Compounds and uses thereof

Abstract

The present disclosure features compounds of Formula I, # imgabs0 # or a pharmaceutically acceptable salt thereof, and formulations containing the same. Also disclosed are methods of treating BAF complex related disorders, such as cancer.

Description

[0001] background

[0002] The present invention relates to compounds useful for modulating the BRG1- or BRM-associated factor (BAF) complex. In particular, the present invention relates to compounds useful for treating disorders associated with BAF complex function.

[0003] Chromatin regulation is crucial for gene expression, and ATP-dependent chromatin remodeling is a mechanism by which such gene expression occurs. The human switch / sucrose non-fermentable (SWI / SNF) chromatin remodeling complex (also known as the BAF complex) has two SWI2-like ATPases, called BRG1 (Brahma-related gene-1) and BRM (Brahma). The transcriptional activator BRG1 (also known as the ATP-dependent chromatin remodeling factor 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 possible global transcription activator SNF2L2 and / or ATP-dependent chromatin remodeling factor SMARCA2) is encoded by the SMARCA2 gene on chromosome 9 and has been shown to be essential for tumor cell growth in cells characterized by BRG1 loss-of-function mutations. Inactivation of BRG and / or BRM leads to downstream effects in cells, including cell cycle arrest and tumor suppression. Summary of the Invention

[0004] The present invention features compounds that can be used to modulate the BAF complex. In some embodiments, the compounds can be used to treat 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 invention, alone or in combination with other pharmaceutical agents, can be used to treat such disorders.

[0005] In one aspect, the present invention provides a compound having the following structure or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in

[0008] m is 0, 1, 2, or 3;

[0009] n is 0, 1, 2, 3, or 4;

[0010] p is 0, 1, 2, or 3;

[0011] X 1It is O, NR 5 or (C(R 5 )(R 6 )), and Z 1 and Z 2 Each independently does not exist or is (C(R 9 )2) or O, if X 1 If it is O, then Z 1 and Z 2 Each independently does not exist or is (C(R 9 )2);

[0012] X 2 Is N or CR 8 ;

[0013] Each R X1 are independently deuterium, optionally substituted C1-C6 alkyl or halogen, or two geminal R X1 The groups, together with the atoms to which they are attached, combine to form a carbonyl group;

[0014] L 1 is an optionally substituted 9-membered or 10-membered bicyclic heterocyclyl, an optionally substituted 9-membered or 10-membered bicyclic heteroaryl, an optionally substituted monocyclic 6-membered heteroarylvinyl, an optionally substituted monocyclic 6-membered heteroaryl-C3-C8-cycloalkyl or an optionally substituted monocyclic 6-membered heteroarylethynyl;

[0015] L 2 is absent, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclyl;

[0016] R 1 is hydrogen or optionally substituted C1-C6 alkyl;

[0017] Each R 2 and each R 3 are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0018] R 4 is hydrogen, halogen, optionally substituted C1-C6 alkyl or optionally substituted C3-C 10 Cycloalkyl;

[0019] R 5 is hydrogen, deuterium or optionally substituted C1-C6 alkyl;

[0020] R 6 is hydrogen, deuterium, optionally substituted C1-C6 alkyl or halogen, and each R 9are independently hydrogen, deuterium, optionally substituted C1-C6 alkyl or halogen; or R 6 and an adjacent R 9 Together with the atoms to which they are attached, they form an optionally substituted C3-C8 cycloalkyl group, and the remaining R 9 The groups, if present, are independently deuterium, optionally substituted C1-C6 alkyl or halogen;

[0021] Each R 7 are independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, halogen, optionally substituted C3-C 10 cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocyclyl, -N(R 7A )2OR-OR 7A , where each R 7A are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclyl, or two geminal R 7A The groups, taken together with the atoms to which they are attached, are combined to form an optionally substituted 5- to 10-membered heteroaryl or an optionally substituted 4- to 10-membered heterocyclyl;

[0022] R 8 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or optionally substituted C3-C 10 cycloalkyl; and

[0023] R 10 is hydrogen or a halogen.

[0024] In some embodiments, Z 1 Yes (C (R 9 )2). In some embodiments, Z 1 In some embodiments, Z 1 It's O.

[0025] In some embodiments, Z 2 Yes (C (R 9 )2). In some embodiments, Z 2 In some embodiments, Z 2 It's O.

[0026] In some embodiments, X 1 Is O. In some embodiments, X 1 It is NR 5In some embodiments, X 1 Yes (C (R 5 )(R 6 ).

[0027] In some embodiments, X 2 It's CR 8 .

[0028] In some embodiments, the group

[0029]

[0030] Is a group of the following structure

[0031]

[0032] In some embodiments, the group

[0033]

[0034] Is a group of the following structure

[0035]

[0036] In some embodiments, the group

[0037]

[0038] Is a group of the following structure

[0039]

[0040] In some embodiments, the group

[0041]

[0042] Is a group of the following structure

[0043]

[0044] In some embodiments, the group

[0045]

[0046] Is a group of the following structure

[0047]

[0048] In some embodiments, the group

[0049]

[0050] Is a group of the following structure

[0051]

[0052] In some embodiments, the group

[0053]

[0054] Is a group of the following structure

[0055]

[0056] In some embodiments, the group

[0057]

[0058] Is a group of the following structure

[0059]

[0060] In some embodiments, the group

[0061]

[0062] Is a group of the following structure

[0063]

[0064] In some embodiments, the group

[0065]

[0066] Is a group of the following structure

[0067]

[0068] In some embodiments, R 8 In some embodiments, R 8 is halogen (e.g., fluorine). 8 is an optionally substituted C2-C6 alkynyl. 8 is an optionally substituted C1-C6 heteroalkyl. 8 is an optionally substituted C3-C 10 Cycloalkyl.

[0069] In some embodiments, X 2 It's N.

[0070] In some embodiments, the group

[0071]

[0072] Is a group of the following structure

[0073]

[0074] In some embodiments, R 4 In some embodiments, R 4 It's a halogen.

[0075] In some embodiments, R 10 In some embodiments, R 10 It's a halogen.

[0076] In some embodiments, at least one R X1 is an optionally substituted C1-C6 alkyl. In some embodiments, at least one R X1 In some embodiments, at least one R X1 It's deuterium.

[0077] In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1. In some embodiments, p is 0.

[0078] In some embodiments, L 1 L is an optionally substituted 9-membered or 10-membered bicyclic heteroaryl. 1 yes

[0079]

[0080] in

[0081] X 3 、X 4 、X 5 、X 6 、X 7 and X 8 Each independently is N or CR L1 ;

[0082] Each R L1 are independently H, halogen, or optionally substituted C1-C6 alkyl;

[0083] A 1 is connected to –(C(R 2 )(R 3 )) m -key; and

[0084] A 2 is connected to L 2 key.

[0085] In some embodiments, L 1 yes In some embodiments, RL1 It's hydrogen.

[0086] In some embodiments, L 1 yes

[0087]

[0088] In some embodiments, L 1 yes

[0089]

[0090] In some embodiments, L 1 is an optionally substituted monocyclic 6-membered heteroarylvinyl group.

[0091] In some embodiments, L 1 yes

[0092]

[0093] in

[0094] X 3 、X 4 and X 5 Each independently is N or CR L1 ;

[0095] Each R L1 are independently H, halogen, or optionally substituted C1-C6 alkyl;

[0096] A 1 is connected to –(C(R 2 )(R 3 )) m -key; and

[0097] A 2 is connected to L 2 key.

[0098] In some embodiments, L 1 yes

[0099]

[0100] In some embodiments, L 1 is an optionally substituted monocyclic 6-membered heteroarylethynyl group.

[0101] In some embodiments, L 1 yes

[0102]

[0103] in

[0104] X 3、X 4 and X 5 Each independently is N or CR L1 ;

[0105] Each R L1 are independently H, halogen, or optionally substituted C1-C6 alkyl;

[0106] A 1 is connected to –(C(R 2 )(R 3 )) m -key; and

[0107] A 2 is connected to L 2 key.

[0108] In some embodiments, L 1 yes

[0109]

[0110] In some embodiments, L 1 is an optionally substituted monocyclic 6-membered heteroaryl-C3-C8-cycloalkyl.

[0111] In some embodiments, L 1 yes

[0112]

[0113] in

[0114] X 3 、X 4 and X 5 Each independently is N or CR L1 ;

[0115] Each R L1 are independently H, halogen, or optionally substituted C1-C6 alkyl;

[0116] A 1 is connected to –(C(R 2 )(R 3 )) m -key; and

[0117] A 2 is connected to L 2 key.

[0118] In some embodiments, L 1 yes

[0119]

[0120] In some embodiments, L1 is an optionally substituted 9-membered or 10-membered bicyclic heterocyclic group.

[0121] In some embodiments, the compound has the structure:

[0122]

[0123] In some embodiments, L 2 is an optionally substituted 5- to 10-membered heteroaryl. In some embodiments, -L 2 -(R 7 ) n Is a group of the following structure:

[0124]

[0125] In some embodiments, -L 2 -(R 7 ) n Is a group of the following structure:

[0126]

[0127] In some embodiments, -L 2 -(R 7 ) n Is a group of the following structure:

[0128]

[0129] In some embodiments, -L 2 -(R 7 ) n Is a group of the following structure:

[0130]

[0131] In some embodiments, -L 2 -(R 7 ) n Is a group of the following structure:

[0132]

[0133] In some embodiments, -L 2 -(R 7 ) n Is a group of the following structure:

[0134]

[0135] In some embodiments, L 2 is an optionally substituted C6-C 10In some embodiments, L 2 is optionally substituted phenyl.

[0136] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0137] In some embodiments, R 7 is an optionally substituted C1-C6 alkyl. 7 is an optionally substituted C1-C6 heteroalkyl. 7 is an optionally substituted 4- to 10-membered heterocyclyl. In some embodiments, R 7 is optionally substituted azetidinyl or 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. 7 Yes-N(R 7A )2. In some embodiments, R 7 is an optionally substituted N-azetidinyl or an optionally substituted N-morpholinyl. 7 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 4- to 10-membered heterocyclyl. In some embodiments, at least one R 7 Yes-OR 7A In some embodiments, R 7A is an optionally substituted C 1-6 alkyl.

[0138] In some embodiments, n is 0.

[0139] In some embodiments, at least one R 7are difluoromethyl, 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, fluorine, chlorine, 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-fluorocyclobutan-1-yl, 3-fluoropyrrolidin-1-yl, 3-methoxypyrrolidin-1-yl, oxetan-3-yl, N-methylindolin-4-yl, 2,2-difluoro-3-methylcyclopropyl-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]hexan-5-yl, 1-fluoromethyl-cyclopropyl, N-(3-tetrahydrofuranyl)methylamino, N-indolyl, N-1,4-oxazepanyl, 2-fluoro-2-propyl, 1,1-difluoro-2-propyl, 2,2-difluoro-1-methylcyclopropyl-1-yl, 1-methylcyclopropyl, 4,4-difluoropiperidin-1-yl, 2-methoxyethoxy, 3,3-difluorocyclobutan-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-difluoropyrrolidinyl, N-methyl-N-3-methoxycyclobutylamino, 1-methylpyrazol-5-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl, cyclopropyloxy, 2,6-dimethylpyridin-4-yl, 2-methylpyrrolidinyl, 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.

[0140] In some embodiments, R 1 It's hydrogen.

[0141] In some embodiments, the group

[0142]

[0143] Is a group of the following structure

[0144]

[0145] In some embodiments, the group

[0146]

[0147] Is a group of the following structure

[0148]

[0149] In some embodiments, the compound is selected from the group consisting of Compound 1-523 and pharmaceutically acceptable salts thereof.

[0150] Table 1. Compounds of the present invention

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259] In some embodiments, the compound has a BRG1 IC of at least 5. 50 With BRM IC 50 In some embodiments, the compound has a BRG1 IC of at least 7. 50 With BRM IC 50 In some embodiments, the compound has a BRG1 IC of at least 10. 50 With BRM IC 50 In some embodiments, the compound has a BRG1 IC of at least 15. 50 With BRM IC 50 In some embodiments, the compound has a BRG1 IC of at least 20. 50 With BRMIC 50 In some embodiments, the compound has a BRG1 IC of at least 25. 50 With BRM IC 50 In some embodiments, the compound has a BRG1 IC of at least 30. 50 With BRM IC 50ratio.

[0260] In another aspect, the invention features a pharmaceutical composition including any of the above-described compounds and a pharmaceutically acceptable excipient.

[0261] In another aspect, the invention features a method of reducing the activity of a BAF complex in a cell, the method involving contacting the cell with an effective amount of any one of the aforementioned compounds or a pharmaceutical composition thereof.

[0262] In some embodiments, the cell is a cancer cell.

[0263] In another aspect, the invention features a method of treating a BAF complex-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any one of the aforementioned compounds or a pharmaceutical composition thereof.

[0264] In some embodiments, the BAF complex-associated disorder is cancer.

[0265] In a further aspect, the invention features a method of inhibiting a BRM, the method involving contacting a cell with an effective amount of any one of the aforementioned compounds or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell.

[0266] In another aspect, the invention features a method of inhibiting BRG1, the method involving contacting a cell with an effective amount of any one of the aforementioned compounds or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell.

[0267] In a further aspect, the invention features a method of inhibiting BRM and BRG1, the method involving contacting a cell with an effective amount of any one of the aforementioned compounds or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell.

[0268] In another aspect, the invention features a method of treating a disorder associated with a BRG1 loss-of-function mutation in a subject in need thereof, the method involving administering to the subject an effective amount of any one of the aforementioned compounds or a pharmaceutical composition thereof.

[0269] In some embodiments, the disorder associated with a BRG1 loss-of-function mutation is cancer. In other embodiments, the subject is determined to have a BRG1 loss-of-function disorder, such as a BRG1 loss-of-function cancer (e.g., a cancer that has been determined to include cancer cells with BRG1 loss-of-function).

[0270] In another aspect, the invention features a method of inducing apoptosis in a cell, the method involving contacting the cell with an effective amount of any one of the aforementioned compounds or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell.

[0271] 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 one of the aforementioned compounds or a pharmaceutical composition thereof.

[0272] In some embodiments of any of the preceding 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, esophageal-gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal carcinoma, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

[0273] In some embodiments of any of the preceding 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.

[0274] In some embodiments of any of the foregoing methods, the cancer is a drug-resistant cancer or has failed to respond to a previous therapy (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, docetaxel, platinum agents such as carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inhibitors, alimta, abraxane, gemcitabine, avastin, halaven, neratinib, PARP inhibitors, ARN810, mTOR inhibitors, topotecan, gemzar, VEGFR2 inhibitors, folate receptor antagonists, demcizumab, fosbretabulin, or PDL1 inhibitors).

[0275] 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.

[0276] In another aspect, the present disclosure provides a method for treating a disorder associated with BAF (e.g., cancer or viral infection) in a subject in need thereof. This method comprises contacting a cell with an effective amount of any one of the aforementioned compounds or a pharmaceutically acceptable salt thereof, or any one of the aforementioned pharmaceutical compositions. In some embodiments, the disorder is a viral infection, which is a retroviridae such as a lentivirus (e.g., human immunodeficiency virus (HIV)) and a delta retrovirus (e.g., human T-cell leukemia virus I (HTLV-I), human T-cell leukemia virus II (HTLV-II)), a hepatoviridae (e.g., hepatitis B virus (HBV)), a flaviviridae (e.g., hepatitis C virus (HCV)), adenoviridae (e.g., human adenovirus), a herpesviridae (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus (HSV), or a combination thereof. - Infection with a virus of the family of 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, HPVE1)), parvoviridae (e.g., parvovirus B19), polyomaviridae (e.g., JC virus and BK virus), paramyxoviridae (e.g., measles virus), togaviridae (e.g., rubella virus). In some embodiments, the disorder is Coffin-Siris syndrome, neurofibromatosis (e.g., NF-1, NF-2, or schwannomatosis), or multiple meningiomas.

[0277] In another aspect, the present disclosure provides a method for treating a viral infection in a subject in need thereof. This method includes administering to the subject an effective amount of any one of the aforementioned compounds or a pharmaceutically acceptable salt thereof, or any one of the aforementioned pharmaceutical compositions. In some embodiments, the viral infection is a retroviridae such as a lentivirus (e.g., human immunodeficiency virus (HIV)) and a delta retrovirus (e.g., human T-cell leukemia virus I (HTLV-I), human T-cell leukemia virus II (HTLV-II)), a hepatoviridae (e.g., hepatitis B virus (HBV)), a 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), a papillomaviridae (e.g., human papillomavirus (HPV, HPV-1), herpes simplex virus type 2 (HSV-2), human herpes virus type 6 (HHV-6), herpes virus K*, CMV, varicella-zoster virus), a papillomaviridae (e.g., human papillomavirus (HPV), HPV-2), adenoviridae (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), adenoviridae (e.g., human papillomavirus (HPV E1)), infection with a virus of the Parvoviridae (e.g., Parvovirus B19), Polyomaviridae (e.g., JC virus and BK virus), Paramyxoviridae (e.g., measles virus), or Togaviridae (e.g., Rubella virus).

[0278] In another aspect, the invention features a method of treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a blood cancer in a subject in need thereof, comprising administering to the subject an effective amount of any one of the foregoing compounds or a pharmaceutical composition thereof.

[0279] In another aspect, the invention features a method of reducing tumor growth of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cancer in a subject in need thereof, comprising administering to the subject an effective amount of any one of the foregoing compounds or a pharmaceutical composition thereof.

[0280] 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 one of the aforementioned compounds or a pharmaceutical composition thereof.

[0281] In another aspect, the invention features a method of inhibiting metastatic colonization of a melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject, comprising administering an effective amount of any one of the aforementioned compounds or a pharmaceutical composition thereof.

[0282] In another aspect, the invention features a method of reducing the level and / or activity of BRG1 and / or BRM in melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer cells, the method comprising contacting the cells with an effective amount of any one of the aforementioned compounds or a pharmaceutical composition thereof.

[0283] In some embodiments of any of the aforementioned aspects, the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer cell is in the subject.

[0284] In some embodiments of any of the aforementioned aspects, the effective amount of the 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. In some embodiments, the effective amount of the 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. In some embodiments, the effective amount of the 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%).

[0285] In some embodiments, an effective amount of the 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. In some embodiments, an effective amount of the 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 for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days or more).

[0286] In some embodiments of any of the aforementioned aspects, the effective amount of the 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. In some embodiments, the effective amount of the 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. In some embodiments, the effective amount of the 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%).

[0287] In some embodiments, an effective amount of the 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. In some embodiments, an effective amount of the 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 for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more).

[0288] In some embodiments, the subject has a 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 a 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, such as 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., cancer has spread to the liver). The metastatic cancer may include cells that exhibit migration and / or invasion of migratory cells, and / or 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 by seeding on the surface 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 through the bloodstream. In some embodiments, the effective amount of the compound of the present invention is an amount that effectively inhibits metastatic colonization of cancer to the liver.

[0289] In some embodiments, the cancer has a mutation in GNAQ. In some embodiments, the cancer has a mutation in GNA11. In some embodiments, the cancer has a mutation in PLCB4. In some embodiments, the cancer has a mutation in CYSLTR2. In some embodiments, the cancer has a mutation in BAP1. In some embodiments, the cancer has a mutation in SF3B1. In some embodiments, the cancer has a mutation in EIF1AX. In some embodiments, the cancer has a TFE3 translocation. In some embodiments, the cancer has a TFEB translocation. In some embodiments, the cancer has a MITF translocation. In some embodiments, the cancer has an EZH2 mutation. In some embodiments, the cancer has a SUZ12 mutation. In some embodiments, the cancer has an EED mutation.

[0290] In some embodiments of any of the aforementioned 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, thermotherapy, 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 antitumor antibiotic, an asparagine-specific enzyme, a bisphosphonate, an antitumor agent, an alkylating agent, a DNA repair enzyme inhibitor, a histone deacetylase inhibitor, a corticosteroid, a demethylating agent, an immunomodulator, a janus-related kinase inhibitor, a phosphatidylinositol 3-kinase inhibitor, a proteasome inhibitor, or a tyrosine kinase inhibitor, or a combination thereof.

[0291] In some embodiments of any of the foregoing methods, the compounds of the present invention are used in combination with another anticancer therapy for treating 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 the 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 the administration of the compound of the present invention.

[0292] In some embodiments, the anti-cancer therapy and the compound of the invention are administered within 28 days of each other, and the respective amounts are together effective to treat the subject.

[0293] In some embodiments, the subject or cancer has and / or has been identified as having a BRG1 loss-of-function mutation.

[0294] In some embodiments, the cancer is resistant to one or more chemotherapeutic or cytotoxic agents (e.g., the cancer has been identified as resistant to a chemotherapeutic or cytotoxic agent, such as by a genetic marker, or is potentially resistant to a chemotherapeutic or cytotoxic agent, such as a cancer that fails to respond to a chemotherapeutic or cytotoxic agent). In some embodiments, the cancer fails to respond to one or more chemotherapeutic or cytotoxic agents. In some embodiments, the cancer is resistant to or fails to respond to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 inhibitor (e.g., nivolumab or pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, or durvalumab), a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binumetinib, or trametinib), and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).

[0295] In some embodiments, the cancer is resistant or unresponsive to a previously administered therapeutic agent for treating uveal melanoma, such as a MEK inhibitor or a PKC inhibitor. For example, in some embodiments, the cancer is resistant or unresponsive to a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, bimetinib, or trametinib) and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).

[0296] In one aspect, the present invention provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in therapy.

[0297] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in reducing the activity of a BAF complex in a cell.

[0298] In some embodiments, the BAF complex is in a cancer cell.

[0299] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in treating a BAF complex-related disorder.

[0300] In some embodiments, the BAF complex-associated disorder is cancer or a viral infection.

[0301] In one aspect, the present invention provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in inhibiting a BRM in a cell.

[0302] In some embodiments, the cell is a cancer cell.

[0303] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in treating a disorder associated with a BRG1 loss-of-function mutation.

[0304] In some embodiments, the disorder associated with a BRG1 loss-of-function mutation is cancer.

[0305] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in inducing apoptosis in a cell.

[0306] In some embodiments, the cell is a cancer cell.

[0307] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in treating cancer.

[0308] In some embodiments, 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-gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal carcinoma, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

[0309] In some embodiments, 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.

[0310] In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is soft tissue sarcoma.

[0311] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in treating a cancer selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and hematological cancer.

[0312] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in reducing tumor growth of a cancer selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and blood cancer.

[0313] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in inhibiting metastatic progression of a cancer selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and hematological cancer.

[0314] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in inhibiting metastatic colonization of a cancer selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and hematological cancer.

[0315] In one aspect, the present invention provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in reducing the level and / or activity of a BRM in a cancer cell selected from the group consisting of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, and a blood cancer.

[0316] In some embodiments, the cell is in a subject.

[0317] In some embodiments, the cancer is metastatic.

[0318] In some embodiments, the use further comprises anti-cancer therapy.

[0319] In some embodiments, the anti-cancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiation therapy, thermotherapy, or photocoagulation.

[0320] In some embodiments, the anti-cancer therapy is surgery.

[0321] In some embodiments, the anti-cancer therapy is a chemotherapeutic or cytotoxic agent.

[0322] In some embodiments, the chemotherapeutic or cytotoxic agent is an antimetabolite, an antimitotic agent, an antitumor antibiotic, an asparagine-specific enzyme, a bisphosphonate, an antitumor agent, an alkylating agent, a DNA repair enzyme inhibitor, a histone deacetylase inhibitor, a corticosteroid, a demethylating agent, an immunomodulator, a janus-related kinase inhibitor, a phosphatidylinositol 3-kinase inhibitor, a proteasome inhibitor, or a tyrosine kinase inhibitor.

[0323] In some embodiments, the one or more chemotherapeutic or cytotoxic agents are dacarbazine, temozolomide, cisplatin, treoxazole, fotemustine, IMCgp100, a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a mitogen-activated protein kinase inhibitor, and / or a protein kinase C inhibitor.

[0324] In some embodiments, the anti-cancer therapy and the compound according to any one of claims 1 to 93 or the pharmaceutical composition according to claim 94 are administered within 28 days of each other, and the respective amounts together are effective to treat the subject.

[0325] In some embodiments, the subject or cancer has and / or has been identified as having a BRG1 loss-of-function mutation.

[0326] In some embodiments, the cancer has failed to respond or has progressed following administration of one or more chemotherapeutic or cytotoxic agents.

[0327] In some embodiments, the cancer is resistant or predicted to be resistant to one or more chemotherapeutic agents.

[0328] In some embodiments, the one or more chemotherapeutic or cytotoxic agents are dacarbazine, temozolomide, cisplatin, treoxazole, fotemustine, IMCgp100, a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a mitogen-activated protein kinase inhibitor, and / or a protein kinase C inhibitor.

[0329] In some embodiments, the cancer is melanoma. In some embodiments, the melanoma is uveal melanoma. In some embodiments, the melanoma is mucosal melanoma. In some embodiments, the melanoma is cutaneous melanoma. In some embodiments, the cancer is a blood cancer. In some embodiments, the blood cancer is 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, diffuse large cell lymphoma, or non-Hodgkin lymphoma. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is 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. In some embodiments, the bone cancer is Ewing's sarcoma. In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the renal cell carcinoma is a microphthalmia transcription factor (MITF) family translocation renal cell carcinoma.

[0330] In one aspect, the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in treating a viral infection.

[0331] In some embodiments, the viral infection is a Retroviridae, Hepadnaviridae, Flaviviridae, Adenoviridae, Herpesviridae, Papillomaviridae, Parvoviridae, Polyomaviridae, Paramyxoviridae, or Togaviridae viral infection.

[0332] In one aspect, the present invention provides the use of any of the aforementioned compounds (e.g., BRM / BRG1 dual inhibitor compounds or BRM selective compounds) or pharmaceutically acceptable salts thereof or any of the aforementioned pharmaceutical compositions in the manufacture of a medicament. In some embodiments, the use is as described for the methods described herein.

[0333] Chemical terms

[0334] The terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting.

[0335] For any of the following chemical definitions, the number following the atomic symbol indicates the total number of atoms of that element present in the particular chemical moiety. As will be understood, other atoms (such as H atoms) or substituents as described herein may be present as needed to satisfy the valence of the atoms. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used for 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 carbon in acyl, ester, carbonate, or carbamate groups. References to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group include only those atoms that form part of the heterocyclic ring.

[0336] As used herein, the term "acyl" represents H or an alkyl group connected to a parent molecular group via a carbonyl group as defined herein, such as formyl (i.e., formaldehyde), acetyl, trifluoroacetyl, propionyl, and butyryl. Exemplary unsubstituted acyl groups include 1 to 6, 1 to 11, or 1 to 21 carbon atoms.

[0337] The term "alkyl" as used herein refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms).

[0338] Alkylene is a divalent alkyl group. The term "alkenyl" as used herein, alone or in combination with other groups, refers to a straight or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms).

[0339] The term "alkynyl" as used herein, alone or in combination with other groups, refers to a straight or branched chain hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms).

[0340] The term "amino" as used herein represents -N(R N1 )2, where each R N1 are independently H, OH, NO2, N(R N2 2. SO2OR N2 、SO2R N2 、SOR N2 , N-protecting group, alkyl, alkoxy, aryl, aralkyl, cycloalkyl, acyl (eg, acetyl, trifluoroacetyl, or other acyl groups described herein), wherein these listed R N1 Each of the groups may be optionally substituted; or two R N1 to form an alkylene or heteroalkylene group, and wherein each R N2 are independently H, alkyl or aryl. The amino group of the present invention can be an unsubstituted amino group (ie, -NH2) or a substituted amino group (ie, -N(R N1 )2).

[0341] As used herein, the term "aryl" refers to an aromatic mono- or polycyclic group of 6 to 12 carbon atoms having at least one aromatic ring. In the case of polycyclic rings, the aryl group contains 2 or 3 rings. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.

[0342] As used herein, the term "aralkyl" represents an alkyl group substituted with an aryl group. Unsubstituted aralkyl groups contain 7 to 30 carbon atoms (e.g., 7 to 16 or 7 to 20 carbon atoms, such as C1-C6 alkyl, C6-C 10 Aryl, C1-C 10 Alkyl C6-C 10 Aryl, or C1-C 20 Alkyl C6-C 10 In some embodiments, the alkyl and aryl groups are each further substituted with 1, 2, 3, or 4 substituents as defined herein for the corresponding groups, as valence permits.

[0343] The term "azido" as used herein represents a -N3 group.

[0344] As used herein, the term "bridged polycycloalkyl" refers to a bridged polycyclic group of 5 to 20 carbons containing 1 to 3 bridges. The bridged polycycloalkyl may be unsubstituted or substituted as defined herein for cycloalkyl.

[0345] The term "cyano" as used herein represents a -CN group.

[0346] As used herein, the term "carbocyclyl" refers to a non-aromatic C3-C4 ring formed by carbon atoms. 12Monocyclic, bicyclic or tricyclic structures.Carbocyclic structures include cycloalkyl and unsaturated carbocyclic groups.

[0347] As used herein, the term "cycloalkyl" refers to a saturated, non-aromatic, monovalent monocyclic, bicyclic, or tricyclic group of 3 to 10, preferably 3 to 6, carbon atoms. A cycloalkyl group may be fully saturated or contain one or more double or triple bonds, provided that no ring is aromatic. The term is further exemplified by groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

[0348] The term "halo" as used herein refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) group.

[0349] As used herein, the term "heteroalkyl" refers to an alkyl group, as defined herein, in which one or more of its constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group is further substituted with 1, 2, 3, or 4 substituents as described herein for alkyl groups. An example of a heteroalkyl group is an "alkoxy" group, which, as used herein, refers to an alkyl group -O- (e.g., methoxy and ethoxy). A heteroalkylene group is a divalent heteroalkyl group. As used herein, the term "heteroalkenyl" refers to an alkenyl group, as defined herein, in which one or more of its constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, as valence permits, a heteroalkenyl group is further substituted with 1, 2, 3, or 4 substituents as described herein for alkenyl groups. An example of a heteroalkenyl group is an "alkenyloxy" group, which, as used herein, refers to an alkenyl group -O-. A heteroalkenylene group is a divalent heteroalkenyl group. As used herein, the term "heteroalkynyl" refers to an alkynyl group, as defined herein, in which one or more of its constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group is further substituted with 1, 2, 3, or 4 substituents as described herein for alkynyl groups, as valence permits. An example of a heteroalkynyl group is "alkynyloxy," which, as used herein, refers to an alkynyl-O- group. A heteroalkynylene group is a divalent heteroalkynyl group.

[0350] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic group of 5 to 12 atoms having at least one aromatic ring and containing 1, 2 or 3 ring atoms selected from nitrogen, oxygen and sulphur and the remaining ring atoms being carbon. One or two ring carbon atoms of a heteroaryl may be replaced by a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl and thiazolyl.

[0351] As used herein, the term "heteroarylalkyl" represents an alkyl group substituted with a heteroaryl group. Unsubstituted heteroarylalkyl contains 7 to 30 carbon atoms (e.g., 7 to 16 or 7 to 20 carbon atoms, such as C1-C6 alkyl, C2-C9 heteroaryl, C1-C 10 Alkyl C2-C9 heteroaryl, or C1-C 20In some embodiments, the alkyl and heteroaryl groups are each further substituted with 1, 2, 3, or 4 substituents as defined herein for the corresponding groups, as valence permits.

[0352] As used herein, the term "heteroarylcycloalkyl" represents a cycloalkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylcycloalkyl groups are 5 to 30 carbon atoms (e.g., 5 to 17 carbon atoms, such as C2-C9 heteroarylC3-C8 cycloalkyl). In some embodiments, the cycloalkyl and heteroaryl groups can each be further substituted with 1, 2, 3, or 4 substituents as defined herein for the corresponding groups.

[0353] As used herein, the term "heteroarylethynyl" refers to a group of the formula -R A -R B - group, wherein R A is a heteroaryl group, and R B is ethynyl. Optionally substituted heteroarylethynyl is heteroarylethynyl wherein the heteroaryl portion is optionally substituted as defined herein for a heteroaryl group.

[0354] As used herein, the term "heteroarylvinyl" refers to a group of the formula -R A -R B - group, wherein R A is a heteroaryl group, and R B is vinyl. Optionally substituted heteroarylvinyl is a heteroarylvinyl wherein the heteroaryl portion is optionally substituted as defined herein for a heteroaryl group.

[0355] As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, or tricyclic group having from 3 to 12 atoms, having at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S, wherein no ring is aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furanyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl.

[0356] As used herein, the term "heterocyclylalkyl" represents an alkyl group substituted with a heterocyclyl group. Unsubstituted heterocyclylalkyl contains 7 to 30 carbon atoms (e.g., 7 to 16 or 7 to 20 carbon atoms, such as C1-C6 alkyl, C2-C9 heterocyclyl, C1-C 10 Alkyl C2-C9 heterocyclic group, or C1-C 20 In some embodiments, the alkyl and heterocyclyl groups are each further substituted with 1, 2, 3, or 4 substituents as defined herein for the corresponding groups.

[0357] The term "hydroxyalkyl" as used herein represents an alkyl group substituted with an -OH group.

[0358] The term "hydroxyl" as used herein represents an -OH group.

[0359] As used herein, the term "N-protecting group" represents those groups intended to protect an amino group from undesirable 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, aroyl or carbamoyl groups such as formyl, acetyl, propionyl, pivaloyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, 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 benzylsulfonyl and p-toluenesulfonyl; carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3, 5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, tert-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, 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 allyloxycarbonyl (alloc), formyl, acetyl, benzoyl, pivaloyl, tert-butylacetyl, alanyl, phenylsulfonyl, benzyl, tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

[0360] The term "nitro" as used herein represents a -NO2 group.

[0361] As used herein, the term "oxo" represents a divalent oxygen atom (e.g., the structure of oxo can be shown as =0). For example, a carbonyl group is a carbon (e.g., an alkyl carbon, an alkenyl carbon, an alkynyl carbon, a heteroalkyl carbon, a heteroalkenyl carbon, a heteroalkynyl carbon, a carbocyclyl carbon, etc.) substituted with oxo. Alternatively, sulfur can be substituted with one or two oxo groups (e.g., -SO- or -SO2- in a substituted heteroalkyl, heteroalkenyl, heteroalkynyl, or heterocyclyl group).

[0362] The term "thiol" as used herein represents a -SH group.

