Compounds and their uses

Abstract

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

Description

[Technical field]

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

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

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

[0004] In one aspect, the invention provides a compound having the structure of Formula I, [ka] During the ceremony, X is halo (e.g., F, Cl, Br, or I); X 1 is absent, O or NR 1 and k is 0, 1, 2, or 3; n is 0, 1, or 2; R 1 is H or optionally substituted C1-C6 alkyl; L 1 is an optionally substituted C1-C6 alkylene, an optionally substituted C2-C6 alkenylene, or an optionally substituted C2-C6 alkynylene; L 2 is absent or optionally substituted C1-C6 alkylene, optionally substituted C1-C 20 heteroalkylene, or an optionally substituted C2-C9 heterocyclylene; Each L 3 are independently optionally substituted C-C 20 Heteroalkylene, optionally substituted C-C 10 Carbocyclylene, optionally substituted C3-C 10 Carbocyclylene-C1-C6 alkylene, optionally substituted C2-C9 heterocyclylene, optionally substituted C2-C9 heterocyclylene-C1-C6 alkylene, optionally substituted C6-C 10 Arylene, optionally substituted C-C 10 arylene-C1-C6 alkylene, optionally substituted C2-C6 alkynylene, O, or NR 1 and A compound in which D is a decomposition moiety, or a pharma- ceutically acceptable salt thereof.

[0005] In some embodiments, k is 0. In some embodiments, k is 1.

[0006] In some embodiments, X 1 In some embodiments, X is absent. 1 is O or NR 1 It is.

[0007] In some embodiments, R 1 is an optionally substituted C-C alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is H.

[0008] In some embodiments, L 1 is an optionally substituted C1-C6 alkylene.

[0009] In some embodiments, L 1 teeth, [ka] It is.

[0010] In some embodiments, L 2 does not exist.

[0011] In some embodiments, L 2 In some embodiments, L 2 is an optionally substituted C1-C6 alkylene.

[0012] In some embodiments, L 2 teeth, [ka] It is.

[0013] In some embodiments, L 2 is an optionally substituted C1-C 20 It is a heteroalkylene.

[0014] In some embodiments, L 2 teeth, [ka] It is.

[0015] In some embodiments, n is 1. In some embodiments, n is 2.

[0016] In some embodiments, at least one L 3 is an optionally substituted C3-C 10 Carbocyclylene-C1-C6 alkylene, optionally substituted C2-C9 heterocyclylene, optionally substituted C2-C9 heterocyclylene-C1-C6 alkylene, optionally substituted C1-C 20 Heteroalkylene, O, or NR 1 In some embodiments, at least one L 3 is an optionally substituted C1-C 20 It is a heteroalkylene.

[0017] In some embodiments, at least one L 3 teeth, [ka] It is.

[0018] In some embodiments, n is 0.

[0019] In some embodiments, the degradation moiety is a ubiquitin ligase binding moiety, hi some embodiments, the ubiquitin ligase binding moiety comprises a cereblon ligand, an IAP (inhibitor of apoptosis) ligand, mouse double minute 2 homolog (MDM2), or a von Hippel-Lindau ligand.

[0020] In some embodiments, the decomposition moiety has the structure of Formula A: [ka] During the ceremony, Y1 but, [ka] and R A5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R A6 is H or optionally substituted C1-C6 alkyl, or R A7 is H or optionally substituted C1-C6 alkyl, or R A6 and R A7 each combines together with the carbon atom to which it is attached to form an optionally substituted C3-C6 carbocyclyl or an optionally substituted C2-C5 heterocyclyl, or R A6 and R A7 each combines together with the carbon atom to which it is attached to form an optionally substituted C3-C6 carbocyclyl or an optionally substituted C2-C5 heterocyclyl; R A8 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R A1 , R A2 , R A3 , and R A4 Each of the above is independently H, A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted —O—C3-C6 carbocyclyl, hydroxyl, thiol, or optionally substituted amino, or R A1 and R A2 , R A2 and R A3, and / or R A3 and R A4 combine with the carbon atoms to which they are attached, [ka] Forming [ka] Optionally substituted C6-C 10 Aryl, optionally substituted C-C 10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, any of which is optionally represented by A 2 is replaced by R A1 , R A2 , R A3 , and R A4 One of them is A 2 or [ka] But, A 2 is replaced by A 2 is the bond between the degradation moiety and the linker.

[0021] In some embodiments, R A5 is H or methyl. In some embodiments, R A5 is H.

[0022] In some embodiments, R A1 , R A2 , R A3 , and R A4 Each of is independently H or A 2 In some embodiments, R A1 A 2 and R A2 , R A3 , and R A4 Each of is H. In some embodiments, R A2 A2 and R A1 , R A3 , and R A4 Each of is H. In some embodiments, R A3 A 2 and R A1 , R A2 , and R A4 Each of is H. In some embodiments, R A4 A 2 and R A1 , R A2 , and R A3 Each of is H.

[0023] In some embodiments, Y 1 teeth, [ka] It is.

[0024] In some embodiments, R A6 is H.

[0025] In some embodiments, R A7 is H.

[0026] In some embodiments, Y 1 teeth, [ka] It is.

[0027] In some embodiments, R A8 is H or optionally substituted C1-C6 alkyl. In some embodiments, R A8 is H or methyl. In some embodiments, R A8 is methyl.

[0028] In some embodiments, the decomposition moiety has the structure of formula A2: [ka] , has.

[0029] In some embodiments, the decomposition moiety has the structure of formula A4: [ka] , has.

[0030] In some embodiments, the decomposition moiety has the structure of formula A5: [ka] , has.

[0031] In some embodiments, the decomposition moiety has the structure of formula A6: [ka] , has.

[0032] In some embodiments, the decomposition moiety has the structure of formula A8: [ka] , has.

[0033] In some embodiments, the decomposition moiety has the structure of formula A10: [ka] , has.

[0034] In some embodiments, the degradation moiety has the following structure: [ka] has.

[0035] In some embodiments, the degradation moiety has the following structure: [ka] has.

[0036] In some embodiments, the moiety has the structure of formula C: [ka] During the ceremony, L 4 But -N(R B1 )(R B2 ), [ka] and R B1 But, H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R B3 But, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkylC3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, R B4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkylC3-C 10 Carbocyclyl or optionally substituted C1-C6 alkylC6-C 10 is aryl, R B5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; Each R B6But independently, A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; R B7 and R B8 each independently represents H, halogen, optionally substituted C-C alkyl, or optionally substituted C-C 10 is aryl, R B9 is H or optionally substituted C1-C6 alkyl; A 2 is the bond between the degradation moiety and the linker, R B1 , R B3 , and R B6 Only one of the 2 It has a structure, where

[0037] In some embodiments, the decomposition moiety has the structure of formula C1: [ka] , has.

[0038] In some embodiments, the decomposition moiety has the structure of formula C2: [ka] , has.

[0039] In some embodiments, R B9 is an optionally substituted C-C alkyl. In some embodiments, R B9 is methyl. In some embodiments, R B9is attached to the (S)-stereocenter. In some embodiments, R B9 is hydrogen.

[0040] In some embodiments, the degradation moiety has the following structure: [ka] has.

[0041] In some embodiments, the degradation moiety has the following structure: [ka] has.

[0042] In some embodiments, the degradation moiety has the following structure: [ka] has.

[0043] In some embodiments, the degradation moiety has the following structure: [ka] has.

[0044] In some embodiments, the degradation moiety is [ka] has.

[0045] In some embodiments, the degradation moiety has the structure [ka] wherein A 2 is the bond between the degradation moiety and the linker.

[0046] In some embodiments, k is 0.

[0047] The compound is selected from the group consisting of compounds 1 to 105 in Table 1, and pharma- ceutically acceptable salts thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

[0048] In some embodiments, the compound is 50 and BRM IC 50 In some embodiments, the compound has a ratio of BRG1 IC 50 and BRM IC 50 In some embodiments, the compound has a ratio of BRG1 IC 50 and BRM IC 50 In some embodiments, the compound has a ratio of BRG1 IC 50 and BRM IC 50 In some embodiments, the compound has a ratio of BRG1 IC50 and BRM IC 50 In some embodiments, the compound has a ratio of BRG1 IC 50 and BRM IC 50 In some embodiments, the compound has a ratio of BRG1 IC 50 and BRM IC 50 The ratio of

[0049] In one aspect, the invention features a pharmaceutical composition including any of the aforementioned compounds and a pharma- ceutically acceptable excipient.

[0050] In another aspect, the invention features a method for decreasing activity of a BAF complex in a cell, comprising contacting the cell with an effective amount of any of the aforementioned compounds, or a pharmaceutical composition thereof.

[0051] In some embodiments, the cell is a cancer cell.

[0052] In another aspect, the invention features a method of treating a BAF complex-associated disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutical composition thereof.

[0053] In some embodiments, the BAF complex-associated disorder is cancer.

[0054] In a further aspect, the invention features a method of inhibiting BRM, the method including contacting a cell with an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutical composition thereof.

[0055] In some embodiments, the cell is a cancer cell.

[0056] In another aspect, the invention features a method of inhibiting BRG1, the method including contacting a cell with an effective amount of any of the aforementioned compounds, or a pharmaceutical composition thereof.

[0057] In some embodiments, the cell is a cancer cell.

[0058] In a further aspect, the invention features a method of inhibiting BRM and BRG1, the method comprising contacting a cell with an effective amount of any of the aforementioned compounds or a pharmaceutical composition thereof.

[0059] In some embodiments, the cell is a cancer cell.

[0060] In another aspect, the invention features a method of treating a disorder associated with a loss-of-function mutation in BRG1 in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutical composition thereof.

[0061] In some embodiments, the disorder associated with BRG1 loss-of-function mutation is cancer.In other embodiments, the subject is determined to have a BRG1 loss-of-function disorder, for example, is determined to have a BRG1 loss-of-function cancer (for example, the cancer is determined to comprise cancer cells with BRG1 loss-of-function).

[0062] In another aspect, the invention features a method of inducing apoptosis in a cell, the method including contacting the cell with an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutical composition thereof.

[0063] In some embodiments, the cell is a cancer cell.

[0064] In a further aspect, the invention features a method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound) or a pharmaceutical composition thereof.

[0065] In some embodiments of any of the aforementioned methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary site, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, CNS cancer, thymic tumor, adrenal cortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

[0066] In some embodiments of any of the aforementioned methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

[0067] In some embodiments of any of the foregoing methods, the cancer is a drug-resistant cancer or has undergone chemotherapy or chemotherapy treatment after prior therapy (e.g., vemurafenib, dacarbazine, CTLA4 inhibitors, PD1 inhibitors, interferon therapy, BRAF inhibitors, MEK inhibitors, radiation therapy, temozolomide, irinotecan, CAR-T therapy, Herceptin®, Perjeta®, tamoxifen, Xeloda®, docetaxel, platinum agents such as carboplatin, paclitaxel, and have not responded to prior chemotherapy or chemotherapy regimens (taxanes such as cyclophosphamide and docetaxel, ALK inhibitors, MET inhibitors, Alimta®, Abraxane®, Adriamycin®, gemcitabine, Avastin®, Halaven®, neratinib, PARP inhibitors, ARN810, mTOR inhibitors, topotecan, Gemzar®, VEGFR2 inhibitors, folate receptor antagonists, demcizumab, fosbretabine, or PDL1 inhibitors).

[0068] 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.

[0069] In another aspect, the disclosure provides a method of treating a BAF-associated disorder (e.g., cancer or viral infection) in a subject in need thereof, comprising contacting a cell with an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound), or a pharma- ceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, the disorder is a retrovirus from the family Retroviridae, such as lentivirus (e.g., human immunodeficiency virus (HIV) and delta retrovirus (e.g., human T-cell leukemia virus type I (HTLV-I)), human T-cell leukemia virus type II (HTLV-II)), Hepadnaviridae (e.g., hepatitis B virus (HBV)), Flaviviridae (e.g., hepatitis C virus (HCV)), Adenoviridae (e.g., human adenovirus), Herpesviridae (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), human herpes virus type 6 (HHV-6), herpes virus K*, CMV, varicella zoster virus), Papillomaviridae (e.g., human papillomavirus (HPV, HPV E1), Parvoviridae family (e.g., parvovirus B19), Polyomaviridae family (e.g., JC virus and BK virus), Paramyxoviridae family (e.g., measles virus), Togaviridae family (e.g., rubella virus). In some embodiments, the disorder is coffin schisis, neurofibromatosis (e.g., NF-1, NF-2, or schwannoma), or multiple meningiomas.

[0070] In another aspect, the disclosure provides a method for treating a viral infection in a subject in need thereof, comprising administering to the subject an effective amount of any of the aforementioned compounds (e.g., a BRM / BRG1 dual inhibitor compound or a BRM selective compound), or a pharma- ceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, the viral infection is a viral infection, such as a retroviridae family, such as lentivirus (e.g., human immunodeficiency virus (HIV) and delta retrovirus (e.g., human T-cell leukemia virus type I (HTLV-I)), human T-cell leukemia virus type II (HTLV-II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., human adenovirus), Herpesviridae family (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), human herpes virus type 6 (HHV-6), herpes virus K*, CMV, varicella zoster virus), Papillomaviridae family (e.g., human papillomavirus (HPV), HPV E1), Parvoviridae (e.g. parvovirus B19), Polyomaviridae (e.g. JC virus and BK virus), Paramyxoviridae (e.g. measles virus), or Togaviridae (e.g. rubella virus).

[0071] In some embodiments of any of the foregoing aspects, the compound is a BRM selective compound. In some embodiments, the BRM selective compound inhibits the level and / or activity of BRM to at least 10 times greater than the compound inhibits the level and / or activity of BRG1, and / or the compound binds to BRM to at least 10 times greater than the compound binds to BRG1. For example, in some embodiments, the BRM selective compound has an IC 50 or IP 50 At least 10-fold lower IC50 or IP 50 In some embodiments of any of the foregoing aspects, the compound is a BRM / BRG1 dual inhibitor compound. In some embodiments, the BRM / BRG1 dual inhibitor compound has similar activity against both BRM and BRG1 (e.g., activity of the compound against BRM and BRG1 within 10-fold (e.g., less than 5-fold, less than 2-fold). In some embodiments, the activity of the BRM / BRG1 dual inhibitor compound is greater against BRM. In some embodiments, the activity of the BRM / BRG1 dual inhibitor compound is greater against BRG1. For example, in some embodiments, the BRM / BRG1 dual inhibitor compound has an IC 50 or IP 50 However, IC 50 or IP 50 is within 10 times.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0093] As used herein, the term "alkyl" refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 3 carbon atoms).

[0094] Alkylene is a divalent alkyl group. As used herein, the term "alkenyl," alone or in combination with other groups, refers to a straight-chain 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).

[0095] As used herein, the term "alkynyl," alone or in combination with other groups, refers to a straight-chain or branched 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).

