol) were added and the mixture was stirred at 120° C. After 12 h, the solution was cooled to room temperature and the reaction mixture was diluted with MeOH (3 mL). The residue was purified by preparative HPLC (0.1% TFA; column: Luna C18 150*25 5u; mobile phase: [water (0.075% TFA)-ACN]; B%: 30% to 60%, 2 min). The appropriate fractions were collected and lyophilized to give compound C (0.079 g, 0.129 mmol, 51.94% yield, 100% purity) as a white solid. LCMS (ESI) m / z: [M+H] += 497.5. 1 H NMR(400 MHz,DMSO-d6)δ 12.27(s,1H),8.17-8.14(m,1H),7.75(s,1H),7.63-7.59(m,1H),7.51(s,1H),7.25(d,J=7.2 Hz,1H),6.96(s,1H),6.79(d,J=8.8 Hz,1H),6.47(s,1H),4.24(d,J=12.4 Hz,2H),4.08(d,J=5.6 Hz,2H),3.64-3.61(m,2H),2.44-2.38(m,2H),1.49(s,9H),1.18(d,J=5.6 Hz,6H).

[0327] Example 16. BRG1 / BRM ATPase inhibitors cause inhibition of uveal melanoma tumor growth in vivo. Procedure: Nude mice (Envigo) were cultured with 5 × 10 6 92-1 uveal melanoma cells were used to implant subcutaneously in the axillary region. Tumors grew to an average size of approximately 200 mm 3The tumors were allowed to grow until the tumors were fully grown, at which point the mice were grouped and dosing was initiated. Mice were dosed once daily by oral gavage with vehicle (20% 2-hydroxypropyl-β-cyclodextrin) or increasing doses of Compound C. Tumor volumes and body weights were measured over a 3-week period, and doses were adjusted by body weight to obtain the appropriate dose in mg / kg. At this point, the animals were sacrificed and the tumors were dissected and imaged.

[0328] Results: Treatment with Compound C resulted in tumor growth inhibition in a dose-dependent manner, with tumor regression observed at the highest (50 mg / kg) dose (Figures 8A and 8B). Both treatments were well tolerated, and no weight loss was observed (Figure 8C).

[0329] Other embodiments While the invention has been described in connection with specific embodiments thereof, it will be understood that the invention is capable of further modifications, and this application is intended to cover any variations, uses, or adaptations of the invention which generally follow the principles of the invention and include departures from the present disclosure which come within known or customary practice within the art to which the invention pertains, and may be applied to the essential features set forth herein above, and which fall within the scope of the claims.

[0330] Other embodiments are within the scope of the claims.

Claims

1. The structure: 【Chemistry 1】 During the ceremony, R 1 is hydrogen or C 1 -C 6 alkyl; each R 2 and each R 3 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl; R 4 is hydrogen, halo, C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl; R 5 is C 1 -C 6 alkyl; R 6 is hydrogen, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 3 -C 10 cycloalkyl, or R 5 and R 6 combine together with the atoms to which they are attached to form a 7-8 membered heterocyclyl which contains an oxygen atom; each R 7 is independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylC 1 -C 6 alkyl, 5-14 membered heteroaryl, 4-14 membered heterocyclyl, -N(R 7A ) 2 , or OR 7A , where each R 7A is independently H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, or two geminal R 7A groups combine with the atom to which they are attached to form a 5- to 10-membered heteroaryl or a 4- to 10-membered heterocyclyl, or two geminal R 7 groups combine with the atom to which they are attached to form a carbonyl; R 8 is hydrogen, halo, C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl; R 9 is hydrogen or halo; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; X 1 is —SO 2 —; X 2 is N or CR 8 ; L 1 is represented by the following formula A: 【Chemistry 2】 During the ceremony, Each of X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is independently N or CR L1 ; each R L1 is independently H, halo, or C 1 -C 6 alkyl; A 1 is a bond to -(C(R 2 )(R 3 )) m -; A 2 is a bond to L 2 ; L 2 is absent, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocyclyl; The following structure: 【Chemistry 3】 is a group having the following structure: 【Chemistry 4】 During the ceremony, Z is CH2 or CO; each R X1 is independently C 1 -C 6 alkyl or halo, or two geminal R X1 groups combine with the atom to which they are attached to form a carbonyl; p is 0, 1, 2, 3, or 4; or A group having the structure: 【Chemistry 5】 During the ceremony, 【Chemistry 6】 each R X1 is independently C 1 -C 6 alkyl or halo; or two geminal R X1 groups combine with the atoms to which they are attached to form a carbonyl; p is 0, 1, 2, 3, or 4; A compound, or a pharma- ceutically acceptable salt thereof.

2. R ８ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or halo.

3. At least one R Ｘ１ But, C １ -C ６ alkyl or at least one R Ｘ１ is halo or at least two geminal R Ｘ１ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein the groups combine with the atom to which they are attached to form a carbonyl.