[0363] Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl can be substituted or unsubstituted. When substituted, unless otherwise indicated, 1, 2, 3, 4, or 5 substituents will be present, as valence permits. The 1 to 5 substituents are each independently selected from the group consisting of: acyl, alkyl (e.g., unsubstituted and substituted, wherein the substituents include any group described herein, such as aryl, halogen, hydroxy), alkenyl, alkynyl, aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluorine), hydroxy, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroalkenyl, heteroalkynyl, heteroaryl, heterocyclyl, amino (e.g., NH or mono- or di-alkylamino), azido, cyano, nitro, thiol, and oxo. Each substituent is unsubstituted or replaced by an unsubstituted substituent as defined herein for each corresponding group. In some embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl are optionally selected from the group consisting of 1, 2, 3, 4 or 5 independently selected from the group consisting of aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluorine), hydroxyl, heteroaryl, heterocyclyl, amino (e.g., NH or mono- or di-alkylamino), azido, cyano, nitro, thiol and oxo. Each substituent is unsubstituted or replaced by an unsubstituted substituent as defined herein for each corresponding group. In some embodiments, the substituent itself is unsubstituted.

[0364] 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 resolving racemates, by asymmetric synthesis or asymmetric chromatography (chromatography using a chiral adsorbent or eluent). 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 non-superimposable, and the most common reason is that they contain asymmetrically substituted carbon atoms that serve as chiral centers. "Enantiomers" refer to one of a pair of molecules that are mirror images and non-superimposable. Diastereomers are stereoisomers that are not related as mirror images, and the most common reason is that 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 can be prepared, for example, by separating the enantiomers from the racemate using one or more well-known techniques and methods (e.g., chiral chromatography and separation methods based thereon). One skilled in the art can readily determine the appropriate techniques and / or methods for separating the enantiomers of the compounds described herein from the racemic mixture. A "racemate" or "racemic mixture" refers to a compound containing two enantiomers, wherein such a mixture does not exhibit optical activity; that is, they do not rotate the plane of polarized light. A "geometric isomer" refers to an isomer that differs in the orientation of substituent atoms associated with a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic ring system. The atoms (non-H) on each side of the carbon-carbon double bond can be in an E (substituents on opposite sides of the carbon-carbon double bond) or Z (substituents oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans" indicate configurations relative to the core molecule. Certain disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about a single bond, where the steric strain barrier to rotation is high enough to separate the conformers. The compounds of the present invention can be prepared as single isomers by isomer-specific synthesis or resolution from a mixture of isomers. Conventional resolution techniques include forming salts of the free bases of each isomer of the isomer pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming salts of the acid forms of each isomer of the isomer pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming esters or amides of each isomer of the isomer pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving isomer mixtures of the starting material or final product using various well-known chromatographic methods.When the stereochemistry of a disclosed compound is named or depicted by structure, the stereoisomer named or depicted 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 depicted by structure, the enantiomer depicted or named is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure by weight. When a single diastereomer is named or depicted by structure, the diastereomer depicted or named is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. The optical purity percentage is the ratio of the weight of an enantiomer to the weight of that enantiomer plus the weight of its optical isomers. 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 depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure on a molar basis relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure on a molar basis. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure on a molar basis. The percent purity on a molar basis is the ratio of the number of moles of an enantiomer to the number of moles of that enantiomer plus the number of moles of its optical isomers. Similarly, the percent purity on a molar basis is the ratio of the number of moles of a diastereomer to the number of moles of that diastereomer plus the number of moles of its isomers. When a disclosed compound is named or depicted by structure without indication of stereochemistry and the compound has at least one chiral center, it is understood that the name or structure encompasses either enantiomer of the compound free of the corresponding optical isomer, the racemic mixture of the compound, or a mixture enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry and has two or more chiral centers, it is understood that the name or structure encompasses one diastereomer free of other diastereomers, a plurality of diastereomers free of other diastereomeric pairs, a mixture of diastereomers, a mixture of diastereomeric pairs, a mixture of diastereomers in which one diastereomer is enriched relative to the other diastereomers, or a mixture of diastereomers in which one or more diastereomers is enriched relative to the other diastereomers. The present invention encompasses all of these forms.

[0365] Compounds of the present disclosure also include all isotopes of atoms present in intermediates or final compounds. "Isotopes" refer to atoms having the same atomic number but different mass numbers due to different numbers of neutrons in the nucleus. For example, isotopes of hydrogen include tritium and deuterium.

[0366] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 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 I. Isotope-labeled compounds (e.g., 3 H and 14 C-labeled) can be used in compound or substrate tissue distribution assays. Due to their ease of preparation and detectability, tritiated (i.e. 3 H) and carbon-14 (i.e. 14 C) isotopes may be useful. In addition, heavier isotopes such as deuterium (i.e. 2 H) substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by 2 H or 3 H is replaced, or one or more carbon atoms are replaced 13 C- or 14 C-enriched carbon substitution. Positron-emitting isotopes such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. The preparation of isotope-labeled compounds is known to those skilled in the art. For example, isotope-labeled compounds can generally be prepared by substituting an isotope-labeled reagent for a non-isotope-labeled reagent following procedures similar to those disclosed for the compounds of the invention described herein.

[0367] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for use in the present disclosure are described herein; other suitable methods and materials known in the art may also be used. These materials, methods, and examples are exemplary only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated herein by reference in their entirety. In the event of a conflict, the present specification (including definitions) will control.

[0368] definition

[0369] In this application, unless the context clearly indicates otherwise, (i) the term "a" or "an" may be understood to mean "at least one"; (ii) the term "or" may be understood to mean "and / or"; and (iii) the term "comprising" may be understood to cover the itemized components or steps, whether presented alone or together with one or more additional components or steps.

[0370] As used herein, the terms "about" and "approximately" refer to values ​​within 10% above or below the value being described. For example, the term "about 5 nM" indicates a range of 4.5 to 5.5 nM.

[0371] As used herein, the term "administering" refers to administering a composition (e.g., a compound as described herein or a formulation 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 appropriate route. For example, in some embodiments, administration can be intrabronchial (including by bronchial instillation), buccal, enteral, intradermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, transmucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreous.

[0372] As used herein, the term "BAF complex" refers to a BRG1- or HRBM-related factor complex in human cells.

[0373] As used herein, the term "BAF complex-associated disorder" refers to a disorder that is caused or affected by the activity level of the BAF complex.

[0374] As used herein, the term "BRG1 loss-of-function mutation" refers to a mutation in BRG1 that results in a decrease in the activity of the protein (e.g., a decrease in BRG1 activity of at least 1%, e.g., a decrease in BRG1 activity of 2%, 5%, 10%, 25%, 50%, or 100%). Exemplary BRG1 loss-of-function mutations include, but are not limited to, homozygous BRG1 mutations and deletions at the C-terminus of BRG1.

[0375] As used herein, the term "BRG1 loss-of-function disorder" refers to a disorder (e.g., cancer) that exhibits reduced BRG1 activity (e.g., at least 1% reduction in BRG1 activity, e.g., 2%, 5%, 10%, 25%, 50% or 100% reduction in BRG1 activity).

[0376] The term "cancer" refers to conditions caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

[0377] As used herein, "combination therapy" or "combination administration" refers to administering two (or more) different agents or treatments to a subject as part of a defined treatment regimen for a specific disease or condition. The treatment regimen defines the dosage and cycle of each agent so that the effects of the individual agents on the subject overlap. In some embodiments, the delivery of two or more agents is simultaneous or concurrent, and these agents can be co-formulated. In some embodiments, two or more agents are not co-formulated and are administered sequentially as part of a prescribed regimen. In some embodiments, the combination of two or more agents or treatments results in a greater reduction in the symptoms or other parameters associated with the disorder than when a single agent or treatment is delivered or when no other agent or treatment is present. The effects of the two treatments can be partially additive, completely additive, or greater than additive (e.g., synergistic). The sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any appropriate route, including but not limited to oral routes, intravenous routes, intramuscular routes, and direct absorption by mucosal tissue. The therapeutic agent can be administered by the same route or different routes. For example, the first therapeutic agent of the combination may be administered by intravenous injection, while the second therapeutic agent of the combination may be administered orally.

[0378] "Determining the level of a protein or RNA" refers to detecting a protein or RNA directly or indirectly by methods known in the art. "Direct determination" refers to performing a process (e.g., performing an assay or test on a sample, or "analyzing a sample," as that term is defined herein) to obtain a physical entity or value. "Indirect determination" refers to receiving a physical entity or value from another party or source (e.g., a third-party laboratory that directly obtains the physical entity or value). 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, immunohistochemical analysis, 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 protein properties (including, but not limited to, enzymatic activity or interactions with other protein partners). Methods of measuring RNA levels are known in the art and include, but are not limited to, quantitative polymerase chain reaction (qPCR) and Northern blot analysis.

[0379] By "reduced levels" or "increased levels" of a protein or RNA is meant a decrease or increase, respectively, in the level of the protein or RNA compared to a reference (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 compared to a reference). The level of a protein can be expressed as a mass / volume (e.g., g / dL, mg / mL, μg / mL, ng / mL) or as a percentage of the total protein in the sample.

[0380] "Reducing the activity of the BAF complex" refers to reducing the level of activity associated with the BAF complex or a related downstream effect. A non-limiting example of reducing the activity of the BAF complex is Sox2 activation. The activity level of the BAF complex can be measured using any method known in the art, such as the method described in Kadoch et al., Cell, 2013, 153, 71-85, which is incorporated herein by reference.

[0381] As used herein, the term "inhibit 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 a BRM ATPase assay, a Nano DSF assay, or a BRM luciferase cell assay.

[0382] As used herein, the term "LXS196," also known as IDE196, refers to a PKC inhibitor having the following structure:

[0383]

[0384] or a pharmaceutically acceptable salt thereof.

[0385] As used herein, the term "pharmaceutical composition" refers to a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient and suitable for administration to a mammal, such as a human. Typically, a pharmaceutical composition is manufactured or sold under the approval of a governmental regulatory agency as part of a therapeutic regimen for treating a disease in a mammal. The pharmaceutical composition can be formulated, for example, for oral administration in a unit dosage form (e.g., tablets, capsules, caplets, gelcaps, or syrups); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution in a solvent system suitable for intravenous use without particulate plugs); or in any other pharmaceutically acceptable formulation.

[0386] As used herein, "pharmaceutically acceptable excipients" refers to any ingredient other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving the active compound) and having substantially non-toxic and non-inflammatory properties to the patient. Excipients may include, for example, anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavorings, fragrances, glidants (flow promoters), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and water of hydration.

[0387] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt of a compound (e.g., any compound of Formula I). ​​Pharmaceutically acceptable salts of any compound described herein may include those suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, and commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (ed. P. H. Stahl and C. G. Wermuth), Wiley-VCH, 2008. The salt can be prepared in situ during the final separation and purification of the compounds described herein, or prepared separately by reacting the free base group with a suitable organic acid.

[0388] The compounds of the present invention may have ionizable groups to enable preparation of pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids, or, in the case of acidic forms of the compounds of the present invention, the salts may be prepared from inorganic or organic bases. The compounds are often prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparing appropriate 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.

[0389] "Reference" refers to any available reference for comparing protein or RNA levels. A reference can be any sample, standard, standard curve, or level for comparison purposes. A reference can be a normal reference sample or reference standard or level. A "reference sample" can be, for example, a control, such as a predetermined 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., a 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 already treated with a compound of the invention; or a sample of a purified protein or RNA (e.g., any of those described herein) at a known normal concentration. A "reference standard or level" refers to a value or number derived from a reference sample. A "normal control value" is a predetermined value indicating a non-disease state, such as 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 ("not higher than X"), or a low threshold ("not lower than X"). A subject whose measured value for a particular biomarker is within a normal control value is generally referred to as being "within normal limits" 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 who has been treated with a compound of the 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, disease stage, and overall health. A standard curve of levels of purified protein or RNA (e.g., any of those described herein) within a normal reference range can also be used as a reference.

[0390] As used herein, the term "subject" refers to any organism to which a composition according to the present invention can be administered, e.g., 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 seeking or in need of treatment, requiring treatment, currently receiving treatment, will be receiving treatment in the future, or is a human or animal under the care of a trained professional for a particular disease or condition.

[0391] As used herein, the terms "treat," "treated," or "treating" refer to therapeutic treatment or any measure thereof for the purpose of alleviating (relieving) an undesirable physiological condition, disorder, or disease, or obtaining a beneficial or desired clinical result. Beneficial or desired clinical results include, but are not limited to: alleviation of symptoms; reduction in the extent of the condition, disorder, or disease; a stable (i.e., non-worsening) state of the condition, disorder, or disease; a delay or slowing of the onset of the progression of the condition, disorder, or disease; an improvement or remission (whether partial or complete) of the condition, disorder, or disease state; an improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or an improvement or improvement of the condition, disorder, or disease. Treatment includes causing a clinically significant response without undue side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. The compounds of the present invention may also be used for "prophylactic treatment" or "prevention" of disorders, for example, in subjects at increased risk of developing the disorder.

[0392] As used herein, the terms "variant" and "derivative" are used interchangeably and refer to naturally occurring, synthetic, and semisynthetic 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.

[0393] 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 be apparent from the description and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0394] Figure 1 is a graph illustrating the inhibition of cell proliferation of several cancer cell lines by a BRG1 / BRM inhibitor (Compound A).

[0395] Figure 2A is a graph illustrating the inhibition of cell proliferation of the uveal melanoma cell line 92-1 by a BRG1 / BRM inhibitor (Compound A), a MEK inhibitor (selumetinib), and a PKC inhibitor (LXS196).

[0396] Figure 2B is a graph illustrating the 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).

[0397] Figure 3 is a graph illustrating the inhibition of cell proliferation of several cancer cell lines by a BRG1 / BRM inhibitor (Compound B).

[0398] Figure 4is a graph illustrating the area under the curve (AUC) calculated from the dose-response curves of cancer cell lines treated with BRG1 / BRM inhibitors.

[0399] Figure 5 is a graph illustrating the inhibition of cell proliferation of uveal melanoma and non-small cell lung cancer cell lines by a BRG1 / BRM inhibitor (Compound B).

[0400] Figure 6A is a graph illustrating the inhibition of cell proliferation of the uveal melanoma cell line 92-1 by a BRG1 / BRM inhibitor (Compound B), a MEK inhibitor (selumetinib), and a PKC inhibitor (LXS196).

[0401] Figure 6B is a graph illustrating the 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).

[0402] Figure 7A is a graph illustrating the inhibition of cell proliferation of parental and PKC inhibitor refractory uveal melanoma cell lines by a PKC inhibitor (LXS196).

[0403] Figure 7B is a graph illustrating the inhibition of cell proliferation of parental and PKC inhibitor refractory uveal melanoma cell lines by a BRG1 / BRM inhibitor (Compound B).

[0404] Figure 8A is a graph illustrating the inhibition of tumor growth by a BRG1 / BRM inhibitor (Compound C) in mice implanted with a uveal melanoma cell line.

[0405] Figure 8B is a graphic representation of tumor size from mice implanted with uveal melanoma cell lines and administered a BRG1 / BRM inhibitor (Compound C).

[0406] Figure 8C is a graph illustrating changes in body weight of mice implanted with uveal melanoma cell lines and administered a BRG1 / BRM inhibitor (Compound C). DETAILED DESCRIPTION

[0407] The present disclosure features compounds that can be used to inhibit BRM and optionally BRG1. These compounds can be used to modulate the activity of the BAF complex, for example, for treating BAF-related disorders such as cancer (e.g., BRG1 loss-of-function disorders). Exemplary compounds described herein include compounds having a structure according to Formula I, or a pharmaceutically acceptable salt thereof:

[0408]

[0409] in

[0410] m is 0, 1, 2, or 3;

[0411] n is 0, 1, 2, 3, or 4;

[0412] p is 0, 1, 2, or 3;

[0413] X 1 It is O, NR 5 or (C(R 5 )(R 6 )), and Z 1 and Z 2 Each independently does not exist or is (C(R 9 )2) or O, if X 1 If it is O, then Z 1 and Z 2 Each independently does not exist or is (C(R 9 )2);

[0414] X 2 Is N or CR 8 ;

[0415] Each R X1 are independently deuterium, optionally substituted C1-C6 alkyl or halogen, or two geminal R X1 The groups, together with the atoms to which they are attached, combine to form a carbonyl group;

[0416] L 1 is an optionally substituted 9-membered or 10-membered bicyclic heterocyclyl, an optionally substituted 9-membered or 10-membered bicyclic heteroaryl, an optionally substituted monocyclic 6-membered heteroarylvinyl, an optionally substituted monocyclic 6-membered heteroaryl-C3-C8-cycloalkyl or an optionally substituted monocyclic 6-membered heteroarylethynyl;

[0417] L 2 is absent, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclyl;

[0418] R 1 is hydrogen or optionally substituted C1-C6 alkyl;

[0419] Each R 2 and each R 3 are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[0420] R 4is hydrogen, halogen, optionally substituted C1-C6 alkyl or optionally substituted C3-C 10 Cycloalkyl;

[0421] R 5 is hydrogen, deuterium or optionally substituted C1-C6 alkyl;

[0422] R 6 is hydrogen, deuterium, optionally substituted C1-C6 alkyl or halogen, and each R 9 are independently hydrogen, deuterium, optionally substituted C1-C6 alkyl or halogen; or R 6 and an adjacent R 9 Together with the atoms to which they are attached, they form an optionally substituted C3-C8 cycloalkyl group, and the remaining R 9 The groups, if present, are independently deuterium, optionally substituted C1-C6 alkyl or halogen;

[0423] Each R 7 are independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, halogen, optionally substituted C3-C 10 cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocyclyl, -N(R 7A )2OR-OR 7A , where each R 7A are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclyl, or two geminal R 7A The groups, taken together with the atoms to which they are attached, are combined to form an optionally substituted 5- to 10-membered heteroaryl or an optionally substituted 4- to 10-membered heterocyclyl;

[0424] R 8 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or optionally substituted C3-C 10 cycloalkyl; and

[0425] R 10 is hydrogen or a halogen.

[0426] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of any one of Compounds 1-330 in Table 1.

[0427] Other embodiments are described herein, as well as exemplary methods for synthesizing or producing these compounds.

[0428] Drug uses

[0429] The compounds described herein are useful in the methods of the present invention and, while not being bound by theory, are believed to exert their ability to modulate the level, status, and / or activity of the BAF complex by inhibiting the activity of BRG1 and / or BRM proteins within the BAF complex in mammals. BAF complex-associated disorders include, but are not limited to, disorders associated with BRG1 loss-of-function mutations.

[0430] One aspect of the present invention relates to a method of treating a disorder associated with a BRG1 loss-of-function mutation, such as cancer (e.g., non-small cell lung cancer, colorectal 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 the following: (a) decreased tumor size, (b) decreased tumor growth rate, (c) increased tumor cell death, (d) reduced tumor progression, (e) decreased number of metastases, (f) decreased metastasis rate, (g) decreased tumor recurrence, (h) improved subject survival, (i) increased progression-free survival of the subject.

[0431] Treating cancer can result in a decrease in the size or volume of a tumor. For example, after treatment, the size of a tumor decreases by more than 5% (e.g., more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%) relative to its size before treatment. Tumor size can be measured by any reproducible measurement means. For example, tumor size can be measured as tumor diameter.

[0432] Treatment of cancer may further result in a decrease in the number of tumors. For example, after treatment, the number of tumors is reduced by more than 5% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) relative to the number before treatment. The number of tumors can be measured by any reproducible measurement means, for example, the number of tumors can be measured by counting tumors visible to the naked eye or visible under a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).

[0433] Treatment of cancer can result in a reduction in the number of metastatic nodules in other tissues or organs away from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by more than 5% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) relative to the number before treatment. The number of metastatic nodules can be measured by any reproducible measurement means. For example, the number of metastatic nodules can be measured by counting metastatic nodules visible to the naked eye or visible under a specified magnification (e.g., 2x, 10x, or 50x).

[0434] Compared to an untreated subject population, treating cancer can result in an increase in the mean survival time of a subject population treated according to the present invention. For example, the mean survival time increases by more than 30 days (more than 60 days, 90 days, or 120 days). The increase in the mean survival time of a population can be measured by any reproducible means. For example, the increase in the mean survival time of a population can be measured by calculating the mean survival time after the group begins treatment with a compound of the present invention. For example, the increase in the mean survival time of a population can also be measured by calculating the mean survival time after the group completes the first round of treatment with a pharmaceutically acceptable salt of the present invention.

[0435] Treatment of cancer can also result in a reduction in mortality in the treated subject population 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 mortality in the treated subject population can be measured by any reproducible means, such as by calculating for the population the average number of disease-related deaths per unit time after the start of treatment with a pharmaceutically acceptable salt of the present invention. For example, the reduction in population mortality can also be measured by calculating for the population the average number of disease-related deaths per unit time after the first round of treatment with a pharmaceutically acceptable salt of the present invention.

[0436] Exemplary cancers that can be treated by the present invention include, but are not limited to, non-small cell lung cancer, small cell lung cancer, colorectal cancer, bladder cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal-gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, CNS cancer, thymic tumors, adrenocortical carcinoma, appendix cancer, small intestine cancer, and penile cancer.

[0437] Combination preparations and their uses

[0438] The compounds of the present invention may be combined with one or more therapeutic agents. In particular, the therapeutic agent may be a therapeutic agent for the treatment or prophylactic treatment of any of the cancers described herein.

[0439] Combination therapy

[0440] The compound of the present invention can be used alone, or in combination with additional therapeutic agents, for example, other medicaments for treating cancer or symptoms associated therewith, or in combination with other treatment types for treating cancer. In combination therapy, the dosage of one or more therapeutic compounds can be reduced compared to the standard dose when applied alone. For example, dosage can be determined empirically by drug combination and arrangement, or can be inferred by isoradiometric analysis (such as Black et al., Neurology 65: S3-S6, 2005). In this case, the dosage of these compounds should provide a therapeutic effect when combined.

[0441] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful for treating 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, adrenocortical suppressants, adrenocortical steroids, progestogens, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), folinic acid (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquinone, meturedopa, and uredopa; ethyleneimines and methylamelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (particularly bullatacin and bullatacinone); camptothecins (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adolesine, carzelesin, and biszelesin); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); 8)); dolastatin; duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, naphthyl mustard, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard;Nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; 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 the neocarcin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycins, actinomycins, authramycin, azaserine, bleomycin, actinomycin C, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detoxibacin, 6-diazo-5-oxo-L-norleucine, (doxorubicin, including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, mexilomycin, mitomycins such as mitomycin C, mycophenolic acid, nogamycin, olivomycin, peplomycin, porfibrinomycin, puromycin, triferon-adriamycin, rhodorubicin, streptozotocin, streptozotocin, tuberculin, ubenimex, zorubicin, daunorubicin; antimetabolites Such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as dimethylfolate, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiopurine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as captestosterone, drostanolone propionate, cyclothiocarbamate, melastane, and testolactone; Antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; aceglucuronolide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; colcemid; diacrazone; elfomithine; elliptonium acetate; epothilones; etoglucose; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansines such as maytansine and ansamitocin; mitoguanidine; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizobactin; sizofuran; spirogermanamine; tricholomanic acid; triazoline; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, baculocin A, and anguidine); urethan; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulcitol; pipobroman; gacytosine; cytarabine ("Ara-C"); cyclophosphamide; thiotepa; taxanes, such as Paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), Cremophor-free, albumin-engineered paclitaxel nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, Ill.) and docetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Vinorelbine; Novantrone; Teniposide; Edatrexate; Daunomycin; Aminopterin; Xeloda; Ibandronate; Irinotecan (eg, CPT-11); Topoisomerase inhibitor RFS2000; Difluoromethylornithine (DMFO); Retinoids such as retinoic acid; Capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a mixture for administration in combination with the first therapeutic agent described herein. Suitable dosing regimens for combination chemotherapy are known in the art and are described in, for example, Saltz et al., (1999) Proc ASCO 18:233a and Douillard et al., (2000) Lancet 355:1041-7.

[0442] In some embodiments, the second therapeutic agent is a therapeutic agent that is a biologic, such as a cytokine used in cancer treatment (e.g., an interferon or an interleukin (e.g., IL-2)). In some embodiments, the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, for example, bevacizumab. In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer. Such agents include Rituxan (rituximab); Daclizumab (daclizumab); Sulaix (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 (tocilizumab); Vectis (vespasmodicab); and Vectis (prednisone). These include ibix (panitumumab); Lucentis (ranibizumab); Soliris (eculizumab); Cimzia (becelimumab); Simponi (golimumab); Ilaris (canakinumab); Sedano (ustekinumab); Arzerra (ofatumumab); Proli (denosumab); Numax (motavizumab); ABThrax (ranibizumab); Benlysta (belimumab); Yervoy (ipilimumab); Ansari (brentuximab); Perjeta (pertuzumab); Kadcyla (trastuzumab emtansine); and Gazyva (otuzumab). Antibody-drug conjugates are also included.

[0443] The second agent can be a non-drug therapeutic agent. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia and / or surgical resection of tumor tissue.

[0444] The second agent can 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 can be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent that interacts with a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an agent that interacts with a ligand of a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or a 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 a small molecule inhibitor) of PD-1 (e.g., In some embodiments, the checkpoint inhibitor is an inhibitor of PDL1 (e.g., an inhibitory antibody or small molecule inhibitor) (e.g., MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS 936559). In some embodiments, the checkpoint inhibitor is an inhibitor of PDL2 (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) (e.g., PDL2 / Ig fusion protein such as AMP 224). In some embodiments, the checkpoint inhibitor is an 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 a combination thereof (e.g., an inhibitory antibody or small molecule inhibitor).

[0445] In any combination embodiment described herein, the first and second therapeutic agents are administered simultaneously or sequentially in either order. The first therapeutic agent can be administered immediately, at most 1 hour, at most 2 hours, at most 3 hours, at most 4 hours, at most 5 hours, at most 6 hours, at most 7 hours, at most 8 hours, at most 9 hours, at most 10 hours, at most 11 hours, at most 12 hours, at most 13 hours, at most 14 hours, at most 16 hours, at most 17 hours, at most 18 hours, at most 19 hours, at most 20 hours, at most 21 hours, at most 22 hours, at most 23 hours, at most 24 hours, or at most 1-7 days, 1-14 days, 1-21 days, or 1-30 days before or after the second therapeutic agent.

[0446] Pharmaceutical composition

[0447] The compounds of the present invention are preferably formulated into pharmaceutical compositions for administration to mammals, preferably humans, in a biocompatible form suitable for in vivo administration. Thus, in one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention admixed with a suitable diluent, carrier or excipient.

[0448] The compound of the present invention can be used in the form of free alkali, in the form of salt, solvate and as prodrug.All forms are within the scope of the present invention.As will be appreciated by those skilled in the art, according to the method of the present invention, described compound or its salt, solvate or prodrug can be applied to the patient in various forms according to selected route of administration.The compound of the present invention can be applied, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and correspondingly formulated pharmaceutical composition.Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, epithelial, nasal, intrapulmonary, intrathecal, rectal and topical application mode.Parenteral administration can be carried out by continuous infusion in the selected time period.

[0449] The compounds of the present invention can be administered orally, for example, with an inert diluent or with an assimilable edible carrier, or they can be encapsulated in a hard or soft shell gelatin capsule, or they can be compressed into tablets, or they can be directly incorporated into the food in the diet. For oral treatment, the compounds of the present invention can be combined with excipients and used in the form of ingestible tablets, buccal tablets, lozenges, 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. Under normal storage and use conditions, these preparations can contain preservatives to prevent the growth of microorganisms. Conventional procedures and ingredients for selecting and preparing suitable preparations are described in, for example, Remington's Pharmaceutical Sciences (2003, 20th edition) and The United States Pharmacopeia: The National Formulary (USP 24NF19) published in 1999. The pharmaceutical form suitable for injection includes sterile aqueous solutions or dispersions, and sterile powders for the immediate preparation of sterile injection solutions or dispersions. In all cases, the form must be sterile and must be a fluid that can be easily applied via a syringe. Compositions for nasal administration can be easily formulated as aerosols, drops, gels, and powders. Aerosol formulations typically include solutions or fine suspensions of active substances in physiologically acceptable aqueous or non-aqueous solvents, and are typically present in a sealed container in a sterile form with a single dose or multiple doses, the container being in the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container can be a unit dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve, which is intended to be discarded after use. In the case where the dosage form comprises an aerosol dispenser, it contains a propellant, which can be a compressed gas, such as compressed air, or an organic propellant. Aerosol formulations can also be in 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 conventional suppository bases. The compounds described herein can be administered intratumorally, for example, as intratumoral injections. Intratumoral injections are injections directly into the tumor vasculature, and are particularly contemplated for discrete, solid, palpable tumors. Local, regional, or systemic administration may also be appropriate. Advantageously, the compounds described herein may be contacted by administering a single injection or multiple injections (e.g., at intervals of approximately 1 cm) to the tumor. In the case of surgical intervention, the present invention can be used before surgery, such as to allow inoperable tumors to be resected. Continuous administration may also be applied where appropriate, for example, by implanting a catheter into the tumor or tumor vasculature.

[0450] The compounds of the invention can be administered to animals, such as humans, alone or in combination with pharmaceutically acceptable carriers as described herein, the proportions of which will depend on the solubility and chemical properties of the compound, the chosen route of administration, and standard pharmaceutical practice.

[0451] dose

[0452] The dosage of the compound of the present invention and / or the composition comprising the compound of the present invention can vary with 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 concurrent treatment (if any); and the clearance rate of the compound in the animal to be treated. Those skilled in the art can determine the appropriate dosage based on the above factors. The compound of the present invention can be initially administered in a suitable dose, which can be adjusted as needed based on the clinical response. In general, when the compound of the present invention is administered to a human at a daily dose of, for example, between 0.05 mg and 3000 mg, satisfactory results can be obtained. The dosage range includes, for example, between 10-1000 mg.

[0453] Alternatively, the patient's body weight can be used to calculate the dosage.For example, the dosage of the compound or pharmaceutical composition thereof administered to the patient can be 0.1-100 mg / kg.

[0454] Example

[0455] The definitions used in the following figures and elsewhere in this document are:

[0456] MeCN or ACN Acetonitrile

[0457] AIBN Azobisisobutyronitrile

[0458] Boc tert-Butoxycarbonyl

[0459] t-BuOK Potassium tert-butoxide

[0460] DAST Diethylaminosulfur trifluoride

[0461] DCE dichloroethane

[0462] DCM dichloromethane

[0463] DCPP-2HBF4 1,3-Bis(dicyclohexylphosphino)propane bis(tetrafluoroborate)

[0464] DEA N,N-diethylamine

[0465] DMP Dess-Martin Oxidant

[0466] DIAD Diisopropyl azodicarboxylate

[0467] DIBAL-H Diisobutylaluminum hydride

[0468] DIEA or DIPEA N,N-diisopropylethylamine

[0469] DMA dimethylacetamide

[0470] DMAP 4-(dimethylamino)pyridine

[0471] DME 1,2-dimethoxyethane

[0472] DMF N,N-dimethylformamide

[0473] DMSO dimethyl sulfoxide

[0474] dppf bis(diphenylphosphino)ferrocene

[0475] EDCl 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0476] ESI electrospray ionization

[0477] Et3N or TEA triethylamine

[0478] EA Ethyl acetate

[0479] EtOH

[0480] FA Formic acid

[0481] FCC flash column chromatography

[0482] g grams

[0483] HATU 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium

[0484] HCl

[0485] HOAc acetic acid

[0486] HOBt Hydroxybenzotriazole

[0487] HPLC high-performance liquid chromatography

[0488] IPA Isopropyl alcohol

[0489] L liter

[0490] LCMS liquid chromatography / mass spectrometry

[0491] m-CPBA 3-Chloroperoxybenzoic acid

[0492] MeCN Acetonitrile

[0493] MeI iodomethane

[0494] MeOH methanol

[0495] mL milliliters

[0496] mmol millimole

[0497] mg milligrams

[0498] MHz Megahertz

[0499] MS

[0500] MTBE methyl tert-butyl ether

[0501] m / z mass / charge ratio

[0502] NBS N-bromosuccinimide

[0503] NIS N-iodosuccinimide

[0504] nm nanometer

[0505] NMR Nuclear Magnetic Resonance

[0506] PE petroleum ether

[0507] PhMe toluene

[0508] ppm parts per million

[0509] rt room temperature

[0510] RT retention time

[0511] SFC Supercritical Fluid Chromatography

[0512] SPhos Pd G3 (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0513] TBS tert-Butyldimethylsilyl

[0514] TBSCl tert-Butyldimethylsilyl chloride

[0515] TBDMS tert-Butyldimethylsilyl chloride

[0516] TFA trifluoroacetic acid

[0517] TFAA trifluoroacetic anhydride

[0518] THF Tetrahydrofuran

[0519] TMSCN trimethylsilyl cyanide

[0520] TosMIC Tosylmethyl isocyanide

[0521] Ziram Zinc dimethyldithiocarbamate

[0522] Table 1 lists compounds of the invention that were prepared using the methods described herein.

[0523] Material

[0524] Unless otherwise stated, 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.

[0525] Example 1. Preparation of compounds

[0526] (2R)-2,6-Difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiazole (benzoxathiepine)-8-carboxylic acid.

[0527]

[0528] Step 1: Preparation of 2-methyl 4-bromo-2-fluoro-6-sulfanyl-benzoate

[0529]

[0530] To a solution of 4-bromo-2,6-difluoro-benzoic acid methyl ester (100 g, 398.37 mmol) in DMF (1000 mL) was added Na2S (34.54 g, 398.37 mmol, 90% purity), and the mixture was stirred at 30 ° C for 16 hours. The reaction mixture was poured into water (1500 mL) and extracted with MTBE (1500 mL * 2). The aqueous phase was adjusted to pH = 2 with 1N HCl and extracted with MTBE (1500 mL * 3). The combined organic layer was washed with water (2000 mL * 2) and brine (5000 mL), dried over Na2SO4, filtered and concentrated to give 4-bromo-2-fluoro-6-sulfanyl-benzoic acid 2-methyl ester (105 g, crude) as a yellow oil. LCMS (ESI) m / z: [Br 79 M+H] + =232.9

[0531] Step 2: Preparation of 3-(4-bromo-2-fluoro-6-sulfanyl-phenyl)methanol

[0532]

[0533] To a solution of 4-bromo-2-fluoro-6-sulfanyl-benzoic acid 2-carboxylate (105 g, 396.08 mmol) in THF (1000 mL) was added LiAlH (15.03 g, 396.08 mmol) at 0°C under N2, and the mixture was stirred at 0°C for 1 hour. The mixture was poured into 1N HCl (1000 mL) and extracted with EtOAc (1000 mL*2). The combined organic phases were washed with brine (2000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 3-(4-bromo-2-fluoro-6-sulfanyl-phenyl)methanol (93 g, crude) as a yellow oil.