[0096] As used herein, the term “amino” refers to —N(R N1 )2, and each R N1 are independently H, OH, NO2, N(R N2 )2, SO2OR N2 , SO2R N2 , SOR N2 , an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), and these enumerated R N1 Each of the groups may be optionally substituted or may have two R N1 combine to form an alkylene or heteroalkylene, and each R N2 is independently H, alkyl, or aryl. The amino group of the present invention can be an unsubstituted amino (i.e., -NH) or a substituted amino (i.e., -N(R N1 )2).

[0097] As used herein, the term "aryl" refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.

[0098] As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are 7-30 carbon (e.g., C1-C6 alkyl, C6 ... 10 Aryl, C1-C 10 Alkyl C6-C 10 Aryl or C1-C 20 Alkyl C6-C 10 aryl, 7-16 or 7-20 carbons. In some embodiments, alkyl and aryl can each be further substituted with 1, 2, 3, or 4 substituents as defined herein for each group.

[0099] As used herein, the term "azido" refers to a -N3 group.

[0100] As used herein, the term "bridged cyclyl" refers to a bridged polycyclic group of 5 to 20 carbons containing 1 to 3 bridges.

[0101] As used herein, the term "cyano" refers to a -CN group.

[0102] As used herein, the term "carbocyclyl" refers to a non-aromatic C-C ring formed by carbon atoms. 12 It refers to a monocyclic, bicyclic or tricyclic structure. The carbocyclyl structure includes a cycloalkyl group and an unsaturated carbocyclyl radical.

[0103] As used herein, the term "cycloalkyl" refers to a saturated non-aromatic monovalent mono- or polycarbocyclic radical of three to ten, preferably three to six, carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

[0104] As used herein, the term "halo" means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0105] As used herein, the term "heteroalkyl" refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms are replaced with nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group may be further substituted with one, two, three, or four substituents, as described herein for alkyl groups. An example of a heteroalkyl group is "alkoxy," which as used herein refers to alkyl-O- (e.g., methoxy and ethoxy). Heteroalkylene 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 the constituent carbon atoms are replaced with nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group may be further substituted with one, two, three, or four substituents, as described herein for alkenyl groups. An example of a heteroalkenyl group is "alkenoxy," which as used herein refers to alkenyl-O-. Heteroalkenylene 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 the constituent carbon atoms is replaced with nitrogen, oxygen, or sulfur. In some embodiments, a heteroalkynyl group can be further substituted with one, two, three, or four substituents as described herein for an alkynyl group. An example of a heteroalkynyl group is "alkynoxy", which as used herein refers to alkynyl-O-. Heteroalkynylene is a divalent heteroalkynyl group.

[0106] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced by a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.

[0107] As used herein, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups include those having 7 to 30 carbons (e.g., C1-C6 alkyl, C2-C9 heteroaryl, C1-C 10 Alkyl C2-C9 Heteroaryl, or C1-C 20 and alkyl, C2-C9, 7-16 or 7-20 carbons, such as heteroaryl. In some embodiments, alkyl and heteroaryl can each be further substituted with 1, 2, 3, or 4 substituents as defined herein for each group.

[0108] As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic radical having 3 to 12 atoms with at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S, and the aromatic ring does not contain any N, O, or S atoms. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl.

[0109] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups include those having 7 to 30 carbons (e.g., C1-C6 alkyl, C2-C9 heterocyclyl, C1-C 10Alkyl C2-C9 heterocyclyl, or C1-C 20 and alkyl, C2-C9 heterocyclyl, 7-16 or 7-20 carbons. In some embodiments, alkyl and heterocyclyl can each be further substituted with 1, 2, 3, or 4 substituents as defined herein for each group.

[0110] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with an --OH group.

[0111] As used herein, the term "hydroxyl" refers to an --OH group.

[0112] As used herein, the term "N-protecting group" refers to a group intended to protect an amino group against undesired reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 3rd Edition (John Wiley & Sons, New York, 1999).N-protecting groups include, but are not limited to, acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D,L, or D,L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl; benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-20 dimethoxybenzyl Oxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl 3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl Carbamate-forming groups such as aryl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups such as trimethylsilyl. Preferred N-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0113] As used herein, the term "nitro" refers to a -NO2 group.

[0114] As used herein, the term "thiol" refers to a --SH group.

[0115] Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. If substituted, there are typically 1-4 substituents present, unless otherwise specified. Substituents include, for example, alkyl (e.g., unsubstituted and substituted, where the substituents include any group described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkylamino), azido, cyano, nitro, or thiol. Another exemplary substituent is oxo. For example, a carbonyl group is a carbon (e.g., an alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, etc.) substituted with an oxo. Alternatively, sulfur may be substituted with one or two oxo groups (e.g., -SO- or -SO2- in a substituted heteroalkyl, heteroalkenyl, heteroalkynyl, or heterocyclyl group). Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted, e.g., arylalkyl (e.g., substituted and unsubstituted benzyl)). In some embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, heteroaryl, heterocyclyl, amino (e.g., NH or mono- or dialkylamino), azido, cyano, nitro, thiol, and oxo. In some embodiments, the substituents are themselves unsubstituted.

[0116] The compounds of the present invention can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, or mixtures of diastereomeric racemates. Optically active forms can be obtained, for example, by resolution of racemates, by asymmetric synthesis or asymmetric chromatography (chromatography using chiral adsorbents or eluents). That is, certain disclosed compounds can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are most commonly pairs of stereoisomers whose mirror images are not superimposable because they contain asymmetrically substituted carbon atoms that function as chiral centers. Enantiomers refer to one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are most commonly stereoisomers that are not related as mirror images because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound may be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. Suitable techniques and / or methods for separating enantiomers of the compounds described herein from racemic mixtures can be readily determined by one of ordinary skill in the art. "Racemate" or "racemic mixture" refers to a compound containing two enantiomers, and such mixtures do not exhibit optical activity, i.e., they do not rotate the plane of polarized light. "Geometric isomer" refers to isomers that differ in the orientation of substituted atoms in relationship to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in the E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. "R", "S", "S*", "R*", "E", "Z", "cis", and "trans" refer to configurations relative to the core molecule. Certain disclosed compounds may exist in atropisomeric forms.Atropisomers are stereoisomers resulting from hindered rotation around a single bond, where the steric strain barrier to rotation is high enough to allow the isolation of the conformers. The compounds of the present invention can be prepared as individual isomers by isomer-specific synthesis or by resolution from an isomeric mixture. Traditional resolution techniques include forming a salt of the free base of each isomer of the isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming a salt of the acid form of each isomer of the isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each isomer of the isomeric pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving the isomeric mixture of either the starting material or the final product using a variety of well-known chromatographic methods. When the stereochemistry of a disclosed compound is named or shown by structure, the named or shown stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers. When a single enantiomer is named or shown by structure, the shown or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure. When a single diastereomer is named or shown by structure, the shown or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure. Percent optical purity is the weight of the enantiomer, or the ratio of the weight of the enantiomer to the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer to the weight of all diastereomers. When the stereochemistry of a disclosed compound is named or shown by structure, the named or shown stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction relative to the other stereoisomer.When a single enantiomer is named or shown by structure, the shown or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction. When a single diastereomer is named or shown by structure, the shown or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction. Percent purity by mole fraction is the ratio of moles of enantiomer, or moles of enantiomer and moles of its optical isomer. Similarly, percent purity by mole fraction is the ratio of moles of diastereomer, or moles of diastereomer and moles of its isomer. When a disclosed compound is named or shown by structure without showing stereochemistry and the compound has at least one chiral center, the name or structure should be understood to encompass any of the enantiomers of the compound free of the corresponding optical isomer, a racemic mixture of the compound, a mixture of the compound, or a mixture enriched in one enantiomer with respect to its corresponding optical isomer. When a disclosed compound is named or shown by structure without showing stereochemistry and the compound has more than one chiral center, the name or structure should be understood to encompass any of the diastereomers free of the other diastereomers, any of the diastereomers free of other diastereomer pairs, mixtures of diastereomers, mixtures of diastereomer pairs, mixtures of diastereomers enriched in one diastereomer with respect to the other diastereomers, or mixtures of diastereomers enriched in one or more diastereomers with respect to the other diastereomers. The present invention encompasses all of these forms.

[0117] The compounds of the present disclosure also include all isotopes of atoms present in intermediate or final compounds. "Isotopes" refers to atoms with the same atomic number but different mass numbers resulting from different numbers of neutrons in the nucleus. For example, isotopes of hydrogen include tritium and deuterium.

[0118] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the invention include: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Isotopically labeled compounds (e.g., 3 H and 14 C) may be useful in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes can be useful for their ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) due to greater metabolic stability. In some embodiments, one or more hydrogen atoms are 2 H or 3 H or one or more carbon atoms are replaced by 13 C or 14 Replaced by C-enriched carbon. 15 O. 13 N, 11 C, and 18Positron-emitting isotopes such as F are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by following procedures similar to those disclosed for the compounds of the present invention described herein, by substituting non-isotopically labeled reagents for isotopically labeled reagents. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Methods and materials for use in this disclosure are described herein. Other suitable methods and materials known in the art can also be used. These materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, shall control.

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

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

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

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

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

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

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

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

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

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

[0129] "Reduce the activity of BAF complex" means to reduce the level of activity or downstream effect associated with BAF complex. A non-limiting example of reducing the activity of BAF complex is activation of Sox2. The activity level of BAF complex can be measured using any method known in the art, for example, the method described in Kadoch et al. Cell, 2013, 153, 71-85, which is incorporated herein by reference.

[0130] As used herein, the term "degrading agent" refers to a small molecule compound that contains a degrading moiety, where the compound interacts with a protein (e.g., BRG1 and / or BRM) in a manner that results in degradation of the protein (e.g., binding of the compound results in at least a 5% reduction in the levels of the protein, e.g., in a cell or subject).

[0131] As used herein, the term "degradation moiety" refers to a moiety that upon binding results in degradation of a protein (e.g., BRG1 and / or BRM). In one example, the moiety binds to a protease or ubiquitin ligase that metabolizes the protein (e.g., BRG1 and / or BRM).

[0132] "Modulating the activity of a BAF complex" means altering the level of activity associated with a BAF complex (e.g., GBAF) or associated downstream effect. The activity level of a BAF complex can be measured using any method known in the art, for example, the method described in Kadoch et al, Cell 153:71-85 (2013), which is incorporated herein by reference.

[0133] "Reducing the activity of BRG1 and / or BRM" means reducing the level of activity or downstream effects associated with BRG1 and / or BRM. A non-limiting example of inhibiting the activity of BRG1 and / or BRM is reducing the level of the BAF complex in a cell. The activity level of BRG1 and / or BRM can be measured using any method known in the art. In some embodiments, the agent that reduces the activity of BRG1 and / or BRM is a small molecule BRG1 and / or BRM degrader.

[0134] "Reducing the level of BRG1 and / or BRM" means decreasing the level of BRG1 and / or BRM in a cell or a subject. The level of BRG1 and / or BRM can be measured using any method known in the art.

[0135] By "level" is meant the level of a protein or of the mRNA encoding the protein, as compared to a reference material. A reference material can be any useful reference material, as defined herein. A "decreased level" or "increased level" of a protein means a decrease or increase in protein level as compared to a reference material (e.g., 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 decrease or increase, as compared to a reference material). about a 10%, 15%, 20%, 50%, 75%, 100%, or greater than about a 200% decrease or increase, about a 0.01-fold, about a 0.02-fold, about a 0.1-fold, about a 0.3-fold, about a 0.5-fold, about a 0.8-fold decrease or increase, or less than about a 1.2-fold, about a 1.4-fold, about a 1.5-fold, about a 1.8-fold, about a 2.0-fold, about a 3.0-fold, about a 3.5-fold, about a 4.5-fold, about a 5.0-fold, about a 10-fold, about a 15-fold, about a 20-fold, about a 30-fold, about a 40-fold, about a 50-fold, about a 100-fold, or greater increase). Protein levels may be expressed as mass / volume (e.g., g / dL, mg / mL, μg / mL, ng / mL) or as a percentage of the total protein or mRNA in the sample.

[0136] As used herein, the term "inhibiting BRM" refers to blocking or reducing the level or activity of the ATPase catalytic binding domain or bromodomain of a protein. BRM inhibition can be determined using methods known in the art, such as the BRM ATPase assay, the Nano DSF assay, or the BRM luciferase cellular assay.

[0137] As used herein, the term "pharmaceutical composition" refers to a composition comprising a compound described herein, formulated with a pharmaceutically acceptable excipient and suitable for administration to a mammal, e.g., a human. Typically, a pharmaceutical composition is manufactured or sold by approval of a government regulatory agency as part of a therapeutic regimen for the treatment of a disease in a mammal. A pharmaceutical composition can be formulated, for example, for oral administration in a unit dosage form (e.g., tablet, capsule, caplet, gelcap, or syrup), for topical administration (e.g., as a cream, gel, lotion, or ointment), for intravenous administration (e.g., as a sterile solution free of particulate embolic material and in a solvent system suitable for intravenous use), or in any other pharmaceutically acceptable formulation.

[0138] As used herein, "pharmaceutical acceptable excipient" refers to any component of a compound described herein (e.g., a vehicle capable of suspending or dissolving an active compound) and having the properties of being substantially non-toxic and non-inflammatory in a patient. Excipients may include, for example, anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film-forming or coating agents, flavors, fragrances, glidants (glidants), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water of hydration.

[0139] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt of a compound, for example, any compound of formula I. The pharmaceutically acceptable salt of any of the compounds described herein may include salts that are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base group with a suitable organic acid.

[0140] The compounds of the present invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts, including inorganic or organic acids, or salts may be prepared from inorganic or organic bases when the compounds of the present invention are in acidic form. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases, as well as methods for preparing suitable salts, are well known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases.

[0141] "Reference material" refers to any useful reference material used to compare protein or RNA levels. A reference material can be any sample, standard, standard curve, or level used for comparison purposes. A reference material can be a normal reference sample or a reference standard or level. A "reference sample" can be, for example, a control, e.g., a predefined negative control value such as a "normal control," or a previous sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., cell or tissue) from a subject without a disease; a sample from a subject diagnosed with a disease but not yet treated with a compound of the invention; a sample from a subject being treated with a compound of the invention; or a sample of a known normal concentration of purified protein or RNA (e.g., any of those described herein). "Reference standard or level" refers to a value or numerical value derived from a reference sample. A "normal control value" is a predefined value indicative of a non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range ("between X and Y"), a high threshold ("below X"), or a low threshold ("above X"). A subject having a measurement within the normal control value of a particular biomarker is typically referred to as being "within the normal range" for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject without a disease or disorder (e.g., cancer); a subject being treated with a compound of the present invention. In a preferred embodiment, the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, stage of disease, and overall health. A standard curve of purified protein or RNA levels within the normal reference range, such as any of those described herein, can also be used as a reference.