4. L １ But the following: 【Chemistry 7】 2. The compound of claim 1, wherein:

5. -L ２ - (R ７ ) ｎ has the following structure: 【Chemistry 8-1】 【Chemistry 8-2】 5. The compound of claim 4, which is a group represented by the formula:

6. -L ２ - (R ７ ) ｎ has the following structure: 【Chemistry 9】 6. The compound of claim 5, which is a group represented by the formula:

7. -L ２ - (R ７ ) ｎ has the following structure: 【Chemistry 10】 6. The compound of claim 5, which is a group represented by the formula:

8. -L ２ - (R ７ ) ｎ has the following structure: 【Chemistry 11】 6. The compound of claim 5, which is a group represented by the formula:

9. L ２ But, C ６ -C １０ 6. The compound of claim 5, or a pharma- ceutically acceptable salt thereof, which is aryl.

10. At least one R ７ are cyclopropyl, 2,2-difluorocyclopropyl, difluoromethoxy, 2,6-dimethylmorpholin-4-yl, N-azetidinyl, 3-fluorocyclobutyl, 2-methoxyethyl, ethoxy, methoxy, 2,2-difluoroethoxy, 2,2-difluoroethyl, trifluoromethyl, isopropyl, methyl, acetyl, fluoro, chloro, 1-methylpyrazol-3-yl, dimethylamino, N-methyl-N-(2-methoxyethyl)-amino, N-ethyl-N-(2-methoxyethyl)-amino, N-(2-propyl)- propyl)-N-(2-methoxyethyl)-amino, 2-methoxyethylamino, 3-aza-8-oxa-bicyclo[4.3.0]non-3-yl, 3-aza-7-oxa-bicyclo[4.3.0]non-3-yl, 1-fluorocyclobut-1-yl, 3-fluoropyrrolidin-1-yl, 3-methoxypyrrolidin-1-yl, oxetan-3-yl, N-methylindolin-4-yl, 2,2-difluoro-3-methylcycloprop-1-yl, 3-methoxyazetidin-1-yl, 3-methoxypiperidin-1-yl, 1,2 -dimethyl-7-azaindole-4-yl, 1-methyl-7-azaindole-4-yl, 2,3-methylenedioxyphenyl, N-methyl-N-(3-oxetanyl)amino, 3-oxetanyloxy, 1,1-difluoro-5-azaspiro[2.3]hex-5-yl, 1-fluoromethyl-cyclopropyl, N-(3-tetrahydrofuranyl)methylamino, N-indolinyl, N-1,4-oxazepanyl, 2-fluoro-2-propyl, 1,1-difluoro-2-propyl, 2,2-difluoro-1-methylcyclopropyl prop-1-yl, 1-methylcyclopropyl, 4,4-difluoropiperidin-1-yl, 2-methoxyethoxy, 3,3-difluorocyclobut-1-yl, N-methyl-N-1-methoxyprop-2-ylamino, 1-methoxyprop-2-ylamino, 1-methoxyethyl, 4-methylpiperazinyl, 3-methylmorpholinyl, 2,2-difluoropropoxy, 3-methoxycyclobutyl, methylamino, 4-dimethylamino-3,3-difluoropiperidinyl, 4-methylamino-3,3-difluoropiperidinyl, 3,The compound according to claim 5, which is 3-difluoropyrrololidinyl, N-methyl-N-3-methoxycyclobutylamino, 1-methylpyrazol-5-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl, cyclopropyloxy, 2,6-dimethylpyrid-4-yl, 2-methylpyrrololidinyl, 4-oxabicyclo[4.1.0]hept-1-yl, N-methyl-N-(2,6-dimethyltetrahydropyran-4-yl)amino, or N-methyl-N-3-methyloxetan-3-ylmethylamino, or a pharma- ceutically acceptable salt thereof.

11. R １ or a pharma- ceutically acceptable salt thereof, according to claim 1, wherein:

12. The following: and pharma- ceutically acceptable salts thereof.

13. the below described: and pharma- ceutically acceptable salts thereof.

14. The compound is a BRG1 IC ５０ and BRM IC ５０ or a pharma- ceutically acceptable salt thereof, wherein the ratio of

15. A pharmaceutical composition comprising the compound of claim 1 and a pharma- ceutically acceptable excipient.

16. 17. A pharmaceutical composition for decreasing the activity of a BAF complex in a cell, comprising an effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 15.

17. A pharmaceutical composition for use in treating a BAF complex-associated disorder, which is cancer or a viral infection, comprising an effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 15.

18. 16. A pharmaceutical composition for the treatment of cancer, comprising an effective amount of a compound according to claim 1 or 2 or a pharmaceutical composition according to claim 15.

19. 19. The pharmaceutical composition of claim 18, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary site, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal and gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenal cortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

20. 16. A pharmaceutical composition for the treatment of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer, comprising an effective amount of a compound of claim 1 or 2 or a pharmaceutical composition of claim 15.

21. A pharmaceutical composition for use in reducing the level and / or activity of BRG1 and / or BRM in cancer cells selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and blood cancer, comprising contacting the cells with an effective amount of a compound described in claim 1 or 2 or a pharmaceutical composition described in claim 15.

22. 22. The pharmaceutical composition of claim 21, further comprising contacting the cells with an anti-cancer therapy.

23. 23. The pharmaceutical composition of claim 22, wherein the anti-cancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiation therapy, thermotherapy, or photocoagulation, or a combination thereof.

24. 24. The pharmaceutical composition of claim 23, wherein the one or more chemotherapeutic or cytotoxic agents are dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, mitogen-activated protein kinase inhibitors, and / or protein kinase C inhibitors.

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