[0534] Step 3: Preparation of 5-(4-bromo-2-fluoro-6-vinylsulfanyl-phenyl)methanol

[0535]

[0536] To a solution of 2-methyl 4-bromo-2-fluoro-6-sulfanyl-benzoate (93 g, 392.26 mmol) in DMF (1800 mL) were added KCO (162.64 g, 1.18 mol) and 1,2-dibromoethane (221.07 g, 1.18 mol, 88.78 mL), and the mixture was stirred at 30°C for 16 hours. The reaction was quenched with water (2000 mL). The mixture was extracted with ethyl acetate (2000 mL*3). The combined organic layers were dried over NaSO and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10:1-1:1), and the solution was concentrated to give 5-(4-bromo-2-fluoro-6-vinylsulfanyl-phenyl)methanol (56 g, 212.83 mmol) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ=7.33(s,1H),7.19-7.17(m,1H),6.50-6.44(m,1H),5.54-5.42(m,2H),4.78(d,J=1.2Hz,2H),2.13(s,1H)ppm

[0537] Step 4: Preparation of (4-bromo-2-fluoro-6-vinylsulfinyl-phenyl)methanol

[0538]

[0539] To a solution of 5-(4-bromo-2-fluoro-6-vinylsulfanyl-phenyl)methanol (10 g, 38.00 mmol) in MeOH (100 mL) and H2O (100 ml) was added potassium persulfate (Oxone) (11.68 g, 19.00 mmol), and the mixture was stirred at 30°C for 16 hours. The reaction mixture was poured into water (1 L), the solution was extracted with EA (1 L*3), and the combined organic layers were washed with saturated Na2SO3 (1 L) and brine (1 L), dried over Na2SO4, filtered and concentrated to give 6-(4-bromo-2-fluoro-6-vinylsulfinyl-phenyl)methanol (10.61 g, crude) as a yellow oil. LCMS (ESI) m / z: [Br 79 M+H] + =263.0

[0540] Step 5: 8-Bromo-6-fluoro-3,5-dihydro-2H-4,1λ4-benzoxathiazole Preparation of 1-oxide

[0541]

[0542] To a solution of 6-(4-bromo-2-fluoro-6-vinylsulfinyl-phenyl)methanol (10.6 g, 37.98 mmol) in THF (110 mL) was added NaH (3.04 g, 75.95 mmol, 60% purity) at 0 ° C, and the mixture was stirred at 20 ° C for 1 hour. The reaction mixture was poured into NH4Cl (500 mL), the solution was extracted with EA (500 mL * 3), and the combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered and concentrated to give a brown residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10: 1-1: 1), and the solution was concentrated to give 8-bromo-6-fluoro-3,5-dihydro-2H-4,1λ4-benzoxathiazole as a white solid. 1-oxide (5.5 g, 19.70 mmol, 51.89% yield). 1 HNMR(400MHz, DMSO-d6)δ=7.78-7.75(m,1H),7.62(s,1H),4.96(d,J=15.2Hz,1H),4.54-4.50(m,1H),4.33-4.24(m,2H),3.41-3.39(m,2H)ppm

[0543] Step 6: 8-Bromo-6-fluoro-3,5-dihydro-2H-4,1λ4-benzoxathiazole 1-oxide&8-bromo-2,6-difluoro-3,5-dihydro-2H-4,1-benzoxathiazole Preparation

[0544]

[0545] To 8-bromo-6-fluoro-3,5-dihydro-2H-4,1λ4-benzoxathiazole To a solution of 1-oxide (1.9 g, 6.81 mmol) in DCM (40 mL) was added SbCl (46.58 mg, 204.21 mmol) followed by DAST (2.19 g, 13.61 mmol, 1.80 mL). The mixture was stirred at 20°C for 16 hours. DAST (5.49 g, 34.03 mmol, 4.50 mL) was then added, and the mixture was stirred at 20°C for 16 hours. SbCl (1.55 g, 6.81 mmol) and DAST (10.97 g, 68.07 mmol, 8.99 mL) were added, and the mixture was stirred at 20°C for 16 hours. The reaction mixture was poured into a NaHCO solution (200 mL), extracted with EA (200 mL*3), and the combined organic layers were washed with brine (500 mL), dried over NaSO, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20:1-5:1), and the peak 1 eluent was concentrated to give 8-bromo-6-fluoro-3,5-dihydro-2H-4,1λ4-benzoxathiazole as a yellow oil. 1-oxide (1.2 g, 4.56 mmol, 67.00% yield). 1 H NMR (400MHz, CDCl3)δ=7.54-7.51(m,1H),7.18–7.15(m,1H),4.91–4.89(m,2H),4.17-4.14(m,2H),2.89-2.86(m,2H)ppm

[0546] The Peak 2 eluate was concentrated to give 8-bromo-2,6-difluoro-3,5-dihydro-2H-4,1-benzoxathiazole as a yellow solid. (600 mg, 2.13 mmol, 31.36% yield). 1 H NMR(400MHz, CDCl3)δ=7.55–7.54(m,1H),7.27-7.24(m,1H),5.63-5.51(m,1H),5 .25(d,J=13.6Hz,1H),4.69–4.65(m,1H),4.43–4.41(m,1H),4.13–4.05(m,1H)ppm

[0547] Step 7: 8-Bromo-2,6-difluoro-3,5-dihydro-2H-4,1-benzoxathiazole Preparation

[0548]

[0549] To 8-bromo-6-fluoro-3,5-dihydro-2H-4,1λ4-benzoxathiazole To a solution of 1-oxide (peak 1 above) (1.2 g, 4.56 mmol) in MeCN (25 mL) was added SelectF (2.02 g, 5.70 mmol), followed by the addition of DAST (147.02 mg, 912.11 umol, 120.51 uL) under an ice bath. The solution was stirred at 20°C for 1 hour. DIEA (884.11 mg, 6.84 mmol, 1.19 mL) was then added to the mixture at 20°C, and the mixture was stirred at 20°C for 1 hour. The reaction mixture was poured into a NaHCO solution (200 mL) and extracted with EA (200 mL*3). The combined organic layers were washed with brine (500 mL), dried over NaSO, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 20: 1-5: 1), and the solution was concentrated to give 8-bromo-2,6-difluoro-3,5-dihydro-2H-4,1-benzoxathiazole as a yellow solid. (500 mg, 1.78 mmol, 39.00% yield). 1 H NMR(400MHz, CDCl3)δ=7.54(m,1H),7.27-7.24(m,1H),5.63-5.51(m,1H),5.25 (d,J=13.6Hz,1H),4.70-4.66(m,1H),4.43-4.42(m,1H),4.13-4.05(m,1H)ppm

[0550] Step 8: 2,6-Difluoro-3,5-dihydro-2H-4,1-benzoxathiazole Preparation of 8-formic acid

[0551]

[0552] To 8-bromo-2,6-difluoro-3,5-dihydro-2H-4,1-benzoxathiazole To a solution of 1.3 g (4.62 mmol) in DMSO (20 mL) and H2O (4 mL) were added K2CO3 (958.71 mg, 6.94 mmol), dicyclohexyl(3-dicyclohexylphosphaniumylpropyl)phosphonium; bis(tetrafluoroborate) (283.13 mg, 462.44 umol), and Pd(OAc)2 (103.82 mg, 462.44 umol). The suspension was degassed under vacuum and purged with CO2 several times. The mixture was stirred at 100°C under CO2 (15 psi) for 2 hours. The reaction mixture was poured into a NaHCO3 solution (100 mL) and extracted with EA (100 mL x 2). The aqueous phase was adjusted to pH=1 with 1N HCl and extracted with EA (50 mL*2), and the combined organic layers were dried over Na2SO4, filtered and concentrated to give 2,6-difluoro-3,5-dihydro-2H-4,1-benzoxathiazole as a yellow solid. -8-carboxylic acid (1.1 g, crude), which was used without purification.

[0553] Step 9: 2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ 6 -Benzoxathia Preparation of 8-formic acid

[0554]

[0555] To 2,6-difluoro-3,5-dihydro-2H-4,1-benzoxathiazole To a solution of 1,4-difluoro-8-carboxylic acid (1.1 g, 4.47 mmol) in MeOH (12 mL) and H2O (12 mL) was added potassium persulfate (5.49 g, 8.93 mmol), and the mixture was stirred at 20°C for 16 hours. The reaction mixture was poured into water (100 mL), the solution was extracted with EA (100 mL*3), and the combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated to give 2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ as a white solid. 6 -Benzoxathia -8-formic acid (1.1 g, 3.95 mmol, 88.50% yield). 1H NMR(400MHz, DMSO-d6)δ=14.03-13.95(m,1H),8.34(d,J=1.2Hz,1H),8.13-8.11(m, 1H),6.27-6.16(m,1H),5.25–5.21(m,1H),4.91–4.86(m,1H),4.47-4.38(m,2H)ppm.

[0556] Step 10: (2R)-2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ 6 -Benzoxathia -8-carboxylic acid (Intermediate 1) and (2S)-2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ 6 -Benzoxathia Preparation of 8-formic acid

[0557]

[0558] 2,6-Difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ 6 -Benzoxathia -8-formic acid (1.1 g, 3.95 mmol) was separated by chiral SFC (column: Daicel ChiralPak IG (250*30 mm, 10 um); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 20%-20%, 4.75; 310 min) to give two phases. The peak 1 eluate was concentrated to give a colorless residue, which was diluted with water (100 mL) and adjusted to pH = 2 with 4N HCl solution. The solution was extracted with EA (100 mL*2), and the combined organic layers were dried over Na2SO4, filtered, and concentrated to give (2R)-2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ as a white solid. 6 -Benzoxathia -8-carboxylic acid (Intermediate 1) (350 mg, 1.25 mmol, 31.69% yield). 1 H NMR(400MHz, DMSO-d6)δ=14.17-13.92(m,1H),8.33(s,1H),8.13–8.11(m,1H), 6.27-6.17(m,1H),5.25–5.21(m,1H),4.91–4.86(m,1H),4.47-4.35(m,2H)ppm

[0559] Chiral SFC: IG-3_5CM_MEOH(DEA)_5_40_3ML_T35.M; Rt=1.408 mins, ee%=98.14%.

[0560] The peak 2 eluate was concentrated to give a residue, which was diluted with water (100 mL) and adjusted to pH = 2 with 4N HCl solution, the solution was extracted with EA (100 mL * 2), and the combined organic layer was dried over Na2SO4, filtered and concentrated to give (2S)-2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ as a white solid. 6 -Benzoxathia -8-formic acid (500 mg, 1.66 mmol, 41.94% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 14.27-13.55 (m, 1H), 8.34 (d, J = 1.2 Hz, 1H), 8.13–8.10 (m, 1H), 6.27–6.16 (m, 1H), 5.26–5.21 (m, 1H), 4.91–4.86 (m, 1H), 4.47–4.38 (m, 2H) ppm. Chiral SFC: IG-3_5CM_MEOH(DEA)_5_40_3ML

[0561] (R)-2,6-Difluoro-N-((2-(7-methyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1,6-naphthyridin-7-yl)methyl)-2,3-dihydro-5H-benzo[e][1,4]oxathia Preparation of 8-formamide 1,1-dioxide (Compound 6)

[0562]

[0563] Step 1: Preparation of 7-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

[0564]

[0565] To a solution of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (350 mg, 1.63 mmol) and methylboronic acid (292.28 mg, 4.88 mmol) in dioxane (5.6 mL) and H₂O (1.4 mL) was added di-tert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (106.07 mg, 162.76 umol) and K₃PO₄ (1.04 g, 4.88 mmol). The reaction was stirred at 80°C for 2 hours. The reaction mixture was poured into H₂O (5 mL), the solution was extracted with EA (5 mL x 2), and the combined organic layers were washed with brine (6 mL), dried over Na₂SO₄, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography using a gradient of 0 to 80% ethyl acetate / petroleum. The desired eluent was concentrated in vacuo to give 7-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (200 mg, 1.33 mmol, 81.83% yield) as a yellow oil. LCMS (ESI) m / z: [M+H] + =151.1.

[0566] Step 2: Preparation of tert-butyl ((2-(7-methyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1,6-naphthyridin-7-yl)methyl)carbamate

[0567]

[0568] To a solution of tert-butyl N-[(2-chloro-1,6-naphthyridin-7-yl)methyl]carbamate (200 mg, 680.86 umol) and 7-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (122.70 mg, 817.03 umol) in dioxane (4 mL) were added Cs2CO3 (1.11 g, 3.40 mmol) and Xantphos (78.79 mg, 136.17 umol) and Pd2(dba)3 (62.35 mg, 68.09 umol, 0.1 eq). The reaction was stirred at 100 ° C for 12 hours. The reaction mixture was filtered. The filtrate was concentrated in vacuo to give the crude product. The residue was purified by flash silica gel chromatography ( 12g Silica Flash Column, eluent: 0-100% ethyl acetate / petroleum ether gradient @ 36 mL / min. The eluent was concentrated in vacuo to afford tert-butyl ((2-(7-methyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1,6-naphthyridin-7-yl)methyl)carbamate (250 mg, 531.33 umol, 78.04% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + =408.1.

[0569] Step 3: Preparation of (2-(7-methyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1,6-naphthyridin-7-yl)methanamine

[0570]

[0571] To a solution of tert-butyl ((2-(7-methyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1,6-naphthyridin-7-yl)methyl)carbamate (250 mg, 613.55 umol) in dioxane (1 mL) was added HCl / dioxane (4M, 4 mL). The reaction was stirred at 25 ° C for 1 hour. The reaction mixture was concentrated in vacuo to give (2-(7-methyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1,6-naphthyridin-7-yl)methanamine (150 mg, crude, HCl) as a yellow solid, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =308.1.

[0572] Step 4: (R)-2,6-difluoro-N-((2-(7-methyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1,6-naphthyridin-7-yl)methyl)-2,3-dihydro-5H-benzo[e][1,4]oxathiapiperidin Preparation of 8-formamide 1,1-dioxide (Compound 6)

[0573]

[0574] To (2R)-2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiazole To a solution of 2-(7-methyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1,6-naphthyridin-7-yl)methanamine (50 mg, 145.43 umol), DIEA (187.95 mg, 1.45 mmol, 253.31 uL), EDCI (55.76 mg, 290.86 umol), and HOBt (39.30 mg, 290.86 umol) was added 8-carboxylic acid (Intermediate 1, described above) (40.46 mg, 145.43 umol) in DCM (1 mL). The reaction was stirred at 25° C. for 2 hours. The reaction mixture was poured into water (5 mL) and the mixture was extracted with EtOAc (5 mL*3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (FA conditions; column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 17%-50%, 11 min). The desired fraction was lyophilized to give (R)-2,6-difluoro-N-((2-(7-methyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1,6-naphthyridin-7-yl)methyl)-2,3-dihydro-5H-benzo[e][1,4]oxathiapiperidin as a yellow solid. -8-Formamide 1,1-dioxide (34.84 mg, 56.78 umol, 39.04% yield, FA). LCMS (ESI) m / z: [M+H] + =568.2. 1 H NMR (400MHz, DMSO-d6) δ=9.71-9.68(m,1H),9.08(s,1H),8.47(d,J=1.2Hz,1H),8.39-8.22(m,4H),7.77-7.76(m,1H),7.53(s,1H),7.20-7.20 (m,1H),6.31-6.15(m,1H),5.24(d,J=14.8Hz,1H),4.91-4.87(m,1H),4.74(d,J=6.0Hz,2H),4.48-4.35(m,2H),4.33(s,4H),2.25(s,3H)ppm.

[0575] The following examples in Table 2 were prepared using standard chemical manipulations and procedures similar to those used to prepare compound 6.

[0576] Table 2. Compounds of the present invention

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588] (2R)-N-[[2-[3-(Difluoromethoxy)phenyl]-1,6-naphthyridin-7-yl]methyl]-2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiazole Preparation of 8-formamide (Compound 297)

[0589]

[0590] Step 1: Preparation of tert-butyl ((2-(3-(difluoromethoxy)phenyl)-1,6-naphthyridin-7-yl)methyl)carbamate

[0591]

[0592] A mixture of tert-butyl N-[(2-chloro-1,6-naphthyridin-7-yl)methyl]carbamate (208.40 mg, 709.46 umol), [3-(difluoromethoxy)phenyl]boronic acid (200 mg, 1.06 mmol), di-tert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (46.24 mg, 70.95 umol) and K 3 PO 4 (451.78 mg, 2.13 mmol) in dioxane (3 mL) and H 2 O (1 mL) was degassed and purged with N 2 three times, and then the mixture was stirred at 80 ° C. under N 2 atmosphere for 14 hours. The reaction mixture was diluted with H 2 O (15 mL) and extracted with EA (15 mL * 3). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 1 / 2), and the fractions were concentrated under reduced pressure to give tert-butyl ((2-(3-(difluoromethoxy)phenyl)-1,6-naphthyridin-7-yl)methyl)carbamate (255 mg, 635.27 umol, 89.54% yield) as a brown oil. LCMS (ESI) m / z: [M + H] + =402.1. 1 H NMR (400MHz, DMSO-d6) δ = 9.36 (s, 1H), 8.68 (d, J = 8.4Hz, 1H), 8.32 (d, J = 8.4Hz, 1H), 8.19 (d, J = 8.0Hz, 1H), 8.1 1(d,J=2.0Hz,1H),7.77(s,1H),7.67-7.59(m,2H),7.58-7.21(m,2H),4.45(d,J=6.0Hz,2H),1.44(s,9H)ppm.

[0593] Step 2: Preparation of (2-(3-(difluoromethoxy)phenyl)-1,6-naphthyridin-7-yl)methanamine

[0594]

[0595] To a solution of tert-butyl ((2-(3-(difluoromethoxy)phenyl)-1,6-naphthyridin-7-yl)methyl)carbamate (250 mg, 622.81 umol) in TFA (1 mL) and DCM (3 mL). The mixture was stirred at 25 ° C for 0.5 hours. The mixture was poured into a NaHCO3 aqueous solution (10 mL) and then extracted with EA (10 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give (2-(3-(difluoromethoxy)phenyl)-1,6-naphthyridin-7-yl)methanamine (185 mg, 614.03 umol, 98.59% yield) as a brown solid. LCMS (ESI) m / z: [M + H] + =302.1.

[0596] Step 3: (2R)-N-[[2-[3-(Difluoromethoxy)phenyl]-1,6-naphthyridin-7-yl]methyl]-2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiazole Preparation of 8-formamide

[0597]

[0598] To a solution of (2-(3-(difluoromethoxy)phenyl)-1,6-naphthyridin-7-yl)methanamine (50 mg, 165.95 umol) in DCM (1 mL) was added (2R)-2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiazole 8-Methyl-2-carboxylic acid (46.17 mg, 165.95 umol), EDCI (47.72 mg, 248.93 umol), HOBt (33.64 mg, 248.93 umol), and DIEA (107.24 mg, 829.76 umol) were added. The mixture was stirred at 25°C for 14 hours. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (5 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase HPLC (acetonitrile and water + 0.1% FA conditions). The solution was then concentrated under reduced pressure and then lyophilized to give (2R)-N-[[2-[3-(difluoromethoxy)phenyl]-1,6-naphthyridin-7-yl]methyl]-2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiazole as an off-white solid. -8-Formamide (20.83 mg, 37.10 umol, 22.35% yield). LCMS (ESI) m / z: [M+H] + =562.2. 1H NMR (400MHz, DMSO-d6) δ = 9.76-9.73 (m, 1H), 9.41 (s, 1H), 8.69 (d, J = 8.8Hz, 1H) ,8.47(s,1H),8.33(d,J=8.4Hz,1H),8.26(d,J=10.4Hz,1H),8.19(d,J=7.6Hz,1 H),8.10(s,1H),7.92-7.82(m,1H),7.65-7.61(m,1H),7.57-7.17(m,2H),6.33 -6.10(m,1H),5.25(d,J=14.4Hz,1H),4.95-4.68(m,3H),4.53-4.32(m,2H)ppm. Chiral SFC: OJ-3-MeOH(DEA)-5-40-3mL-35T.1cm; Rt=2.427mins, ee%=100.00%.

[0599] The following examples in Table 3 were prepared using standard chemical manipulations and procedures similar to those used to prepare compound 297.

[0600] Table 3. Compounds of the present invention

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612] Intermediate 2(4R)-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole Preparation of 7-formic acid

[0613]

[0614] Step 1: Preparation of 3-chlorosulfonyl-5-fluoro-4-hydroxy-benzoic acid

[0615]

[0616] To a solution of HOSO₂Cl (175.00 g, 1.50 mol, 100 mL) was added 3-fluoro-4-hydroxy-benzoic acid (12 g, 76.87 mmol) in 10 portions at 0°C. The mixture was stirred at 30°C for 16 hours and then at 80°C for 2 hours. The reaction solution was added dropwise to ice water (100 mL). The mixture was filtered, and the filter cake was washed with water (3*10 mL) and dried in vacuo to give 3-chlorosulfonyl-5-fluoro-4-hydroxy-benzoic acid (15 g, 55.97 mmol, 72.81% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d₆) δ = 11.52-11.09 (m, 1H), 7.90-7.85 (m, 1H), 7.65-7.62 (m, 1H) ppm.

[0617] Step 2: Preparation of 3-fluoro-4-hydroxy-5-sulfanyl-benzoic acid

[0618]

[0619] To a solution of 3-chlorosulfonyl-5-fluoro-4-hydroxy-benzoic acid (15 g, 58.91 mmol) in toluene (300 mL) was added PPh (54.08 g, 206.19 mmol) at 30°C, and the mixture was stirred at 90°C for 16 hours. The reaction mixture was quenched by the addition of saturated NaHCO (100 mL) and extracted with MTBE (100 mL*3). The aqueous layer was adjusted to pH 3 with 12N HCl and extracted with EA (100 mL*3). The EA layer was dried over NaSO, filtered, and concentrated under reduced pressure to give 3-fluoro-4-hydroxy-5-sulfanyl-benzoic acid (8.5 g, 45.17 mmol, 76.68% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 12.96-12.89 (m, 1H), 11.57-11.51 (m, 1H), 7.82-7.74 (m, 1H), 7.61-7.42 (m, 1H) ppm.

[0620] Step 3: Preparation of 3-fluoro-4-hydroxy-5-sulfanyl-benzoic acid methyl ester

[0621]

[0622] To a solution of 3-fluoro-4-hydroxy-5-sulfanyl-benzoic acid (8 g, 42.51 mmol) in MeOH (80 mL) was added H2SO4 (14.72 g, 150.08 mmol, 8 mL). The mixture was stirred at 80 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (100 mL). The pH was adjusted to 3 with aqueous NaHCO3 solution and extracted with EA (100 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 80g Silica Flash Column, eluent: 0-100% ethyl acetate / petroleum ether gradient @ 100 mL / min), the eluent was concentrated under reduced pressure to give 3-fluoro-4-hydroxy-5-sulfanyl-benzoate (8 g, 19.78 mmol, 93.06% yield) as a white solid. LCMS (ESI) m / z: [M+H] + =202.9. 1 H NMR (400MHz, DMSO-d6) δ = 12.27-11.29 (m, 1H), 7.86-7.78 (m, 1H), 7.65-7.43 (m, 1H), 3.81 (d, J = 8.4Hz, 3H) ppm.

[0623] Step 4: 9-Fluoro-3,4-dihydro-2H-1,5-benzoxathiazole Preparation of methyl-7-formate

[0624]

[0625] To a solution of 3-fluoro-4-hydroxy-5-sulfanyl-benzoic acid methyl ester (7 g, 34.62 mmol) and 1,3-dibromopropane (6.99 g, 34.62 mmol, 3.53 mL) in DMF (350 mL) was added Cs2CO3 (56.40 g, 173.09 mmol). The mixture was stirred at 25 ° C for 12 hours. The mixture was diluted with H2O (200 mL) and extracted with MTBE (200 mL*2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to provide a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1). The eluent was concentrated to provide 9-fluoro-3,4-dihydro-2H-1,5-benzoxathiazole as a yellow oil. -7-Methyl formate (7.5 g, 30.96 mmol, 89.42% yield). LCMS (ESI) m / z: [M+H] + =242.9.1 HNMR (400MHz, CDCl3) δ = 7.81 (s, 1H), 7.60-7.57 (m, 1H), 4.45-4.43 (m, 2H), 3.89 (s, 3H), 3.08-3.05 (m, 2H), 2.34-2.29 (m, 2H) ppm.

[0626] Step 5: 9-Fluoro-5-oxo-3,4-dihydro-2H-1,5λ4-benzoxathiazole Preparation of methyl-7-formate

[0627]

[0628] 9-Fluoro-3,4-dihydro-2H-1,5-benzoxathiazole was added at 0 °C. To a solution of methyl 7-formate (7 g, 28.89 mmol) in MeOH (140 mL) and H2O (70 mL) was added potassium persulfate (9.77 g, 15.89 mmol). The mixture was stirred at 30 ° C for 12 hours. The mixture was diluted with H2O (300 mL) and extracted with EA (300 mL*2). The combined organic layers were washed with saturated Na2SO3 (300 mL), dried over anhydrous Na2SO4, filtered and concentrated to provide a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The eluent was concentrated to provide 9-fluoro-5-oxo-3,4-dihydro-2H-1,5λ4-benzoxathiazole as a white solid. -7-Methyl formate (7 g, 27.10 mmol, 93.81% yield). LCMS (ESI) m / z: [M+H] + =258.9. 1 H NMR (400MHz, CDCl3) δ=8.19-8.18(m,1H),7.90-7.87(m,1H),4.57-4.53(m,1H),3.93(s,3H),3. 91-3.89(m,1H),3.32-3.29(m,1H),3.23-3.19(m,1H),2.70-2.66(m,1H),2.40-2.39(m,1H)ppm.

[0629] Step 6: 4,9-difluoro-3,4-dihydro-2H-1,5-benzoxathiazole Preparation of methyl-7-formate

[0630]

[0631] To 9-fluoro-5-oxo-3,4-dihydro-2H-1,5λ4-benzoxathiazole To a solution of methyl-7-formate (500 mg, 1.94 mmol) in CHCl (5 mL) was added DAST (6.10 g, 37.84 mmol, 5.00 mL). The mixture was stirred at 50 ° C for 96 hours. The reaction mixture was combined with four other batches for post-processing. The reaction mixture was added to saturated NaHCO (200 mL) at 0 ° C and extracted with DCM (200 mL * 2). The combined organic layer was dried over anhydrous Na SO, filtered and concentrated to provide a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1). The eluent was concentrated to provide 4,9-difluoro-3,4-dihydro-2H-1,5-benzoxathiazole as a yellow solid. -7-Methyl formate (1.3 g, 5.00 mmol, 51.60% yield).

[0632] 1 H NMR(400MHz, CDCl3)δ=7.94-7.93(m,1H),7.76-7.73(m,1H),5.96-5.83(m,1 H),4.63-4.58(m,1H),4.16-4.10(m,1H),3.91(s,3H),2.64-2.57(m,2H)ppm.

[0633] Step 7: 4,9-difluoro-3,4-dihydro-2H-1,5-benzoxathiazole Preparation of 7-formic acid

[0634]

[0635] To 4,9-difluoro-3,4-dihydro-2H-1,5-benzoxathiazole To a mixture of methyl 7-formate (1.95 g, 7.49 mmol) in THF (10 mL), MeOH (5 mL) and H2O (5 mL) was added NaOH (599.41 mg, 14.99 mmol). The mixture was stirred at 25 ° C for 2 hours. The mixture was diluted with H2O (50 mL) and 1N HCl was added to adjust the pH to 3, and then extracted with EA (50 mL * 2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to provide 4,9-difluoro-3,4-dihydro-2H-1,5-benzoxathiazole as a white solid. -7-carboxylic acid (1.8 g, 7.31 mmol, 97.57% yield), which was used directly in the next step.

[0636] Step 8: 4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole Preparation of 7-formic acid

[0637]

[0638] At 0 ° C to 4,9-difluoro-3,4-dihydro-2H-1,5-benzoxathiazole To a solution of 4-(4-fluoro-7-carboxylic acid) (1.8 g, 7.31 mmol) in MeOH (40 mL) and H₂O (20 mL) was added potassium persulfate (13.48 g, 21.93 mmol). The mixture was stirred at 30°C for 12 hours. The mixture was diluted with H₂O (100 mL) and extracted with DCM (100 mL*2). The combined organic layers were washed with aqueous Na₂SO₃ (100 mL) and dried over anhydrous Na₂SO₄, filtered and concentrated to afford 4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole as a white solid. -7-carboxylic acid (1.9 g, 6.83 mmol, 93.42% yield). 1 H NMR (400MHz, DMSO-d6)δ=8.33-8.25(m,1H),8.19-8.15(m,1H),6.33-6.20(m,1H) ,4.63-4.59(m,1H),4.19-4.13(m,1H),2.84-2.74(m,1H),2.61-2.57(m,1H)ppm.

[0639] Step 9: Intermediate 2 (4R) -4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole -7-carboxylic acid&(4S)-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole Preparation of 7-formic acid

[0640]

[0641] 4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole -7-Formic acid (1.88 g, 6.76 mmol) was separated by chiral SFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 um); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 15%-15%, 8.5 min; 750 minmin).

[0642] Intermediate 2: (4R)-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole -7-formic acid

[0643] The eluent of peak 1 was concentrated to provide a residue. The residue was diluted with H2O (50 mL) and 1N HCl was added to adjust pH = 2, then extracted with DCM (50 mL * 2), the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to provide (4R)-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole as a white solid. -7-carboxylic acid (Intermediate 2) (850 mg, 2.99 mmol, 44.22% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 13.84-13.73 (m, 1H), 8.20-8.15 (m, 2H), 6.34-6.21 (m, 1H), 4.63-4.58 (m, 1H), 4.19-4.13 (m, 1H), 2.75-2.71 (m, 1H), 2.61-2.56 (m, 1H) ppm. Chiral SFC: AD-3-MeOH(DEA)-5-40-3ML-35 T.1 cm. Rt = 1.304 mins, ee% = 96.54%. The eluent from peak 2 was concentrated to provide a residue. The residue was diluted with H2O (50 mL) and 1N HCl was added to adjust pH = 2, then extracted with DCM (50 mL * 2), the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to afford (4S)-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole as a white solid. -7-carboxylic acid (800 mg, 2.81 mmol, 41.65% yield). 1 H NMR(400MHz, DMSO-d6)δ=13.80-13.73(m,1H),8.19-8.15(m,2H),6.34-6.21(m,1H) ),4.63-4.58(m,1H),4.19-4.13(m,1H),2.85-2.75(m,1H),2.61-2.56(m,1H)ppm. Chiral SFC: AD-3-MeOH(DEA)-5-40-3ML-35T.lcm.Rt=1.410mins, ee%=99.25%.

[0644] (4R)-N-[[6-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyrazin-2-yl]-3-isoquinolinyl]methyl]-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole Preparation of -7-formamide (Compound 19)

[0645]

[0646] Step 1: Preparation of (2S,6R)-4-(6-chloropyrazin-2-yl)-2,6-dimethylmorpholine

[0647]

[0648] To a solution of 2,6-dichloropyrazine (1 g, 6.71 mmol) in ACN (50 mL) were added KCO (2.78 g, 20.14 mmol) and (2S,6R)-2,6-dimethylmorpholine (850.40 mg, 7.38 mmol). The mixture was stirred at 90°C for 3 hours. 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 NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO, PE:EA = 20:1-1:1), and the fractions were concentrated under reduced pressure to give (2S,6R)-4-(6-chloropyrazin-2-yl)-2,6-dimethylmorpholine (1.2 g, 5.27 mmol, 78.52% yield) as a white solid. LCMS (ESI) m / z: [M+H]+=228.1. 1 H NMR(400MHz, DMSO-d6)δ=8.40-8.23(m,1H),7.91-7.78(m,1H),4.21-4.10(m,2H ),3.67-3.52(m,2H),3.31(s,1H),2.53(d,J=2.4Hz,1H),1.17-1.14(m,6H)ppm.

[0649] Step 2: Preparation of tert-butyl N-[[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-isoquinolinyl]methyl]carbamate

[0650]

[0651] A mixture of tert-butyl N-[(6-bromo-3-isoquinolyl)methyl]carbamate (200 mg, 593.10 umol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (180.73 mg, 711.72 umol), Pd(dppf)Cl2 (43.40 mg, 59.31 umol), and KOAc (174.62 mg, 1.78 mmol) in dioxane (5 mL) was degassed and purged with N2 three times, and then stirred at 100°C under a N2 atmosphere for 2 hours. The mixture was diluted with H2O (30 mL) and extracted with EA (30 mL*2). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford tert-butyl N-[[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-isoquinolinyl]methyl]carbamate (220 mg, crude) as a brown oil, which was used directly in the next step.

[0652] Step 3: Preparation of tert-butyl N-[[6-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyrazin-2-yl]-3-isoquinolinyl]methyl]carbamate

[0653]

[0654] A mixture of (2S,6R)-4-(6-chloropyrazin-2-yl)-2,6-dimethyl-morpholine (from step 1) (100 mg, 439.19 umol), N-[[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-isoquinolinyl]methyl]carbamate (202.53 mg, 527.03 umol), K3PO4 (279.68 mg, 1.32 mmol) and di-tert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (28.62 mg, 43.92 umol) in dioxane (2.5 mL) and H2O (0.5 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100°C for 12 hours. The reaction mixture was poured into H2O (30 mL) and extracted with EA (30 mL*3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, PE:EA = 20:1–1:1), and the fractions were concentrated under reduced pressure to give tert-butyl N-[[6-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyrazin-2-yl]-3-isoquinolinyl]methyl]carbamate (150 mg, 333.67 umol, 75.97% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + =450.1.