[0142] As used herein, the term "subject" refers to any organism to which a composition according to the invention may be administered, for example, for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may be a human or animal seeking or in need of treatment, requesting treatment, undergoing treatment, will be undergoing treatment in the future, or being treated by a trained professional for a particular disease or condition.

[0143] As used herein, the terms "treat", "treated" or "treating" refer to a therapeutic treatment or any procedure, the purpose of which is to slow (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; attenuation of the severity of the condition, disorder, or disease; stabilization (i.e., not worsening) of the condition, disorder, or disease; delaying or slowing the onset of progression of the condition, disorder, or disease; improvement or remission (partial or complete) of the condition, disorder, or disease state; improvement of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or amelioration of the condition, disorder, or disease. Treatment includes eliciting a clinically significant response without an excessive level of side effects. Treatment also includes prolonging survival compared to the expected survival in the absence of treatment. The compounds of the invention can also be used to "prophylactically treat" or "prevent" disorders, for example, in subjects at increased risk of developing the disorder.

[0144] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will become apparent from the description and the claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0145] The present disclosure features compounds useful for inhibiting BRG1 and optionally BRM. These compounds may be used to modulate the activity of the BAF complex, for example, for the treatment of BAF-related disorders (e.g., loss-of-function disorders of BRG1), such as cancer. Exemplary compounds described herein include compounds having a structure according to Formula I, or a pharma- ceutically acceptable salt thereof.

[0146] Formula I: [ka] During the ceremony, X is a halo; X 1 is absent, O or NR 1 and k is 0, 1, 2, or 3; n is 0, 1, or 2; R 1 is H or optionally substituted C1-C6 alkyl; L 1 is an optionally substituted C1-C6 alkylene, an optionally substituted C2-C6 alkenylene, or an optionally substituted C2-C6 alkynylene; L 2 is absent or optionally substituted C1-C6 alkylene, optionally substituted C1-C 20 heteroalkylene, or an optionally substituted C2-C9 heterocyclylene; Each L 3 are independently optionally substituted C-C 20 Heteroalkylene, optionally substituted C-C 10 Carbocyclylene, optionally substituted C3-C 10 Carbocyclylene-C1-C6 alkylene, optionally substituted C2-C9 heterocyclylene, optionally substituted C2-C9 heterocyclylene-C1-C6 alkylene, optionally substituted C6-C 10 Arylene, optionally substituted C-C 10arylene-C1-C6 alkylene, optionally substituted C2-C6 alkynylene, O, or NR 1 and D is the decomposition portion.

[0147] In some embodiments, the compound has the structure of any one of compounds 1-105 in Table 1, or a pharma- ceutically acceptable salt thereof.

[0148] Other embodiments, and exemplary methods for the synthesis of the production of these compounds, are described herein.

[0149] Pharmaceutical Use The compounds described herein are useful in the methods of the invention and, without being bound by theory, are believed to exert their ability to modulate the level, status, and / or activity of the BAF complex, i.e., by inhibiting the activity of the BRG1 and / or BRM proteins within the mammalian BAF complex. BAF complex-associated disorders include, but are not limited to, disorders associated with loss-of-function mutations in BRG1.

[0150] One aspect of the invention relates to a method of treating a disorder associated with a loss-of-function mutation in BRG1, such as cancer (e.g., non-small cell lung cancer, colon cancer, bladder cancer, cancer of unknown primary site, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer) in a subject in need thereof. In some embodiments, the compound is administered in an amount and for a time effective to result in one or more (e.g., two or more, three or more, four or more) of: (a) a reduction in tumor size; (b) a reduction in tumor growth rate; (c) an increase in tumor cell death; (d) a reduction in tumor progression; (e) a reduction in the number of metastases; (f) a reduction in the rate of metastasis; (g) a reduction in tumor recurrence; (h) an increase in the subject's survival rate; (i) an increase in the subject's progression-free survival time.

[0151] Treating cancer can result in a reduction in tumor size or volume. For example, after treatment, the tumor size is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) relative to its size before treatment. The size of the tumor may be measured by any reproducible means of measurement. For example, the size of the tumor may be measured as the diameter of the tumor.

[0152] Treating cancer may further result in a reduction in the number of tumors. For example, after treatment, the number of tumors is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) relative to the number before treatment. The number of tumors may be measured by any reproducible means of measurement, for example, the number of tumors may be measured by counting tumors visible to the naked eye or at a particular magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).

[0153] Treatment of cancer may result in a decrease in the number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) compared to the number before treatment. The number of metastatic nodules may be measured by any reproducible measurement means. For example, the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a particular magnification (e.g., 2x, 10x, or 50x).

[0154] Treating cancer may result in an increase in the average survival time of a population of subjects treated according to the present invention compared to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). The increase in the average survival time of a population may be measured by any reproducible means. The increase in the average survival time of a population may be measured, for example, by calculating the average length of survival of a population after the start of treatment with a compound of the present invention. The increase in the average survival time of a population may also be measured, for example, by calculating the average length of survival of a population after the completion of the first round of treatment with a pharma- ceutically acceptable salt of a compound of the present invention.

[0155] Treating cancer may also result in a reduction in the mortality rate of a population of treated subjects compared to an untreated population. For example, the mortality rate is reduced by more than 2% (e.g., more than 5%, 10%, or 25%). The reduction in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating the average number of disease-related deaths per unit time for a population after the start of treatment with a pharma-ceutically acceptable salt of the present invention. The reduction in the mortality rate of a population may also be measured, for example, by calculating the average number of disease-related deaths per unit time for a population after the completion of the first round of treatment with a pharma-ceutically acceptable salt of the present invention.

[0156] Exemplary cancers that may be treated by the present invention include, but are not limited to, non-small cell lung cancer, small cell lung cancer, colon cancer, bladder cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, CNS cancer, thymic tumors, adrenal cortical carcinoma, appendix cancer, small intestine cancer, and penile cancer.

[0157] Combination preparations and their uses The compounds of the invention may be combined with one or more therapeutic agents. In particular, the therapeutic agents may be those that treat or prophylactically treat any of the cancers described herein.

[0158] Combination therapy The compounds of the present invention can be used alone or in combination with additional therapeutic agents, such as other drugs that treat cancer or related symptoms, or in combination with other types of treatments to treat cancer. In combination treatment, the dosage of one or more therapeutic compounds can be reduced from the standard dosage when administered alone. For example, dosage can be empirically determined from drug combinations and permutations, or estimated by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, the dosage of the compounds when combined should provide a therapeutic effect.

[0159] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other compound useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocorticotropic inhibitors, adrenocorticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelanamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelanin; acetogenins (especially bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its adozelesin, carzelesin, and cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictin; spongistatins; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine;Antibiotics such as enediyne antibiotics (e.g., the calicheamicins, particularly calicheamicin gamma and calicheamicin omegal (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); the dynemicins, including dynemicin A; bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, doxorubicin, 6-diazo-5-oxo-L-norleucine, Adriamycin® (doxorubicin including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potofilomycin, puromycin, keramycin, rodorubicin, streptomycin, putonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxacin, Pyrimidine analogues such as lysine;androgens such as calsterone, drostanolone propionate, epithiostanol, mepitiostane, and testolactone;antiadrenalins such as aminoglutethimide, mitotane, and trilostane;folic acid supplements such as floric acid;aceglatone;aldophosphamide glycosides;aminolevulinic acid;eniluracil;amsacrine;bestrabucil;bisantrene;edatraxate;defofamine;demecolcine;diaziquone;elfomitine;elliptinium acetate;epothilones;Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidynin; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidamol; Nitraerin; Pentostatin; Phenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK® Polysaccharide Complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidin); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids such as Taxol® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABraxane®, a cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and Taxotere® docetaxel (Rhone-Poulenc Rorer, Antony, France); Chlorambucil; Gemzar® gemcitabine; 6-thioguanine; Mercaptopurine; Methotrexate; Platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine; Navelbine® vinorelbine; Novantrone; Teniposide; Edatrexate; Daunomycin; Aminopterin; Xeloda; Ibandronate; Irinotecan (e.g., CPT-11); Topoisomerase inhibitors RFS2000; Difluoromethylornithine (DMFO); Retinoids such as retinoic acid; Capecitabine;and pharmaceutically acceptable salts or acids of any of the above. Two or more chemotherapeutic agents can be used in a cocktail administered in combination with a first therapeutic agent as described herein. Suitable dosing regimens for combination chemotherapy are known in the art and are described, for example, in Saltz et al. (1999) Proc ASCO 18:233a and Douillard et al. (2000) Lancet 355:1041-7.

[0160] In some embodiments, the second therapeutic agent is a therapeutic agent that is a biologic, such as a cytokine (e.g., an interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments, the biologic is an anti-VEGF agent, e.g., an anti-angiogenic agent, such as bevacizumab (Avastin®). In some embodiments, the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, fully human antibody, Fc fusion protein, or functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important to the cancer. Such medications include Rituxan (rituximab), Zenapax (daclizumab), Simulect (basiliximab), Synagis (palivizumab), Remicade (infliximab), Herceptin (trastuzumab), Mylotarg (gemtuzumab ozogamicin), Campath (alemtuzumab), Zevalin (ibritumomab tiuxetan), Humira (adalimumab), Xolair (omalizumab), Bexxar (tositumomab-I-131), Raptiva (efalizumab), Erbitux (cetuximab), Avastin (bevacizumab), Tysabri (natalizumab), Actemra (tosilis), and others. (abtuzumab), Vectibix (panitumumab), Lucentis (ranibizumab), Soliris (eculizumab), Cimzia (certolizumab pegol), Simponi (golimumab), Ilaris (canakinumab), Stelara (ustekinumab), Arzerra (ofatumumab), Prolia (denosumab), Numax (motavizumab), ABThrax (raxibacumab), Benlysta (belimumab), Yervoy (ipilimumab), Adcetris (brentuximab vedotin), Perjeta (pertuzumab), Kadcyla (Ado-trastuzumab emtansine), and Gazyva (obinutuzumab). Antibody-drug conjugates are also included.

[0161] The second agent can be a therapeutic agent that is a non-drug treatment, for example, the second therapeutic agent is radiation therapy, cryotherapy, thermotherapy, and / or surgical removal of tumor tissue.

[0162] 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, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a ligand of the checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody such as ipilimumab / Yervoy or tremelimumab). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab / Opdivo®; pembrolizumab / Keytruda®; pidilizumab / CT-011). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS 936559). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2 / Ig fusion protein such as AMP 224). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligand, or combinations thereof.

[0163] In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately before, immediately after, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7, 1-14, 1-21, or 1-30 days before or after the second therapeutic agent.

[0164] Pharmaceutical Compositions The compounds of the invention are preferably formulated into pharmaceutical compositions for administration to mammals, preferably humans, in a biologically compatible form suitable for administration in vivo. Thus, in one aspect, the invention provides a pharmaceutical composition comprising a compound of the invention in admixture with a suitable diluent, carrier, or excipient.

[0165] The compounds of the present invention can be used in the form of free base, salt, solvate, and prodrug. All forms are within the scope of the present invention. According to the method of the present invention, as understood by those skilled in the art, the described compounds, or their salts, solvates, or prodrugs, can be administered to patients in various forms depending on the selected route of administration. The compounds of the present invention can be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, by patch, pump, or transdermal administration, and the pharmaceutical composition is formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration can also be by continuous infusion over a selected period of time.

[0166] The compounds of the present invention can be administered orally, for example, with an inert diluent or an assimilable edible carrier, or can be enclosed in hard or soft shell gelatin capsules, or can be compressed into tablets, or can be directly incorporated with dietary food. For oral therapeutic administration, the compounds of the present invention can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. The compounds of the present invention can also be administered parenterally. Solutions of the compounds of the present invention can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof, with or without alcohol, and in oils. These preparations can contain a preservative to prevent the growth of microorganisms under ordinary conditions of storage and use. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003, 20th ed.) and The United States Pharmacopeia: The National Formulary, published in 1999 (USP 24 NF19). Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be sufficiently fluid to be easily administered via a syringe. Compositions for nasal administration can be conveniently formulated as aerosols, drops, gels, and powders. Aerosol formulations typically contain a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent, and are usually provided in single or multiple doses in sterile form in a sealed container that can be in the form of a cartridge or refill for use with a nebulizer device. Alternatively, the sealed container may be a single-dispensing device, such as a single-dose nasal inhaler or aerosol dispenser fitted with a metering valve, intended for disposal after use.Where the dosage form comprises an aerosol dispenser, it contains a propellant which may be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage form may also take the form of a pump-atomizer. Suitable compositions for buccal or sublingual administration include tablets, lozenges, and pastilles, in which the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, gelatin, and glycerin. Compositions for rectal administration are conveniently in the form of a suppository containing a conventional suppository base such as cocoa butter. The compounds described herein may be administered intratumorally, for example, as an intratumoral injection. Intratumoral injection is a direct injection into the tumor vasculature and is particularly contemplated for individual solid accessible tumors. Local, regional, or systemic administration may also be appropriate. The compounds described herein may be advantageously contacted by administering an injection or multiple injections to the tumor, for example spaced approximately 1 cm apart. In the case of surgical intervention, the present invention may be used prior to surgery, such as to subject an inoperable tumor to resection. Continuous administration can also be applied where appropriate, for example, by implanting a catheter into the tumor or tumor vasculature.

[0167] The compounds of the invention, as described herein, may be administered to animals, e.g., humans, alone or in combination with pharma- ceutically acceptable carriers, the ratio of which will be determined by the solubility and chemical properties of the compound, the chosen route of administration, and standard pharmaceutical practice.

[0168] Dosage The dosage of the compound of the present invention and / or the composition comprising the compound of the present invention may vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of treatment and the type of concomitant treatment, if any; and the clearance rate of the compound in the treated animal. Those skilled in the art can determine the appropriate dosage based on the above factors. The compound of the present invention may be administered at a suitable dosage initially, which may be adjusted as necessary depending on the clinical response. In general, satisfactory results can be obtained when the compound of the present invention is administered to humans at a daily dose of, for example, 0.05 mg to 3000 mg (measured as solid form). The dosage range includes, for example, 10 to 1000 mg (for example, 50 to 800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound are administered.

[0169] 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 may be in the range of 0.1-100 mg / kg (e.g., 0.25-25 mg / kg). In exemplary, non-limiting embodiments, the dosage may be in the range of 0.5-5.0 mg / kg (e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg / kg) or 5.0-20 mg / kg (e.g., 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg / kg). EXAMPLES

[0170] The following abbreviations are used throughout the examples below: [Table 2-1] [Table 2-2]

[0171] Example 1. Preparation of 2-(6-amino-5-[bicyclo[1.1.1]pentan-1-yl(methyl)amino]pyridazin-3-yl)phenol [ka] Step 1: Preparation of N4-[bicyclo[1.1.1]pentan-1-yl]-6-chloro-N4-methylpyridazine-3,4-diamine [ka] To a stirred solution of 4-bromo-6-chloropyridazin-3-amine (200 mg, 0.960 mmol) and N-methylbicyclo[1.1.1]pentan-1-amine (112 mg, 1.15 mmol) in DMSO (1.00 mL) was added DIEA (18.6 mg, 0.144 mmol) at room temperature. The resulting mixture was stirred overnight at 130° C. The reaction mixture was purified by reverse phase C18 flash chromatography with the following conditions to give N4-[bicyclo[1.1.1]pentan-1-yl]-6-chloro-N4-methylpyridazine-3,4-diamine (71 mg, 32.3%) as a white solid. LCMS (ESI) m / z: [M+H] + =225.

[0172] Step 2: Preparation of 2-(6-amino-5-[bicyclo[1.1.1]pentan-1-yl(methyl)amino]pyridazin-3-yl)phenol [ka] To a stirred mixture of N4-[bicyclo[1.1.1]pentan-1-yl]-6-chloro-N4-methylpyridazine-3,4-diamine (30.0 mg, 0.134 mmol) and 2-hydroxyphenylboronic acid (36.8 mg, 0.267 mmol) in 1,4-dioxane (4.00 ml) and H2O (1.00 ml) was added XPhos Pd G3 (11.3 mg, 0.013 mmol) and Cs2CO3 (131 mg, 0.401 mmol) at room temperature. The resulting mixture was stirred overnight at 100° C. The reaction mixture was filtered through a short pad of Celite and concentrated in vacuo. The residue was purified by preparative HPLC using the following conditions (water:ACN:NH4HCO3) to give the title compound (8 mg, 21.1%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 14.04(s,1H),7.87(dd,J=8.3,1.6Hz,1H),7.67(s,1H),7.25(td,J=7.6,7.0,1.6Hz,1H),6 .94-6.86(m,2H),6.38(s,2H),2.76(s,3H),2.45(s,1H),1.97(s,6H).LCMS(ESI)m / z:[M+H] + =283.25.

[0173] Example 2. Preparation of 3-amino-N-methylbicyclo[1.1.1]pentane-1-carboxamide [ka] Step 1: Preparation of tert-butyl N-[3-(methylcarbamoyl)bicyclo[1.1.1]pentan-1-yl]carbamate [ka] To a stirred mixture of 3-[(tert-butoxycarbonyl)amino]bicyclo[1.1.1]pentane-1-carboxylic acid (1.40 g, 6.16 mmol), HOBT (1.00 g, 7.39 mmol), and EDC·HCl (1.42 g, 7.39 mmol) in DCM (60.0 mL) was added DIEA (3.98 g, 30.8 mmol) at room temperature under nitrogen atmosphere. After stirring at room temperature for 0.5 h, methylamine (2 M in THF, 15.4 mL, 30.8 mmol) was added to the reaction mixture. After stirring at room temperature for 16 h, the resulting mixture was diluted with EtOAc and quenched with ice water at 0 °C. The resulting mixture was extracted three times with EtOAc. The combined organic layers were washed twice with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase C18 flash chromatography to give tert-butyl N-[3-(methylcarbamoyl)bicyclo[1.1.1]pentan-1-yl]carbamate (800 mg, 54.0%) as a white solid. LCMS (ESI) m / z [M+H] + =241.

[0174] Step 2: Preparation of 3-amino-N-methylbicyclo[1.1.1]pentane-1-carboxamide hydrochloride [ka] A solution of tert-butyl N-[3-(methylcarbamoyl)bicyclo[1.1.1]pentane-1-yl]carbamate (900 mg, 3.75 mmol) in HCl in 1,4-dioxane (20.00 mL) and DCM (20.00 mL) was stirred at room temperature for 3 h. The resulting mixture was filtered and the filter cake was washed twice with DCM. The filter cake was dried under reduced pressure. (3-amino-N-methylbicyclo[1.1.1]pentane-1-carboxamide hydrochloride (750 mg, crude) was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + =141.

[0175] Example 3. Preparation of intermediates The following compounds in Table A1 were prepared according to the procedure of Example 1 using the common starting material 4-bromo-6-chloropyridazin-3-amine and the appropriate amine. [Table 3]

[0176] Example 4. Preparation of 2-(6-amino-5-((3-aminobicyclo[1.1.1]pentan-1-yl)amino)pyridazin-3-yl)phenol [ka] An 8 mL sealed tube was charged with intermediate C (40.0 mg, 0.104 mmol), DCM (2.00 mL), and TFA (1.00 mL). The resulting solution was stirred at room temperature for 1 h. The solids were removed by filtration, and the filtrate was concentrated. The crude product was purified by preparative HPLC (water, ACN, NH4HCO3) to give the title compound (9.3 mg, 31%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)14.86(s,1H),δ 7.69(dd,J=8.0,1.6Hz,1H),7.22(ddd,J=8.4,7.2,1.6Hz,1H),7.00(s,1H),6.95-6.81(m,3H),6.30(s,2H),2.15(s,6H).LCMS(ESI)m / z:[M+H] + =284.15.

[0177] Example 5. Preparation of 2-(6-amino-5-[[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]amino]pyridazin-3-yl)phenol [ka] The title compound was prepared according to the procedure of Example 4 using tert-butyl ((3-(((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)amino)methyl)bicyclo[1.1.1]pentan-1-yl)methyl)carbamate. 1H NMR(400MHz,DMSO-d6)δ 8.19(s,1H),7.69(d,J=7.2Hz,1H),,7.24(td,J=7.7,1.5Hz,1H),7.02(d,J=9.3Hz,2H ),6.89(t,J=7.7Hz,2H),6.32(s,2H),3.10(s,2H),2.21(s,6H).LCMS(ESI)m / z:[M+H] + =298.1.

[0178] Example 6. Preparation of 3-([[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]oxy]methyl)bicyclo[1.1.1]pentane-1-carbonitrile [ka] Step 1: Preparation of 3-[[(3-amino-6-chloropyridazin-4-yl)oxy]methyl]bicyclo[1.1.1]pentane-1-carbonitrile [ka] To a stirred solution of 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carbonitrile (2.00 g, 16.2 mmol) and 4-bromo-6-chloropyridazin-3-amine (6.77 g, 0.032 mmol) in DMF (20.0 mL) was added NaH (1.17 g, 0.049 mmol) at room temperature. The resulting mixture was stirred overnight at 60° C. The residue was purified by C18 reverse phase flash chromatography to give 3-[[(3-amino-6-chloropyridazin-4-yl)oxy]methyl]bicyclo[1.1.1]pentane-1-carbonitrile (2.3 g, 53.7%) as a tan solid. LCMS (ESI) m / z: [M+H] + =251.1

[0179] Step 2: Preparation of 3-([[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]oxy]methyl)bicyclo[1.1.1]pentane-1-carbonitrile [ka] To a stirred mixture of 3-[[(3-amino-6-chloropyridazin-4-yl)oxy]methyl]bicyclo[1.1.1]pentane-1-carbonitrile (30.0 mg, 0.120 mmol) and 2-hydroxyphenylboronic acid (33.0 mg, 0.239 mmol) in dioxane (3.00 mL) and HO (0.50 ml) was added Xphos Pd G3 (10.1 mg, 0.012 mmol) and Cs2CO3 (117 mg, 0.359 mmol) at room temperature. The resulting mixture was stirred at 100 °C overnight. The crude product was purified by preparative HPLC (water:ACN:FA) to give the title compound (14 mg, 37.1%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 14.34(s,1H),7.93(dd,J=8.4,1.6Hz,1H),7.56(s,1H),7.25(td,J=7.6,1.5Hz,1H ),6.95-6.83(m,2H),6.62(s,2H),4.29(s,2H),2.39(s,6H).LCMS(ESI)m / z:[M+H] + =309.15

[0180] Example 7: Preparation of N-[3-(2-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl]acetamide [ka] Step 1: Preparation of methyl 2-[3-acetamidobicyclo[1.1.1]pentan-1-yl]acetate [ka] To a stirred solution of methyl 2-[3-aminobicyclo[1.1.1]pentan-1-yl]acetate hydrochloride (100 mg, 0.522 mmol) in DCM (10.0 mL) was added Ac2O (63.9 mg, 0.626 mmol) and TEA (158 mg, 1.57 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was then quenched with water at room temperature. The resulting mixture was extracted three times with CHCl2. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl 2-[3-acetamidobicyclo[1.1.1]pentan-1-yl]acetate (130 mg, crude) as an off-white solid. LCMS (ESI) m / z: [M+H] + =198.

[0181] Step 2: Preparation of N-[3-(2-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl]acetamide [ka] To a stirred solution of 2-[3-acetamido bicyclo[1.1.1]pentan-1-yl]acetate (110 mg, 0.558 mmol) in DCM (10.0 mL) was added DIBAL-H (1 M, 2.8 mL, 2.8 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h and then quenched with water. The resulting mixture was extracted three times with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give N-[3-(2-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl]acetamide (88 mg, crude) as a colorless oil. LCMS (ESI) m / z: [M+H] + =170.

[0182] Example 8. Preparation of intermediates The following compounds in Table A2 were prepared according to the procedure of Example 6 using the common starting material 4-bromo-6-chloropyridazin-3-amine and the appropriate alcohol. [Table 4]

[0183] Example 9. Preparation of 2-(6-amino-5-[[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]methoxy]pyridazin-3-yl)phenol [ka] To a solution of 2-(6-amino-5-[[3-(cyano)bicyclo[1.1.1]pentan-1-yl]methoxy]pyridazin-3-yl)phenol (120 mg, 0.389 mmol) in MeOH (10 mL) was added Pd / C (10%, 100 mg) in a pressure tank. The mixture was hydrogenated at room temperature under 30 psi hydrogen pressure overnight. The reaction mixture was filtered through a short pad of Celite and concentrated under reduced pressure. The residue was purified by reverse phase C18 flash chromatography using the following conditions (MeOH:water) to give 2-(6-amino-5-[[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]methoxy]pyridazin-3-yl)phenol (29 mg, 23.9%) as an off-white solid. LCMS (ESI) m / z [M+H] + =313.

[0184] Example 10. Preparation of N-(3-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)acetamide [ka] A 25 mL round bottom flask was charged with 2-(6-amino-5-[[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]methoxy]pyridazin-3-yl)phenol (40.0 mg, 0.141 mmol), DCM (2.00 mL), DIEA (36.5 mg, 0.282 mmol), and Ac2O (14.4 mg, 0.141 mmol). The resulting solution was stirred for 2 h at 0 °C in a water / ice bath. The resulting mixture was concentrated in vacuo. The residue was dissolved in 2 mL of DMF. The solid was filtered off. The crude product was purified by preparative HPLC (water:ACN:NH4HCO3) to give the title compound (5.2 mg, 11.3%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 14.77(s,1H),8.57(s,1H),7.72(dd,J=8.1,1.6Hz,1H),7.22(ddd,J=8.5,7.2,1.6Hz,1H),6.99( d,J=13.9Hz,2H),6.92-6.80(m,2H),6.31(s,2H),2.42(s,6H),1.81(s,3H).LCMS(ESI)m / z:[M+H] + =325.9.

[0185] Example 11. Preparation of intermediates The following compounds in Table A3 were synthesized following the synthetic procedure described in Example 10 using the appropriate amine. [Table 5]

[0186] Example 12. Preparation of 3-([[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]amino]methyl)bicyclo[1.1.1]pentane-1-carboxylic acid [ka] 3-([[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]amino]methyl)bicyclo[1.1.1]penta[1,2-dihydropyridazin-4-yl]amino]methyl) To a solution of 1-methyl-1-carbonitrile (10.0 mg, 0.033 mmol) was added KOH (110 mg, 1.95 mmol). The resulting solution was stirred for 8 h at 80° C. The crude reaction solution was directly purified by preparative HPLC (water:MeCN:FA) to give the title compound (10.3 mg, 31.7%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.87(dd,J=8.0,1.6Hz,1H),7.37-7.12(m,1H),7.02(s,1H),6.95-6.71(m,2H),6 .33(s,2H),6.16(s,1H),3.45(d,J=5.5Hz,2H),1.96(s,6H).LCMS(ESI)m / z:[M+H] + =327.00.

[0187] Example 13. Preparation of 3-([[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]oxy]methyl)bicyclo[1.1.1]pentane-1-carboxylic acid [ka] FHT-0015071-001 was prepared according to the procedure of Example 12 using 3-([[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]oxy]methyl)bicyclo[1.1.1]pentane-1-carbonitrile and sodium hydroxide. 1 H NMR(300MHz,DMSO-d6)δ 7.95(dd,J=8.3,1.6Hz,1H),7.58(s,1H),7.25(td,J=7.6,7.0,1.5Hz,1H),6. 95-6.84(m,2H),6.58(s,2H),4.31(s,2H),2.08(s,6H).LCMS(ESI)m / z:[M+H] + =328.15.

[0188] Example 14. 3-([[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]amino]methyl)bicycle[1.1.1]pentane-1-carboxamide [ka] To a solution of 3-([[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]amino]methyl)bicyclo[1.1.1]pentane-1-carbonitrile (40.0 mg, 0.130 mmol) and K2CO3 (36.0 mg, 0.260 mmol) in DMSO (2.00 mL) was added HO2 (30% in HO, 44.3 mg, 1.30 mmol). The resulting solution was stirred at 25 °C for 15 h. The crude reaction mixture was directly purified by preparative HPLC (water:ACN:NH4HCO3) to give the title compound (11.2 mg, 26.3%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 15.12(s,1H),7.87(dd,J=8.0,1.6Hz,1H),7.37-7.12(m,2H),7.02(s,1H),6.92-6.58(m,3H) ,6.32(s,2H),6.22(t,J=5.6Hz,1H),3.46(d,J=5.6Hz,2H),1.88(s,6H).LCMS(ESI)m / z:[M+H] + =326.05.

[0189] Example 15. Preparation of 3-[2-[3-amino-6-(2-hydroxyphenyl)pyridazin-4yl]ethynyl]bicycleo[1.1.1]pentane-1-carboxylic acid [ka] Step 1: Preparation of methyl 3-[2-(3-amino-6-chloropyridazin-4-yl)ethynyl]bicyclo[1.1.1]pentane-1-carboxylate [ka] To a stirred mixture of methyl 3-ethynylbicyclo[1.1.1]pentane-1-carboxylate (450 mg, 3.00 mmol) and 4-bromo-6-chloropyridazin-3-amine (899 mg, 4.32 mmol) in THF, Pd(PPh3)4 (693 mg, 0.599 mmol) and Et3N (5.00 mL) were added dropwise or in portions at 80 °C and stirred overnight at 80 °C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (water:ACN:FA) to give methyl 3-[2-(3-amino-6-chloropyridazin-4-yl)ethynyl]bicyclo[1.1.1]pentane-1-carboxylate (120 mg, 14.4%) as a white solid. LCMS (ESI) m / z: [M+H] + =278.