[0655] Step 4: Preparation of [6-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyrazin-2-yl]-3-isoquinolinyl]methanamine

[0656]

[0657] To a solution of tert-butyl N-[[6-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyrazin-2-yl]-3-isoquinolinyl]methyl]carbamate (150 mg, 333.67 umol) in dioxane (2 mL) was added HCl / dioxane (4 M, 4 mL). The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was concentrated to give [6-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyrazin-2-yl]-3-isoquinolinyl]methanamine (120 mg, crude, HCl salt) as a light yellow solid, which was used in the next step without further purification. LCMS (ESI) m / z: [M+H] + = 350.2

[0658] Step 5: (4R)-N-[[6-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyrazin-2-yl]-3-isoquinolinyl]methyl]-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole Preparation of -7-formamide (Compound 19)

[0659]

[0660] To a solution of [6-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyrazin-2-yl]-3-isoquinolinyl]methanamine hydrochloride (70 mg, 200.33 umol) in DCM (2 mL) was added (4R)-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole -7-Formic acid (Intermediate 2) (55.74 mg, 200.33 μmol), EDCI (76.81 mg, 400.65 μmol), HOBt (54.14 mg, 400.65 μmol), and DIEA (155.35 mg, 1.20 mmol, 209.36 μL) were added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (15 mL) and extracted with EA (15 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (FA)-ACN]; B%: 55%-8%, 5 min). The fractions were concentrated in vacuo to remove MeCN and lyophilized to give (4R)-N-[[6-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyrazin-2-yl]-3-isoquinolinyl]methyl]-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole as a yellow solid. -7-formamide (39.15 mg, 63.38 umol, 31.64% yield). LCMS (ESI) m / z: [M+H]+=610.3. 1H NMR (400MHz, DMSO-d6) δ = 9.66-9.58 (m, 1H), 9.36-9.31 (m, 1H), 8.71-8.6 2(m,2H),8.39-8.19(m,5H),7.87(s,1H),6.41-6.12(m,1H),4.80-4.73(m ,2H),4.65-4.57(m,1H),4.44-4.33(m,2H),4.13-4.15(m,1H),3.71-3.6 2(m,2H),2.90-2.72(m,1H),2.61-2.55(m,3H),1.20(d,J=6.4Hz,6H)ppm. Chiral SFC: OD-MeOH+CAN(DEA)-40-3mL-35T.lcm, T=0.904, ee%=100%.

[0661] (2R)-6-Chloro-N-[[6-[6-(difluoromethoxy)-2-pyridinyl]-3-isoquinolinyl]methyl]-2-fluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiazole Preparation of 8-formamide (Compound 235)

[0662]

[0663] Step 1: Preparation of 2-bromo-6-(difluoromethoxy)pyridine

[0664]

[0665] To a solution of 1-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (3.38 g, 12.64 mmol) in MeCN (20 mL) was added 6-bromopyridin-2-ol (2.00 g, 11.49 mmol) and KF (1.34 g, 22.99 mmol). The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was then diluted with H2O (100 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PE / EA=50 / 1 to 5 / 1). The eluent was concentrated under reduced pressure to give 2-bromo-6-(difluoromethoxy)pyridine (1.2 g, 5.36 mmol, 46.61% yield) as a colorless oil. LCMS (ESI) m / z: [81BrM+H] + =226.2. 1 H NMR (400MHz, CDCl3) δ = 7.66-7.43 (m, 2H), 7.32-7.30 (m, 1H), 6.87 (d, J = 8.0Hz, 1H) ppm.

[0666] Step 2: Preparation of 2-(difluoromethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0667]

[0668] To a solution of Xphos (106.41 mg, 223.21 μmol) in dioxane (5 mL) was added Pd2(dba)3 (81.76 mg, 89.28 μmol), the mixture was then degassed and purged with N2 three times, and then the mixture was stirred at 25°C under a N2 atmosphere for 30 minutes. 2-Bromo-6-(difluoromethoxy)pyridine (200 mg, 892.85 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (272.07 mg, 1.07 mmol), and KOAc (262.88 mg, 2.68 mmol) were then added to the mixture. The resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered and the filter cake was washed with EA (20 mL * 3). The combined filtrates were concentrated under reduced pressure to give 2-(difluoromethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (240 mg, 885.39 umol, 99.16% yield) as a brown oil, which was used directly in the next step without further purification.

[0669] Step 3: Preparation of tert-butyl N-[[6-[6-(difluoromethoxy)-2-pyridyl]-3-isoquinolinyl]methyl]carbamate

[0670]

[0671] To a solution of 2-(difluoromethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (240 mg, 885.39 umol) in dioxane (2 mL) and H₂O (0.2 mL) was added tert-butyl N-[(6-bromo-3-isoquinolyl)methyl]carbamate (149.28 mg, 442.69 umol), di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (28.85 mg, 44.27 umol); and K₃PO₄ (281.91 mg, 1.33 mmol). The mixture was degassed and purged with N₂ three times, then stirred at 80°C under a N₂ atmosphere for 16 hours. The mixture was diluted with H₂O (30 mL) and extracted with EA (50 mL*3). The combined organic phase was washed with brine (50 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give a residue, which was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 1 / 3). The eluent was concentrated under reduced pressure to give tert-butyl N- [ [6- [6- (difluoromethoxy) -2-pyridyl] -3-isoquinolinyl] methyl] carbamate (160 mg, 398.60 umol, 90.04% yield) as a yellow solid. LCMS (ESI) m / z: [M + H] + =402.2. 1 H NMR (400MHz, CDCl3) δ = 9.25 (s, 1H), 8.39 (s, 1H), 8.20 (d, J = 8.8Hz, 1H), 8.06 (d, J = 8.8Hz, 1H), 7.91-7.8 5(m,1H),7.78-7.49(m,3H),6.95(d,J=8.0Hz,1H),5.53(s,1H),4.62(d,J=5.6Hz,2H),1.49(s,9H)ppm.

[0672] Step 4: Preparation of [6-[6-(difluoromethoxy)-2-pyridyl]-3-isoquinolinyl]methanamine

[0673]

[0674] A mixture of tert-butyl N-[[6-[6-(difluoromethoxy)-2-pyridinyl]-3-isoquinolinyl]methyl]carbamate (160 mg, 398.60 umol) in HCl / dioxane (4 M) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give [6-[6-(difluoromethoxy)-2-pyridinyl]-3-isoquinolinyl]methanamine (130 mg, 384.90 umol, 96.56% yield, HCl) as a gray solid, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + =302.1.

[0675] Step 5: (2R)-6-chloro-N-[[6-[6-(difluoromethoxy)-2-pyridinyl]-3-isoquinolinyl]methyl]-2-fluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiazole Preparation of 8-formamide

[0676]

[0677] [6-[6-(difluoromethoxy)-2-pyridyl]-3-isoquinolinyl]methanamine (30 mg, 88.82 umol) and (2R)-6-chloro-2-fluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiazole To a mixture of -8-formic acid (Intermediate 1) (31.41 mg, 106.59 umol) in DCM (1 mL) were added EDCI (22.14 mg, 115.47 umol), HOBt (15.60 mg, 115.47 umol), and DIEA (68.88 mg, 532.94 umol). The mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (20 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by reverse phase flash chromatography (0.1% FA conditions). The eluate was concentrated under reduced pressure to remove MeCN and the residue was lyophilized to give (2R)-6-chloro-N-[[6-[6-(difluoromethoxy)-2-pyridinyl]-3-isoquinolinyl]methyl]-2-fluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiazole as a white solid. -8-Formamide (19.12 mg, 33.08 umol, 37.24% yield). LCMS (ESI) m / z: [M+H] + =578.1 1H NMR (400MHz, DMSO-d6) δ=9.76-9.73(m,1H),9.35(s,1H),8.73(s,1H),8.58(d,J=1.6Hz,1H),8.50(d,J=1.6Hz,1H),8.39-8.37(m,1H),8.27-7 .83(m,5H),7.13-7.11(m,1H),6.36-6.10(m,1H),5.41(d,J=14.8Hz,1H ), 5.09 (d, J = 14.8Hz, 1H), 4.78 (d, J = 5.2Hz, 2H), 4.52-4.36 (m, 2H) ppm. Chiral SFC: OD-3-MeOH+ACN(DEA)-40-3ML-35T.1cm, Rt=0.853min, ee%=97.36%.

[0678] The following examples in Table 4 were prepared using standard chemical manipulations and procedures similar to those used to prepare compound 235.

[0679] Table 4. Compounds of the present invention

[0680]

[0681]

[0682]

[0683] (R)-N-((4-((E)-2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)vinyl)pyridin-2-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathia Preparation of 7-formamide 5,5-dioxide (Compound 52)

[0684]

[0685] Step 1: Preparation of (2S,6R)-4-(6-bromopyridin-2-yl)-2,6-dimethylmorpholine

[0686]

[0687] To a solution of 2-bromo-6-fluoro-pyridine (2 g, 11.36 mmol) in DMF (20 mL) was added (2S,6R)-2,6-dimethylmorpholine (1.96 g, 17.05 mmol) and Cs2CO3 (7.41 g, 22.73 mmol). The mixture was stirred at 80°C for 1 hour. The reaction mixture was poured into water (200 mL) and extracted with EA (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by normal phase flash chromatography (column: SiO2, 40 g; PE:EA = 1:0 to 0:1, RF = 0.3). The eluent was concentrated under vacuum to give (2S,6R)-4-(6-bromopyridin-2-yl)-2,6-dimethylmorpholine (2.9 g, 10.30 mmol, 90.63% yield) as a white solid. LCMS (ESI) m / z: [M+H] + =270.8 1 H NMR (400 MHz, chloroform-d) δ = 7.31-7.27 (m, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 4.03-4.00 (m, 2H), 3.76-3.62 (m, 2H), 2.55-2.49 (m, 2H), 1.27 (d, J = 6.2 Hz, 6H) ppm.

[0688] Step 2: Preparation of (2S,6R)-2,6-dimethyl-4-(6-vinylpyridin-2-yl)morpholine

[0689]

[0690] To a solution of (2S,6R)-4-(6-bromopyridin-2-yl)-2,6-dimethylmorpholine (1 g, 3.69 mmol) in dioxane (10 mL) were added potassium hydride, trifluoro(vinyl)boron (988.00 mg, 7.38 mmol), Pd(dtbpf)Cl2 (240.36 mg, 368.80 umol), K3PO4 (2.35 g, 11.06 mmol), and H2O (2 mL). The mixture was degassed and purged with N2 three times and stirred at 80°C for 2 hours. The mixture was poured into water (100 mL) and extracted with EA (30 mL*3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by normal phase flash chromatography (column: SiO2, 40 g, PE:EA = 1:0 to 0:1, Rf = 0.4). The eluent was concentrated under vacuum to give (2S,6R)-2,6-dimethyl-4-(6-vinylpyridin-2-yl)morpholine (850 mg, 3.64 mmol, 98.81% yield) as a brown oil. LCMS (ESI) m / z: [M+H] + =218.9. 1 H NMR (400MHz, chloroform-d) δ = 7.47-7.43 (m, 1H), 6.73-6.63 (m, 2H), 6.54 (d, J = 8.4Hz, 1H), 6.23 (d, J = 1.8Hz, 1H), 6.19 (d, J =1.8Hz,1H),5.39-5.36(m,1H),4.15-4.12(m,2H),3.75-3.72(m,2H),2.55-2.49(m,2H),1.28(d,J=6.2Hz,6H)ppm.

[0691] Step 3: Preparation of tert-butyl ((4-bromopyridin-2-yl)methyl)carbamate

[0692]

[0693] To a solution of (4-bromo-2-pyridyl)methanamine (2 g, 10.69 mmol) in DCM (20 mL) was added tert-butyl carbonate (4.20 g, 19.25 mmol, 4.42 mL) and TEA (2.16 g, 21.39 mmol, 2.98 mL). The mixture was stirred at 25°C for 2 hours. The mixture was poured into water (50 mL) and extracted with DCM (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under vacuum. The residue was purified by normal phase flash chromatography (column: SiO, 80 g, PE:EA = 1:0 to 1:1, RF = 0.4). The eluent was concentrated to give tert-butyl ((4-bromopyridin-2-yl)methyl)carbamate (3 g, 10.19 mmol, 95.28% yield) as a colorless oil. LCMS (ESI) m / z: [M+H-56] + =230.8. 1 H NMR (400 MHz, chloroform-d) δ = 8.34 (d, J = 5.4 Hz, 1H), 7.46 (d, J = 1.2 Hz, 1H), 7.35-7.27 (m, 1H), 5.51 (br s, 1H), 4.42 (br d, J = 5.2 Hz, 2H), 1.46 (s, 9H) ppm.

[0694] Step 4: Preparation of tert-butyl ((4-((E)-2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)vinyl)pyridin-2-yl)methyl)carbamate

[0695]

[0696] To a solution of (2S,6R)-2,6-dimethyl-4-(6-vinylpyridin-2-yl)morpholine (100 mg, 458.10 umol) in DMF (2 mL) was added tert-butyl ((4-bromopyridin-2-yl)methyl)carbamate (197.32 mg, 687.15 umol), Pd(OAc)2 (10.28 mg, 45.81 umol), tri-o-tolylphosphane (34.86 mg, 114.52 umol), and DIEA (177.61 mg, 1.37 mmol, 239.37 uL). The mixture was degassed and purged with N2 and stirred at 100°C for 1 hour. The reaction mixture was poured into water (15 mL) and extracted with EA (10 mL*3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by normal phase flash chromatography (column: SiO2, 12 g, PE:EA = 1:0 to 0:1, Rf = 0.4). The eluent was concentrated to give tert-butyl ((4-((E)-2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)vinyl)pyridin-2-yl)methyl)carbamate (190 mg, 399.62 umol, 87.23% yield) as a white solid. LCMS (ESI) m / z: [M+H] + =425.1. 1 H NMR (400MHz, chloroform-d) δ = 8.51 (br d, J = 5.4Hz, 1H), 7.59-7.39 (m, 4H), 7.28 (br s, 1H), 7.24 (br s,1H),6.76(d,J=7.2Hz,1H),6.63(d,J=8.4Hz,1H),5.85-5.70(m,1H),4.52(br d,J=4.8Hz,2H),4.17(brd,J=12.6Hz,2H),3.82-3.73(m,2H),2.61-2.55(m,2H),1.47(s,9H),1.32(d,J=6.2Hz,6H)ppm.

[0697] Step 5: Preparation of (4-((E)-2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)vinyl)pyridin-2-yl)methanamine

[0698]

[0699] To a mixture of tert-butyl ((4-((E)-2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)vinyl)pyridin-2-yl)methyl)carbamate (100 mg, 235.55 umol) in DCM (1 mL) was added TFA (0.3 mL). The mixture was stirred at 25 ° C for 1 hour. The mixture was poured into saturated NaHCO (5 mL) and extracted with DCM (5 mL * 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na SO, filtered and concentrated under vacuum to give (4-((E)-2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)vinyl)pyridin-2-yl)methanamine (75 mg, crude) as a yellow oil. LCMS (ESI) m / z: [M + H] + =325.0

[0700] Step 6: (R)-N-((4-((E)-2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)vinyl)pyridin-2-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathia Preparation of 7-formamide 5,5-dioxide (Compound 52)

[0701]

[0702] To (4R)-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole To a solution of 7-carboxylic acid (Intermediate 2) (64.32 mg, 231.18 umol) in DCM (2 mL) were added HATU (131.85 mg, 346.77 umol) and DIEA (89.64 mg, 693.55 umol, 120.80 uL). Then, (4-((E)-2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)vinyl)pyridin-2-yl)methanamine (75 mg, 231.18 umol) was added. The mixture was stirred at 25°C for 2 hours. The mixture was poured into water (20 mL) and extracted with EA (10 mL*3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenexluna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 10 min). The eluate was then concentrated and lyophilized to give (R)-N-((4-((E)-2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)vinyl)pyridin-2-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin as a yellow solid. -7-Formamide 5,5-dioxide (28.28 mg, 43.20 umol, 18.69% yield, FA). LCMS (ESI) m / z: [M+H] + =585.1. 1 H NMR (400 MHz, chloroform-d) δ = 8.53 (d, J = 5.4 Hz, 1H), 8.30-8.26 (m, 1H), 8.15 (s, 1H), 8.08-8.05 (m, 2H), 7.56-7.50 (m, 3H), 7.46-7.44 (m, 1H), 7.30 (s, 1H), 7.26 (br s,1H),6.78(d,J=7.2Hz,1H),6.63(d,J=8.4Hz,1H),5.76-5.38(m,1H),4.80(d,J=5.2Hz,2H),4.67-4.65(m,1H),4.19-4.16(m ,2H),4.11-4.09(m,1H),3.85-3.68(m,2H),3.21-2.96(m,1H),2.59-5.28(m,2H),2.52-2.42(m,1H),1.32(d,J=6.4Hz,7H)ppm. Chiral SFC: OJ-3-EtOH(DEA)-5-40-3ML-35T.1cm, Rt=1.847mins, ee%=100%.

[0703] Intermediate 4(2R)-2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiazole Preparation of 8-formic acid

[0704]

[0705] Step 1: Preparation of 4-bromo-2-fluoro-6-sulfanyl-benzoic acid methyl ester

[0706]

[0707] To a solution of 4-bromo-2,6-difluoro-benzoic acid methyl ester (100 g, 398.37 mmol) in DMF (1000 mL) was added Na2S (34.54 g, 398.37 mmol, 90% purity) and the mixture was stirred at 30 ° C for 16 hours. The reaction mixture was poured into water (1500 mL) and extracted with MTBE (1500 mL * 2). The aqueous phase was adjusted to pH = 2 with 1N HCl and extracted with MTBE (1500 mL * 3). The combined organic layer was washed with water (2000 mL * 2) and brine (5000 mL), dried over Na2SO4, filtered and concentrated to give 4-bromo-2-fluoro-6-sulfanyl-benzoic acid methyl ester (105 g, crude) as a yellow oil. LCMS (ESI) m / z: [Br 79 M+H] + =232.9

[0708] Step 2: Preparation of (4-bromo-2-fluoro-6-sulfanyl-phenyl)methanol

[0709]

[0710] To a solution of 4-bromo-2-fluoro-6-sulfanyl-benzoic acid methyl ester (105 g, 396.08 mmol) in THF (1000 mL) was added LiAlH (15.03 g, 396.08 mmol) at 0°C under N2, and the mixture was stirred at 0°C for 1 hour. The mixture was poured into 1N HCl (1000 mL) and extracted with EtOAc (1000 mL*2). The combined organic phases were washed with brine (2000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give (4-bromo-2-fluoro-6-sulfanyl-phenyl)methanol (93 g, crude) as a yellow oil and used directly in the next step.

[0711] Step 3: Preparation of (4-bromo-2-fluoro-6-vinylsulfanyl-phenyl)methanol

[0712]

[0713] To a solution of (4-bromo-2-fluoro-6-sulfanyl-phenyl)methanol (93 g, 392.26 mmol) in DMF (1800 mL) were added KCO (162.64 g, 1.18 mol) and 1,2-dibromoethane (221.07 g, 1.18 mol, 88.78 mL), and the mixture was stirred at 30°C for 16 hours. The reaction was quenched with water (2000 mL). The mixture was extracted with ethyl acetate (2000 mL*3). The combined organic layers were dried over NaSO and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10:1-1:1), and the solution was concentrated to give (4-bromo-2-fluoro-6-vinylsulfanyl-phenyl)methanol (56 g, 212.83 mmol) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ=7.33(s,1H),7.19-7.17(m,1H),6.50-6.44(m,1H),5.54-5.42(m,2H),4.78(d,J=1.2Hz,2H),2.13(s,1H)ppm

[0714] Step 4: Preparation of (4-bromo-2-fluoro-6-vinylsulfinyl-phenyl)methanol

[0715]

[0716] To a solution of (4-bromo-2-fluoro-6-vinylsulfanyl-phenyl)methanol (10 g, 38.00 mmol) in MeOH (100 mL) and H2O (100 ml) was added potassium hydrogen persulfate (11.68 g, 19.00 mmol), and the mixture was stirred at 30°C for 16 hours. The reaction mixture was poured into water (1 L), the solution was extracted with EA (1 L*3), and the combined organic layers were washed with saturated Na2SO3 (1 L) and brine (1 L), dried over Na2SO4, filtered and concentrated to give (4-bromo-2-fluoro-6-vinylsulfinyl-phenyl)methanol (10.61 g, crude) as a yellow oil. LCMS (ESI) m / z: [Br 79 M+H] + =263.0

[0717] Step 5: 8-Bromo-6-fluoro-3,5-dihydro-2H-4,1λ4-benzoxathiazole Preparation of 1-oxide

[0718]

[0719] To a solution of (4-bromo-2-fluoro-6-vinylsulfinyl-phenyl)methanol (10.6 g, 37.98 mmol) in THF (110 mL) was added NaH (3.04 g, 75.95 mmol, 60% purity) at 0 ° C, and the mixture was stirred at 20 ° C for 1 hour. The reaction mixture was poured into NH4Cl (500 mL), the solution was extracted with EA (500 mL * 3), and the combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered and concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10: 1-1: 1), and the solution was concentrated to obtain 8-bromo-6-fluoro-3,5-dihydro-2H-4,1λ4-benzoxathiazole as a white solid. 1-oxide (5.5 g, 19.70 mmol, 51.89% yield). 1 H NMR (400MHz, DMSO-d6) δ=7.78-7.75(m,1H),7.62(s,1H),4.96(d,J=15.2Hz,1H),4.54-4.50(m,1H),4.33-4.24(m,2H),3.41-3.39(m,2H)ppm

[0720] Step 6: 8-Bromo-6-fluoro-3,5-dihydro-2H-4,1λ4-benzoxathiazole 1-oxide&8-bromo-2,6-difluoro-3,5-dihydro-2H-4,1-benzoxathiazole Preparation

[0721]

[0722] To 8-bromo-6-fluoro-3,5-dihydro-2H-4,1λ4-benzoxathiazole To a solution of 1-oxide (1.9 g, 6.81 mmol) in DCM (40 mL) was added SbCl (46.58 mg, 204.21 mmol), followed by DAST (2.19 g, 13.61 mmol, 1.80 mL). The mixture was stirred at 20°C for 16 hours. DAST (5.49 g, 34.03 mmol, 4.50 mL) was then added, and the mixture was stirred at 20°C for 16 hours. SbCl (1.55 g, 6.81 mmol) and DAST (10.97 g, 68.07 mmol, 8.99 mL) were added, and the mixture was stirred at 20°C for 16 hours. The reaction mixture was poured into a NaHCO solution (200 mL), extracted with EA (200 mL * 3), and the combined organic layers were washed with brine (500 mL), dried over NaSO, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20:1-5:1), and the peak 1 eluent was concentrated to give 8-bromo-6-fluoro-3,5-dihydro-2H-4,1λ4-benzoxathiazole as a yellow oil. 1-oxide (1.2 g, 4.56 mmol, 67.00% yield). 1 H NMR (400 MHz, CDCl3) δ = 7.54-7.51 (m, 1H), 7.18-7.15 (m, 1H), 4.91-4.89 (m, 2H), 4.17-4.14 (m, 2H), 2.89-2.86 (m, 2H) ppm. The peak 2 eluate was concentrated to give 8-bromo-2,6-difluoro-3,5-dihydro-2H-4,1-benzoxathiazole as a yellow solid. (600 mg, 2.13 mmol, 31.36% yield). 1 H NMR(400MHz, CDCl3)δ=7.55–7.54(m,1H),7.27-7.24(m,1H),5.63-5.51(m,1H),5 .25(d,J=13.6Hz,1H),4.69–4.65(m,1H),4.43–4.41(m,1H),4.13–4.05(m,1H)ppm

[0723] Step 7: 8-Bromo-2,6-difluoro-3,5-dihydro-2H-4,1-benzoxathiazole Preparation

[0724]

[0725] To 8-bromo-6-fluoro-3,5-dihydro-2H-4,1λ4-benzoxathiazole To a solution of 1-oxide (1.2 g, 4.56 mmol) in MeCN (25 mL) was added Select F (2.02 g, 5.70 mmol), followed by the addition of DAST (147.02 mg, 912.11 umol, 120.51 uL) under an ice bath. The solution was stirred at 20°C for 1 hour. DIEA (884.11 mg, 6.84 mmol, 1.19 mL) was then added to the mixture at 20°C, and the mixture was stirred at 20°C for 1 hour. The reaction mixture was poured into a NaHCO solution (200 mL) and extracted with EA (200 mL*3). The combined organic layers were washed with brine (500 mL), dried over NaSO, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 20: 1-5: 1), and the solution was concentrated to give 8-bromo-2,6-difluoro-3,5-dihydro-2H-4,1-benzoxathiazole as a yellow solid. (500 mg, 1.78 mmol, 39.00% yield). 1 H NMR(400MHz, CDCl3)δ=7.54(m,1H),7.27-7.24(m,1H),5.63-5.51(m,1H),5.25 (d,J=13.6Hz,1H),4.70-4.66(m,1H),4.43-4.42(m,1H),4.13-4.05(m,1H)ppm

[0726] Step 8: 2,6-Difluoro-3,5-dihydro-2H-4,1-benzoxathiazole Preparation of 8-formic acid

[0727]

[0728] To 8-bromo-2,6-difluoro-3,5-dihydro-2H-4,1-benzoxathiazole To a solution of 1.3 g (4.62 mmol) in MSO (20 mL) and H2O (4 mL) was added K2CO3 (958.71 mg, 6.94 mmol), dicyclohexyl(3-dicyclohexylphosphoniumpropyl)phosphonium bistetrafluoroborate (283.13 mg, 462.44 umol), and Pd(OAc)2 (103.82 mg, 462.44 umol). The suspension was degassed under vacuum and purged with CO2 several times. The mixture was stirred at 100°C under CO2 (15 psi) for 2 hours. The reaction mixture was poured into a NaHCO3 solution (100 mL) and extracted with EA (100 mL x 2). The aqueous phase was adjusted to pH=1 with 1N HCl and extracted with EA (50 mL*2), the combined organic layers were dried over Na2SO4, filtered and concentrated to give 2,6-difluoro-3,5-dihydro-2H-4,1-benzoxathiazole as a yellow solid. -8-carboxylic acid (1.1 g, crude), which was used without purification.

[0729] Step 9: 2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ 6 -Benzoxathia Preparation of 8-formic acid

[0730]

[0731] To 2,6-difluoro-3,5-dihydro-2H-4,1-benzoxathiazole To a solution of 1-8-carboxylic acid (1.1 g, 4.47 mmol) in MeOH (12 mL) and H2O (12 mL) was added potassium hydrogen persulfate (5.49 g, 8.93 mmol), and the mixture was stirred at 20°C for 16 hours. The reaction mixture was poured into water (100 mL), the solution was extracted with EA (100 mL*3), and the combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated to give 2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiazole as a white solid. -8-formic acid (1.1 g, 3.95 mmol, 88.50% yield). 1 H NMR(400MHz, DMSO-d6)δ=14.03-13.95(m,1H),8.34(d,J=1.2Hz,1H),8.13-8.11(m, 1H),6.27-6.16(m,1H),5.25–5.21(m,1H),4.91–4.86(m,1H),4.47-4.38(m,2H)ppm.

[0732] Step 10: (2R)-2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ 6 -Benzoxathia -8-carboxylic acid (Intermediate 4) and (2S)-2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ 6 -Benzoxathia Preparation of 8-formic acid

[0733]

[0734] 2,6-Difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiazole -8-carboxylic acid (1.1 g, 3.95 mmol) was separated by chiral SFC (column: Daicel ChiralPak IG (250*30 mm, 10 um); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 20%-20%, 4.75; 310 min) to give two phases. The peak 1 eluate was concentrated to give a residue, which was diluted with water (100 mL) and adjusted to pH = 2 with 4N HCl solution. The solution was extracted with EA (100 mL*2), and the combined organic layers were dried over Na2SO4, filtered and concentrated to give (2R)-2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiazole as a white solid. -8-carboxylic acid (Intermediate 4) (350 mg, 1.25 mmol, 31.69% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 14.17-13.92 (m, 1H), 8.33 (s, 1H), 8.13–8.11 (m, 1H), 6.27-6.17 (m, 1H), 5.25–5.21 (m, 1H), 4.91–4.86 (m, 1H), 4.47–4.35 (m, 2H) ppm. Chiral SFC: IG-3_5CM_MEOH(DEA)_5_40_3ML_T35.M; Rt = 1.408 mins, ee% = 98.14%. The peak 2 eluate was concentrated to give a residue, which was diluted with water (100 mL) and adjusted to pH = 2 with 4N HCl solution, the solution was extracted with EA (100 mL * 2), and the combined organic layer was dried over Na2SO4, filtered and concentrated to give (2S)-2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ6-benzoxathiazole as a white solid. -8-formic acid (500 mg, 1.66 mmol, 41.94% yield). 1HNMR(400MHz, DMSO-d6)δ=14.27-13.55(m,1H),8.34(d,J=1.2Hz,1H),8.13–8.10(m, 1H),6.27-6.16(m,1H),5.26-5.21(m,1H),4.91-4.86(m,1H),4.47-4.38(m,2H)ppm. Chiral SFC: IG-3_5CM_MEOH(DEA)_5_40_3ML_T35.M; Rt=1.624mins,ee%=98.96%

[0735] (R)-N-((4-((6-(difluoromethoxy)pyridin-2-yl)ethynyl)pyridin-2-yl)methyl)-2,6-difluoro-3,5-dihydro-2H-benzo[e][1,4]oxathia Preparation of 8-formamide 1,1-dioxide (Compound 184)

[0736]

[0737] Step 1: Preparation of 2-bromo-6-(difluoromethoxy)pyridine

[0738]

[0739] To a solution of 6-bromopyridin-2-ol (2 g, 11.49 mmol) in MeCN (20 mL) was added KF (1.34 g, 22.99 mmol, 538.55 uL) and 1-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (3.38 g, 12.64 mmol). The mixture was stirred at 25°C for 1.5 hours. The reaction mixture was poured into water (100 mL) and extracted with DCM (100 mL*3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (column: SiO2, 80 g; PE / EA = 1 / 0 to 0 / 1, 40 mL / min, Rf = 0.80). The eluate was concentrated in vacuo to give 2-bromo-6-(difluoromethoxy)pyridine (2.23 g, 9.59 mmol, 83.47% yield) as a yellow oil. LCMS (ESI) m / z: [M+H] + =225.7 1 H NMR (400MHz, DMSO-d6) δ = 7.91-7.80 (m, 1H), 7.66-7.54 (m, 1H), 7.50 (d, J = 28.8Hz, 1H), 7.15 (d, J = 8.0Hz, 1H) ppm.

[0740] Step 2: Preparation of tert-butyl ((4-((6-(difluoromethoxy)pyridin-2-yl)ethynyl)pyridin-2-yl)methyl)carbamate

[0741]

[0742] To a solution of 2-bromo-6-(difluoromethoxy)pyridine (100 mg, 446.42 umol) and tert-butyl N-[(4-ethynyl-2-pyridyl)methyl]carbamate (103.69 mg, 446.42 umol) in DMF (1 mL) was added TEA (451.73 mg, 4.46 mmol, 621.36 uL), Pd(PPh3)2Cl2 (31.33 mg, 44.64 umol) and CuI (8.50 mg, 44.64 umol). The mixture was degassed and purged with N2 and stirred at 80°C for 1.5 hours. The reaction mixture was poured into water (5 mL) and extracted with EA (5 mL*3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (column: SiO2, 20 g; PE / EA = 1 / 0 to 1 / 0, 40 mL / min, Rf = 0.30). The eluent was concentrated in vacuo to give tert-butyl ((4-((6-(difluoromethoxy)pyridin-2-yl)ethynyl)pyridin-2-yl)methyl)carbamate (116 mg, 289.24 umol, 64.79% yield) as a yellow oil.

[0743] LCMS (ESI) m / z: [M+H] + =375.9. 1 H NMR (400MHz, chloroform-d) δ=8.77-8.39(m,1H),7.79-7.73(m,1H),7.55(s,1H),7.48-7.47(m,1H),7.37(d,J=6.8Hz,1H),6.93(d,J=8.4Hz,1H),5.53(br s,1H),4.47(br s,2H),1.48(s,9H)ppm.

[0744] Step 3: Preparation of (4-((6-(difluoromethoxy)pyridin-2-yl)ethynyl)pyridin-2-yl)methanamine

[0745]

[0746] To a solution of tert-butyl ((4-((6-(difluoromethoxy)pyridin-2-yl)ethynyl)pyridin-2-yl)methyl)carbamate (110 mg, 293.05 umol) in DCM (1 mL) was added TFA (0.3 mL). The mixture was stirred at 25 ° C for 2 hours. The reaction mixture was poured into a NaHCO3 aqueous solution (10 mL) and extracted with EA (10 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to give (4-((6-(difluoromethoxy)pyridin-2-yl)ethynyl)pyridin-2-yl)methanamine (80 mg, 257.81 umol, 87.98% yield) as a yellow solid.

[0747] LCMS (ESI) m / z: [M+H] + =275.8

[0748] Step 4: (R)-N-((4-((6-(difluoromethoxy)pyridin-2-yl)ethynyl)pyridin-2-yl)methyl)-2,6-difluoro-3,5-dihydro-2H-benzo[e][1,4]oxathia Preparation of 8-formamide 1,1-dioxide (Compound 184)

[0749]

[0750] To (2R)-2,6-difluoro-1,1-dioxo-3,5-dihydro-2H-4,1λ 6 -Benzoxathia To a solution of 8-carboxylic acid (Intermediate 4) (80.86 mg, 290.64 umol) in DCM (1 mL) were added EDCI (83.57 mg, 435.96 umol), HOBt (58.91 mg, 435.96 umol), and DIEA (112.69 mg, 871.93 umol, 151.87 uL). (4-((6-(difluoromethoxy)pyridin-2-yl)ethynyl)pyridin-2-yl)methanamine (80 mg, 290.64 umol) was then added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 42%-72%, 10 min). The eluate was concentrated and lyophilized to give (R)-N-((4-((6-(difluoromethoxy)pyridin-2-yl)ethynyl)pyridin-2-yl)methyl)-2,6-difluoro-3,5-dihydro-2H-benzo[e][1,4]oxathiapiperidin as a yellow solid. -8-formamide 1,1-dioxide (13.44 mg, 25.10 umol, 8.64% yield).

[0751] LCMS (ESI) m / z: [M+H] + =536.0. 1 H NMR (400MHz, chloroform-d) δ = 8.63 (d, J = 5.2Hz, 1H), 8.41 (s, 1H), 8.05-8.00 (m, 1H), 7.86 (br s,1H),7.77-7.75(m,1H),7.56(s,1H),7.45(d,J=5.2Hz,1H),7.41-7.37(m,1H),6.96(d,J=8.4Hz,1H) ,5.44-5.29(m,2H),4.99-4.95(m,1H),4.83(d,J=4.8Hz,2H),4.54-4.49(m,1H),4.48-4.44(m,1H)ppm. Chiral SFC: OJ-3-MeOH(DEA)-5-40-3ML-35T.1cm, Rt=1.676mins, ee%=100%.