[0190] Step 2: Preparation of methyl 3-[2-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]ethynyl]bicyclo[1.1.1]pentane-1-carboxylate [ka] To a stirred mixture of methyl 3-[2-(3-amino-6-chloropyridazin-4-yl)ethynyl]bicyclo[1.1.1]pentane-1-carboxylate (120 mg, 0.432 mmol) and 2-hydroxyphenylboronic acid (179 mg, 1.30 mmol) in dioxane (4.00 mL) and HO (1.00 mL) was added CsCO (422 mg, 1.30 mmol) and XPhos Pd G (73.2 mg, 0.086 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (mg) was purified by preparative HPLC (water:ACN:FA) to give methyl 3-[2-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]ethynyl]bicyclo[1.1.1]pentane-1-carboxylate (50 mg, 34.5%) as a white solid. LCMS (ESI) m / z: [M+H] + =336.

[0191] Step 3: Preparation of 3-[2-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]ethynyl]bicyclo[1.1.1]pentane-1-carboxylic acid [ka] To a stirred solution of methyl 3-[2-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]ethynyl]bicyclo[1.1.1]pentane-1-carboxylate (5.00 mg, 0.015 mmol) in THF was added LiOH (1.07 mg, 0.045 mmol) and HO (0.20 mg) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (water:ACN:FA) to give the title compound (8.5 mg, 29.6%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 13.20(s,1H),12.40(s,1H),8.22(s,1H),7.88(dd,J=8.0,1.6Hz,1H),7.24(dd d,J=8.4,7.2,1.6Hz,1H),6.95-6.84(m,4H),2.38(s,6H).LCMS(ESI)m / z:[M+H] + =322.20.

[0192] Example 16. Preparation of 3-(2-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethyl)bicyclo[1.1.1]pentane-1-carboxylic acid [ka] Step 1: Preparation of methyl 3-(2-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethyl)bicyclo[1.1.1]pentane-1-carboxylate [ka] To a solution of methyl 3-[2-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]ethynyl]bicyclo[1.1.1]pentane-1-carboxylate (200 mg, 0.596 mmol) in 10 MeOH (10 mL) was added Pd / C (10%, 200 mg) in a 50 mL round bottom flask under nitrogen atmosphere. The mixture was hydrogenated under a hydrogen balloon at room temperature for 2 h. The mixture was filtered through a Celite pad and concentrated under reduced pressure to give methyl 3-(2-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethyl)bicyclo[1.1.1]pentane-1-carboxylate (150 mg, 74.1%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =340.

[0193] Step 2: Preparation of 3-(2-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethyl)bicyclo[1.1.1]pentane-1-carboxylic acid [ka] To a stirred solution of methyl 3-(2-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethyl)bicyclo[1.1.1]pentane-1-carboxylate (200 mg, 0.589 mmol) in THF (10.0 mL) was added lithium hydroxide monohydrate (247 mg, 5.89 mmol) in HO (2.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The crude product was purified by preparative HPLC using the following conditions (water:ACN:FA) to give the title compound (4.8 mg, 2.50%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.94(s,1H),7.89(dd,J=8.3,1.7Hz,1H),7.30-7.21(m,1H),6.96-6.88(m,2H),2.57-2.46(m,2H),1.95-1.77(m,8H).LCMS(ESI)m / z:[M+H] + =326.15.

[0194] Example 17. Preparation of 3-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid [ka] To a stirred solution of 3-([3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]amino)-N-methylbicyclo[1.1.1]pentane-1-carboxamide (195 mg, 0.599 mmol) in aqueous HCl (12N, 10.0 mL). The resulting mixture was stirred at 90° C. for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash chromatography (water:ACN:FA) to give the title compound (90 mg, 48.1%) as an off-white solid. 1 H NMR(300MHz,DMSO-d6)δ 13.87(s,1H),7.82(d,J=7.8Hz,1H),7.23-7.20(m,1H),7.07(s,1H),7.01 (s,1H),6.95-6.82(m,2H),6.32(s,2H),2.44(s,6H).LCMS(ESI)m / z:[M+H] + =313.10.

[0195] Example 18. Preparation of 3-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)bicyclo[1.1.1]pentane-1-carboxamide [ka] To a stirred solution of 3-[2-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]ethynyl]bicyclo[1.1.1]pentane-1-carboxylic acid (28.0 mg, 0.087 mmol) and NH4Cl (14.0 mg, 0.261 mmol) in DMF (2.00 mL) was added HATU (66.3 mg, 0.174 mmol) and DIEA (56.3 mg, 0.436 mmol) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The residue was purified by reverse phase C18 flash chromatography (water:ACN:FA) to give the title compound (3.5 mg, 12.5%) as an off-white solid.1 H NMR(300MHz,DMSO-d6)δ 13.24(s,1H),8.23(s,1H),7.89(dd,J=8.0,1.6Hz,1H),7.38(s,1H),7.31-7. 19(m,1H),7.04(s,1H),6.96-6.82(m,4H),2.32(s,6H).LCMS(ESI)m / z:[M+H] + =321.10.

[0196] Example 19. Preparation of intermediates The following compounds in Table A4 were synthesized following the synthetic procedure described in Example 18 using the appropriate carboxylic acid. [Table 6]

[0197] Example 20. Preparation of 3-([[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]oxy]methyl)-N-methylbicyclo[1.1.1]pentane-1-carboxamide [ka] To a stirred mixture of 3-([[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]oxy]methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (30.0 mg, 0.092 mmol) and methylamine (5.69 mg, 0.184 mmol) in DMF (1.50 mL) was added EDCI (35.1 mg, 0.184 mmol), HOBT (24.8 mg, 0.184 mmol), and DIEA (35.5 mg, 0.276 mmol) at room temperature. The resulting mixture was stirred for 4 h at room temperature. The crude product was purified by preparative HPLC (water:ACN:FA) to give the title compound (21 mg, 66.7%) as a white solid. 1H NMR(300MHz,DMSO-d6)δ 14.38(s,1H),7.95(dd,J=8.4,1.6Hz,1H),7.70(d,J=4.8Hz,1H),7.59(s,1H),7.25(td,J=7.6,7.0,1.5Hz, 1H),6.97-6.82(m,2H),6.56(s,2H),4.33(s,2H),2.56(d,J=4.6Hz,3H),2.00(s,6H).LCMS(ESI)m / z:[M+H] + =341.2

[0198] Example 21. Preparation of 3-([[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]amino]methyl)-N-methylbicyclo[1.1.1]pentane-1-carboxamide [ka] To a stirred solution of 3-([[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]amino]methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (44.0 mg, 0.135 mmol), HOBt (36.5 mg, 0.270 mmol), and EDCI (51.7 mg, 0.270 mmol) in DMF (1 mL) was added methylamine, hydrochloride (18.3 mg, 0.270 mmol), and DIEA (87.2 mg, 0.674 mmol). The resulting mixture was stirred for 5 h at 25° C. The crude reaction mixture was directly purified by preparative HPLC (water:ACN:NH4HCO3) to give the title compound (7.5 mg, 15.4%) as a white solid. 1 H NMR(300MHz, methanol-d4)δ 7.74(dd,J=8.3,1.6Hz,1H),7.27-7.18(m,1H),7.04(s,1H),6.94-6.83(m,2H),3.52(s,2H),2.68(s,3H),2.01(s,6H).LCMS(ESI)m / z:[M+H] + =340.05.

[0199] Example 22. Preparation of 3-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-N-methylbicyclo[1.1.1]pentane-1-carboxamide [ka] To a stirred solution of 3-[2-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]ethynyl]bicyclo[1.1.1]pentane-1-carboxylic acid (28.0 mg, 0.087 mmol) and methylamine, hydrochloride (11.8 mg, 0.174 mmol) in DMF (2.0 mL) was added HATU (66.3 mg, 0.174 mmol) and DIEA (56.3 mg, 0.436 mmol) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The crude product was purified by preparative HPLC (water:ACN:FA) to give the title compound (7.6 mg, 26.1%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 13.11(s,1H),8.23(s,1H),7.90-7.80(m,2H),7.29-7.21(m,1H),7.01(s,2H) ,6.95-6.84(m,2H),2.57(d,J=4.6Hz,3H),2.32(s,6H).LCMS(ESI)m / z:[M+H] + =335.25.

[0200] Example 23. Preparation of intermediates The following compounds in Table A5 were synthesized according to the synthetic procedure described in Example 22 using the appropriate carboxylic acid and amine. [Table 7]

[0201] Example 24. Preparation of (2S,4R)-1-[(2S)-2-(10-aminodecanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (I-1) [ka] Step 1: Preparation of tert-butyl N-(9-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]nonyl)carbamate [ka] To a stirred solution of (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (1.00 g, 0.002 mmol) and 10-[(tert-butoxycarbonyl)amino]decanoic acid (0.73 g, 0.003 mmol) in DCM (20.0 mL) was added DIEA (0.90 g, 0.007 mmol). The mixture was stirred at room temperature for 5 min, and then HATU (1.32 g, 0.003 mmol) was added. After stirring at room temperature for 2 h, water was added to the mixture and the mixture was extracted four times with DCM. The organic fractions were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel flash chromatography (DCM / MeOH) to give tert-butyl N-(9-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]nonyl)carbamate (1.67 g, 92.5%). LCMS (ESI) m / z[M+H] + =700.

[0202] Step 2: Preparation of (2S,4R)-1-[(2S)-2-(10-aminodecanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (I-1) [ka] To a stirred solution of tert-butyl N-(9-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]nonyl)carbamate (1.67 g, 2.39 mmol) in DCM (10 mL) was added TFA (2 mL, 26.9 mmol) and the mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. A solution of 5% K2CO3 (MeOH / water = 5 / 2) was added to the reaction mixture to adjust the pH to about 8-9. The mixture was stirred at room temperature for 2 h. The final mixture was concentrated in vacuo and the crude material was purified by reverse C18 phase flash chromatography (water:ACN:NH4HCO3) to give (2S,4R)-1-[(2S)-2-(10-aminodecanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (I-1, 1.11 g, 73.68%). LCMS (ESI) m / z: [M+H] + =600.40.

[0203] Example 25. Preparation of intermediates The following intermediates in Table B1 were prepared by a route similar to that used to prepare intermediate I-1 in Example 24. [Table 8]

[0204] Example 26. Preparation of 5-(2-(4-aminopiperidin-1-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione TFA (I-6) [ka] Step 1: Preparation of 5-(2-bromoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (1.37 g, 5.00 mmol) in THF (35 mL) was added 2-bromoethanol (0.94 g, 7.49 mmol), PPh3 (1.97 g, 7.49 mmol), and DIAD (1.52 g, 7.49 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 h. The residue was purified by reverse phase 18 flash chromatography (water:ACN) to give 5-(2-bromoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.52 g, 79.82%) as a black solid. LCMS (ESI) m / z: [M+H] += 381.38.

[0205] Step 2: Preparation of tert-butyl (1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperidin-4-yl)carbamate [ka] To a solution of 5-(2-bromoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.52 g, 3.99 mmol) in ACN (35.0 mL) was added tert-butyl N-(piperidin-4-yl)carbamate (0.80 g, 3.99 mmol), KI (0.66 g, 3.99 mmol), and K2CO3 (1.65 g, 12.0 mmol). The resulting solution was stirred at 70° C. for 2 h. The residue was purified by reverse phase C18 flash chromatography (water:ACN) to give a colorless solid tert-butyl (1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperidin-4-yl)carbamate (1.402 g, 70.24%). LCMS (ESI) m / z: [M+H] + =501.

[0206] Step 3: Preparation of 5-(2-(4-aminopiperidin-1-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione TFA (I-6) [ka] To a solution of tert-butyl (1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperidin-4-yl)carbamate (1.66 g, 3.32 mmol) in DCM (10.0 mL) was added TFA (10.0 mL, 135 mmol). The resulting solution was stirred at room temperature for 3 h and then concentrated under reduced pressure. The residue was purified by reverse phase C18 flash chromatography (water:ACN) to give 5-(2-(4-aminopiperidin-1-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formate (I-6, 840 mg, 62.52%) as a white solid. LCMS (ESI) m / z: [M+H] + =401.17.

[0207] Example 27. Preparation of intermediates The following intermediates in Table B2 were prepared by a route similar to that described in Example 26 using the appropriate substituted bromoalcohol and N-Boc-diamine. [Table 9]

[0208] Example 28. Preparation of 4-(azetidin-3-ylmethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione TFA (I-7) [ka] Step 1: Preparation of tert-butyl 3-((tosyloxy)methyl)azetidine-1-carboxylate [ka] To a stirred solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (1.87 g, 9.99 mmol) in DCM (50.0 mL) was added DMAP (0.18 g, 1.50 mmol), TEA (2.53 g, 25.0 mmol), and p-toluenesulfonyl chloride (2.86 g, 15.0 mmol) at 0° C. The resulting mixture was stirred for 2 h at 0° C. and then allowed to warm to room temperature and stirred for an additional 5 h. The residue was purified by silica gel column chromatography (petroleum ether / THF) to give tert-butyl 3-((tosyloxy)methyl)azetidine-1-carboxylate (2.65 g, 77.7%) as a colorless oil. LCMS (ESI) m / z: [M+H] + =342.

[0209] Step 2: Preparation of tert-butyl 3-([[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]methyl)azetidine-1-carboxylate [ka] To a solution of tert-butyl 3-((tosyloxy)methyl)azetidine-1-carboxylate (2.30 g, 8.39 mmol) in DMF (15.0 mL) was added 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (2.86 g, 8.39 mmol) and Na2CO3 (1.33 g, 12.6 mmol). The resulting mixture was stirred at 80° C. for 5 h under dry nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted three times with EtOAc. The combined organic layer was washed three times with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a pale yellow solid tert-butyl 3-([[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]methyl)azetidine-1-carboxylate (3.37 g, 90.6%). LCMS (ESI) m / z: [M+H] + =444.

[0210] Step 3: Preparation of 4-(azetidin-3-ylmethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione TFA (I-7) [ka] To a solution of tert-butyl 3-([[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]methyl)azetidine-1-carboxylate (2.39 g, 5.39 mmol) in DCM (10.0 mL) was added TFA (10.0 mL, 135 mmol). The resulting solution was stirred at room temperature for 3 h. The residue was purified by reverse phase C18 flash chromatography (water:ACN) to give 4-(azetidin-3-ylmethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione TFA (I-7, 1.71 g, 87.7%) as a light yellow solid. LCMS (ESI) m / z: [M+H] + =344.12.

[0211] Example 29. Preparation of intermediates The following intermediates in Table B3 were prepared by a route similar to that described in Example 28 using the appropriate substituted phenol and N-Boc-amino alcohol. [Table 10]

[0212] Example 30. Preparation of 3-[5-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-methyl-4-oxoquinazolin-3-yl]piperidine-2,6-dione TFA (I-11) [ka] Step 1: Preparation of tert-butyl (2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)amino)ethoxy)ethoxy)ethyl)carbamate [ka] To a stirred solution of 4-hydroxy-2,2-dimethyl-3,8,11-trioxa-5-azatridecan-13-al (1.25 g, 5.00 mmol) and 3-(5-amino-2-methyl-4-oxoquinazolin-3-yl)piperidine-2,6-dione (1.43 g, 5.00 mmol) in MeOH (30.0 mL) was added NaBHCN (0.63 g, 9.99 mmol) at room temperature and the resulting mixture was stirred for 1 h. The reaction was quenched with saturated aqueous NH4Cl at 0 °C, the solvent was evaporated and the resulting residue was purified by silica gel column chromatography (petroleum ether / EtOAc) to give tert-butyl (2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)amino)ethoxy)ethoxy)ethyl)carbamate (1.29 g, 49.7%) as a yellow solid. LCMS (ESI) m / z [M+H] + =518.

[0213] Step 2: Preparation of 3-[5-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-methyl-4-oxoquinazolin-3-yl]piperidine-2,6-dione TFA (I-11) [ka] A solution of tert-butyl (2-(2-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)amino)ethoxy)ethoxy)ethyl)carbamate (1.29 g, 2.48 mmol) and TFA (8.49 g, 74.5 mmol) in DCM (6.00 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated and the resulting residue was purified by reverse phase C18 flash chromatography using the following conditions (water:ACN) to give 3-[5-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-methyl-4-oxoquinazolin-3-yl]piperidine-2,6-dione TFA (I-11, 1.56 g, 95.1%) as a light brown solid. LCMS(ESI)m / z:[M+H]+= 418.20.

[0214] Example 31. Preparation of intermediates The following intermediates in Table B4 were prepared by routes similar to those described in Example 30 using the appropriate substituted anilines and aldehydes. [Table 11]

[0215] Example 32. Preparation of 5-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione TFA (I-22) [ka] Step 1: Preparation of tert-butyl N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]octyl)carbamate [ka] To a stirred mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (5.00 g, 18.1 mmol) and tert-butyl N-(8-aminooctyl)carbamate (6.64 g, 27.2 mmol) in NMP (50.0 mL) was added DIEA (7.02 g, 54.3 mmol) at 90° C. After 3 h, water was added to the mixture, followed by extraction with EtOAc three times. The residue was purified by reverse-phase C18 flash chromatography (water; ACN) to give tert-butyl N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]octyl)carbamate (3.50 g, 36.69%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =501.

[0216] Step 3: Preparation of 5-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione trifluoroacetate (I-22) [ka] To a stirred mixture of tert-butyl N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]octyl)carbamate (3.85 g, 7.69 mmol) in DCM (9.00 mL) was added TFA (3.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography to give I-22 (2.22 g, 56.2%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 11.08(s,1H),7.80-7.72(m,1H),7.72-7.67(m,2H),7.55(dd,1H),7.14(s,1H),6.95(d,1H),6.88-6.77(m,1H),5.08-4.98(m,1H),3. 21-3.05(m,1H),2.95-2.75(m,2H),2.66-2.51(m,2H),2.12-1.94(m,1H),1.63-1.49(m,3H),1.45-1.31(m,4H).LCMS(ESI)m / z:[M+H] + =401.21.

[0217] Example 33. Preparation of tert-butyl (4-((3-aminopropyl)sulfonyl)butyl)carbamate [ka] Step 1: Preparation of 4-((tert-butoxycarbonyl)amino)butyl 4-methylbenzenesulfonate [ka] To a stirred solution of tert-butyl N-(4-hydroxybutyl)carbamate (30.6 g, 162 mmol) in DCM (400 mL) was added DMAP (2.96 g, 24.2 mmol), TEA (40.9 g, 404 mmol), and p-toluenesulfonyl chloride (46.2 g, 242 mmol) at 0° C. The resulting mixture was stirred for 2 h at 0° C. and then for 5 h at room temperature. The solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / THF) to give 4-((tert-butoxycarbonyl)amino)butyl 4-methylbenzenesulfonate (45.6 g, 82.2%) as a light yellow oil. LCMS (ESI) m / z: [M+H] + =344.

[0218] Step 2: Preparation of S-(4-((tert-butoxycarbonyl)amino)butyl)ethanethioate [ka] To a stirred solution of 4-((tert-butoxycarbonyl)amino)butyl 4-methylbenzenesulfonate (45.6 g, 133 mmol) in ACN (300 mL) was added ethanethio S acid (15.2 g, 199 mmol) and K2CO3 (55.1 g, 398 mmol). The resulting mixture was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / THF) to give S-(4-((tert-butoxycarbonyl)amino)butyl)ethanethioate (28.7 g, 87.4%) as a pale yellow oil. LCMS (ESI) m / z: [M+H] + =248.

[0219] Step 3: Preparation of benzyl N-[3-([4-[(tert-butoxycarbonyl)amino]butyl]sulfanyl)propyl]carbamate [ka] To a solution of S-(4-((tert-butoxycarbonyl)amino)butyl)ethanethioate (3.60 g, 14.6 mmol) in MeOH (90.0) was added benzyl (3-bromopropyl)carbamate (4.36 g, 16.0 mmol) and NaOMe (3.15 g, 58.2 mmol). The resulting solution was stirred at room temperature for 3 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted three times with EtOAc. The combined organic layers were washed three times with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash chromatography (water:ACN:NH4HCO3) to give N-[3-([4-[(tert-butoxycarbonyl)amino]butyl]sulfanyl)propyl]benzylcarbamate (4.122 g, 71.42%) as a light yellow oil. LCMS(ESI)m / z:[M+H] + =397.

[0220] Step 4: Preparation of benzyl N-(3-[4-[(tert-butoxycarbonyl)amino]butanesulfonyl]propyl)carbamate [ka] To a solution of benzyl N-[3-([4-[(tert-butoxycarbonyl)amino]butyl]sulfanyl)propyl]carbamate (4.13 g, 10.4 mmol) in MeOH (60.0 mL) was added Oxone® (3.50 g, 20.8 mmol). The resulting solution was stirred at room temperature for 12 h and then concentrated under reduced pressure. The residue was purified by reverse phase C18 flash chromatography (water:ACN:NH4HCO3) to give benzyl N-(3-[4-[(tert-butoxycarbonyl)amino]butanesulfonyl]propyl)carbamate (2 g, 44.8%) as a white solid. LCMS (ESI) m / z: [M+H] + =429.

[0221] Step 5: Preparation of tert-butyl (4-((3-aminopropyl)sulfonyl)butyl)carbamate [ka] To a solution of benzyl N-(3-[4-[(tert-butoxycarbonyl)amino]butanesulfonyl]propyl)carbamate (1.95 g, 4.55 mmol) in EtOH (30.0 mL) was added ammonium formate (574 mg, 9.10 mmol) and 5% Pd(OH)2 / C (978 mg, 6.96 mmol). The resulting solution was stirred at 60° C. for 12 h under 1 atm of hydrogen. The resulting mixture was filtered, the filter cake was washed three times with MeOH, and the filtrate was concentrated under reduced pressure to give tert-butyl (4-((3-aminopropyl)sulfonyl)butyl)carbamate (1.12 g, crude) as a black solid. LCMS (ESI) m / z: [M+H] + =295.

[0222] Example 34. Preparation of tert-butyl N-[2-(2-aminoethanesulfonyl)ethyl]carbamate [ka] Step 1: Preparation of tert-butyl N-(2-[[2-(1,3-dioxoisoindol-2-yl)ethyl]furfanyl]ethyl)carbamate [ka] To a stirred mixture of tert-butyl N-(2-sulfanylethyl)carbamate (5.00 g, 28.2 mmol) and N-(2-bromoethyl)phthalimide (7.17 g, 0.028 mol) in ACN (10.0 mL) was added K2CO3 (11.7 g, 0.085 mol) at 70 °C under dry nitrogen atmosphere. After 5 h, the resulting mixture was extracted three times with EtOAc. The combined organic layers were washed three times with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc) to give tert-butyl N-(2-[[2-(1,3-dioxoisoindol-2-yl)ethyl]sulfanyl]ethyl)carbamate (8.20 g, 82.96%) as a white solid. LCMS (ESI) m / z: [M+H] +=351.

[0223] Step 2: Preparation of tert-butyl N-[2-[2-(1,3-dioxoisoindol-2-yl)ethanesulfonyl]ethyl]carbamate [ka] To a stirred mixture of tert-butyl N-(2-[[2-(1,3-dioxoisoindol-2-yl)ethyl]sulfanyl]ethyl)carbamate (8.20 g, 23.4 mmol) in DCM (100 mL) was added m-CPBA (12.1 g, 70.2 mmol) at room temperature under dry nitrogen atmosphere. The reaction was then quenched with saturated aqueous Na2S2O3 at room temperature. To the resulting mixture was added saturated aqueous NaHCO3, and the mixture was extracted three times with EtOAc. The organic phase was separated and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc) to give tert-butyl N-[2-[2-(1,3-dioxoisoindol-2-yl)ethanesulfonyl]ethyl]carbamate (8.40 g, 87.3%) as a white solid. LCMS(ESI)m / z:[M+H] + =383.

[0224] Step 3: Preparation of tert-butyl N-[2-(2-aminoethanesulfonyl)ethyl]carbamate [ka] To a stirred solution of tert-butyl N-[2-[2-(1,3-dioxoisoindol-2-yl)ethanesulfonyl]ethyl]carbamate (3.40 g, 8.89 mmol) in EtOH (100 mL) was added hydrazine hydrate (0.89 g, 17.8 mmol) at 80° C. under a dry nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 1 h under a dry nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOH, and the filtrate was concentrated under reduced pressure to give tert-butyl N-[2-(2-aminoethanesulfonyl)ethyl]carbamate (1.88 g, 77.9%) as a white solid. LCMS (ESI) m / z: [M+H] += 253.

[0225] Example 35. Preparation of tert-butyl 4-(azetidin-3-ylmethyl)piperazine-1-carboxylate [ka] Step 1: tert-Butyl 4-([1-[(benzyloxy)carbonyl]azetidin-3-yl]methyl)piperazine-1-carboxylate [ka] To a stirred solution of benzyl 3-formylazetidine-1-carboxylate (2.0 g, 9.1 mmol) and tert-butyl piperazine-1-carboxylate (1.9 g, 10.2 mmol) in DMF (20 mL) was added NaBH(OAc)3 (7.6 g, 35.8 mmol) in portions. The mixture was stirred at 50° C. overnight. Aqueous NH4Cl was added to the mixture and the mixture was extracted three times with EtOAc. The combined organic phases were concentrated to dryness under reduced pressure. The residue was purified by reversed-phase C18 flash chromatography (water:ACN) to give tert-butyl 4-([1-[(benzyloxy)carbonyl]azetidin-3-yl]methyl)piperazine-1-carboxylate (2.8 g, 79.1%) as a colorless oil. LCMS (ESI) m / z [M+H] + =390.

[0226] Step 2: Preparation of tert-butyl 4-(azetidin-3-ylmethyl)piperazine-1-carboxylate [ka] A solution of tert-butyl 4-([1-[(benzyloxy)carbonyl]azetidin-3-yl]methyl)piperazine-1-carboxylate (2.8 g, 7.2 mmol) and Pd / C (0.28 g) in methanol (30 mL) was stirred at room temperature under H2 atmosphere for 2 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give tert-butyl 4-(azetidin-3-ylmethyl)piperazine-1-carboxylate (1.8 g, quantitative). LCMS (ESI) m / z [M+H] + =256.

[0227] Example 36. Preparation of tert-butyl 7-(3-aminopropyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate [ka] tert-Butyl 7-(3-aminopropyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate was prepared according to the synthesis scheme of Example 35 starting from benzyl N-(3-oxopropyl)carbamate and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate. LCMS (ESI) m / z: [M+H] + =284.

[0228] Example 37. Preparation of benzyl N-[2-[3-(2-aminoethoxy)phenoxy]ethyl]carbamate [ka] Step 1: Preparation of tert-butyl N-[2-(3-hydroxyphenoxy)ethyl]carbamate [ka] To a stirred solution of resorcinol (10.0 g, 90.8 mmol) and tert-butyl N-(2-bromoethyl)carbamate (20.4 g, 90.8 mmol) in DMF (250 mL) was added Cs2CO3 (88.8 g, 272 mmol) in portions at 40 °C. The resulting mixture was washed three times with EtOAc. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase C18 flash chromatography (water:MeOH) to give tert-butyl N-[2-(3-hydroxyphenoxy)ethyl]carbamate (4.45 g, 19.3%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =254.

[0229] Step 2: Preparation of benzyl N-[2-(3-[2-[(tert-butoxycarbonyl)amino]ethoxy]phenoxy)ethyl]carbamate [ka] To a stirred solution of tert-butyl N-[2-(3-hydroxyphenoxy)ethyl]carbamate (4.30 g, 17.0 mmol) and benzyl N-(2-hydroxyethyl)carbamate (3.31 g, 17.0 mmol) in THF (25.0 mL) was added PPh3 (6.68 g, 25.5 mmol) and DIAD (5.15 g, 25.5 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash chromatography (water:MeOH) to give benzyl N-[2-(3-[2-[(tert-butoxycarbonyl)amino]ethoxy]phenoxy)ethyl]carbamate (5 g, 68.4%) as a yellow oil. LCMS (ESI) m / z: [M+H] + =431.

[0230] Step 3: Preparation of benzyl N-[2-[3-(2-aminoethoxy)phenoxy]ethyl]carbamate [ka] A solution of benzyl N-[2-(3-[2-[(tert-butoxycarbonyl)amino]ethoxy]phenoxy)ethyl]carbamate (2.85 g, 6.62 mmol) and Pd / C (1.43 g, 13.4 mmol) in MeOH (15.0 mL) was stirred under hydrogen atmosphere at 50° C. overnight. The resulting mixture was filtered and the filter cake was washed three times with MeOH. The filtrate was concentrated under reduced pressure to give benzyl N-[2-[3-(2-aminoethoxy)phenoxy]ethyl]carbamate (2.07 g, 86.9%) as an off-white oil. LCMS (ESI) m / z: [M+H] + =297.