[0752] Intermediate 3(R)-9-chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathia Preparation of 7-formic acid 5,5-dioxide

[0753]

[0754] Step 1: Preparation of 3-chloro-5-(chlorosulfonyl)-4-hydroxybenzoic acid

[0755]

[0756] 3-Chloro-4-hydroxy-benzoic acid (60 g, 347.69 mmol) was added to HSO₃Cl (525.00 g, 4.51 mol, 300.00 mL) at 20°C. The mixture was stirred at 80°C for 16 hours. The reaction mixture was slowly poured into ice water (2000 mL) and a large amount of solid formed. The solid was then collected by filtration, washed with water (1000 mL), and the filter cake was diluted with EA (3000 mL) and washed with water (1000 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated to give 3-chloro-5-(chlorosulfonyl)-4-hydroxybenzoic acid (78 g, 244.58 mmol, 70.34% yield, 85% purity) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 12.29-11.14 (m, 1H), 8.01 (d, J = 2.0Hz, 1H), 7.86 (d, J = 2.0Hz, 1H) ppm.

[0757] Step 2: Preparation of 3-chloro-4-hydroxy-5-mercaptobenzoic acid

[0758]

[0759] To a solution of 3-chloro-5-(chlorosulfonyl)-4-hydroxybenzoic acid (78 g, 287.74 mmol) in toluene (1600 mL) was added PPh (264.15 g, 1.01 mol, 3.5 eq). The mixture was stirred at 90°C for 2 hours. The reaction mixture was quenched by adding 10% NaOH (aq) until pH = 9, then extracted with DCM (1000 mL). The organic layer was discarded, and the aqueous layer was adjusted to pH = 3 with 1N HCl, then diluted with H2O (8000 mL) and extracted with EtOAc (1000 mL*2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3-chloro-5-(chlorosulfonyl)-4-hydroxybenzoic acid (70 g, crude) as a white solid, which was used directly in the next step.

[0760] Step 3: Preparation of methyl 3-chloro-4-hydroxy-5-mercaptobenzoate

[0761]

[0762] To a solution of 3-chloro-5-(chlorosulfonyl)-4-hydroxybenzoic acid (70 g, 342.08 mmol, 1 eq) in MeOH (700 mL) was added HSO (33.55 g, 342.08 mmol, 18.23 mL, 1 eq). The mixture was stirred at 70°C for 16 hours. The reaction mixture was diluted with HO (2000 mL) and extracted with EtOAc (1000 mL*3). The combined organic layers were washed with brine (1000 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give methyl 3-chloro-4-hydroxy-5-mercaptobenzoate (61.4 g, 280.80 mmol, 82.09% yield) as a white solid, which was used directly in the next step. 1 H NMR (400MHz, DMSO-d6) δ = 8.00-7.69 (m, 2H), 3.78 (s, 3H) ppm.

[0763] Step 4: 9-Chloro-3,4-dihydro-2H-benzo[b][1,4]oxathia Preparation of methyl-7-formate

[0764]

[0765] To a mixture of methyl 3-chloro-4-hydroxy-5-mercaptobenzoate (30 g, 137.20 mmol, 1 eq) and Cs2CO3 (223.51 g, 686.01 mmol, 5 eq) in DMF (1200 mL) was added 1,3-dibromopropane (30.47 g, 150.92 mmol, 15.39 mL, 1.1 eq). The mixture was stirred at 25 °C for 16 hours. The mixture was diluted with water (1500 mL) and extracted with MTBE (methyl tert-butyl ether) (1500 mL x 2). The organic layer was dried over Na2SO4 (1000 mL), filtered and concentrated. The material was purified by silica gel chromatography using petroleum ether / ethyl acetate (gradient: 0-50% ethyl acetate), and the eluent was concentrated in vacuo to give 9-chloro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin as a yellow solid. -7-carboxylate (43 g, 56% yield). 1 H NMR (400MHz, DMSO-d6) δ = 7.90-7.76 (m, 2H), 4.38-4.22 (m, 2H), 3.83 (s, 3H), 3.12-2.97 (m, 2H), 2.26-2.15 (m, 2H) ppm.

[0766] Step 5: 9-Chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathia Preparation of methyl-7-formate

[0767]

[0768] To 9-chloro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin To a solution of -7-carboxylate (43 g, 166.20 mmol, 1 eq) in MeCN (800 mL) was added DAST (5.36 g, 33.24 mmol, 4.39 mL, 0.2 eq) followed by Select F (73.60 g, 207.75 mmol, 1.25 eq) at 0 ° C. The mixture was stirred at 0 ° C for 1 hour. The reaction mixture was poured into NaHCO 3 (1000 mL) and extracted with EA (1000 mL*2). The combined organic layers were washed with brine (300 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether / ethyl acetate (gradient: 0-50% ethyl acetate) to give 9-chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin as a white solid. -7-Methyl formate (27 g, 97.57 mmol, 58.71% yield). 1 H NMR (400MHz, DMSO-d6) δ = 7.98 (d, J = 2.0Hz, 1H), 7.90 (d, J = 2.0Hz, 1H), 6.37-6.20 (m, 1H), 4 .63-4.58(m,1H),4.07-3.98(m,1H),3.85(s,3H),2.61-2.52(m,1H),2.49-2.46(m,1H)ppm.

[0769] Step 6: 9-Chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathia Preparation of 7-formic acid

[0770]

[0771] To 9-chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin To a solution of methyl 7-formate (27 g, 97.57 mmol, 1 eq) in THF (280 mL), MeOH (140 mL) and water (70 mL) was added LiOH.HO (8.19 g, 195.15 mmol, 2 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into ice-cold NaHCO (900 mL) and extracted with EA (300 mL*2). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether / ethyl acetate (gradient: 0-50% ethyl acetate) to give 9-chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin as a white solid. -7-carboxylic acid (25.6 g, 97.46 mmol, 99.88% yield). 1 H NMR(400MHz,DMSO-d6)δ=13.38(br s,1H),7.95(d,J=2.0Hz,1H),7.88(d,J=2.0Hz,1H),6.43-6.12(m,1H),4.6 1-4.57(m,1H),4.09-3.92(m,1H),2.61-2.53(m,1H),2.48-2.44(m,1H)ppm.

[0772] Step 7: 9-Chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathia Preparation of 7-formic acid 5,5-dioxide

[0773]

[0774] To 9-chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin To a solution of 7-carboxylic acid (25.6 g, 97.46 mmol, 1 eq) in MeOH (500 mL) and water (200 mL) was added potassium persulfate (119.82 g, 194.91 mmol, 2 eq). The mixture was stirred at 40 °C for 48 hours. The mixture was diluted with water (1000 mL) and extracted with EA (1000 mL x 2). The organic layer was washed with a mixed solution of 1 M HCl (250 mL) and saturated Na2SO3 (250 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using petroleum ether / ethyl acetate (gradient: 0-80% ethyl acetate) to give 9-chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperazine as a white solid. -7-carboxylic acid 5,5-dioxide (16 g, 54.30 mmol, 55.71% yield). 1 H NMR (400MHz, DMSO-d6) δ=14.40-13.23(m,1H),8.34(d,J=2.0Hz,1H),8.30(d,J=2.0 Hz,1H),6.44-6.10(m,1H),4.64-4.58(m,1H),4.16-4.04(m,1H),2.93-2.60(m,2H). Chiral SFC: AD-3-MeOH(DEA)-5-40-3ML-35T.lcm, Rt=1.411mins, 1.640mins.

[0775] Step 8: (R)-9-chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathia -7-carboxylic acid 5,5-dioxide (Intermediate 3) & (S)-9-chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin Preparation of 7-formic acid 5,5-dioxide

[0776]

[0777] 9-Chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathia -7-formic acid 5,5-dioxide (1 g, 3.39 mmol) was separated by chiral SFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 um); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 35%-35%, 2.4; 80 min) to give peak 1 and peak 2. The eluent of peak 1 was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (30 mL) and adjusted to pH = 4 with 1 M HCl aqueous solution and extracted with EA (20 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give (R)-9-chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin as a white solid. -7-carboxylic acid 5,5-dioxide (Intermediate 3) (400 mg, 1.35 mmol, 39.64% yield). 1H NMR (400 MHz, DMSO-d6) δ = 8.34 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 6.37-6.16 (m, 1H), 4.64-4.58 (m, 1H), 4.16-4.04 (m, 1H), 2.94-2.72 (m, 2H), 2.64-2.53 (m, 1H). Chiral SFC: AD-3-MeOH(DEA)-5-40-3ML-35 T.1 cm, Rt = 1.401 mins, ee% = 100%. The eluent from peak 2 was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (30 mL) and adjusted to pH = 4 with 1 M aqueous HCl solution, and extracted with EA (20 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give (S)-9-chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin -7-Carboxylic acid 5,5-dioxide. 1 H NMR (400MHz, DMSO-d6) δ = 8.35 (d, J = 2.0Hz, 1H), 8.30 (d, J = 2.0Hz, 1H), 6.40-6.15 ( m,1H),4.64-4.58(m,1H),4.16-4.04(m,1H),2.92-2.73(m,1H),2.66-2.54(m,1H). Chiral SFC: AD-3-MeOH(DEA)-5-40-3ML-35T.lcm, Rt=1.626mins, ee%=99%.

[0778] (R)-9-Chloro-N-((2-(7-((3R,4R)-3,4-difluoropyrrolidin-1-yl)-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1,6-naphthyridin-7-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin-1-yl)methyl)- Preparation of 7-formamide 5,5-dioxide (Compound 258)

[0779]

[0780] Step 1: (R)-9-Chloro-N-((2-(7-((3R,4R)-3,4-difluoropyrrolidin-1-yl)-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1,6-naphthyridin-7-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin Preparation of 7-formamide 5,5-dioxide

[0781]

[0782] To (4R)-9-chloro-4-fluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole To a solution of -7-carboxylic acid (Intermediate 2, above) (24.41 mg, 82.83 umol) in DCM (1 mL) was added EDCI (21.65 mg, 112.95 umol), HOBt (15.26 mg, 112.95 umol) and DIEA (29.20 mg, 225.90 umol, 39.35 uL). Then, [2-[7-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]-2,3-dihydropyrido[ 3,2-b][1,4]oxazin-4-yl]-1,6-naphthyridin-7-yl]methanamine (prepared in a similar manner to that described for Example 1) (30 mg, 75.30 umol). The mixture was stirred at 25°C for 2 hours. The mixture was poured into water (10 mL) and extracted with EA (5 mL*3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex C18150*25mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 33%-63%, 8 mins). The eluate was then concentrated and lyophilized to obtain (R)-9-chloro-N-((2-(7-((3R,4R)-3,4-difluoropyrrolidin-1-yl)-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1,6-naphthyridin-7-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin as a yellow solid. -7-Formamide 5,5-dioxide (4.73 mg, 6.48 umol, 8.61% yield). LCMS (ESI) m / z: [M+H] + =675.0. 1H NMR (400MHz, DMSO-d6) δ=9.62-9.59(m,1H),9.02(s,1H),8.53(d,J=2.0Hz,1H),8.45(d,J =2.0Hz,1H),8.24-8.18(m,2H),7.49-7.44(m,2H),6.73(d,J=2.4Hz,1H),6.37-6.17(m,1H ),5.58-5.42(m,2H),4.71(d,J=5.8Hz,2H),4.65-4.59(m,1H),4.37-4.29(m,4H),4.14-4. 08(m,1H),3.77-3.70(m,1H),3.68-3.57(m,3H),2.94-2.75(m,1H),2.61-2.58(m,1H)ppm. Chiral SFC: AS-3-MeOH+ACN(DEA)-50-3mL-35T.lcm, Rt=0.805min, ee%=100%.

[0783] The following examples in Table 5 were prepared using standard chemical manipulations and procedures similar to those used to prepare compound 258.

[0784] Table 5. Compounds of the present invention

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816] (R)-9-Chloro-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin Preparation of 7-formamide 5,5-dioxide (Compound 148)

[0817]

[0818] Step 1: Preparation of (2S,6R)-4-(6-bromo-2-pyridyl)-2,6-dimethyl-morpholine

[0819]

[0820] To a solution of 2,6-dibromopyridine (50 g, 211.07 mmol) and (2S,6R)-2,6-dimethylmorpholine (36.46 g, 316.60 mmol) in DMSO (500 mL) was added KCO (87.51 g, 633.20 mmol), and the mixture was stirred at 80°C for 16 hours. The reaction mixture was poured into water (2 L), extracted with EA (2 L * 3), and the combined organic layers were washed with brine (2 L mL), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10:1 to 1:1), and the solution was concentrated to give (2S,6R)-4-(6-bromo-2-pyridyl)-2,6-dimethylmorpholine (54 g, 199.15 mmol, 94.35% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ=7.31-7.27(m,1H),6.76(d,J=7.6Hz,1H),6.50(d,J=8.0Hz ,1H),4.03-3.99(m,2H),3.69-3.66(m,2H),2.55-2.49(m,2H),1.28-1.25(m,5H)ppm

[0821] Step 2: Preparation of [6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-pyridyl]-trimethyl-stannane

[0822]

[0823] To a solution of (2S,6R)-4-(6-bromo-2-pyridinyl)-2,6-dimethyl-morpholine (20 g, 73.76 mmol) and trimethyl(trimethylstannyl)stannane (29.00 g, 88.51 mmol) in dioxane (200 mL) was added Pd(PPh3)4 (4.26 g, 3.69 mmol), and the mixture was stirred at 100°C under N2 for 2 hours. The reaction mixture was poured into water (500 mL), the solution was extracted with EA (500 mL*3), and the combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered and concentrated to give [6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-pyridinyl]-trimethyl-stannane (26.1 g, crude) as a brown oil, which was used directly in the next step.

[0824] Step 3: Preparation of tert-butyl N-[[2-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-2-pyridinyl]-1,6-naphthyridin-7-yl]methyl]carbamate

[0825]

[0826] To a mixture of [6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-pyridinyl]-trimethyl-stannane (26 g, 73.23 mmol) and tert-butyl N-[(2-chloro-1,6-naphthyridin-7-yl)methyl]carbamate (described in Example 1) (10.76 g, 36.61 mmol) in dioxane (120 mL) was added Pd(PPh)Cl (2.57 g, 3.66 mmol), and the mixture was stirred under N at 100° C. for 2 hours. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1: 1-0: 1), and the solution was concentrated to give N-[[2-[6-[(2S, 6R)-2,6-dimethylmorpholin-4-yl]-2-pyridinyl]-1,6-naphthyridin-7-yl]methyl]carbamate (15 g, 32.78 mmol, 89.52% yield) as a yellow solid. LCMS (ESI) m / z: [ 79 BrM+H] + =450.2. 1 H NMR (400MHz, DMSO-d6) δ = 9.35 (s, 1H), 8.66-8.59 (m, 2H), 7.93 (d, J = 7.2Hz, 1 H),7.79-7.74(m,2H),7.62(7.63-7.61,1H),7.04(d,J=8.4Hz,1H),4.45(br d,J=6.0Hz,2H),4.32(brd,J=11.2Hz,2H),3.69–3.65(m,2H),2.52(br s,2H),1.44-1.36(m,9H),1.22(d,J=6.0Hz,6H)ppm

[0827] Step 4: Preparation of [2-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-2-pyridinyl]-1,6-naphthyridin-7-yl]methanamine

[0828]

[0829] To HCl / dioxane (200 mL, 4 M) was added a solution of N-[[2-[6-[(2S, 6R)-2,6-dimethylmorpholin-4-yl]-2-pyridinyl]-1,6-naphthyridin-7-yl]methyl]carbamate (15 g, 33.37 mmol) in DCM (200 mL) and the mixture was stirred at 30 ° C for 2 hours. The reaction mixture was concentrated to give a residue. The residue was poured into MTBE (100 mL), the solution was filtered and the filter cake was dried in vacuo to give [2-[6-[(2S, 6R)-2,6-dimethylmorpholin-4-yl]-2-pyridinyl]-1,6-naphthyridin-7-yl]methanamine (15.5 g, crude, HCl salt) as a yellow solid. LCMS (ESI) m / z: [M+H] + =350.1 1 H NMR (400MHz, DMSO-d6) δ=9.56(s,1H),8.82-8.70(m,5H),8.21(s,1H),7.94(d,J=7.6Hz,1H),7.82–7.78(m ,1H),7.08(d,J=8.4Hz,1H),4.42-4.31(m,4H),3.70-3.65(m,2H),2.54-2.52(m,2H),1.22–1.16(m,6H)ppm

[0830] Step 5: (R)-9-Chloro-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin Preparation of 7-formamide 5,5-dioxide

[0831]

[0832] To a solution of Intermediate 3 (30 mg, 101.80 umol), [2-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-pyridinyl]-1,6-naphthyridin-7-yl]methanamine (46.71 mg, 101.80 umol), HOBt (17.88 mg, 132.35 umol), and EDCI (25.37 mg, 132.35 umol) in DCM (1 mL) was added DIEA (65.79 mg, 509.02 umol). The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (10 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by reverse phase HPLC (0.1% FA conditions) and the eluate was lyophilized to give (R)-9-chloro-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin as a yellow solid. -7-Formamide 5,5-dioxide (43.55 mg, 69.30 umol, 68.07% yield). LCMS (ESI) m / z: [M+H]+=626.2. 1 H NMR (400MHz, DMSO-d6) δ = 9.74-9.63 (m, 1H), 9.40 (s, 1H), 8.67-8.63 (m 2H),8.54(d,J=2.0Hz,1H),8.46(d,J=2.0Hz,1H),8.14(s,1H),7.92(d,J=7.6Hz,1H),7.8 5(s,1H),7.78-7.74(m,1H),7.04(d,J=8.6Hz,1H),6.36-6.17(m,1H),4.81(d,J=5.6Hz,2 H),4.69-4.57(m,1H),4.32(d,J=11.6Hz,2H),4.14-4.08(t,J=11.6Hz,1H),3.71-3.63(m ,2H),2.94-2.72(m,1H),2.64-2.56(m,1H),2.53(d,J=2.4Hz,2H),1.22(d,J=6.0Hz,6H). Chiral SFC: IG-3-MeOH+ACN(DEA)-60-3ML-5MIN-35T.lcm, Rt=1.655min, ee%=100%

[0833] The following examples in Table 6 were prepared using standard chemical manipulations and procedures similar to those used to prepare Example 8.

[0834] Table 6. Compounds of the present invention

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851] Intermediate 5 (2S,4S)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin Preparation of 7-formamide 5,5-dioxide

[0852]

[0853] Step 1: Preparation of 3-(chlorosulfonyl)-5-fluoro-4-hydroxybenzoic acid

[0854]

[0855] To a solution of HSO3Cl (33.25 g, 285.35 mmol, 19 mL) was added 3-fluoro-4-hydroxy-benzoic acid (4 g, 25.62 mmol) in 10 portions at 0°C. The mixture was stirred at 30°C for 2 hours and then at 80°C for 2 hours. The reaction mixture was poured into ice water (100 mL). The solid precipitated, was collected by filtration and dried under reduced pressure to give 3-(chlorosulfonyl)-5-fluoro-4-hydroxybenzoic acid (6.3 g, crude) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.89 (s, 1H), 7.64-7.61 (m, 1H) ppm.

[0856] Step 2: Preparation of 3-fluoro-4-hydroxy-5-mercaptobenzoic acid

[0857]

[0858] To a solution of 3-(chlorosulfonyl)-5-fluoro-4-hydroxybenzoic acid (4.3 g, 16.89 mmol) in toluene (80 mL) was added PPh (15.50 g, 59.11 mmol). The mixture was stirred at 90°C for 16 hours. The reaction mixture was poured into saturated NaHCO (100 mL) and extracted with MTBE (100 mL*3). The MTBE layer was discarded. The aqueous layer was adjusted to pH = 3 with 12N aqueous HCl and extracted with EA (100 mL*3). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give 3-fluoro-4-hydroxy-5-mercaptobenzoic acid (3 g, crude) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ = 7.71-7.69 (m, 1H), 7.48-7.45 (m, 1H) ppm.

[0859] Step 3: Preparation of methyl 3-fluoro-4-hydroxy-5-mercaptobenzoate

[0860]

[0861] To a solution of 3-(chlorosulfonyl)-5-fluoro-4-hydroxybenzoic acid (3 g, 15.94 mmol) in MeOH (30 mL) was added H₂SO₄ (5.52 g, 56.28 mmol, 3 mL). The mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the MeOH and diluted with H₂O (100 mL). The aqueous layer was adjusted to pH 3 with saturated NaHCO₃ and extracted with EA (500 mL*2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by normal phase flash chromatography (column SiO₂, 20 g, PE / EA = 1 / 0 to 9 / 1, Rf = 0.5). The eluate was concentrated to afford 3-fluoro-4-hydroxy-5-mercaptobenzoate (2.4 g, 11.87 mmol, 74.45% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.86 (s, 1H), 7.77 (s, 1H), 7.63 (br d, J = 10.8Hz, 1H), 7.46-7.43 (m, 1H), 3.80 (s, 3H), 3.78 (s, 2H) ppm.

[0862] Step 4: 9-Fluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathia Preparation of methyl-7-formate

[0863]

[0864] To a solution of methyl 3-fluoro-4-hydroxy-5-mercaptobenzoate (1.2 g, 5.93 mmol) and 1,3-dibromobutane (1.28 g, 5.93 mmol, 719.87 uL) in DMF (50 mL) was added Cs2CO3 (9.67 g, 29.67 mmol). The mixture was stirred at 25 °C for 12 hours. The mixture was diluted with H2O (200 mL) and extracted with MTBE (200 mL*2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by normal phase flash chromatography (column SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1, Rf = 0.4). The eluent was concentrated to give 9-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin as a colorless oil. -7-Methyl formate (1.5 g, 5.54 mmol, 93.43% yield). LCMS (ESI) m / z: [M+H] + =256.8. 1H NMR(400MHz, DMSO-d6)δ=7.69-7.66(m,1H),7.60-7.57(m,1H),4.40-4.30(m,1H),3.83(s,3H),3.3 1-3.15(m,1H),2.91-2.86(m,1H),2.27-2.20(m,1H),2.09-2.00(m,1H),1.38(d,J=6.4Hz,3H)ppm.

[0865] Step 5: 4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathia Preparation of methyl-7-formate

[0866]

[0867] 9-Fluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin was added at 0 °C. To a solution of methyl-7-carboxylate (1.3 g, 5.07 mmol) in ACN (13 mL) was added Select F (2.70 g, 7.61 mmol) and DAST (163.52 mg, 1.01 mmol, 134.03 uL). The mixture was stirred at 25° C. for 1 hour. DIEA (983.34 mg, 7.61 mmol, 1.33 mL) was then added at 0° C. The mixture was stirred at 25° C. for 1 hour. The mixture was added to aqueous NaHCO 3 solution (100 mL) at 0° C. and extracted with DCM (40 mL*3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford 4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin which was obtained as a yellow oil. -7-Methyl formate (1.3 g, crude). LCMS (ESI) m / z: [M+H] + =274.9.

[0868] Step 6: (trans)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathia -7-Methyl carboxylate 5,5-dioxide and (cis)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin Preparation of methyl 7-formate 5,5-dioxide

[0869]

[0870] 4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin was added at 0 °C. To a solution of methyl 7-formate (1.3 g, 4.74 mmol) in DCM (33 mL) was added m-CPBA (3.37 g, 16.59 mmol, 85% purity). The mixture was stirred at 25°C for 2 hours. The mixture was poured into water (50 mL) and extracted with EA (50 mL*3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by normal phase flash chromatography (column SiO2, PE / EA = 1 / 0 to 0 / 1). The eluate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (0.1% FA conditions). The eluate was concentrated in vacuo to remove MeCN and extracted with EA (50 mL*3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The product was purified by normal phase flash chromatography (column SiO2, PE / EA = 1 / 0 to 0 / 1, Rf = 0.3, 0.2). The eluent was concentrated in vacuo to give (trans)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiapine as a yellow oil. -7-formate 5,5-dioxide (390 mg, 1.27 mmol, 26.87% yield). LCMS (ESI) m / z: [M+H] + =306.9. 1 H NMR (400 MHz, DMSO-d6) δ = 8.24-8.16 (m, 2H), 6.35-6.19 (m, 1H), 4.39-4.31 (m, 1H), 3.91 (s, 3H), 2.80-2.60 (m, 2H), 1.50 (d, J = 6.4 Hz, 3H) ppm and (cis)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin as a colorless oil. -7-formate 5,5-dioxide (60 mg, 195.90 umol, 4.13% yield). LCMS (ESI) m / z: [M+H] + =306.8. 1 H NMR (400MHz, DMSO-d6)δ=8.25-8.18(m,2H),6.21-6.05(m,1H),4.71-4.61(m,1H) ), 3.91 (s, 3H), 2.78-2.69 (m, 1H), 2.63-2.54 (m, 1H), 1.47 (d, J = 6.8Hz, 3H) ppm.

[0871] Step 7: (cis)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathia Preparation of 7-formic acid 5,5-dioxide

[0872]

[0873] To (cis)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin To a mixture of 5,5-dioxide of benzoylmethane (60.00 mg, 195.90 umol) in THF (0.8 mL) and MeOH (0.8 mL) was added LiOH (14.08 mg, 587.69 umol) and H2O (0.4 mL). The mixture was stirred at 25°C for 1 hour. The reaction mixture was adjusted to pH 3-4 by aqueous HCl solution (1 N) and extracted with EA (5 mL*3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum to give (cis)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin as a yellow oil. -7-carboxylic acid 5,5-dioxide (60 mg, crude). 1 H NMR (400MHz, DMSO-d6) δ = 8.29-8.12 (m, 2H), 6.24-6.04 (m, 1H), 4.76-4.57 (m, 1H), 3.92 (s, 3H), 2.80-2.55 (m, 2H), 1.48 (d, J = 6.4Hz, 3H) ppm.

[0874] Step 8: (2R,4R)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathia -7-carboxylic acid 5,5-dioxide and (2S,4S)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin Preparation of 7-formic acid 5,5-dioxide

[0875]

[0876] (cis)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathia -7-carboxylic acid (60 mg, crude) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [MeOH (0.1% IPAm)]; B%: 20%-20%, A5.4; 54 min). The eluate was concentrated under vacuum to give impure (2S,4S)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin -7-carboxylic acid 5,5-dioxide and pure (2R,4R)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin as yellow oil -7-carboxylic acid 5,5-dioxide (Intermediate 5) (23 mg, 77.30 umol, 37.65% yield). 1 H NMR (400MHz, DMSO-d6) δ = 8.29-8.12 (m, 2H), 6.24-6.04 (m, 1H), 4.76-4.57 (m, 1H), 3.92 (s, 3H), 2.80-2.55 (m, 2H), 1.48 (d, J = 6.4Hz, 3H) ppm. Chiral SFC: G-3-MeOH(DEA)-5-40-3mL-35T.lcm, Rt=1.313mins, ee%=100%.

[0877] (2R,4R)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathia Preparation of 7-formamide 5,5-dioxide

[0878]

[0879] Step 1: Preparation of (2S,6R)-2,6-dimethyl-4-(6-(trimethylstannyl)pyridin-2-yl)morpholine

[0880]

[0881] To a solution of (2R,6S)-4-(6-bromo-2-pyridyl)-2,6-dimethyl-morpholine (prepared according to the method in Example 6) (600 mg, 2.21 mmol) and trimethyl(trimethylstannyl)stannane (869.96 mg, 2.66 mmol, 550.60 uL) in dioxane (7 mL) was added Pd(PPh3)4 (127.85 mg, 110.64 umol). The mixture was degassed and purged with N2 and stirred at 100°C for 2 hours. The mixture was poured into water (100 mL) and extracted with EA (30 mL*3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give (2S,6R)-2,6-dimethyl-4-(6-(trimethylstannyl)pyridin-2-yl)morpholine (780 mg, crude) as a yellow oil, which was used directly in the next step. LCMS (ESI) m / z: [M+H] + =356.7.

[0882] Step 2: Preparation of tert-butyl ((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)carbamate

[0883]

[0884] To a solution of (2S,6R)-2,6-dimethyl-4-(6-(trimethylstannyl)pyridin-2-yl)morpholine (779.63 mg, 2.20 mmol) and tert-butyl N-[(2-chloro-1,6-naphthyridin-7-yl)methyl]carbamate (430 mg, 1.46 mmol) in dioxane (5 mL) was added Pd(PPh)Cl (102.75 mg, 146.38 umol). The mixture was degassed and purged with N and stirred at 100°C for 2 hours. The mixture was poured into water (100 mL) and extracted with EA (30 mL*3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under vacuum. The residue was purified by normal phase flash chromatography (column: SiO, PE:EA = 1:0 to 0:1, RF = 0.2). The eluate was concentrated under vacuum to give ((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)carbamate (600 mg, 1.27 mmol, 86.62% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + =450.0. 1 H NMR (400MHz, DMSO-d6) δ = 9.35 (s, 1H), 8.71-8.55 (m, 2H), 7.93 (d, J = 7.4Hz, 1H), 7.82-7.73 (m, 2H), 7.60-7.58 (m, 1H), 7.03 (d, J = 8.4Hz, 1H), 4.45 (br d,J=5.8Hz,2H),4.31(br d,J=12.6Hz,2H),3.76-3.57(m,2H),1.44(s,9H),1.22(d,J=6.2Hz,6H)ppm.

[0885] Step 3: Preparation of (2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methanamine

[0886]

[0887] To a solution of ((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)carbamate (200 mg, 444.90 umol) in DCM (2 mL) was added TFA (0.6 mL). The mixture was stirred at 25 ° C for 6 hours. The mixture was poured into saturated NaHCO (20 mL) and extracted with DCM (10 ml * 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give (2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methanamine (160 mg, crude) as a yellow oil. LCMS (ESI) m / z: [M + H] + =350.0

[0888] Step 4: (2S,4S)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathia Preparation of 7-formamide 5,5-dioxide (Compound 34)

[0889]

[0890] To (2R,4R)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin To a solution of 5,5-dioxide of 7-carboxylic acid (Intermediate 5) (18.40 mg, 62.96 umol) in DCM (1 mL) were added EDCI (16.46 mg, 85.86 umol), HOBT (11.60 mg, 85.86 umol), and DIEA (36.99 mg, 286.20 umol, 49.85 uL). (2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methanamine (20 mg, 57.24 umol) was then added. The mixture was stirred at 25°C for 2 hours. The mixture was poured into water (10 mL) and extracted with EA (5 mL*3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 10 min). The eluate was then concentrated and lyophilized to give (2S,4S)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin as a yellow solid. -7-Formamide 5,5-dioxide (7.23 mg, 11.35 umol, 19.83% yield). LCMS (ESI) m / z: [M+H] + =623.9. 1 H NMR(400MHz, DMSO-d6)δ=9.68-9.66(m,1H),9.40(s,1H),8.71-8.58(m,2H),8.40-8.30(m,2H),7.91 (d,J=7.6Hz,1H),7.83(s,1H),7.78-7.75(m,1H),7.04(d,J=8.4Hz,1H),6.24-6.01(m,1H),4.82(br d,J=6.0Hz,2H),4.67-4.56(m,1H),4.32(br d,J=12.0Hz,2H),3.72-3.64(m,2H),2.80-2.56(m,4H),1.49(br d,J=6.2Hz,3H),1.22(d,J=6.2Hz,6H)ppm.

[0891] Chiral SFC: (S,S)Whelk-O1-IPA+ACN(DEA)-40-3mL-35T.1cm, Rt=2.237mins, ee%=97.69%.

[0892] The following examples in Table 7 were prepared using standard chemical manipulations and procedures similar to those used to prepare compound 34.

[0893] Table 7. Compounds of the present invention

[0894]

[0895]

[0896] (S)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-2-fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Preparation of 8-formamide 1,1-dioxide (Compound 1)

[0897]

[0898] Step 1: Preparation of methyl 4-bromo-2-mercaptobenzoate

[0899]

[0900] To a solution of methyl 4-bromo-2-fluoro-benzoate (5 g, 21.46 mmol) in DMF (50 mL) was added Na2S (1.95 g, 22.53 mmol, 90% purity). The mixture was stirred at 25 ° C for 12 hours. The mixture of methyl 4-bromo-2-mercaptobenzoate (5.3 g, crude) in DMF (50 mL) as a brown liquid was used directly in the next step without further purification. LCMS (ESI) m / z: [Br 81 M+H] + =204.0.

[0901] Step 2: 8-Bromo-3,4-dihydrobenzo[f][1,4]thiazepine Preparation of -5(2H)-ketone

[0902]

[0903] To a solution of methyl 4-bromo-2-mercaptobenzoate (5.3 g, 21.45 mmol) in DMF (50 mL) and THF (50 mL) was added 2-chloroethylamine (4.98 g, 42.90 mmol), and then NaH (2.57 g, 64.34 mmol, 60% purity) was added to the mixture at 0°C under an N2 atmosphere. The mixture was stirred at 25°C for 12 hours. The mixture was diluted with NH4Cl solution (500 mL) and extracted with EA (500 mL*2), and the combined organic layers were washed with brine (300 mL*2). The organic layer was then dried over anhydrous Na2SO4 and concentrated to provide a residue. The residue was diluted with MTBE and filtered. The filter cake was dried in vacuo to give 8-bromo-3,4-dihydrobenzo[f][1,4]thiazepine as an off-white solid. -5(2H)-one (1 g, 3.87 mmol, 18.06% yield). LCMS (ESI) m / z: [Br 81 M+H] + =260.2

[0904] Step 3: 8-Bromo-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Preparation

[0905]

[0906] To 8-bromo-3,4-dihydrobenzo[f][1,4]thiazepine at 25 °C To a solution of 5-(2H)-one (1 g, 3.87 mmol) in THF (10 mL) was added BH3-Me2S (10 M, 774.79 uL). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was diluted with MeOH (2 mL) and stirred at 60 °C for 12 hours. The mixture was concentrated to give 8-bromo-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine as a yellow oil. (945 mg, crude). LCMS (ESI) m / z: [Br 81 M+H] + =246.0.