[0231] Example 38. Preparation of intermediates The following intermediates in Table B5 were prepared in a similar manner as described in the preparation of I-22 using the appropriate amine (Example 32). [Table 12-1] [Table 12-2]

[0232] Example 39. Preparation of 4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]butanoic acid (I-29) [ka] Step 1: Preparation of tert-butyl 4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]butanoate [ka] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindole-1,3-dione (2.00 g, 7.29 mmol) and tert-butyl 4-bromobutanoate (1.95 g, 8.752 mmol) in DMF (10.0 mL) was added KI (0.12 g, 0.729 mmol) and KHCO3 (1.10 g, 10.9 mmol). The resulting solution was stirred at 60° C. for 5 h. The mixture was diluted with EtOAc and washed three times with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by reverse phase C18 flash chromatography (water:ACN) to give tert-butyl 4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]butanoate (1.5 g, 49.4%) as an off-white solid. LCMS (ESI) m / z [M+H] += 417.

[0233] Step 2: Preparation of 4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]butanoic acid (I-29) [ka] To a stirred solution of tert-butyl 4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]butanoate (450 mg, 1.08 mmol) in DCM (5 mL) was added TFA (1 mL). The resulting solution was stirred for 2 h at 25° C. The resulting mixture was concentrated. This afforded I-29 (360 mg, 92.5%) as a white solid. 1 H NMR(400MHz, methanol-d4)δ 7.79(t,J=8.4,7.4Hz,1H),7.47(d,J=7.8Hz,2H),5.12(dd,J=12.6,5.5Hz,1H),4.30(t,J=6 .2Hz,2H),2.95-2.66(m,3H),2.60(t,J=7.3Hz,2H),2.25-2.18(m,3H).LCMS(ESI)m / z:[M+H] + =361.10.

[0234] Example 40. Preparation of intermediates The following intermediates in Table B6 were prepared in a similar manner as described in the preparation of intermediate I-29 using the appropriate alkyl bromide (Example 39). [Table 13]

[0235] Example 41. Preparation of 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoic acid (I-34) [ka] Step 1: Preparation of tert-butyl 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoate [ka] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (1.00 g, 3.62 mmol) in NMP (10.0 mL) was added tert-butyl 3-[2-(2-aminoethoxy)ethoxy]propanoate (929 mg, 3.98 mmol). The resulting mixture was stirred overnight at 90° C. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc. The organic layer was washed five times with water and then with brine. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc) to give a yellow solid tert-butyl 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoate (1.14 g, 64.3%). LCMS (ESI) m / z: [M+H] + =490.

[0236] Step 2: Preparation of 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoic acid (I-34) [ka] To a stirred solution of tert-butyl 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoate (1.14 g, 2.33 mmol) in DCM (10.0 mL) was added TFA (0.52 mL, 4.55 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo and the residue was purified by reverse phase C18 flash chromatography (water:ACN) to give I-34 (896 mg, 70.3%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 12.15(s,1H),11.09(s,1H),7.63-7.55(m,1H),7.15(d,1H),7.05(d,1H),6.61(t,1H),5.06(dd, 1H),3.65-3.44(m,8H),2.87(d,1H),2.59(d,2H),2.43(t,2H),2.04(m,1H);LCMS(ESI)m / z:[M+H] += 434.15.

[0237] Example 42. Preparation of intermediates The following intermediates in Table B7 were prepared in a similar manner as described in the preparation of intermediate I-34, starting with the appropriate aryl fluoride and amine (Example 41). [Table 14]

[0238] Example 43. Preparation of 2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetamido)methyl]cyclopropane-1-carboxylic acid (I-42) [ka] Step 1: Preparation of tert-butyl 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetate [ka] To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (5.50 g, 20.1 mmol) and tert-butyl 2-bromoacetate (3.91 g, 20.1 mmol) in DMF (15.0 mL) was added K2CO3 (8.32 g, 60.2 mmol). The resulting mixture was stirred overnight at room temperature, then taken up in water, extracted three times with EtOAc, and concentrated. The residue was purified by reverse phase C18 flash chromatography (water:ACN) to give tert-butyl 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetate (3.2 g, 45.2%) as an off-white solid. LCMS (ESI) m / z: [M+H] + =389.

[0239] Step 2: Preparation of [[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetic acid [ka] A solution of tert-butyl 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetate (3.20 g, 8.24 mmol) in dioxane (15.0 mL, 494 mmol) and dry HCl was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. This gave [[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetic acid (1.12 g) as a yellow solid. LCMS (ESI) m / z: [M+H] + =289.

[0240] Step 3: Preparation of methyl 2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetamido)methyl]cyclopropane-1-carboxylate [ka] To a stirred solution of [[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetic acid (670 mg, 2.02 mmol) and methyl 2-(aminomethyl)cyclopropane-1-carboxylate (260 mg, 2.02 mmol) in DMF (15.0 mL) was added dropwise at room temperature over 2 h with HATU (1.15 g, 3.03 mmol) and DIEA (782 mg, 6.05 mmol). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash chromatography (water:ACN) to give methyl 2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetamido)methyl]cyclopropane-1-carboxylate (779 mg, 78.4%) as a yellow oil. LCMS(ESI)m / z:[M+H] + =444.

[0241] Step 4: Preparation of 2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetamido)methyl]cyclopropane-1-carboxylic acid (I-42) [ka] A mixture of methyl 2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetamido)methyl]cyclopropane-1-carboxylate (764 mg) in dioxane (4N, 5.00 mL, 20 mmol) and HCl was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash chromatography using the following conditions (water:ACN) to give I-42 (338 mg) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ 12.17(s,1H),11.12(s,1H),8.33(t,1H),7.88(d,1H),7.46(d,1H),7.39(dd,1H),5.13(dd,1H),4.74(s,2H),2.96-2.8 3(m,1H),2.65-2.52(m,1H),2.08(s,4H),1.66(td,1H),1.48(h,1H),1.02(td,1H),0.85(dt,1H).LCMS(ESI)m / z:[M+H] + =430.05.

[0242] Example 44. Preparation of methyl 2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamido)methyl]cyclopropane-1-carboxylate (I-43) [ka] A white solid, I-43 (423 mg, 35.74%), was prepared in a similar manner as described in the preparation of I-42 starting from the appropriate phenol (Example 43). 1 H NMR(300MHz,DMSO-d6)δ 12.16(s,1H),11.12(s,1H),8.10(s,1H),7.82(t,1H),7.51(d,1H),7.41(d,1H),5.17-5.07(m,1H),4.80(s,2) H),2.60(d,2H),2.08(s,3H),1.70-1.60(m,1H),1.47(d,1H),1.03(d,1H),0.84(d,1H).LCMS(ESI)m / z:[M+H] + =430.12.

[0243] Example 45. Preparation of 6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoic acid [ka] Step 1: Preparation of methyl 6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoate [ka] To a solution of (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methyl thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (300 mg, 0.697 mmol) and 6-methoxy-6-oxo-hexanoic acid (93.0 μL, 0.627 mmol) in DCM (3 mL) was added HATU (265 mg, 0.697 mmol) and DIEA (485 μL, 2.79 mmol). The mixture was stirred at 30° C. for 2 h. The reaction mixture was diluted with water and extracted twice with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The reaction was purified by reverse phase (0.1% FA condition) and the eluent was concentrated to remove MeCN. The residue was extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give methyl 6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoate (340 mg, 85.2%) as a colorless oil. LCMS (ESI) m / z=[M+H] += 573.6.

[0244] Step 2: Preparation of 6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoic acid [ka] To a solution of methyl 6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoate (340 mg, 0.594 mmol) in THF / MeOH / H2O (2 / 1 / 1, 4 mL) was added LiOH·H2O (42.7 mg, 1.78 mmol). The mixture was stirred at 30 °C for 4 h. The reaction mixture was diluted with water and washed twice with EtOAc. The pH of the aqueous phase was adjusted to 5 with 1N HCl. The mixture was then extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was lyophilized to give 6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoic acid (185 mg, 55.9%) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ 8.87(s,1H),7.47-7.40(m,4H),4.63-4.49(m,5H),4.37(d,J=15.6Hz,1H),3.89-3.82(m,1H),3.81-3.79(m, 1H),2.48(s,3H),2.31-2.27(m,5H),2.10-2.08(m,1H),1.66-1.60(m,4H),1.03(s,9H).LCMS(ESI)m / z=[M+H] += 559.2.

[0245] Example 46. Preparation of intermediates The following intermediates in Table B8 were prepared in a similar manner to that described in Example 45 using (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide the appropriate carboxylic acid. [Table 15-1] [Table 15-2]

[0246] Example 47. Preparation of (S)-16-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-17,17-dimethyl-14-oxo-3,6,9,12-tetraoxa-15-azaoctadecane-1-oic acid [ka] Step 1: Preparation of 3-oxo-1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-oic acid [ka] To a mixture of 2-[2-[2-[2-(carboxymethoxy)ethoxy]ethoxy]ethoxy]acetic acid (1 g, 3.76 mmol) and TEA (1.34 mL, 9.66 mmol) in acetone (5 mL) was added benzyl bromide (0.468 mL, 3.94 mmol) dropwise at 0 °C. The mixture was stirred at 20 °C for 16 h. The mixture was filtered and the filter cake was washed with acetone. The filtrate was concentrated and the residue was dissolved in water. The mixture was extracted three times with EtOAc and then treated with HCl (2 M) to adjust the pH to 3-5. The mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, then dried over Na2SO4, filtered and concentrated in vacuo to give 3-oxo-1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-oic acid (690 mg, 51.6% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.32-7.25(m,5H),5.12(s,2H),4.13(s,2H),4.08(s,2H),3.69-3.65(m,4H),3.64-3.59(m,8H).

[0247] Step 2: Preparation of (S)-benzyl 16-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-17,17-dimethyl-14-oxo-3,6,9,12-tetraoxa-15-azaoctadecane-1-oate [ka] To a solution of 3-oxo-1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-oic acid (572 mg, 1.61 mmol) in DCM (6 mL) was added HATU (795 mg, 2.09 mmol) and DIEA (728 μL, 4.18 mmol). (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (600 mg, 1.28 mmol) was added to the mixture. The mixture was stirred at 30° C. for 2 h. The mixture was concentrated in vacuo to give a yellow solid. The residue was purified by reverse-phase flash chromatography (FA conditions) to give (S)-benzyl 16-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-17,17-dimethyl-14-oxo-3,6,9,12-tetraoxa-15-azaoctadecane-1-oate (810 mg, 72.0%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 8.70(s,1H),7.41-7.34(m,10H),4.77-4.76(m,1H),4.63-4.47(m,3H),4.38-4.33(m,1H),4.22(s,2H),4.13(d,J=11.2Hz,1H) ,4.08-3.96(m,2H),3.75-3.59(m,12H),2.64-2.55(m,1H),2.54(s,3H),2.19-2.09(m,1H),0.97(s,9H).LCMS(ESI)m / z:[M+H] += 769.4.

[0248] Step 3: Preparation of (S)-16-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-17,17-dimethyl-14-oxo-3,6,9,12-tetraoxa-15-azaoctadecane-1-oic acid [ka] To a mixture of (S)-benzyl 16-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-17,17-dimethyl-14-oxo-3,6,9,12-tetraoxa-15-azaoctadecan-1-oate (780 mg, 1.01 mmol) in MeOH (5 mL) was added Pd / C (10%, 216 mg, 0.203 mmol). The mixture was purged with H2 and then pressurized with H2 (15 psi) and stirred at 25 °C for 12 h and then at 40 °C for 8 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (NHOH condition) to give (S)-16-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-17,17-dimethyl-14-oxo-3,6,9,12-tetraoxa-15-azaoctadecane-1-oic acid (300 mg, 42.9%) as a white solid. 1 H NMR(400MHz, methanol-d4)δ 8.90(s,1H),7.55-7.39(m,4H),4.62-4.51(m,3H),4.42-4.35(m,1H),4.16-4.12(m,2H),4.08(d,J=3.6Hz,2H),3.93-3.79( m,2H),3.75-3.64(m,13H),2.52-2.49(m,3H),2.29-2.21(m,1H),2.17-2.06(m,1H),1.08-1.04(m,9H).LCMS(ESI)m / z:[M+H] += 679.2.

[0249] Example 48. Preparation of 1-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)piperidine-4-carboxylic acid (I-61) [ka] Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(prop-2-en-1-yloxy)isoindole-1,3-dione [ka] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (5.48 g, 20.0 mmol) and allyl bromide (3.63 g, 30.0 mmol) in DMF (50.0 mL) was added KI (332 mg, 2.00 mmol) and KHCO3 (3.00 g, 30.0 mmol). The resulting mixture was stirred at 65 °C for 12 h, then diluted with water and extracted three times with EtOAc. The combined organic layer was washed three times with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc) to give 2-(2,6-dioxopiperidin-3-yl)-5-(prop-2-en-1-yloxy)isoindole-1,3-dione (6.7 g, crude) as a yellow-green solid. LCMS(ESI)m / z:[M+H] + =315.

[0250] Step 2: Preparation of 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetaldehyde [ka] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(prop-2-en-1-yloxy)isoindole-1,3-dione (3.14 g, 9.99 mmol) in dioxane (30.0 mL) was added NaIO4 (10.7 g, 50.0 mmol), water (3.00 mL), and 2,6-lutidine (3.21 g, 30.0 mmol). To the above mixture was added K2OsO4 dihydrate (0.37 g, 0.999 mmol) at room temperature. The resulting mixture was stirred for another 2 h at room temperature. The reaction was quenched with water at room temperature, and the resulting mixture was extracted with EtOAc three times. The combined organic layers were washed with brine three times and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetaldehyde (1.83 g, 57.9%) as a light brown solid. LCMS (ESI) m / z: [M+H] + =317.

[0251] Step 3: Preparation of tert-butyl 1-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)piperidine-4-carboxylate [ka] To a solution of 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetaldehyde (1.83 g, 5.79 mmol) and tert-butyl piperidine-4-carboxylate (1.07 g, 5.79 mmol) in DMF (35.0 mL) was added NaBH(OAc)3 (3.68 g, 17.4 mmol). The resulting mixture was stirred at room temperature for 3 h. The residue was purified by reverse phase C18 flash chromatography (water:ACN:FA) to give tert-butyl 1-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)piperidine-4-carboxylate (1.16 g, 41.3%) as an off-white solid. LCMS (ESI) m / z: [M+H] + =401.

[0252] Step 4: Preparation of 1-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)piperidine-4-carboxylic acid (I-61) [ka] To a solution of tert-butyl 1-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)piperidine-4-carboxylate (1.16 g, 2.39 mmol) in DCM (10.0 mL) was added TFA (10.0 mL, 135 mmol). The resulting mixture was stirred at room temperature for 5 h. The residue was purified by reverse-phase C18 flash chromatography (water:ACN:FA) to give I-61 (845 mg, 73.4%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 11.11(s,1H),8.15(d,1H),7.84(d,1H),7.47(d,1H),7.37(dd,1H),5.12(dd,1H),4.31(t,2H),3.02-2.85(m,3H),2.79(t,2H),2.6 6-2.60(m,1H),2.59-2.54(m,1H),2.29-2.12(m,3H),2.15-1.99(m,1H),1.87-1.75(m,2H),1.66-1.47(m,2H).LCMS(ESI)m / z:[M+H] += 430.15.