[0907] Step 4: 8-Bromo-2,3-dihydrobenzo[f][1,4]thiazepine Preparation of tert-butyl 4(5H)-formate

[0908]

[0909] To 8-bromo-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine To a solution of (945 mg, 3.87 mmol) in THF (10 mL) were added (Boc)2O (1.69 g, 7.74 mmol), DMAP (47.29 mg, 387.06 umol), and TEA (1.17 g, 11.61 mmol). The mixture was stirred at 25°C for 4 hours. The mixture was diluted with water (20 mL) and extracted with EA (20 mL*2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to provide a residue. The residue was purified by flash silica gel chromatography ( 12g Silica Flash Column, eluent 0-100% ethyl acetate / petroleum ether). The eluent was concentrated to give 8-bromo-2,3-dihydrobenzo[f][1,4]thiazepine as a white solid. -tert-Butyl 4(5H)-formate (600 mg, 1.74 mmol, 45.03% yield). LCMS (ESI) m / z: [Br 81 M+H] + =290.0. 1 HNMR(400MHz,DMSO-d6)δ=7.70-7.64(m,1H),7.52-7.43(m,1H),7.33-7.25 (m,1H),4.49-4.39(m,2H),3.79(s,2H),2.89-2.76(m,2H),1.33(s,9H)ppm.

[0910] Step 5: 2,3-Dihydrobenzo[f][1,4]thiazepine Preparation of 8-methyl 4-(tert-butyl)-4,8(5H)-dicarboxylate

[0911]

[0912] To 8-bromo-2,3-dihydrobenzo[f][1,4]thiazepine To a solution of tert-butyl-4(5H)-formate (600 mg, 1.74 mmol) in DMSO (6 mL) and MeOH (279.22 mg, 8.71 mmol) were added dicyclohexyl(3-dicyclohexylphosphoniumpropyl)phosphonium; bistetrafluoroborate (106.71 mg, 174.28 umol), K2CO3 (361.32 mg, 2.61 mmol) and Pd(OAc)2 (39.13 mg, 174.28 umol). The mixture was then degassed and purged with CO3 three times and stirred at 100°C under a CO (15 psi) atmosphere for 2 hours. The mixture was filtered and the filter cake was washed with EA (100 mL) and water (100 mL). The mixture was then diluted with water (100 mL) and extracted with EA (100 mL*2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to provide the product. The residue was purified by flash silica gel chromatography ( 12g SilicaFlash Column, eluent 0-100% ethyl acetate / petroleum ether). The eluent was concentrated to give 2,3-dihydrobenzo[f][1,4]thiazepine as a white solid. -4,8(5H)-dicarboxylic acid 4-(tert-butyl) 8-methyl ester (450 mg, 1.39 mmol, 79.84% yield). LCMS (ESI) m / z: [M+H] + =224.1 1 HNMR (400MHz, DMSO-d6) δ = 8.04-7.98 (m, 1H), 7.88-7.80 (m, 1H), 7.54-7.46 (m, 1H) ),4.58-4.49(m,2H),3.88-3.77(m,5H),2.93-2.82(m,2H),1.34-1.29(m,9H)ppm.

[0913] Step 6: (S)-2-Fluoro-2,3-dihydrobenzo[f][1,4]thiazepine Preparation of 8-methyl 4-(tert-butyl)-4,8(5H)-dicarboxylate

[0914]

[0915] To 2,3-dihydrobenzo[f][1,4]thiazepine To a solution of 4-(tert-butyl)-8-methyl-4,8(5H)-dicarboxylate (450 mg, 1.39 mmol) in ACN (6 mL) was added SelectF (985.86 mg, 2.78 mmol), followed by the addition of DAST (44.86 mg, 278.29 umol) in an ice bath (0°C). The solution was stirred at 25°C for 0.5 hours. DIEA (269.75 mg, 2.09 mmol) was then added in an ice bath (0°C), and the solution was stirred at 25°C for 12 hours. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL*2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford (S)-2-fluoro-2,3-dihydrobenzo[f][1,4]thiazepine as a black solid. -4-(tert-Butyl)-4,8(5H)-dicarboxylic acid 8-methyl ester (475 mg, crude), which was used without purification.

[0916] Step 7: (S)-2-Fluoro-2,3-dihydrobenzo[f][1,4]thiazepine Preparation of 4-(tert-butyl)-4,8(5H)-dicarboxylic acid 8-methyl ester 1,1-dioxide

[0917]

[0918] To (S)-2-fluoro-2,3-dihydrobenzo[f][1,4]thiazepine at 0°C To a solution of 4-(tert-butyl)-4,8(5H)-dicarboxylic acid 8-methyl ester (475 mg, 1.39 mmol) in DCM (6 mL) was added m-CPBA (1.41 g, 6.96 mmol, 85% purity). The mixture was stirred at 25°C for 12 hours. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL*2). The combined organic layers were then washed with saturated Na2SO3 (30 mL*2) and saturated NaHCO3 solution (30 mL*2), then dried over Na2SO4, filtered and concentrated to obtain a residue. The residue was purified by flash silica gel chromatography ( 20g Silica Flash Column, eluent 0-100% ethyl acetate / petroleum ether). The eluent was concentrated to give (S)-2-fluoro-2,3-dihydrobenzo[f][1,4]thiazepine as a white solid. -4,8(5H)-dicarboxylic acid 4-(tert-butyl) 8-methyl ester 1,1-dioxide (180 mg, 448.32 umol, 32.22% yield). LCMS (ESI) m / z: [M+H] + =318.0.1 HNMR (400MHz, DMSO-d6) δ = 8.48 (d, J = 2.8Hz, 1H), 8.38-8.28 (m, 1H), 7.85-7.73 (m, 1H), 6.28- 6.10(m,1H),4.91-4.79(m,1H),4.69-4.49(m,2H),3.99-3.81(m,4H),1.35-1.26(m,9H)ppm.

[0919] Step 8: 2-Fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Preparation of 8-methyl formate 1,1-dioxide

[0920]

[0921] To (S)-2-fluoro-2,3-dihydrobenzo[f][1,4]thiazepine To a solution of 4-(tert-butyl)-4,8(5H)-dicarboxylate 8-methyl ester 1,1-dioxide (180 mg, 482.06 umol) in DCM (2 mL) was added TFA (1.10 g, 9.64 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was diluted with ice water (10 mL) and the pH was adjusted to 8 with saturated NaHCO3 solution. The mixture was then extracted with DCM (10 mL*2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give 2-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine as a yellow solid. -8-Methyl formate 1,1-dioxide (130 mg, 475.70 umol, 98.68% yield). LCMS (ESI) m / z: [M+H] + =274.0

[0922] Step 9: 2-Fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Preparation of 8-methyl formate 1,1-dioxide

[0923]

[0924] To 2-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine To a solution of methyl 1,1-dioxide (130 mg, 475.70 umol) in MeOH (2 mL) were added HCHO (115.83 mg, 1.43 mmol, 37% purity) and AcOH (2.86 mg, 47.57 umol), and then NaBH3CN (89.68 mg, 1.43 mmol) was added at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to provide a residue. The residue was purified by flash silica gel chromatography ( 20g Silica Flash Column, eluent 0-100% ethyl acetate / petroleum ether). The eluent was concentrated to give 2-fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine as a brown oil. -8-Methyl formate 1,1-dioxide (120 mg, 417.67 umol, 87.80% yield). LCMS (ESI) m / z: [M+H] + =288.1. 1 HNMR (400MHz, DMSO-d6) δ = 8.48 (d, J = 1.6Hz, 1H), 8.29-8.26 (m, 1H), 7.77 (d, J = 7.6Hz, 1H), 6.12-6 .08(m,1H),4.50-4.44(m,1H),4.10-4.06(m,1H),3.92(s,3H),3.61-3.53(m,2H),2.52(s,3H)ppm.

[0925] Step 10: (R)-2-Fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -8-Methyl carboxylate 1,1-dioxide and (S)-2-fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Preparation of 8-methyl formate 1,1-dioxide

[0926]

[0927] 2-Fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -8-Methyl formate 1,1-dioxide (120 mg, 417.67 umol) was separated by SFC. The solid was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 25%-25%, 6.8 min). The eluent of peak 1 was concentrated to provide (R)-2-fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine as a white solid. -8-Methyl formate 1,1-dioxide (30 mg, 104.42 umol, 25.00% yield). Chiral SFC: AD-3-MeOH(DEA)-5-40-3 mL-35 T.1 cm; Rt = 1.127 mins, ee% = 100%.

[0928] The eluate of Peak 2 was concentrated to provide (S)-2-fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine as a white solid. -8-formate 1,1-dioxide (35 mg, 118.17 umol, 28.29% yield). Chiral SFC: AD-3-MeOH(DEA)-5-40-3 mL-35 T.1 cm; Rt = 1.957 mins, ee% = 99.49%.

[0929] Step 11: (R)-2-Fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Preparation of 8-formic acid 1,1-dioxide

[0930]

[0931] To (R)-2-fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine To a solution of methyl-8-formate 1,1-dioxide (20 mg, 69.61 umol) in THF (0.2 mL) and water (0.1 mL) was added LiOH·H2O (8.76 mg, 208.84 umol). The mixture was stirred at 25°C for 2 hours. The reaction mixture was adjusted to pH = 5 by 1N HCl, after which the mixture was adjusted to pH = 9 by solid NaHCO3. The mixture was then concentrated to give (R)-2-fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine as a yellow solid. -8-Formic acid 1,1-dioxide (19 mg, 69.53 umol, 99.88% yield). LCMS (ESI) m / z: [M+H] +=274.1.

[0932] Step 12: (R)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-2-fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Preparation of 8-formamide 1,1-dioxide (Compound 1)

[0933]

[0934] To (R)-2-fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine To a solution of 1,1-dioxide of 8-carboxylic acid (19 mg, 69.53 umol) and [2-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-pyridinyl]-1,6-naphthyridin-7-yl]methanamine (26.83 mg, 69.53 umol) (prepared according to the method in Example 9) in DMF (0.5 mL) was added HOBt (14.09 mg, 104.29 umol), EDCI (19.99 mg, 104.29 umol), and DIPEA (26.96 mg, 208.58 umol). The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL*2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to provide a residue. The residue was purified by reverse phase HPLC (0.1% NH3·H2O). The eluate was concentrated to remove ACN and lyophilized to give (R)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-2-fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine as a yellow solid. -8-Formamide 1,1-dioxide (2.65 mg, 4.38 umol, 6.30% yield). LCMS (ESI) m / z: [M+H] + =605.3. 1H NMR (400MHz, DMSO-d6) δ = 9.70-9.61 (m, 1H), 9.40 (s, 1H), 8.70-8.60 (m, 2H), 8.58 (s, 1H), 8.32 (d, J=7.6Hz,1H),7.92(d,J=7.6Hz,1H),7.84(s,1H),7.78-7.72(m,2H),7.03(d,J=8.0Hz,1H),6.11-5 .94(m,1H),4.82(d,J=5.6Hz,2H),4.47(d,J=14.8Hz,1H),4.31(d,J=12.8Hz,2H),4.14-4.03(m,1H ),3.75-3.62(m,3H),3.57-3.48(m,1H),2.63-2.56(m,2H),2.30(s,3H),1.21(d,J=6.0Hz,6H)ppm. Chiral SFC: IA-3-ETOH(DEA)-40_1ML_T35.M; Rt=4.133mins, ee%=100%.

[0935] The following examples in Table 8 were prepared using standard chemical manipulations and procedures similar to those used to prepare Compound 1.

[0936] Table 8. Compounds of the present invention

[0937]

[0938]

[0939] (R)-9-Bromo-4-fluoro-N-((2-(7-((S)-2-(fluoromethyl)azetidin-1-yl)-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1,6-naphthyridin-7-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin Preparation of 7-formamide 5,5-dioxide (Compound 210)

[0940]

[0941] Step 1: Preparation of N'-(3-(benzyloxy)cyclobutylidene)-4-methylbenzenesulfonylhydrazide

[0942]

[0943] To a solution of 3-benzyloxycyclobutanone (10 g, 56.75 mmol) in MeOH (100 mL) was added 4-methylbenzenesulfonylhydrazide (10.57 g, 56.75 mmol). The mixture was stirred at 25°C for 5 minutes. The reaction mixture was filtered, and the filter cake was washed with MeOH (20 mL) and dried under reduced pressure to afford N'-(3-(benzyloxy)cyclobutylidene)-4-methylbenzenesulfonylhydrazide (13.88 g, 40.30 mmol, 71.01% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 10.34 (s, 1H), 7.69 (d, J = 8.4Hz, 2H), 7.39 (d, J = 8.0Hz, 3H), 7.34- 7.30(m,5H),4.39(d,J=2.8Hz,2H),4.16-4.13(m,1H),3.12-2.98(m,3H),2.38(s,4H)ppm.

[0944] Step 2: Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinecarbonitrile

[0945]

[0946] To a solution of 4-bromopyridine-2-carbonitrile (20 g, 109.29 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (83.26 g, 327.86 mmol) in dioxane (200 mL) was added KOAc (32.18 g, 327.86 mmol) and Pd(dppf)Cl2 (8.00 g, 10.93 mmol). The mixture was stirred at 130°C under N2 for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 1:0-3:1). The eluate was concentrated to provide 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (20 g, 86.93 mmol, 79.54% yield) as a white solid. LCMS (ESI) m / z: [M+H] + =231.4. 1 H NMR (400MHz, CDCl3) δ = 8.75-8.74 (m, 1H), 8.04 (s, 1H), 7.84-7.83 (m, 1H), 1.37 (s, 12H) ppm.

[0947] Step 3: Preparation of 4-(3-(benzyloxy)cyclobutyl)pyridinecarbonitrile

[0948]

[0949] To a solution of N'-(3-(benzyloxy)cyclobutylidene)-4-methylbenzenesulfonylhydrazide (12.88 g, 37.40 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (12.91 g, 56.09 mmol) in dioxane (260 mL) was added Cs2CO3 (36.55 g, 112.19 mmol). The mixture was stirred at 130 ° C for 48 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:EA=1:0-3:1). The eluent was concentrated to provide 4-(3-(benzyloxy)cyclobutyl)picolinonitrile (1.53 g, 5.79 mmol, 15.48% yield) as a red oil, which was used directly in the next step. LCMS (ESI) m / z: [M+H] + =265.2;

[0950] Step 4: Preparation of 4-(3-hydroxycyclobutyl)pyridinecarbonitrile

[0951]

[0952] To a solution of 4-(3-(benzyloxy)cyclobutyl)picolinonitrile (1.53 g, 5.79 mmol) in DCM (45 mL) and H2O (4.5 mL) was added DDQ (7.23 g, 31.84 mmol). The mixture was stirred at 30 ° C for 12 hours. The mixture was diluted with aqueous Na2SO3 (100 mL) and extracted with DCM (100 mL*2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA=1:0-0:1). The eluent was concentrated to provide 4-(3-hydroxycyclobutyl)picolinonitrile (670 mg, 3.85 mmol, 66.45% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + =175.1.

[0953] Step 5: Preparation of 4-(3-oxocyclobutyl)pyridinecarbonitrile

[0954]

[0955] To a solution of 4-(3-hydroxycyclobutyl)picolinonitrile (670 mg, 3.85 mmol) in DCM (7 mL) was added Dess-Martin periodinane (4.89 g, 11.54 mmol) at 0 ° C. The mixture was stirred at 30 ° C for 4 hours. The mixture was added to a NaHCO3 aqueous solution to adjust the pH to 9 and extracted with DCM (50 mL*2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, PE:EA=10:1). The eluent was concentrated to provide 4-(3-oxocyclobutyl)picolinonitrile (576 mg, 3.35 mmol, 86.98% yield) as a white solid. LCMS (ESI) m / z: [M+H] + =173.2. 1 H NMR (400MHz, CDCl3) δ = 8.71 (d, J = 4.8Hz, 1H), 7.65 (s, 1H), 7.47-7.46 (m, 1H), 3.74-3.66 (m, 1H), 3.62-3.59 (m, 2H), 3.32-3.25 (m, 2H) ppm.

[0956] Step 6: Preparation of 4-(3-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-3-hydroxycyclobutyl)picolinonitrile

[0957]

[0958] To a solution of (2S,6R)-4-(6-bromo-2-pyridyl)-2,6-dimethylmorpholine (629.92 mg, 2.32 mmol) (EW9303-1833-P1) in THF (4 mL) was added n-BuLi (2.5 M, 929.24 uL) at -78°C under N2, and the mixture was stirred at -78°C for 0.5 hours. This mixture was then added to a solution of 4-(3-oxocyclobutyl)picolinonitrile (200 mg, 1.16 mmol) in THF (4 mL) at -78°C under N2, and the mixture was stirred at -78°C for 2 hours. The mixture was poured into aqueous NH4Cl (50 mL) and extracted with EA (50 mL*2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO 2 , PE:EA=1:0-1:1). The eluent was concentrated to provide 4-(3-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-3-hydroxycyclobutyl)picolinonitrile (455 mg, crude) as a yellow solid. LCMS (ESI) m / z: [M+H] +=365.1. 1 H NMR (400MHz, DMSO-d6) δ=8.67(d,J=4.4Hz,1H),8.08(s,1H),7.71-7.69(m,1H),7.57-7.53(m,1H),6.92(d,J=7.2Hz,1H),6.73(d,J=8.8 Hz,1H),5.82(s,1H),4.20-4.17(m,2H),3.66-3.63(m,2H),3.50(m,1H),2.97-2.92(m,2H),2.42-2.37(m,4H),1.18(d,J=6.0Hz,6H)ppm.

[0959] Step 7: Preparation of O-(3-(2-cyanopyridin-4-yl)-1-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)S-methyl dithiocarbonate

[0960]

[0961] To a solution of NaH (111.12 mg, 2.78 mmol, 60% purity) in THF (4 mL) was added dropwise a solution of 4-(3-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-3-hydroxycyclobutyl)picolinonitrile (405 mg, 1.11 mmol) in THF (4 mL) at 0°C under N2. The mixture was stirred at 0°C for 0.5 hours under N2. CS2 (359.27 uL, 5.95 mmol) was then added dropwise at 0°C, and the mixture was stirred at 0°C for 1 hour. MeI (179.88 uL, 2.89 mmol) was then added dropwise at 0°C, and the mixture was stirred at 0°C for 1 hour. The mixture was poured into aqueous NH4Cl (50 mL) and extracted with EA (50 mL*2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 1:0-3:1). The eluent was concentrated to provide O-(3-(2-cyanopyridin-4-yl)-1-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)S-methyl dithiocarbonate (490 mg, 1.08 mmol, 96.99% yield) as a yellow solid.

[0962] LCMS (ESI) m / z: [M+H] + =455.0. 1H NMR (400MHz, CDCl3) δ = 8.66 (d, J = 5.2Hz, 1H), 7.61 (s, 1H), 7.51-7.47 (m, 1H), 7.43-7.42 (m, 1H), 6.65 (d, J = 7.6Hz, 1H), 6.55 (d, J = 8.4Hz, 1 H),4.12-4.08(m,2H),3.77-3.76(m,2H),3.69(s,1H),3.43-3.40(m,2H),2.80-2.74(m,2H),2.61-2.55(m,5H),1.30(d,J=6.0Hz,6H)ppm.

[0963] Step 8: Preparation of 4-(3-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)picolinonitrile

[0964]

[0965] To a solution of O-(3-(2-cyanopyridin-4-yl)-1-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)S-methyl dithiocarbonate (300 mg, 659.91 umol) in toluene (7.5 mL) was added BuSnH (663.64 uL, 2.51 mmol), and then AIBN (21.67 mg, 131.98 umol) was added to the mixture. The reaction mixture was stirred at 110°C for 2 hours. The mixture was quenched with saturated KF 50 mL and extracted with EA (50 mL*3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO, PE:EA = 1:0-3:1). The eluate was concentrated to provide 4-(3-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)picolinonitrile (150 mg, 430.49 umol, 65.23% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + =349.2. 1 H NMR(400MHz, CDCl3)δ=8.65-8.61(m,1H),7.65-7.64(m,1H),7.48-7.41(m,2H),6.56-6.47(m,2H), 4.14-4.09(m,2H),3.77-3.74(m,2H),2.78-2.75(m,2H),2.55-2.49(m,4H),1.31-1.28(m,6H)ppm.

[0966] Step 9: Preparation of tert-butyl ((4-(3-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)carbamate

[0967]

[0968] To a solution of 4-(3-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)picolinonitrile (150 mg, 430.49 umol) in MeOH (3 mL) was added Boc2O (197.80 uL, 860.98 umol), TEA (179.76 uL) and Raney nickel (100 mg, 1.17 mmol). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 ° C. under H2 (15 psi) for 2 hours. The mixture was diluted with MeOH (10 mL) and allowed to stand for 10 minutes, then the supernatant was removed and filtered. This post-treatment was repeated 3 times. The filtrate was concentrated to provide a crude product. The crude product was purified by column chromatography (SiO2, PE:EA=1:0-1:1). The eluate was concentrated to give tert-butyl ((4-(3-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)carbamate (140 mg, 309.33 umol, 71.86% yield) as a colorless oil. LCMS (ESI) m / z: [M+H] + =453.3. 1 H NMR (400MHz, CDCl3) δ=8.48-8.44(m,1H),7.44-7.40(m,1H),7.22-7.15(m,2H),6.57-6.45(m,2H),5.59(br d,J=2.4Hz,1H),4.45-4.43(m,2H),4.14-4.10(m,2H),3.77-3.73(m,2H),2.77-2.72(m,2H),2.54-2.46(m,4H),1.31-1.27(m,6H)ppm. Chiral SFC: AD-3_5CM_ETOH(DEA)_5_40_3ML_T35.M, Rt=1.198mins, 1.504mins.

[0969] Step 10: Preparation of tert-butyl ((4-((1R,3r)-3-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)carbamate and tert-butyl ((4-((1S,3s)-3-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)carbamate

[0970]

[0971] 4-(3-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)picolinonitrile (140 mg, 309.33 umol) was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 30%-30%, 4.3 min). The eluent of Peak 1 was concentrated to provide tert-butyl ((4-((1R,3r)-3-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)carbamate and tert-butyl (40 mg, 88.38 umol, 28.57% yield) as a colorless oil. LCMS (ESI) m / z: [M+H] + =453.3. 1 H NMR (400MHz, CDCl3) δ = 8.47 (d, J = 4.8Hz, 1H), 7.47-7.43 (m, 1H), 7.21 (s, 1H), 7.14 (d, J = 5.2Hz, 1H), 6.57-6.48 (m, 2H), 5.58 (br s, 1H), 4.45 (br d,J=5.2Hz,2H),4.16(br d,J=11.6Hz,2H),3.79-3.75(m,3H),2.81-2.77(m,2H),2.56-2.51(m,4H),1.48(s,9H),1.30(d,J=6.4Hz,6H)ppm. Chiral SFC: AD-3_5CM_ETOH(DEA)_5_40_3ML_T35.M; Rt=1.177 mins, ee%=98.82%.

[0972] The eluent of Peak 2 was concentrated to give tert-butyl ((4-((1S,3s)-3-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)carbamate (86 mg, 189.11 umol, 61.13% yield) as a colorless oil. LCMS (ESI) m / z: [M+H] + =453.3. 1H NMR (400MHz, CDCl3) δ = 8.45 (d, J = 4.8Hz, 1H), 7.44-7.40 (m, 1H), 7.17 (d, J = 5.2Hz, 1H), 7.13 (s, 1H), 6.53-6.45 (m, 2H), 5.57 (br s, 1H), 4.43 (br d,J=5.2Hz,2H),4.13-4.10(m,2H),3.75-3.73(m,2H),2.74-2.71(m,2H),2.54-2.46(m,4H),1.47(s,9H),1.28(d,J=6.4Hz,6H)ppm. Chiral SFC: AD-3_5CM_ETOH(DEA)_5_40_3ML_T35.M; Rt=1.505 mins, ee%=100%.

[0973] Step 11: Preparation of 4-((1R,3r)-3-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)pyridine-2-methamine

[0974]

[0975] To the product was added tert-butyl ((4-((1R, 3r)-3-(6-((2S, 6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)carbamate (40 mg, 88.38 umol) in HCl / dioxane (4M, 1 mL). The mixture was stirred at 25 ° C for 1 hour. The mixture was concentrated to provide 4-((1R, 3r)-3-(6-((2S, 6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)carbamate (40 mg, 88.38 umol) in HCl / dioxane (4M, 1 mL). The mixture was stirred at 25 ° C for 1 hour. The mixture was concentrated to provide 4-((1R, 3r)-3-(6-((2S, 6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)pyridine-2-methamine (35 mg, crude, HCl) as a colorless oil. LCMS (ESI) m / z: [M+H] + =353.3.

[0976] Step 12: Compound 210 (R)-9-bromo-4-fluoro-N-((2-(7-((S)-2-(fluoromethyl)azetidin-1-yl)-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1,6-naphthyridin-7-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin Preparation of 7-formamide 5,5-dioxide

[0977]

[0978] To 4-((1R,3r)-3-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)cyclobutyl)pyridin-2-amine (35 mg, 89.99 umol) and (4R)-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ 6 -Benzoxathia To a solution of 7-carboxylic acid (25 mg, 89.85 umol) (Intermediate 2) in DCM (1 mL) was added HOBt (18.21 mg, 134.78 umol), DIEA (78.25 uL, 449.27 umol), and EDCI (25.84 mg, 134.78 umol). The mixture was stirred at 25°C for 3 hours. The mixture was diluted with aqueous NaHCO₃ (5 mL) and extracted with DCM (5 mL*3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase chromatography (0.1% FA conditions). The eluate was concentrated to remove ACN and lyophilized to provide (R)-9-bromo-4-fluoro-N-((2-(7-((S)-2-(fluoromethyl)azetidin-1-yl)-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1,6-naphthyridin-7-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin as a white solid. -7-Formamide 5,5-dioxide (14.02 mg, 21.95 umol, 24.43% yield). LCMS (ESI) m / z: [M+H] + =613.2; 1 H NMR (400MHz, DMSO-d6)δ=9.50-9.47(m,1H),8.46-8.45(m,1H),8.29-8.24(m,2H),7.49-7.45(m,1H),7.30(s ,2H),6.67-6.59(m,2H),6.32-6.21(m,1H),4.61-4.58(m,3H),4.20-4.16(m,3H),3.64-3.60(m,1H),2.61(br s, 4H), 2.46-2.34 (m, 3H), 1.14 (d, J = 6.4Hz, 6H) ppm. Chiral SFC: IC-3-MeOH+ACN(DEA)-40-3ML-35T.1cm; Rt=1.113mins, ee%=100%.

[0979] (R)-9-Chloro-N-((2-(6-(difluoromethyl)-2-ethoxypyridin-3-yl)-1,6-naphthyridin-7-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin Preparation of 7-formamide 5,5-dioxide (Compound 331)

[0980]

[0981] Step 1: Preparation of methyl 5-bromo-6-ethoxypicolinate

[0982]

[0983] To a solution of 5-bromo-6-hydroxy-pyridine-2-carboxylic acid methyl ester (100 g, 430.98 mmol) in DMF (1000 mL) was added KCO (119.13 g, 861.95 mmol) and iodoethane (73.94 g, 474.07 mmol, 37.92 mL). The mixture was stirred at 25 ° C for 14 hours. The reaction mixture was diluted with H O (1000 mL) and extracted with MTBE (1000 mL) and EA (1000 mL * 2). The combined organic layer was washed with brine (800 mL * 3), dried over anhydrous Na SO, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1). The fractions were concentrated under reduced pressure to give methyl 5-bromo-6-ethoxypicolinate (54 g, 140.44 mmol, 48.17% yield) as an off-white solid.

[0984] LCMS (ESI) m / z: [ 81 Br M+H] + =262.1.

[0985] 1 H NMR (400MHz, DMSO-d6) δ = 8.20 (d, J = 8.0Hz, 1H), 7.56 (d, J = 8.0Hz, 1H), 4.44-4.39 (m, 2H), 3.86 (s, 3H), 1.43-1.28 (m, 3H) ppm

[0986] Step 2: Preparation of (5-bromo-6-ethoxypyridin-2-yl)methanol

[0987]

[0988] To a solution of methyl 5-bromo-6-ethoxypicolinate (54 g, 207.63 mmol) in DCM (550 mL) was added DIBAL-H (1 M, 415.25 mL) dropwise at -78°C. After the dropwise addition was complete, the mixture was stirred at 25°C for 3 hours. The reaction mixture was poured into HCl (1 M) (1500 mL), and then the pH was adjusted to 8 with saturated NaHCO₃. The mixture was extracted with DCM (2000 mL*3), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give (5-bromo-6-ethoxypyridin-2-yl)methanol (46 g, 130.01 mmol, 62.62% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ = 7.97 (d, J = 8.0Hz, 1H), 6.98 (d, J = 8.0Hz, 1H), 5.66-5.12 (m, 1H), 4.43 (s, 2H), 4.36-4.31 (m, 2H), 1.33-1.30 (m, 3H) ppm.

[0989] Step 3: Preparation of 5-bromo-6-ethoxypyridinecarboxaldehyde

[0990]

[0991] To a solution of (5-bromo-6-ethoxypyridin-2-yl)methanol (46 g, 198.21 mmol) in DCM (460 mL) at 0°C was added Dess-Martin periodinane (100.88 g, 237.86 mmol). The mixture was stirred at 25°C for 14 hours. The reaction mixture was filtered to remove the white solid. The filtrate was then diluted with saturated NaHCO₃ (1000 mL) and extracted with DCM (1000 mL*3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1). The fractions were concentrated under reduced pressure to obtain 5-bromo-6-ethoxypicolinaldehyde (35 g, 152.14 mmol, 76.75% yield) as an off-white solid.

[0992] 1 H NMR (400MHz, DMSO-d6) δ=9.84(s,1H),8.27(d,J=8.0Hz,1H),7.46(d,J=8.0Hz,1H),4.49-4.44(m,2H),1.40-1.36(m,3H)ppm

[0993] Step 4: Preparation of 3-bromo-6-(difluoromethyl)-2-ethoxypyridine

[0994]

[0995] To a solution of 5-bromo-6-ethoxypicolinaldehyde (35 g, 152.14 mmol) in DCM (350 mL) was added DAST (60.30 mL, 456.41 mmol). The mixture was stirred at 25 ° C for 14 hours. The reaction mixture was poured into saturated NaHCO (500 mL) and extracted with DCM (500 mL * 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1). The fractions were concentrated under reduced pressure to obtain 3-bromo-6-(difluoromethyl)-2-ethoxypyridine (29 g, 100.21 mmol, 65.87% yield) as a yellow oil.

[0996] LCMS (ESI) m / z: [ 81 Br M+H] + =252.1.

[0997] 1 H NMR (400MHz, DMSO-d6) δ = 8.20 (d, J = 8.0Hz, 1H), 7.20 (d, J = 8.0Hz, 1H), 7.07-6.66 (m, 1H), 4.42-4.37 (m, 2H), 1.37-1.33 (m, 3H) ppm.

[0998] Step 5: Preparation of 6-(difluoromethyl)-2-ethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0999]

[1000] To a solution of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (BPD) (34.96 g, 137.66 mmol) and 3-bromo-6-(difluoromethyl)-2-ethoxypyridine (29 g, 115.05 mmol) in dioxane (400 mL) was added AcOK (33.77 g, 344.15 mmol) and cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (4.20 g, 5.74 mmol) under N2. The reaction mixture was stirred at 80°C for 2 hours under N2 atmosphere. The reaction mixture was diluted with EA (100 mL) and then filtered. The filtrate was concentrated in vacuo to give 6-(difluoromethyl)-2-ethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (33.5 g, 111.99 mmol, 97.63% yield) as a brown oil.

[1001] LCMS (ESI) m / z: [M+H] + =300.3.

[1002] Step 6: Preparation of tert-butyl ((2-(6-(difluoromethyl)-2-ethoxypyridin-3-yl)-1,6-naphthyridin-7-yl)methyl)carbamate

[1003]

[1004] A mixture of (2-chloro-1,6-naphthyridin-7-yl)methanamine (25 g, 85.11 mmol), 6-(difluoromethyl)-2-ethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (33.09 g, 110.64 mmol), K PO (54.20 g, 255.32 mmol), and di-tert-butyl(cyclopentyl)phosphine; dichloropalladium; and iron (2.77 g, 4.26 mmol) in dioxane (400 mL) and H O (40 mL) was degassed and purged with N three times, then stirred at 80° C. under an N atmosphere for 2 hours. The reaction mixture was diluted with H O (300 mL) and extracted with EA (300 mL*3). The combined organic layers were dried over anhydrous Na SO , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 3). The fraction was concentrated under reduced pressure to obtain a brown solid. PE (100 mL) was then added to the brown solid, and the mixture was stirred for 30 minutes. The mixture was filtered to obtain a solid. The solid was washed with PE (40 mL * 2), filtered and concentrated in vacuo to obtain tert-butyl ((2-(6-(difluoromethyl)-2-ethoxypyridin-3-yl)-1,6-naphthyridin-7-yl)methyl)carbamate (21 g, 41.77 mmol, 49.08% yield) as a yellow solid.

[1005] LCMS (ESI) m / z: [M+H] + =431.3.

[1006] 1 H NMR (400MHz, DMSO-d6) δ=9.37(s,1H),8.62(d,J=8.8Hz,1H),8.46(d,J=7.6Hz,1H),8.21(d,J=8.8Hz,1H),7.74(s,1H),7.63-7 .61(m,1H),7.48(d,J=8.0Hz,1H),7.15-6.80(m,1H),4.53-4.47(m,2H),4.47-4.43(m,2H),1.43(s,9H),1.38-1.35(m,3H)ppm.

[1007] Step 7: Preparation of (2-(6-(difluoromethyl)-2-ethoxypyridin-3-yl)-1,6-naphthyridin-7-yl)methanamine

[1008]

[1009] A mixture of tert-butyl ((2-(6-(difluoromethyl)-2-ethoxypyridin-3-yl)-1,6-naphthyridin-7-yl)methyl)carbamate (21 g, 48.79 mmol) in HCl / dioxane (4M, 180 mL) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give (2-(6-(difluoromethyl)-2-ethoxypyridin-3-yl)-1,6-naphthyridin-7-yl)methanamine (17.5 g, 47.71 mmol, 97.80% yield, HCl salt) as a yellow solid.

[1010] LCMS (ESI) m / z: [M+H] + =331.3.

[1011] Step 8: (R)-9-Chloro-N-((2-(6-(difluoromethyl)-2-ethoxypyridin-3-yl)-1,6-naphthyridin-7-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathia Preparation of 7-formamide 5,5-dioxide

[1012]

[1013] To (4R)-9-chloro-4-fluoro-5,5-dioxo-3,4-dihydro-2H-1,5-benzoxathiazole To a solution of -7-carboxylic acid (15.47 g, 52.48 mmol) in DCM (30 mL) were added (2-(6-(difluoromethyl)-2-ethoxypyridin-3-yl)-1,6-naphthyridin-7-yl)methanamine (17.5 g, 47.71 mmol), EDCl (13.72 g, 71.57 mmol), HOBt (9.67 g, 71.57 mmol) and DIEA (41.55 mL, 238.55 mmol). The reaction mixture was stirred at 25 ° C for 14 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (100 mL * 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 330g Silica Flash Column, eluent 0-80% ethyl acetate / petroleum ether gradient @ 200 mL / min). The fractions were then concentrated under reduced pressure to give a residue. The residue was dissolved in MeCN (20 mL) and H2O (200 mL), and the mixture was then concentrated under reduced pressure to remove MeCN and then lyophilized to give Compound 331, (R)-9-chloro-N-((2-(6-(difluoromethyl)-2-ethoxypyridin-3-yl)-1,6-naphthyridin-7-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiapiperidin, as an off-white solid. -7-formamide 5,5-dioxide (21.37 g, 35.21 mmol, 73.79% yield).

[1014] LCMS (ESI) m / z: [M+H] + =607.2.

[1015] 1 H NMR (400MHz, DMSO-d6) δ=9.69-9.66(m,1H),9.41(s,1H),8.64(d,J=8.8Hz,1H),8.52(d,J =2.0Hz,1H),8.50-8.42(m,2H),8.24(d,J=8.8Hz,1H),7.85(s,1H),7.45(d,J=7.6Hz,1H) ,7.13-6.78(m,1H),6.34-6.14(m,1H),4.81(d,J=5.6Hz,2H),4.63-4.58(m,1H),4.51-4. 46(m,2H),4.12-4.06(m,1H),2.93-2.71(m,1H),2.64-2.55(m,1H),1.38-1.34(m,3H)ppm.

[1016] Chiral SFC: OJ-3-IPA(DEA)-5-40-3ML-35T.1cm, Rt=2.084mins, ee%=100%.

[1017] (4R)-N-[[2-[2-(Cyclopropylmethoxy)-6-(difluoromethyl)-3-pyridinyl]-1,6-naphthyridin-7-yl]methyl]-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5-benzoxathiazole Preparation of -7-formamide (Compound 332)

[1018]

[1019] Step 1: Preparation of methyl 5-bromo-6-(cyclopropylmethoxy)pyridine-2-carboxylate

[1020]

[1021] To a solution of 5-bromo-6-hydroxy-pyridine-2-carboxylic acid methyl ester (146 g, 629.23 mmol) and bromomethylcyclopropane (254.84 g, 1.89 mol, 180.23 mL) in CHCl 3 (1500 mL) was added Ag 2 CO 3 (208.21 g, 755.07 mmol), and the mixture was stirred at 60 ° C for 12 hours. The reaction mixture was filtered, and the filter cake was washed with EA (200 mL * 2) to obtain a yellow filtrate. The filtrate was concentrated under reduced pressure to obtain a yellow oil, which was purified by column chromatography (SiO 2, PE / EA = 20: 1) and the eluate was concentrated under reduced pressure to obtain 5-bromo-6- (cyclopropylmethoxy) picolinic acid methyl ester (166 g, 580.17 mmol, 92.20% yield) as a light yellow oil.

[1022] 1 H NMR (400MHz, DMSO-d6) δ = 8.20 (d, J = 7.6Hz, 1H), 7.55 (d, J = 7.6Hz, 1H), 4.22 (d, J = 7. 2Hz,2H),3.86(s,3H),1.30-1.28(m,1H),0.64-0.50(m,2H),0.47-0.31(m,2H)ppm.

[1023] Step 2: Preparation of 5-bromo-6-(cyclopropylmethoxy)-2-pyridinyl]methanol

[1024]

[1025] To a solution of methyl 5-bromo-6-(cyclopropylmethoxy)picolinate (83000 mg, 290.09 mmol) in DCM (850 mL) was added DIBAL-H (1 M, 638.19 mL) under N2 at -60°C, and the mixture was warmed to 0°C over 2 hours. The reaction mixture was slowly poured into 1N HCl (1600 mL) and extracted with DCM (500 mL*2), and the combined organic layers were concentrated under reduced pressure to give (5-bromo-6-(cyclopropylmethoxy)pyridin-2-yl)methanol (140 g, crude) as a pale yellow oil, which was used directly in the next step without further purification.

[1026] Step 3: Preparation of 5-bromo-6-(cyclopropylmethoxy)picolinaldehyde

[1027]

[1028] To a solution of (5-bromo-6-(cyclopropylmethoxy)pyridin-2-yl)methanol (140 g, 542.40 mmol) in DCM (1500 mL) was added MnO (398.92 g, 4.59 mol) and the mixture was warmed to 40° C. for 12 hours. The reaction mixture was filtered and the filter cake was washed with DCM (2 L). The filtrate was concentrated under reduced pressure to give 5-bromo-6-(cyclopropylmethoxy)picolinaldehyde (144 g, crude) as a light yellow oil, which was used directly in the next step without further purification.

[1029] 1 H NMR (400MHz, DMSO-d6) δ = 9.84 (s, 1H), 8.27 (d, J = 7.6Hz, 1H), 7.46 (d, J = 7.6Hz, 1H), 4.27 (d, J = 7.2Hz, 2H), 1.42-1.21 (m, 1H), 0.65-0.35 (m, 4H) ppm.

[1030] Step 4: Preparation of 3-bromo-2-(cyclopropylmethoxy)-6-(difluoromethyl)pyridine

[1031]

[1032] To a solution of 5-bromo-6-(cyclopropylmethoxy)picolinaldehyde (144 g, 562.29 mmol) in DCM (1500 mL) was added DAST (226.59 g, 1.41 mol) at 0° C., and the mixture was stirred at 20° C. for 12 hours. The reaction mixture was slowly poured into saturated NaHCO 3 (2 L) and extracted with DCM (500 mL*2). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO 2 , PE) and the eluate was concentrated under reduced pressure to give 3-bromo-2-(cyclopropylmethoxy)-6-(difluoromethyl)pyridine (130 g, 466.39 mmol, 82.95% yield) as a light yellow oil.

[1033] LCMS (ESI) m / z: [ 79 BrM+H] + =278.0.

[1034] 1H NMR (400MHz, DMSO-d6) δ = 8.21 (d, J = 7.6Hz, 1H), 7.20 (d, J = 8.0Hz, 1H), 7.03-6.64 (m, 1 H), 4.21 (d, J = 7.2Hz, 2H), 1.34-1.20 (m, 1H), 0.63-0.50 (m, 2H), 0.44-0.29 (m, 2H) ppm.

[1035] Step 5: Preparation of 2-(cyclopropylmethoxy)-6-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[1036]

[1037] To a solution of 3-bromo-2-(cyclopropylmethoxy)-6-(difluoromethyl)pyridine (20 g, 71.92 mmol) in dioxane (400 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (21.92 g, 86.30 mmol), Pd(dppf)Cl2 (5.26 g, 7.19 mmol), and KOAc (21.17 g, 215.76 mmol). The mixture was degassed and purged with N2 three times, and then stirred at 110°C under N2 for 2 hours. The reaction mixture was filtered, and the filter cake was washed with EA (30 mL*3). The combined filtrates were concentrated under reduced pressure to give 2-(cyclopropylmethoxy)-6-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (23.38 g, crude) as a brown oil, which was used directly in the next step without further purification.

[1038] Step 6: Preparation of 2-[[2-[2-(cyclopropylmethoxy)-6-(difluoromethyl)-3-pyridinyl]-1,6-naphthyridin-7-yl]methyl]isoindoline-1,3-dione

[1039]

[1040] To a solution of 2-(cyclopropylmethoxy)-6-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (22.60 g, 69.50 mmol) in dioxane (300 mL) and H₂O (30 mL) was added 4,2-[(2-chloro-1,6-naphthyridin-7-yl)methyl]isoindoline-1,3-dione (15 g, 46.33 mmol), di-tert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (3.02 g, 4.63 mmol) and K₃PO₄ (29.51 g, 139.00 mmol). The mixture was degassed and purged with N₂ three times, and the mixture was stirred at 80° C. under N₂ for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H2O (200 mL) and extracted with EA (300 mL * 2). The combined layers were washed with brine (500 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). The eluate was concentrated under reduced pressure to give 2- ((2- (2- (cyclopropylmethoxy) -6- (difluoromethyl) pyridin-3-yl) -1, 6- naphthyridin-7-yl) methyl) isoindoline -1, 3- dione (16.31 g, 33.53 mmol, 72.36% yield) as a yellow solid.

[1041] LCMS (ESI) m / z: [M+H] + =487.2.

[1042] 1 H NMR (400MHz, DMSO-d6) δ = 9.35 (s, 1H), 8.64-8.62 (m, 1H), 8.47 (d, J = 7.6Hz, 1H), 8.29-8.26 (m, 1H), 8.02-7.84 (m, 5H), 7.45 (d, J=7.6Hz,1H),7.14-6.78(m,1H),5.12(s,2H),4.31-4.29(m,2H),1.34-1.26(m,1H),0.60-0.50(m,2H),0.42-0.35(m,2H)ppm.

[1043] Step 7: Preparation of [2-[2-(cyclopropylmethoxy)-6-(difluoromethyl)-3-pyridinyl]-1,6-naphthyridin-7-yl]methanamine

[1044]

[1045] To a solution of 2-((2-(2-(cyclopropylmethoxy)-6-(difluoromethyl)pyridin-3-yl)-1,6-naphthyridin-7-yl)methyl)isoindoline-1,3-dione (16.31 g, 33.53 mmol) in 200 mL of ethanol was added NH₂NH₂·H₂O (35.62 g, 697.31 mmol). The mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into H₂O (300 mL) and extracted with EA (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 (2-(2-(cyclopropylmethoxy)-6-(difluoromethyl)pyridin-3-yl)-1,6-naphthyridin-7-yl)methanamine (11.71 g, 32.86 mmol, 98.01% yield) as a yellow solid, which was used directly in the next step without further purification.

[1046] LCMS (ESI) m / z: [M+H] + =357.1.

[1047] 1H NMR (400MHz, DMSO-d6) δ = 9.36 (s, 1H), 8.63-9.61 (m, 1H), 8.48 (d, J = 7.6Hz, 1H), 8.25-8.23 (m, 1H), 7.99 (s, 1H), 7.50-7.48 (m, 1H), 7. 21-6.77(m,1H),4.32-4.30(m,2H),4.09-3.98(m,2H),2.23-2.00(m,2H),1.41-1.24(m,1H),0.67-0.49(m,2H),0.40-0.39(m,2H)ppm.

[1048] Step 8: (4R)-N-[[2-[2-(cyclopropylmethoxy)-6-(difluoromethyl)-3-pyridinyl]-1,6-naphthyridin-7-yl]methyl]-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5-benzoxathiazole Preparation of 7-formamide

[1049]

[1050] To (4R)-9-chloro-4-fluoro-5,5-dioxo-3,4-dihydro-2H-1,5-benzoxathiazole To a solution of 1,7-difluoro-2-carboxylic acid (9.14 g, 32.86 mmol) in DCM (150 mL) were added EDCl (8.19 g, 42.72 mmol), HOBt (5.77 g, 42.72 mmol), and DIEA (12.74 g, 98.58 mmol), followed by (2-(2-(cyclopropylmethoxy)-6-(difluoromethyl)pyridin-3-yl)-1,6-naphthyridin-7-yl)methanamine (11.71 g, 32.86 mmol). The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with H2O (200 mL) and extracted with DCM (100 mL*2). The combined organic layers were washed with brine (300 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PE / EA=10 / 1 to 1 / 2). The eluent was concentrated under reduced pressure to give a yellow gum. The gum was dissolved in MeCN (100 mL) and H2O (300 mL), and the solution was then concentrated under reduced pressure to remove MeCN and lyophilized to give the title compound, Compound 332 (16.34 g, 26.37 mmol, 80.24% yield), as an off-white solid.

[1051] LCMS (ESI) m / z: [M+H] + =617.3.

[1052] 1 H NMR (400MHz, DMSO-d6) δ=9.69-9.67(m,1H),9.41(s,1H),8.65(d,J=8.4Hz,1H),8.46(d,J=7 .6Hz,1H),8.38-8.23(m,3H),7.84(s,1H),7.46-7.44(m,1H),7.17-6.76(m,1H),6.41-6.16( m,1H),4.81(d,J=5.6Hz,2H),4.63-4.59(m,1H),4.31-4.29(m,2H),4.19-4.16(m,1H),2.93- 2.71(m,1H),2.65-2.53(m,1H),1.39-1.22(m,1H),0.59-0.51(m,2H),0.40-0.37(m,2H)ppm.

[1053] Chiral SFC: AD-3-IPA+ACN(DEA)-40-3ML-35T.1cm, Rt=0.836min, ee%=100.00%

[1054] Step 9: Preparation of (2-chloro-1,6-naphthyridin-7-yl)methanamine

[1055]

[1056] A mixture of tert-butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate (30 g, 102.13 mmol) in HCl / dioxane (4 M, 100 mL) was stirred at 25 °C for 6 hours. The reaction mixture was concentrated under reduced pressure to give (2-chloro-1,6-naphthyridin-7-yl)methanamine (23.5 g, 102.13 mmol, 100.00% yield, HCl salt) as a brown solid, which was used directly in the next step without further purification.

[1057] LCMS (ESI) m / z: [M+H] + =294.1.

[1058] 1 H NMR (400MHz, DMSO-d6) δ = 9.53 (s, 1H), 8.73-8.70 (m, 3H), 8.05 (s, 1H), 7.82 (d, J = 8.8Hz, 1H), 4.39-4.34 (m, 2H) ppm.

[1059] Step 10: Preparation of intermediate 4,2-[(2-chloro-1,6-naphthyridin-7-yl)methyl]isoindoline-1,3-dione

[1060]

[1061] To a solution of (2-chloro-1,6-naphthyridin-7-yl)methanamine (23.5 g, 102.13 mmol) in toluene (700 mL) was added TEA (31.00 g, 306.40 mmol) and isobenzofuran-1,3-dione (15.13 g, 102.13 mmol). The mixture was stirred at 120°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove toluene, and the residue was diluted with H2O (100 mL) and extracted with EA (200 mL*3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 1 / 1). The eluate was concentrated under reduced pressure to give 9 (25.35 g, 78.31 mmol, 76.67% yield) as a yellow solid.

[1062] LCMS (ESI) m / z: [M+H] + =324.1.

[1063] 1H NMR (400MHz, DMSO-d6) δ = 9.35 (s, 1H), 8.62-8.60 (m, 1H), 8.06-7.83 (m, 5H), 7.75-7.73 (m, 1H), 5.10 (s, 2H) ppm.

[1064] (4R)-N-[[2-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-pyridinyl]pyrido[3,4-b]pyrazin-7-yl]methyl]-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole Preparation of -7-formamide (Compound 405)

[1065]

[1066] Step 1: Preparation of [6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-pyridyl]-trimethyl-stannane

[1067]

[1068] To a solution of (2R, 6S) -4- (6-bromo-2-pyridinyl) -2,6-dimethyl-morpholine (prepared according to the method in FG-A4398) (500 mg, 1.84 mmol) and trimethyl (trimethylstannyl) stannane (0.94 g, 2.87 mmol) in dioxane (5 mL) was added Pd (PPh 3) 4 (106.54 mg, 92.20 umol) and the reaction was stirred at 100 ° C. under N 2 for 2 hours. EA (10 mL) was added to the reaction mixture, filtered, and the filtrate was concentrated to give [6- [(2R, 6S) -2,6-dimethylmorpholin-4-yl] -2-pyridinyl] -trimethyl-stannane (650 mg, crude) as a yellow solid, which was used in the next step without further purification.

[1069] LCMS (ESI) m / z: [M+H] + =357.0.

[1070] Step 2: Preparation of [2-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-pyridyl]pyrido[3,4-b]pyrazin-7-yl]methyl acetate

[1071]

[1072] To a solution of 4 (650 mg, 1.83 mmol) in dioxane (6 mL) was added acetic acid (2-chloropyrido [3, 4-b] pyrazin-7-yl) methyl ester (290.03 mg, 1.22 mmol) and dichloropalladium; triphenylphosphine (85.66 mg, 122.04 umol), and the reaction was stirred at 100 ° C. under N2 for 12 hours. The reaction mixture was poured into water (10 mL), the solution was extracted with EA (10 mL * 3), and the combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10: 1-5: 1), and the solution was concentrated to give [2- [6- [(2R, 6S) -2,6-dimethylmorpholin-4-yl] -2-pyridinyl] pyrido [3,4-b] pyrazin-7-yl] methyl acetate (160 mg, crude) as a yellow solid.

[1073] LCMS (ESI) m / z: [M+H] + =294.1.

[1074] Step 3: Preparation of [2-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-pyridyl]pyrido[3,4-b]pyrazin-7-yl]methanol

[1075]

[1076] To a solution of 5 (160 mg, 406.67 umol) in MeOH (3 mL) was added NaOMe (43.94 mg, 813.34 umol), and the reaction was stirred at 25° C. under N 2 for 2 hours. The reaction mixture was poured into water (10 mL), extracted with EA (10 mL*3), and the combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10:1-5:1), and the solution was concentrated to give [2-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-pyridyl]pyrido[3,4-b]pyrazin-7-yl]methanol (100 mg, 284.57 umol, 69.98% yield) as a yellow solid.

[1077] LCMS (ESI) m / z: [M+H] + =352.2.

[1078] Step 4: Preparation of 2-[[2-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-pyridyl]pyrido[3,4-b]pyrazin-7-yl]methyl]isoindoline-1,3-dione

[1079]

[1080] To a solution of 6 (100 mg, 284.57 umol) and isoindoline-1,3-dione (46.06 mg, 313.03 umol) in THF (2 mL) was added PPh 3 (89.57 mg, 341.49 umol), and then DIAD (86.31 mg, 426.86 umol) was added to the mixture at 0° C. The reaction was stirred under N 2 at 25° C. for 2 hours. The reaction mixture was poured into water (20 mL), the solution was extracted with EA (20 mL*3), and the combined organic layers were washed with brine (20 mL*3), dried over Na 2 SO 4 , filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10: 1-5: 1), and the solution was concentrated to give 2-[[2-[6-[(2R, 6S)-2,6-dimethylmorpholin-4-yl]-2-pyridinyl]pyrido[3,4-b]pyrazin-7-yl]methyl]isoindoline-1,3-dione (90 mg, 187.30 umol, 65.82% yield) as a yellow solid.

[1081] LCMS (ESI) m / z: [M+H] + =481.0.

[1082] Step 5: Preparation of [2-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-pyridyl]pyrido[3,4-b]pyrazin-7-yl]methanamine

[1083]

[1084] To a solution of 8 (50 mg, 104.05 umol) in THF (0.5 mL) was added hydrazine; hydrate (0.14 g, 2.74 mmol) at 25° C., and the reaction was stirred at 25° C. for 12 hours. The reaction mixture was poured into water (10 mL), the solution was extracted with EA (10 mL*3), and the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give [2-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-pyridyl]pyrido[3,4-b]pyrazin-7-yl]methanamine (35 mg, crude) as a yellow solid, which was used directly in the next step.

[1085] LCMS (ESI) m / z: [M+H] + =351.1.

[1086] Step 6: Preparation of Compound 405

[1087] (4R)-N-[[2-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-pyridinyl]pyrido[3,4-b]pyrazin-7-yl]methyl]-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole -7-formamide.

[1088]

[1089] To a solution of 9 (35 mg, 99.88 umol) in DCM (1.5 mL) was added (4R)-4,9-difluoro-5,5-dioxo-3,4-dihydro-2H-1,5λ6-benzoxathiazole -7-carboxylic acid (prepared according to the method in FG-A5321A) (27.79 mg, 99.88 umol), EDCI (28.72 mg, 149.82 umol), HOBt (20.24 mg, 149.82 umol) and DIEA (64.54 mg, 499.41 umol) were added and the reaction was stirred at 25 ° C for 12 hours. The reaction mixture was diluted with H2O (10 mL), the solution was extracted with EA (10 mL*3), and the combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to obtain a residue. The residue was purified by reverse phase HPLC (0.1% FA conditions). The solution was lyophilized to obtain compound 405 (12.96 mg, 19.74 umol, 19.76% yield, FA) as a yellow solid.

[1090] LCMS (ESI) m / z: [M+H] + =611.4.

[1091] 1H NMR (400MHz, DMSO-d6) δ = 9.96 (s, 1H), 9.75-9.69 (m, 1H), 9.50 (s, 1H), 8.44 (s, 1H), 8.39-8.28 (m, 2H) ,7.94(s,1H),7.90-7.84(m,1H),7.83-7.76(m,1H),7.11(d,J=8.4Hz,1H),6.37-6.19(m,1H),4.85(br d,J=5.6Hz,2H),4.66-4.56(m,1H),4.35(br d,J=11.6Hz,2H),4.19-4.15(m,1H),3.75-3.62(m,2H),2.92-2.73(m,1H),2.66-2.55(m,3H),1.22(d,J=6.2Hz,6H)ppm.

[1092] Chiral SFC: OJ-3-IPA(DEA)-5-40-3ML-35T.1cm, Rt=2.121mins, ee%=100%.

[1093] Step 7: Preparation of (4,5-diaminopyridin-2-yl)methanol

[1094]

[1095] To a solution of methyl 4,5-diaminopyridine-2-carboxylate (8 g, 47.86 mmol) in THF (80 mL) was added LiBH4 (2 M, 103.98 mL) dropwise at 0°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was slowly poured into an aqueous NaHCO3 solution (300 mL). The suspension was filtered. The filtrate was concentrated to remove THF and then lyophilized to obtain a crude product.

[1096] The crude product was washed by column (Al 2 O 3 , DCM / MeOH=10:1 to 2:1) to give (4,5-diaminopyridin-2-yl)methanol (12 g, crude) as a white solid.

[1097] LCMS (ESI) m / z: [M+H] + =140.4

[1098] Step 8: Preparation of 7-(hydroxymethyl)pyrido[3,4-b]pyrazin-2-ol

[1099]

[1100] To a solution of 2A (5 g, 35.93 mmol) in n-BuOH (50 mL) was added ethyl 2-oxoacetate (7.70 g, 37.73 mmol, 50% in toluene) and the mixture was stirred at 100° C. for 8 hours.

[1101] The reaction mixture was filtered. The filter cake was washed with MeOH (50 mL) to give filtrate A and filter cake B. Filtrate A was concentrated to give a residue. The residue was triturated with PE:EA (1:1, 100 mL) and then with MeOH (20 mL) to give 7-(hydroxymethyl)pyrido[3,4-b]pyrazin-2-ol (3.3 g, 18.63 mmol, 51.84% yield) as an off-white solid.

[1102] 1 H NMR (400MHz, DMSO-d6) δ = 8.81 (s, 1H), 8.15 (s, 1H), 7.33 (s, 1H), 5.79-5.46 (m, 1H), 4.62 (s, 2H) ppm.

[1103] Step 9: Preparation of (2-hydroxypyrido[3,4-b]pyrazin-7-yl)methyl acetate

[1104]

[1105] To a solution of 4A (150 mg, 846.69 μmol) and DMAP (51.72 mg, 423.35 μmol) in DCM (3 mL) was added AcO (259.31 mg, 2.54 mmol) and TEA (128.51 mg, 1.27 mmol). The mixture was stirred at 25 ° C for 2 hours. The reaction was concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to obtain (2-hydroxypyrido [3,4-b] pyrazine-7-yl) methyl acetate (100 mg, 456.21 μmol, 53.88% yield) as a yellow solid.

[1106] 1 H NMR (400MHz, DMSO-d6) δ = 12.65 (br s, 1H), 8.89 (s, 1H), 8.21 (s, 1H), 7.22 (s, 1H), 5.20 (s, 2H), 2.15 (s, 3H) ppm.

[1107] Step 10: Preparation of (2-chloropyrido[3,4-b]pyrazin-7-yl)methyl acetate

[1108]

[1109] To a solution of PPh3 (344.62 mg, 1.31 mmol) in toluene (4 mL) was added trichloroisocyanuric acid (101.79 mg, 437.96 μmol). The resulting mixture was stirred at 25 ° C for 12 hours. To the above mixture was added 5A (60 mg, 273.73 μmol). The resulting mixture was stirred at 110 ° C for 5 hours. The reaction was concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain (2-chloropyrido [3, 4-b] pyrazine-7-yl) methyl acetate (40 mg, 164.95 μmol, 60.26% yield) as a white solid.

[1110] LCMS (ESI) m / z: [M+H] + =238.1

[1111] 1 H NMR (400MHz, DMSO-d6) δ = 9.52 (s, 1H), 9.14 (s, 1H), 7.97 (s, 1H), 5.39 (s, 2H), 2.18 (s, 3H) ppm.

[1112] (2R)-N-[[2-[3-(Difluoromethoxy)-4-fluoro-pyrazol-1-yl]-1,6-naphthyridin-7-yl]methyl]-6-(difluoromethyl)-2-fluoro-1,1-dioxo-3,5-dihydro-2H-4,1-benzoxathiazole Preparation of 8-formamide (Compound 514)

[1113]

[1114] Step 1: Preparation of 1-(3-hydroxy-1H-pyrazol-1-yl)ethan-1-one

[1115]

[1116] To a solution of 1H-pyrazol-3-ol (3 g, 35.68 mmol) in pyridine (50 mL) was added a solution of Ac2O (3.82 g, 37.47 mmol) in pyridine (20 mL) at 95 ° C for 30 minutes, and then the mixture was stirred at 95 ° C for 2 hours. The reaction mixture was concentrated to give a residue. The residue was triturated with MeOH (100 mL) and filtered. The filter cake was washed with MeOH (20 mL * 3) and dried to give 1-(3-hydroxy-1H-pyrazol-1-yl)ethan-1-one (4 g, 31.72 mmol, 88.89% yield) as a yellow solid.

[1117] Step 2: Preparation of 1-(3-(difluoromethoxy)-1H-pyrazol-1-yl)ethan-1-one

[1118]

[1119] To a solution of 1-(3-hydroxy-1H-pyrazol-1-yl)ethan-1-one (2 g, 15.86 mmol) in ACN (20 mL) was added 1-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (8.47 g, 31.72 mmol) and KF (1.84 g, 31.72 mmol). The mixture was stirred at 25°C for 6 hours. The reaction was diluted with water (100 mL) and extracted with EA (20 mL*4). The combined organic layers were 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 3 / 1) to give 1-(3-(difluoromethoxy)-1H-pyrazol-1-yl)ethan-1-one (860 mg, 4.88 mmol, 30.79% yield) as a colorless oil.

[1120] 1 H NMR (400MHz, DMSO-d6) δ = 8.41 (d, J = 2.8Hz, 1H), 7.64-7.28 (m, 1H), 6.48 (d, J = 3.2Hz, 1H), 2.57 (s, 3H) ppm.

[1121] Step 3: Preparation of 3-(difluoromethoxy)-1H-pyrazole

[1122]

[1123] To a solution of 1-(3-(difluoromethoxy)-1H-pyrazol-1-yl)ethan-1-one (700 mg, 3.97 mmol) in MeOH (10 mL) was added NaOMe (429.44 mg, 7.95 mmol). The mixture was stirred at 25°C for 1 hour. The reaction was diluted with water (100 mL) and extracted with EA (50 mL*3). The combined organic layers were dried over NaSO, filtered, and concentrated to afford 3-(difluoromethoxy)-1H-pyrazole (460 mg, 3.43 mmol, 86.32% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ = 12.49 (br s, 1H), 7.69 (s, 1H), 7.41-7.04 (m, 1H), 5.97 (s, 1H) ppm.

[1124] Step 4: Preparation of 3-(difluoromethoxy)-4-fluoro-1H-pyrazole

[1125]

[1126] To a solution of 3-(difluoromethoxy)-1H-pyrazole (400 mg, 2.98 mmol) in ACN (10 mL) was added Select F (1.27 g, 3.58 mmol). The mixture was stirred at 80°C for 3 hours. The reaction mixture was filtered to obtain a filtrate. The filtrate was purified by reverse phase HPLC (0.1% FA conditions). The fractions were concentrated to remove MeCN. The liquid was extracted with EA (20 mL*3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain 3-(difluoromethoxy)-4-fluoro-1H-pyrazole (180 mg, 1.18 mmol, 39.68% yield) as a colorless oil.

[1127] 1 H NMR (400MHz, DMSO-d6) δ = 12.56 (br s, 1H), 7.91-7.90 (m, 1H), 7.41-7.05 (m, 1H) ppm.

[1128] Step 5: Preparation of tert-butyl ((2-(3-(difluoromethoxy)-4-fluoro-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methyl)carbamate

[1129]

[1130] A mixture of tert-butyl N-[(2-chloro-1,6-naphthyridin-7-yl)methyl]carbamate (prepared according to the method in FG-A3432C) (120 mg, 408.51 μmol), 3-(difluoromethoxy)-4-fluoro-1H-pyrazole (68.34 mg, 449.36 μmol), Pd(dba) (37.41 mg, 40.85 μmol), Xantphos (47.27 mg, 81.70 μmol) and CsCO (399.30 mg, 1.23 mmol) in dioxane (2 mL) was degassed and purged with N3 three times, and then the mixture was stirred at 100 ° C under N2 atmosphere for 2 hours. The reaction was diluted with water (10 mL) and extracted with EA (5 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 47%-77%, 10 min). Fractions were concentrated to remove MeCN. The liquid was extracted with DCM (5 mL*3). The combined organic layers were dried over NaSO, filtered, and concentrated to yield tert-butyl ((2-(3-(difluoromethoxy)-4-fluoro-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methyl)carbamate (120 mg, 293.14 μmol, 71.76% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 9.33 (s, 1H), 9.08 (d, J = 4.0Hz, 1H), 8.74 (d, J = 8.8Hz, 1H), 8.08(d,J=9.2Hz,1H),7.75-7.36(m,3H),4.42(brd,J=6.0Hz,2H),1.43(s,9H)ppm.

[1131] Step 6: Preparation of (2-(3-(difluoromethoxy)-4-fluoro-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methanamine

[1132]

[1133] A mixture of tert-butyl ((2-(3-(difluoromethoxy)-4-fluoro-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methyl)carbamate (80 mg, 195.43 μmol) in TFA (0.2 mL) and DCM (1 mL) was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with aqueous NaHCO 3 solution (5 mL) and extracted with EA (3 mL * 5). The combined organic layers were dried over Na 2 SO 4, filtered and concentrated to give (2-(3-(difluoromethoxy)-4-fluoro-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methanamine (60 mg, 194.02 μmol, 99.28% yield) as a yellow solid.

[1134] LCMS (ESI) m / z: [M+H] + =310.0

[1135] Step 7: (2R)-N-[[2-[3-(Difluoromethoxy)-4-fluoro-pyrazol-1-yl]-1,6-naphthyridin-7-yl]methyl]-6-(difluoromethyl)-2-fluoro-1,1-dioxo-3,5-dihydro-2H-4,1-benzoxathiazole Preparation of 8-formamide

[1136]

[1137] To (2R)-6-(difluoromethyl)-2-fluoro-1,1-dioxo-3,5-dihydro-2H-4,1-benzoxathiazole To a solution of 8-carboxylic acid (60.19 mg, 194.02 μmol) in DCM (1 mL) were added EDCI (37.19 mg, 194.02 μmol), HOBt (26.22 mg, 194.02 μmol), and DIEA (62.69 mg, 485.05 μmol), followed by [2-[3-(difluoromethoxy)-4-fluoropyrazol-1-yl]-1,6-naphthyridin-7-yl]methanamine (50 mg, 161.68 μmol). The mixture was stirred at 25 ° C for 12 hours. The reaction mixture was filtered and the filter cake was washed with PE (1 mL * 3). The resulting solid was filtered under reduced pressure to give compound 514 (54.32 mg, 90.31 μmol, 55.86% yield) as a white solid.

[1138] LCMS (ESI) m / z: [M+H] + =602.1.

[1139] 1H NMR (400MHz, DMSO-d6) δ = 9.91-9.88 (m, 1H), 9.38 (s, 1H), 9.05 (d, J = 4.4Hz, 1H), 8.83-8.71 (m, 2H), 8.60 (s, 1H), 8.11-8.09 ( m,1H),7.77-7.33(m,3H),6.35-6.12(m,1H),5.31-5.27(m,1H),5.12-5.08(m,1H),4.83-4.82(m,2H),4.58-4.41(m,2H)ppm.

[1140] Chiral SFC: OJ-3-EtOH(DEA)-5-40-3ML-35T.1cm, Rt=2.043mins, ee%=100%.

[1141] The following examples in Table 9 were prepared using standard chemical manipulations and procedures similar to those described herein.

[1142] Table 9. Compounds of the present invention

[1143]

[1144]

[1145]

[1146]

[1147]

[1148]

[1149]

[1150]

[1151]

[1152]

[1153]

[1154]

[1155]

[1156]

[1157]

[1158]

[1159]

[1160]

[1161]

[1162] Example 2. Determination of ATPase catalytic activity of BRM and BRG-1

[1163] By using ADP-Glo TM (Promega, V9102) in vitro biochemical assay to measure the ATPase catalytic activity of BRM or BRG-1. Once the reaction is complete, ADP-Glo TM Kinase assay. The first step is to deplete any unconsumed ATP in the reaction. The second step is to convert the reaction product ADP into ATP, which is used by luciferase to emit light and detected by a luminescence reader such as Envision.

[1164] The assay reaction mixture (10 μL) contained 30 nM BRM or BRG-1, 20 nM salmon sperm DNA (from Invitrogen, UltraPure TM Salmon Sperm DNA Solution, cat# 15632011) and 400 μM ATP in an ATPase assay buffer containing 20 mM Tris, pH 8, 20 mM MgCl2, 50 mM NaCl, 0.1% Tween-20, and 1 mM fresh DTT (Pierce TM 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-384plus plate (PerkinElmer, cat# 6008280) and incubated at room temperature for 1 hour. Then, 5 μL of ADP-Glo ​​provided in the kit was added. TM After adding the reagent, the reaction was incubated at room temperature for 40 minutes. Then, 10 μL of the kinase detection reagent provided in the kit was added to convert ADP to ATP, and the reaction was incubated at room temperature for 60 minutes. Finally, luminescence measurements were collected using a plate reader luminometer such as Envision.

[1165] BRM and BRG-1 were synthesized by a high five insect cell line with a purity greater than 90%. IC values ​​from the ATPase catalytic activity assay described herein were50 The data are shown in Table 10 below.

[1166] Table 10. BRM and BRG-1 inhibition data for compounds of the present invention

[1167]

[1168]

[1169]

[1170]

[1171]

[1172]

[1173]

[1174] *Ratio is calculated by adding BRG1 IC 50 (μM) divided by BRMIC 50 Example 3. Determination of the inhibitory effect on BRG1 and BRM-dependent transcription

[1175] The potential inhibitory effects of compounds on BRG1- and BRM-dependent transcription were investigated by testing their activity against the BRG1-mutant lung cancer cell line A549 and the MDA cell line in which BRM was deleted by CRISPR. Both cell lines were genetically engineered with BRG1- or BRM-dependent mouse mammary tumor virus-mediated luciferase reporter genes. Luciferase transcription was induced by dexamethasone in the presence of various compound concentrations, and luminescence was measured using a microplate reader 6 hours after stimulation.

[1176] IC from the assay described herein 50 The data are shown in Table 11 below.

[1177] Table 11. BRM and BRG-1 inhibition data for compounds of the present invention

[1178] *Ratio is calculated by applying MDA-MMTV IC 50 (μM) divided by A549-MMTV IC 50 (μM) and the resulting value

[1179]

[1180]

[1181]

[1182]

[1183] Example 4. Synthesis of Compound A BRG1 / BRM Inhibitor Compound A has the structure:

[1184]

[1185] Compound A

[1186] Compound A was synthesized as shown in Scheme 1 below.

[1187] Scheme 1. Synthesis of Compound A

[1188]

[1189] By using the above ADP-Glo TM (Promega, V9102) in vitro biochemical assay to measure the ATPase catalytic activity of BRM or BRG-1 in the presence of Compound A. Compound A was found to have an IC of 10.4 nM for BRM in this assay. 50 and an IC of 19.3 nM for BRG1 50 .

[1190] Example 5. Effect of BRG1 / BRM ATPase Inhibition on the Growth of Uveal Melanoma and Hematological Cancer Cell Lines

[1191] Procedure: Uveal melanoma cell lines (92-1, MP41, MP38, MP46), prostate cancer cell lines (LNCAP), lung cancer cell lines (NCI-H1299) and immortalized embryonic kidney lines (HEK293T) were plated into 96-well plates with growth medium (see Table 9). BRG1 / BRM ATPase inhibitor compound A was dissolved in DMSO and added to the cells at a concentration gradient of 0 to 10 micromolar when plated. The cells were incubated at 37°C for 3 days. After treatment for 3 days, the culture medium was removed from the cells and 30 microliters of TrypLE (Gibco) were added to the cells for 10 minutes. The cells were separated from the plate and resuspended by adding 170 microliters of growth medium. The cells from the two DMSO-treated control wells were counted and the initial cell number plated at the beginning of the experiment was re-plated at 37°C to a plate containing fresh compound for another 4 days. On the 7th day, cells were harvested as described above. On days 3 and 7, relative cell growth was measured by adding Cell-titer glo (Promega) and measuring luminescence on an Envision microplate reader (Perkin Elmer). The compound concentration that inhibited the growth of each cell line by 50% (GI) was calculated using Graphpad Prism. 50), and plotted below. For multiple myeloma cell lines (OPM2, MM1S, LP1), ALL cell lines (TALL1, JURKAT, RS411), DLBCL cell lines (SUDHL6, SUDHL4, DB, WSUDLCL2, PFEIFFER), AML cell line (OCIAML5), MDS cell line (SKM1), ovarian cancer cell line (OV7, TYKNU), esophageal cancer cell line (KYSE150), rhabdoid tumor cell line (RD, G402, G401, HS729, A204), hepatocellular carcinoma cell line (HLF, HLE, PLCRPF5), and lung cancer cell line (SW1573, NCIH2444), the above method was performed with the following modifications: cells were plated in 96-well plates, and on the next day, the BRG1 / BRM ATPase inhibitor Compound A was dissolved in DMSO and added to the cells at a concentration gradient from 0 to 10 micromolar. At day 3 and day 7, cells were split into new 96-well plates and fresh compounds were added 4 h after re-plating.

[1192] Table 12 lists the cell lines tested and the growth media used.

[1193] Table 12. Cell lines and growth media

[1194] cell lines source Growth medium 92-1 SIGMA RPMI1640 + 20% FBS A204 ATCC <![CDATA[McCov 1 s 5A+10%FBS]]> DB ATCC RPMI1640 + 10% FBS G401 ATCC <![CDATA[McCoy 1 s 5A+10%FBS]]> G402 ATCC <![CDATA[McCoy 1 s 5A+10%FBS]]> HEK293T ATCC DMEM + 10% FBS HLE JCRB DMEM + 10% FBS HLF JCRB DMEM + 10% FBS HS729 ATCC DMEM + 10% FBS JURKAT ATCC RPMI1640 + 10% FBS KYSE150 DSMZ <![CDATA[RPMI1640 / Ham 1 s F12+10%FBS]]> LNCAP ATCC RPMI1640 + 10% FBS LP1 DSMZ IMDM + 20% FBS MMlS ATCC RPMI1640 + 10% FBS MP38 ATCC RPMI1640 + 20% FBS MP41 ATCC RPMI1640 + 20% FBS MP46 ATCC RPMI1640 + 20% FBS NCIH1299 ATCC RPMI1640 + 10% FBS NCIH2444 ATCC RPMI1640 + 20% FBS OCIAML5 DSMZ alpha-MEM+20%FBS+10ng / ml GM-CSF OPM2 DSMZ RPMI1640 + 10% FBS OV7 ECACC <![CDATA[DMEM / Ham 1 s F12 (1:1) + 2mM glutamine + 10% FBS + 0.5ug / ml hydrocortisone + 10ug / ml insulin]]> PFEIFFER ATCC RPMI1640 + 10% FBS PLCPRF5 ATCC EMEM + 10% FBS RD ATCC DMEM + 10% FBS RS411 ATCC RPMI1640 + 10% FBS SKM1 JCRB RPMI1640 + 10% FBS SUDHL4 DSMZ RPMI1640 + 10% FBS SUDHL6 ATCC RPMI1640 + 20% FBS SW1573 ATCC DMEM + 10% FBS TALL1 JCRB RPM11640+10%FBS TYKNU JCRB EMEM + 20% FBS WSUDLCL2 DSMZ RPMI1640 + 10% FBS

[1195] Results: As Figure 1 As shown in , uveal melanoma and hematological cancer cell lines were more sensitive to BRG1 / BRM inhibition than other tested cell lines. Inhibition of uveal melanoma and hematological cancer cell lines was maintained until day 7.

[1196] Example 6. Comparison of BRG1 / BRM inhibitors with clinical PKC and MEK inhibitors in uveal melanoma cell lines

[1197] Procedure: Uveal melanoma cell lines 92-1 or MP41 were plated in 96-well plates in the presence of growth medium (see Table 12). 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 plating in a concentration gradient from 0 to 10 micromolar. The cells were incubated at 37°C for 3 days. After 3 days of treatment, cell growth was measured using Cell-titerglow (Promega) and luminescence was read on an Envision microplate reader (Perkin Elmer).

[1198] Results: As Figure 2A and Figure 2B As shown in , Compound A exhibited growth inhibition of uveal melanoma cells comparable to that of clinical PKC and MEK inhibitors. In addition, Compound A was found to bring about a faster onset of inhibition than clinical PKC and MEK inhibitors.

[1199] Example 7. Synthesis of Compound B

[1200] BRG1 / BRM inhibitor compound B has the structure:

[1201]

[1202] Compound B

[1203] Compound B was synthesized as shown in Scheme 2 below.

[1204] Scheme 2. Synthesis of Compound B

[1205]

[1206] 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)

[1207]

[1208] 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 hours. The mixture was poured into H 2 O (100 mL) and the precipitate was collected by filtration. The solid was triturated in MeOH (20 mL) and the precipitate was collected by filtration. The solid was dissolved in DMSO (10 mL), and the mixture was poured into MeOH (50 mL). The formed precipitate 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. 1H NMR (400MHz, DMSO) δ12.49 (s, 1H), 8.68-8.66 (m, 2H), 8.46 (d, J = 7.2Hz, 1 H),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,1 H),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%.

[1209] Example 8. Effects of BRG1 / BRM ATPase Inhibition on the Growth of Uveal Melanoma, Hematological Cancer, Prostate Cancer, Breast Cancer, and Ewing's Sarcoma Cell Lines

[1210] Procedure: All cell lines described above in Example 4 were also tested with Compound B as described above. In addition, the following cell lines were also tested as follows. Briefly, for 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, B T474, HCC1419, DU4475, BT549), B-ALL cell line (SUPB15), CML cell line (K562, MEG01), Burkitt lymphoma cell line (RAMOS2G64C10, DAUDI), mantle cell lymphoma cell line (JEKO1, REC1), bladder cancer cell line (HT1197), and lung cancer cell line (SBC5) were subjected to the above method with the following modifications: cells were plated in 96-well plates, and on the second day, the BRG1 / BRM ATPase inhibitor Compound B was dissolved in DMSO and added to the cells in a concentration gradient from 0 to 10 micromolar. At the time of cell splitting on days 3 and 7, cells were split into new 96-well plates, and fresh compound was added 4 hours after replated.

[1211] Table 13 lists the cell lines tested and the growth media used.

[1212] Table 13. Cell lines and growth media

[1213] cell lines source Growth medium 22RV1 ATCC RPMI1640 + 10% FBS A375 ATCC DMEM + 10% FBS BT474 ATCC Hybricare medium + 1.5g / L sodium bicarbonate + 10% FBS BT549 ATCC RPMI1640 + 0.023 lU / ml insulin + 10% FBS CADOES1 DSMZ RPMI1640 + 10% FBS CAMA1 ATCC EMEM + 10% FBS COL0829 ATCC RPMI1640 + 10% FBS DAUDl ATCC RPMI1640 + 10% FBS DU145 ATCC EMEM + 10% FBS DU4475 ATCC RPMI1640 + 10% FBS HCC1419 ATCC RPMI1640 + 10% FBS HT1197 ATCC EMEM + 10% FBS JEKO1 ATCC RPMI1640 + 20% FBS K562 ATCC IMDM + 10% FBS KASUMI1 ATCC RPMI1640 + 10% FBS MCF7 ATCC EMEM + 0.01 mg / ml bovine insulin + 10% FBS MDAMB415 ATCC Leibovitz's L-15 + 2mM L-glutamine + 10mcg / ml insulin + 10mcg / ml glutathione + 15% FBS MEG01 ATCC RPMI1640 + 10% FBS PC3 ATCC F-12K+10% FBS RAMOS2G64C10 ATCC RPMI1640 + 10% FBS RDES ATCC RPMI1640 + 15% FBS REC1 ATCC RPM11640+10%FBS REH ATCC RPMI1640 + 10% FBS SBC5 JCRB EMEM + 10% FBS SH4 ATCC DMEM + 10% FBS SKESl ATCC McCoy's 5A + 15% FBS SKMEL28 ATCC EMEM + 10% FBS SKMEL3 ATCC McCoy's 5A + 15% FBS SUPB15 ATCC 1MDM + 4mM L-glutamine + 1.5g / L sodium bicarbonate + 0.05mM 2-mercaptoethanol + 20% FBS WERIRB1 ATCC RPMI1640 + 10% FBS WM115 ATCC EMEM + 10% FBS

[1214] Results: As Figure 3 As shown in , uveal melanoma, hematological cancer, prostate cancer, breast cancer and Ewing's sarcoma cell lines were more sensitive to BRG1 / BRM inhibition than other tested cell lines. Inhibition of uveal melanoma, hematological cancer, prostate cancer, breast cancer and Ewing's sarcoma cell lines was maintained until day 7.

[1215] Example 9. Effect of BRG1 / BRM ATPase Inhibition on Cancer Cell Line Growth

[1216] Procedure: Confluent cell viability assays were performed using PRISM (Profiling Relative Inhibition Simultaneously 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 Encuclopedia (CCLE) collection and adapted to RPMI-1640 medium without phenol red and supplemented with 10% heat-inactivated fetal bovine serum (FBS), thereby applying a unique infection and pooling protocol to such a large compendium of cell lines. Using blasticidin as a selection marker, a lentiviral spin-infection protocol was performed to introduce a 24-nucleotide barcode in each cell line, with an estimated multiplicity of infection (MOI) of 1 for all cell lines. More than 750 stably barcoded PRISM cancer cell lines were then pooled together in 25 pools based on their doubling time. For screening, rather than plating a pool of 25 cell lines per well as previously described (Yu et al.), all adherent or all suspension cell line pools were plated together using T25 flasks (100,000 cells / flask) or 6-well plates (50,000 cells / well), respectively. Cells were treated in triplicate with DMSO or compound at an 8-point 3-fold dose response, starting at a maximum concentration of 10 μM. As a control for assay robustness, cells were treated in parallel with two previously validated compounds (pan-Raf inhibitor AZ-628 and proteasome inhibitor bortezomib) using a maximum concentration of 2.5 μM and 0.039 μM, respectively.

[1217] After 3 days of compound treatment, cells were lysed, genomic DNA was extracted, 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 controls and day 0 controls. A dose-response curve was fitted for each cell line, and the corresponding area under the curve (AUC) was calculated and compared with the median AUC for all cell lines ( Figure 4 ). Cell lines with an AUC less than the median value were considered the most sensitive.

[1218] Example 10. Effect of BRG1 / BRM ATPase inhibitors on the growth of uveal melanoma cell lines

[1219] Procedure: Uveal melanoma cell lines (92-1, MP41, MP38, MP46) and non-small cell lung cancer cells (NCIH1299) were plated into 96-well plates with growth medium (see Table 9). The BRG1 / BRM ATPase inhibitor compound 67 was dissolved in DMSO and added to the cells at the time of plating in a concentration gradient from 0 to 10 micromolar. The cells were incubated at 37°C for 3 days. After 3 days of treatment, cell growth was measured using Cell-titerglow (Promega) and luminescence was read on an Envision microplate reader (Perkin Elmer).

[1220] Results: Figure 5 As shown in , Compound B caused potent growth inhibition in uveal melanoma cell lines.

[1221] Example 11. Comparison of BRG1 / BRM inhibitors with clinical PKC and MEK inhibitors in uveal melanoma cell lines

[1222] Procedure: Uveal melanoma cell lines 92-1 or MP41 were plated in 96-well plates in the presence of growth medium (see Table 9). BAF ATPase inhibitor (Compound B), PKC inhibitor (LXS196; MedChemExpress), or MEK inhibitor (selumetinib; Selleck Chemicals) were dissolved in DMSO and added to the cells at the time of plating in a concentration gradient from 0 to 10 micromolar. The cells were incubated at 37°C for 3 days. After 3 days of treatment, cell growth was measured using Cell-titerglow (Promega) and luminescence was read on an Envision microplate reader (Perkin Elmer).

[1223] Results: Figure 6A and Figure 6B As shown in , Compound B exhibited a more potent effect on the growth inhibition of uveal melanoma cells compared to clinical PKC and MEK inhibitors. In addition, Compound B was found to bring about a faster onset of growth inhibition than clinical PKC and MEK inhibitors.

[1224] Example 12. BRG1 / BRM ATPase inhibitors effectively inhibit the growth of PKC inhibitor-resistant cells

[1225] Procedure: MP41 uveal melanoma cells were rendered resistant to a PKC inhibitor (LXS196; MedChemExpress) by long-term culture in growth medium containing increasing concentrations (up to 1 micromolar) of compounds (see Table 9). After 3 months, parental MP41 cells and PKC inhibitor (PKCi)-resistant cells were tested for sensitivity to a PKC inhibitor (LXS196) or a BRG1 / BRM ATPase inhibitor (Compound B) in a 7-day growth inhibition assay as described above in Example 6.

[1226] Results: Although PKCi-resistant cells could tolerate growth at higher concentrations of LXS196 than the parental MP41 cell line ( Figure 7A ), but the BRG1 / BRM ATPase inhibitor (Compound B) still caused strong growth inhibition of PKCi-resistant cell lines and parental cell lines ( Figure 7B PKCi-resistant cells are more sensitive to compound B than parental MP41 cells ( Figure 7B ).

[1227] Example 13. Synthesis of Compound C

[1228]

[1229] Step 1. Preparation of 6-fluoropyridine-2-carbonyl chloride (Intermediate B)

[1230]

[1231] 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 the complete addition of oxalyl chloride, the reaction mixture was warmed to room temperature and stirred for another 0.5 hours. The mixture was concentrated under vacuum to give Intermediate B (56.50 g) as a white solid, which was used in the next step without further purification.

[1232] Step 2. Preparation of 2-chloro-1-(6-fluoro-2-pyridyl) ketene (Intermediate C)

[1233]

[1234] 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 2M trimethylsilyldiazomethane in hexane (351 mL). The resulting reaction mixture was stirred at 25 ° C for 10 hours. The reaction mixture was then quenched with a 4M HCl solution in 1,4-dioxane (500 mL). After stirring for 2 hours, the reaction solution was concentrated under vacuum to give an oil. The residue was diluted with a saturated aqueous NaHCO solution (500 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (300 mL x 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.

[1235] Step 3. Preparation of 4-(6-fluoro-2-pyridyl)thiazol-2-amine (Intermediate E)

[1236]

[1237] 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 hours, the reaction mixture was partially concentrated under vacuum to remove the MeOH, and the resulting solution was acidified to pH ~3 with 2M aqueous HCl. After 15 minutes, the solution was extracted with ethyl acetate (200 mL x 3). The organic layer was discarded, and the aqueous phase was basified with NaHCO₃ (500 mL) and stirred for 30 minutes, then extracted with ethyl acetate (325 mL x 3). The combined organic layers were washed with brine (225 mL x 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 minutes, and filtered. The resulting solid was dried under vacuum to afford Intermediate E (28.00 g, 143.43 mmol, 70.13% yield, 100% purity) as a white solid. LCMS (ESI) m / z: [M+H] + =195.8.; 1 H NMR (400MHz, DMSO-d6) δ8.00-7.96 (m, 1H), 7.72 (d, J = 7.2Hz, 1H), 7.24 (s, 1H), 7.16 (s, 2H), 7.02 (d, J = 8.0Hz, 1H).

[1238] Step 4. Preparation of tert-butyl N-[2-[[4-(6-fluoro-2-pyridyl)thiazol-2-yl]amino]-2-oxo-ethyl]carbamate (Intermediate G)

[1239]

[1240] To N-Boc-glycine (5.92g, 33.81mmol), HATU (12.86g, 33.81mmol) and DIEA (15.89g, 122.94mmol, 21.41mL) in dichloromethane (100mL) solution, add intermediate E (6.00g, 30.74mmol). After stirring for 2 hours, the reaction mixture is concentrated, then diluted with water (100mL) and extracted with ethyl acetate (60mL x 4). The organic layer merged is washed with salt water (100mL x 2), through Na2SO4 drying, filtered and concentrated under reduced pressure to obtain residue. Residue is triturated with a 1:1 mixture (40mL) of petroleum ether and MeOH. After stirring at 25°C for 20 minutes, the suspension was filtered, and the filter cake was washed with MTBE (20 mL) and dried in vacuo 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.

[1241] Step 5. Preparation of 2-((4-(6-fluoropyridin-2-yl)thiazol-2-yl)amino)-2-oxoethan-1-aminium chloride (Intermediate H)

[1242]

[1243] A solution of Intermediate G (5.40 g, 15.32 mmol) in 4M HCl / 1,4-dioxane (35 mL) was stirred at 25° C. for 1.5 hours. The mixture was concentrated under vacuum 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.

[1244] 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)

[1245]

[1246] 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) in sequence. After stirring for 4 hours, the mixture was concentrated under vacuum. The residue was diluted with water (250 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (300 mL x 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 the suspension was filtered after 30 minutes. The solid was washed with MTBE (85 mL x 3) and then dried under vacuum to give Intermediate J (3.10 g, 7.64 mmol, 73.6% yield, 99.0% purity) as a white solid.

[1247] LCMS (ESI) m / z: [M+H] + =402.3.

[1248] 1 H NMR(400MHz,DMSO-d6)δ12.40(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=8.0Hz,1H),6.97(m,1H),6.47(s,1H),4.10(d,J=5.6Hz,2H),1.49(s,9H).

[1249] 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)

[1250]

[1251] To a solution of intermediate J (0.100 g, 0.249 mmol) in DMSO (1 mL) was added DIEA (0.130 mL, 0.747 mmol) and cis-2,6-dimethylmorpholine (0.057 g, 0.498 mmol) and the mixture was stirred at 120 ° C. After 12 hours, 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 C18150*255u; mobile phase: [water (0.075% TFA)-ACN]; B%: 30%-60%, 2 min). 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(400MHz,DMSO-d6)δ12.27(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=7.2Hz,1H),6.96(s,1H),6.79(d, J=8.8Hz,1H),6.47(s,1H),4.24(d,J=12.4Hz,2H),4.08(d,J=5.6Hz,2H), 3.64-3.61(m,2H),2.44-2.38(m,2H),1.49(s,9H),1.18(d,J=5.6Hz,6H).

[1252] Example 14. BRG1 / BRM ATPase inhibitors cause uveal melanoma tumor growth inhibition in vivo

[1253] Procedure: Nude mice (Envigo) were implanted subcutaneously in the axillary region with 5x10 6 92-1 uveal melanoma cells. The tumors were grown to an average size of 200 mm. 3 At this time, the mice were divided into groups and dosing began. Mice were administered vehicle (20% 2-hydroxypropyl-β-cyclodextrin) or increasing doses of Compound C once daily by oral gavage. Tumor volume and body weight were measured over the course of 3 weeks, and the dose was adjusted based on body weight to achieve the appropriate dose in mg / kg. At this time, the animals were sacrificed, and the tumors were excised and imaged.

[1254] 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. Figure 8A and Figure 8BAll treatments were well tolerated and no weight loss was observed ( Figure 8C ).

[1255] Other implementation plans

[1256] Although the invention has been described with reference to specific embodiments thereof, it will be understood that the invention is capable of further modifications, and this application is intended to cover any changes, uses, or adaptations of the invention which generally follow the principles of the invention and which depart from the present disclosure as are known or customary in the art to which the invention pertains and which are applicable to the basic characteristics hereinbefore set forth, and which fall within the purview of the appended claims.

[1257] Other embodiments are within the claims.

Claims

1. A compound having the following structure or a pharmaceutically acceptable salt thereof: in m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; X 1 Yes O, NR 5 or (C(R 5 )(R 6 )), and Z 1 and Z 2 Each independently does not exist or is (C(R 9 )2) or O, if X 1 is O, then Z 1 and Z 2 Each independently does not exist or is (C(R 9 )2); X 2 Is N or CR 8 ; Each R X1 are independently deuterium, optionally substituted C1-C6 alkyl or halogen, or two geminal R X1 The groups, together with the atoms to which they are attached, combine to form a carbonyl group; L 1 is an optionally substituted 9-membered or 10-membered bicyclic heterocyclyl, an optionally substituted 9-membered or 10-membered bicyclic heteroaryl, an optionally substituted monocyclic 6-membered heteroarylvinyl, an optionally substituted monocyclic 6-membered heteroaryl-C3-C8-cycloalkyl or an optionally substituted monocyclic 6-membered heteroarylethynyl; L 2 is absent, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclyl; R 1 is hydrogen or optionally substituted C1-C6 alkyl; Each R 2 and each R 3 are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 4 is hydrogen, halogen, optionally substituted C1-C6 alkyl or optionally substituted C3-C 10 Cycloalkyl; R 5 is hydrogen, deuterium or optionally substituted C1-C6 alkyl; R 6 is hydrogen, deuterium, optionally substituted C1-C6 alkyl or halogen, and each R 9 are independently hydrogen, deuterium, optionally substituted C1-C6 alkyl or halogen; or R 6 and an adjacent R 9 Together with the atoms to which they are attached, they form an optionally substituted C3-C8 cycloalkyl group, and the remaining R 9 The groups, if present, are independently deuterium, optionally substituted C1-C6 alkyl or halogen; Each R 7 are independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, halogen, optionally substituted C3-C 10 cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocyclyl, -N(R 7A )2OR 7A , where each R 7A are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclyl, or two geminal R 7A The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 5- to 10-membered heteroaryl or an optionally substituted 4- to 10-membered heterocyclyl; R 8 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C3-C 10 Cycloalkyl; and R 10 is hydrogen or a halogen.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z 1 Yes (C (R 9 )2).

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z 1 Does not exist.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z 1 It's O.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein Z 2 Yes (C (R 9 )2).

6. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein Z 2 Does not exist.

7. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Z 2 It's O.

8. The compound according to claim 1, 2, 3, 5 or 6, or a pharmaceutically acceptable salt thereof, wherein X 1 It's O.

9. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein X 1 YesNR 5 .

10. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein X 1 Yes (C (R 5 )(R 6 ).

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein X 2 Yes CR 8 .

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Is a group of the following structure 13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Is a group of the following structure 14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein Is a group of the following structure 15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Is a group of the following structure 16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Is a group of the following structure 17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Is a group of the following structure 18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Is a group of the following structure 19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Is a group of the following structure 20. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Is a group of the following structure 21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Is a group of the following structure 22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R 8 It's hydrogen.

23. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R 8 It's a halogen.

24. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein R 8 It's fluorine.

25. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R 8 It is an optionally substituted C2-C6 alkynyl group.

26. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R 8 is an optionally substituted C1-C6 heteroalkyl group.

27. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R 8 is an optionally substituted C3-C 10 Cycloalkyl.

28. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein X 2 It is N.

29. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Is a group of the following structure 30. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R 4 It's hydrogen.

31. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R 4 It's a halogen.

32. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 10 It's hydrogen.

33. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 10 It's a halogen.

34. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein at least one R X1 is an optionally substituted C1-C6 alkyl group.

35. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein at least one R X1 It's a halogen.

36. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein at least one R X1 It's deuterium.

37. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein p is 3.

38. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein p is 2.

39. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein p is 1.

40. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein p is 0.

41. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein L 1 is an optionally substituted 9- or 10-membered bicyclic heteroaryl.

42. A compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein L 1 yes in X 3 , X 4 , X 5 , X 6 , X 7 and X 8 Each independently is N or CR L1 ; Each R L1 are independently H, halogen, optionally substituted C1-C6 alkyl; A 1 is connected to –(C(R 2 )(R 3 )) m -key; and A 2 is connected to L 2 key.

43. A compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein L 1 yes 44. The compound according to claim 43 or a pharmaceutically acceptable salt thereof, wherein R L1 It's hydrogen.

45. A compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein L 1 yes 46. ​​A compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein L 1 yes 47. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein L 1 is an optionally substituted monocyclic 6-membered heteroarylvinyl group.

48. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein L 1 yes in X 3 , X 4 and X 5 Each independently is N or CR L1 ; Each R L1 are independently H, halogen, optionally substituted C1-C6 alkyl; A 1 is connected to –(C(R 2 )(R 3 )) m -key; and A 2 is connected to L 2 key.

49. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein L 1 yes 50. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein L 1 is an optionally substituted monocyclic 6-membered heteroarylethynyl group.

51. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein L 1 yes in X 3 , X 4 and X 5 Each independently is N or CR L1 ; Each R L1 are independently H, halogen, optionally substituted C1-C6 alkyl; A 1 is connected to –(C(R 2 )(R 3 )) m -key; and A 2 is connected to L 2 key.

52. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein L 1 yes 53. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein L 1 is an optionally substituted monocyclic 6-membered heteroaryl-C3-C8-cycloalkyl.

54. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein L 1 yes in X 3 , X 4 and X 5 Each independently is N or CR L1 ; Each R L1 are independently H, halogen, optionally substituted C1-C6 alkyl; A 1 is connected to –(C(R 2 )(R 3 )) m -key; and A 2 is connected to L 2 key.

55. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein L 1 yes 56. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein L 1 is an optionally substituted 9- or 10-membered bicyclic heterocyclic group.

57. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:

58. A compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein L 2 is an optionally substituted 5- to 10-membered heteroaryl.

59. A compound according to any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, wherein -L 2 -(R 7 ) n Is a group of the following structure:

60. The compound according to claim 59 or a pharmaceutically acceptable salt thereof, wherein -L 2 -(R 7 ) n Is a group of the following structure:

61. The compound according to claim 60 or a pharmaceutically acceptable salt thereof, wherein -L 2 -(R 7 ) n Is a group of the following structure:

62. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein -L 2 -(R 7 ) n Is a group of the following structure:

63. The compound according to claim 60 or a pharmaceutically acceptable salt thereof, wherein -L 2 -(R 7 ) n Is a group of the following structure:

64. The compound according to claim 60 or a pharmaceutically acceptable salt thereof, wherein -L 2 -(R 7 ) n Is a group of the following structure:

65. The compound according to claim 60 or a pharmaceutically acceptable salt thereof, wherein -L 2 -(R 7 ) n Is a group of the following structure:

66. A compound according to claims 1 to 58, or a pharmaceutically acceptable salt thereof, wherein L 2 is an optionally substituted C6-C 10 Aryl.

67. The compound according to claim 66 or a pharmaceutically acceptable salt thereof, wherein L 2 is optionally substituted phenyl.

68. A compound according to any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, wherein n is 1.

69. A compound according to any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, wherein n is 2.

70. A compound according to any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, wherein n is 3.

71. A compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, wherein R 7 is an optionally substituted C1-C6 alkyl group.

72. A compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, wherein R 7 is an optionally substituted C1-C6 heteroalkyl group.

73. A compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, wherein R 7 is an optionally substituted 4- to 10-membered heterocyclic group.

74. The compound according to claim 73, or a pharmaceutically acceptable salt thereof, wherein R 7 is optionally substituted azetidinyl or optionally substituted morpholinyl.

75. A compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, wherein R 7 is an optionally substituted C3-C 10 Cycloalkyl.

76. The compound according to claim 75 or a pharmaceutically acceptable salt thereof, wherein R 7 is optionally substituted cyclopropyl or optionally substituted cyclobutyl.

77. A compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, wherein R 7 Yes-N(R 7A )2.

78. The compound according to claim 77 or a pharmaceutically acceptable salt thereof, wherein R 7 is optionally substituted N-azetidinyl or optionally substituted N-morpholinyl.

79. A compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, wherein the two geminal R 7 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 4- to 10-membered heterocyclyl.

80. A compound according to any one of claims 1 to 79, or a pharmaceutically acceptable salt thereof, wherein at least one R 7 Yes-OR 7A .

81. The compound according to claim 80 or a pharmaceutically acceptable salt thereof, wherein R 7A is an optionally substituted C 1-6 alkyl.

82. A compound according to any one of claims 1 to 81, or a pharmaceutically acceptable salt thereof, wherein n is 0.

83. A compound according to any one of claims 1 to 82, or a pharmaceutically acceptable salt thereof, wherein at least one R 7 is difluoromethyl, 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, fluorine, chlorine, 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-fluorocyclobutane-1-yl, 3-fluoropyrrolidin-1-yl, 3-methoxypyrrolidin-1-yl, oxetan-3-yl, N-methylindolin-4-yl, 2,2-difluoro-3-methylcyclopropan-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]hexan-5-yl, 1-fluoromethyl-cyclopropyl, N-(3-tetrahydrofuranyl)methylamino, N-indolyl, N-1,4-oxazepanyl, 2-fluoro-2-propyl, 1,1-difluoro-2-propyl, 2,2-difluoro-1-methylcyclopropyl-1-yl, 1-methylcyclopropyl, 4,4-difluoropiperidin-1-yl, 2-methoxyethoxy, 3,3-difluorocyclobutan-1-yl, N-methyl-N-1-methoxypropyl-2-ylamino, 1-methoxypropyl-2-ylamino, 1-methoxyethyl, 4-methylpiperazinyl, 3-methylmorpholinyl, 2,2-difluoro propoxy, 3-methoxycyclobutyl, methylamino, 4-dimethylamino-3,3-difluoropiperidinyl, 4-methylamino-3,3-difluoropiperidinyl, 3,3-difluoropyrrolidinyl, N-methyl-N-3-methoxycyclobutylamino, 1-methylpyrazol-5-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl, cyclopropoxy, 2,6-dimethylpyridin-4-yl, 2-methylpyrrolidinyl, 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.

84. A compound according to any one of claims 1 to 56 and 58 to 83, or a pharmaceutically acceptable salt thereof, wherein R 1 It's hydrogen.

85. A compound according to any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof, wherein Is a group of the following structure 86. A compound according to any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof, wherein Is a group of the following structure 87. A compound selected from the group consisting of Compound 1-523 and pharmaceutically acceptable salts thereof.

88. A compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, wherein the compound has a BRG1 IC of at least 5. 50 With BRMIC 50 ratio.

89. A compound according to any one of claims 1 to 88, or a pharmaceutically acceptable salt thereof, wherein the compound has a BRG1 IC of at least 10. 50 With BRMIC 50 ratio.

90. A compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, wherein the compound has a BRG1 IC of at least 20. 50 With BRMIC 50 ratio.

91. A compound according to any one of claims 1 to 90, or a pharmaceutically acceptable salt thereof, wherein the compound has a BRG1 IC of at least 30. 50 With BRMIC 50 ratio.

92. A pharmaceutical composition comprising a compound according to any one of claims 1 to 91 and a pharmaceutically acceptable excipient.

93. 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 a compound according to any one of claims 1 to 91 or a pharmaceutical composition according to claim 92.

94. The method of claim 93, wherein the BAF complex-associated disorder is cancer or a viral infection.

95. A method of treating a disorder associated with a BRG1 loss-of-function mutation in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 91 or a pharmaceutical composition according to claim 92.

96. The method of claim 95, wherein the disorder associated with a BRG1 loss-of-function mutation is cancer.

97. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 91 or a pharmaceutical composition according to claim 92.

98. The method of any one of claims 93 to 97, wherein 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, esophageal-gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin 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, adrenocortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

99. The method of claim 98, wherein 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, soft tissue sarcoma, or penile cancer.

100. The method of claim 99, wherein the cancer is non-small cell lung cancer.

101. The method of claim 99, wherein the cancer is a soft tissue sarcoma.

102. A compound according to any one of claims 1 to 91 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 92, for use in the treatment of cancer.

103. A compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 102, 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-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, adrenocortical carcinoma, appendix cancer, small intestine cancer or penile cancer.

104. The compound for use according to claim 102, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary focus, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer or penile cancer.

105. The compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition for use according to claim 102, wherein the cancer is non-small cell lung cancer.

106. The compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition for use according to claim 102, wherein the cancer is a soft tissue sarcoma.

107. A compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 102 to 106, wherein the cancer is metastatic.

108. A compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 102 to 107, further comprising an anti-cancer therapy.

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