[0253] Example 49. Preparation of N-[2-[(2-aminoethyl)(methyl)amino]ethyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]acetamide hydrochloride (I-63) [ka] Step 1: Preparation of tert-butyl 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetate [ka] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindole-1,3-dione (5.50 g, 20.1 mmol) in DMF (65.0 mL) was added tert-butyl 2-bromoacetate (3.91 g, 20.1 mmol) and K2CO3 (8.32 g, 60.2 mmol). The resulting solution was stirred at room temperature for 12 h. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc) to give tert-butyl 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetate (5.2 g, 66.8%) as a white solid. LCMS (ESI) m / z: [M+H] + =389.

[0254] Step 2: Preparation of [[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetic acid [ka] A solution of tert-butyl 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetate (5.32 g, 13.7 mmol) in HCl in dioxane (4N, 50.0 mL, 200 mmol) was stirred at room temperature for 12 h. The solution was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash chromatography (water:ACN) to give [[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetic acid (4.66 g, 100%) as a white solid. LCMS (ESI) m / z: [M+H] + =333.

[0255] Step 3: Preparation of tert-butyl N-(2-[[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamido)ethyl](methyl)amino]ethyl)carbamate [ka] To a solution of [[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetic acid (926 mg, 2.79 mmol) in DCM (35.0 mL) was added tert-butyl N-[2-[(2-aminoethyl)(methyl)amino]ethyl]carbamate (908 mg, 4.18 mmol), HATU (1.59 g, 4.18 mmol), and DIEA (1.08 g, 8.36 mmol). The resulting solution was stirred at room temperature for 3 h. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc) to give a pale yellow solid of tert-butyl N-(2-[[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamido)ethyl](methyl)amino]ethyl)carbamate (1.53 g, crude). LCMS (ESI) m / z: [M+H] + =532.

[0256] Step 4: Preparation of N-[2-[(2-aminoethyl)(methyl)amino]ethyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]acetamide hydrochloride (I-63) [ka] A solution of tert-butyl N-(2-[[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamido)ethyl](methyl)amino]ethyl)carbamate (600 mg, 1.13 mmol) was prepared in 4 NM HCl (123 mg, 3.39 mmol) in dioxane (20.0 mL) and stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash chromatography (water:ACN) to give N-[2-[(2-aminoethyl)(methyl)amino]ethyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]acetamide (I-63, 200 mg, 41.1%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =432.18.

[0257] Example 50. Preparation of intermediates The intermediates in Table B9 were prepared in a similar manner as described in Example 49, starting with the appropriate substituted phenol and amine. [Table 16]

[0258] Example 51. Preparation of 4-(2-[2-[(2-aminoethyl)(methyl)amino]ethoxy]ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-29) [ka] Step 1: Preparation of benzyl N-[2-(2-hydroxyethoxy)ethyl]-N-methylcarbamate [ka] To a solution of 2-(2-(methylamino)ethoxy)ethan-1-ol (10.0 g, 83.9 mmol) in THF (30.0 mL) was added benzyl chloroformate (2.29 g, 13.4 mmol), K2CO3 (3.83 g, 27.7 mmol), and water (30.0 mL). The resulting mixture was stirred at room temperature for 12 h and then extracted three times with EtOAc. The combined organic layers were washed three times with brine and dried over anhydrous Na2SO4. After filtration, the liquid was concentrated under reduced pressure and purified by reverse phase C18 flash chromatography (water:ACN:NH4HCO3) to give N-[2-(2-hydroxyethoxy)ethyl]-N-benzyl methylcarbamate (2.14 g, 17.5%) as a colorless oil. LCMS (ESI) m / z: [M+H] += 254.

[0259] Step 2: Preparation of benzyl N-methyl-N-(2-[2-[(4-methylbenzenesulfonyl)oxy]ethoxy]ethyl)carbamate [ka] To a stirred solution of N-[2-(2-hydroxyethoxy)ethyl]-benzyl N-methylcarbamate (2.14 g, 8.45 mmol) in DCM (30.0 mL) was added DMAP (0.15 g, 1.27 mmol), TEA (2.14 g, 21.1 mmol), and p-toluenesulfonyl chloride (2.42 g, 12.7 mmol) at 0° C. The resulting mixture was stirred for 2 h at 0° C. and then for an additional 5 h at room temperature. The residue was purified by silica gel column chromatography (petroleum ether / THF) to give N-methyl-N-(2-[2-[(4-methylbenzenesulfonyl)oxy]ethoxy]ethyl)benzyl carbamate (3.51 g, crude) as a colorless oil. LCMS (ESI) m / z: [M+H] + =408.

[0260] Step 3: Preparation of benzyl N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethoxy)ethyl]-N-methylcarbamate [ka] To a solution of N-methyl-N-(2-[2-[(4-methylbenzenesulfonyl)oxy]ethoxy]ethyl)benzylcarbamate (3.51 g, 8.61 mmol) in DMF (30.0 mL) was added 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindole-1,3-dione (2.36 g, 8.61 mmol) and Na2CO3 (1.37 g, 12.9 mmol). The resulting mixture was stirred at 80° C. for 12 h and then concentrated. The residue was purified by reverse phase flash C18 chromatography under the following conditions (water:ACN) to give a pale yellow solid N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethoxy)ethyl]-N-methylcarbamate benzyl (1.53 g, 34.8%). LCMS (ESI) m / z: [M+H] + =510.

[0261] Step 4: Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-[2-[2-(methylamino)ethoxy]ethoxy]isoindole-1,3-dione [ka] To a solution of N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethoxy)ethyl]-benzyl N-methylcarbamate (1.52 g, 3.00 mmol) in EtOH (30.0 mL) was added ammonium formate (378 mg, 5.99 mmol) and Pd(OH)2 / C (5.43 mmol). The resulting suspension was stirred at 60° C. for 12 h under 1 atm of hydrogen and then filtered. The filter cake was washed three times with MeOH and the filtrate was concentrated under reduced pressure to give 2-(2,6-dioxopiperidin-3-yl)-4-[2-[2-(methylamino)ethoxy]ethoxy]isoindole-1,3-dione (1.06 g, 94.8%) as a pale yellow solid. LCMS(ESI)m / z[M+H] += 376.

[0262] Step 5: Preparation of tert-butyl N-(2-[[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethoxy)ethyl](methyl)amino]ethyl)carbamate [ka] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-[2-[2-(methylamino)ethoxy]ethoxy]isoindole-1,3-dione (1.06 g, 2.82 mmol) in DMF (10.0 mL) was added tert-butyl N-(2-oxoethyl)carbamate (539 mg, 3.39 mmol) and NaBH(OAc)3 (1.80 g, 8.47 mmol). The resulting solution was stirred at room temperature for 2 h. After aqueous workup, extraction with DCM, and concentration under reduced pressure, the residue was purified by silica gel column chromatography (DCM / MeOH) to give tert-butyl N-(2-[[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethoxy)ethyl](methyl)amino]ethyl)carbamate (386 mg, 26.4%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =519.

[0263] Step 6: Preparation of 4-(2-[2-[(2-aminoethyl)(methyl)amino]ethoxy]ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-29) [ka] To a solution of tert-butyl N-(2-[[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethoxy)ethyl](methyl)amino]ethyl)carbamate (511 mg, 0.985 mmol) in DCM (5.00 mL) was added TFA (5.00 mL, 67.3 mmol). The resulting solution was stirred at room temperature for 3 h. The solution was concentrated and the residue was purified by reverse phase C18 flash chromatography under the following conditions (water:ACN) to give I-29 (307 mg, 73.9%) as a brown oil. 1 H NMR(300MHz,DMSO-d6)δ 11.70-10.30(m,1H),8.18(s,1H,formic acid),7.83(dd,1H),7.51(dd,2H),5.09(dd,1H),4.41-4.32(m,2H),3.84-3.75(m,2H) ,3.63(d,2H),2.99-2.80(m,3H),2.65-2.58(m,5H),2.24(s,3H),2.08(s,1H),1.98-2.06(m,1H);LCMS(ESI)m / z:[M+H] + =419.

[0264] Example 52. Preparation of 5-(azetidin-3-yloxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (I-33) [ka] Step 1: Preparation of tert-butyl 3-[(4-methylbenzenesulfonyl)oxy]azetidine-1-carboxylate [ka] To a stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.50 g, 14.4 mmol) and p-toluenesulfonyl chloride (4.13 g, 21.7 mmol) in DCM, DMAP (264 mg, 2.17 mmol) and TEA (4.38 g, 43.3 mmol) were added in portions at 0° C. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc) to give tert-butyl 3-[(4-methylbenzenesulfonyl)oxy]azetidine-1-carboxylate (4.4 g, 93.1%) as a brown oil. LCMS (ESI) m / z: [M+H] + =328.

[0265] Step 2: Preparation of tert-butyl 3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]azetidine-1-carboxylate [ka] To a stirred solution of tert-butyl 3-[(4-methylbenzenesulfonyl)oxy]azetidine-1-carboxylate (4.40 g, 13.4 mmol) and KI (0.22 g, 1.34 mmol) in DMF was added KHCO3 (4.04 g, 40.3 mmol) in portions. After stirring for 8 h at 100 °C, the resulting mixture was extracted three times with EtOAc and the organic extracts were concentrated under reduced pressure. The residue was purified by reverse phase C18 flash chromatography (water:ACN) to give tert-butyl 3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]azetidine-1-carboxylate (1.73 g, 30.0%) as an off-white solid. LCMS (ESI) m / z: [M+H] + =430.

[0266] Step 3: Preparation of 5-(azetidin-3-yloxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-33) [ka] A solution of tert-butyl 3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]azetidine-1-carboxylate (1.53 g, 3.56 mmol) and TFA (5.00 mL, 67.3 mmol) in DCM was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase C18 flash chromatography under the following conditions (water:ACN) to give I-33 (1.08 g, 96.4%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 11.11(s,1H),8.25(s,formic acid,1H),7.88(d,1H),7.32(d,2H),5.30(p,1H),5.13(dd,1H),4.31(dd,2 H),3.89(dd,2H),2.99-2.80(m,1H),2.68-2.52(m,2H),2.13-1.97(m,1H).LCMS(ESI)m / z:[M+H] + =330.05.

[0267] Example 53. Preparation of 5-[7-azaspiro[3.5]nonan-2-yloxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-35) [ka] Step 1: Preparation of tert-butyl 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]-7-azaspiro[3.5]nonane-7-carboxylate [ka] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (1.37 g, 4.99 mmol) and tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (1.81 g, 7.49 mmol) in THF (30.0 mL) was added PPh3 (1.97 g, 7.49 mmol). To this mixture was added DIAD (1.52 g, 7.49 mmol) dropwise over 10 min at 0° C. The reaction was stirred at room temperature for an additional 5 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse-phase C18 flash chromatography (water:ACN:FA) to give tert-butyl 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]-7-azaspiro[3.5]nonane-7-carboxylate (1.96 g, 79.0%) as a white solid. LCMS (ESI) m / z: [M+H] += 498.

[0268] Step 2: Preparation of 5-[7-azaspiro[3.5]nonan-2-yloxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-35) [ka] To a solution of tert-butyl 2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]-7-azaspiro[3.5]nonane-7-carboxylate (1.96 g, 3.94 mmol) in DCM (10.0 mL) was added TFA (10.0 mL, 135 mmol). The resulting mixture was stirred at room temperature for 5 h, then concentrated and purified by reverse phase C18 flash chromatography (water:ACN:FA) to give I-35 (1.63 g, 93.1%) as a light grey solid. 1H NMR(300MHz,DMSO-d6)δ 8.39(s, formic acid, 1H), 7.84(d, 1H), 7.35-7.24(m, 2H), 5.12(dd, 1H), 5.00(p, 1H), 3.00-2.81(m, 5H), 2.67-2.43 (m,2H),2.51-2.43(m,3H),2.16-1.95(m,1H),1.95-1.82(m,2H),1.65-1.78(m,4H);LCMS(ESI)m / z:[M+H] += 398.16.

[0269] Example 54. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-[2-(piperazin-1-yl)ethoxy]isoindole-1,3-dione formate (I-36) [ka] Step 1: Preparation of tert-butyl 4-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)piperazine-1-carboxylate [ka] To a solution of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetaldehyde (628 mg, 1.99 mmol) and tert-butyl piperazine-1-carboxylate (370 mg, 1.99 mmol) in DMF (10.0 mL) was added NaBH(OAc)3 (1.26 g, 5.96 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h, then quenched with water, extracted into DCM and concentrated. The residue was purified by reverse phase C18 flash chromatography under the following conditions (water:ACN:FA) to give tert-butyl 4-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)piperazine-1-carboxylate (812 mg, 84.05%) as an off-white solid. LCMS (ESI) m / z: [M+H] + =487.

[0270] Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-[2-(piperazin-1-yl)ethoxy]isoindole-1,3-dione formate (I-36) [ka] To a solution of tert-butyl 4-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)piperazine-1-carboxylate (2.10 g, 4.32 mmol) in DCM (10.0 mL) was added TFA (10.0 mL, 135 mmol). The resulting mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. The residue was purified by reverse-phase C18 flash chromatography (water:ACN:FA) to give I-36 (1.43 g, 74.2%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 11.07(s,1H),8.34(s,1H),7.84(d,1H),7.47(d,1H),7.37(dd,1H),5.12(dd,1H),4.30(t,2H) ,2.99-2.86(m,5H),2.77(t,2H),2.67-2.55(m,5H),2.13-1.96(m,1H).;LCMS(ESI)m / z:[M+H] + =387.16.

[0271] Example 55. Preparation of 5-[4-(azetidin-3-ylmethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-40) [ka] Step 1: tert-Butyl 3-([4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]methyl)azetidine-1-carboxylate [ka] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione formate (1.10 g, 3.21 mmol) and tert-butyl 3-formylazetidine-1-carboxylate (595 mg, 3.21 mmol) in DMF (10.0 mL) was added NaBH(OAc)3 (2.04 g, 9.64 mmol). The resulting mixture was stirred at room temperature for 3 h. After aqueous workup, DCM extraction, and concentration, the residue was purified by reverse phase C18 flash chromatography under the following conditions (water:ACN:FA) to give tert-butyl 3-([4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]methyl)azetidine-1-carboxylate (991 mg, 60.3%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =512.

[0272] Step 2: Preparation of 5-[4-(azetidin-3-ylmethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formate (I-40) [ka] To a solution of tert-butyl 3-([4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]methyl)azetidine-1-carboxylate (991 mg, 1.94 mmol) in DCM (10.0 mL) was added TFA (10.0 mL, 135 mmol). The resulting mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. The residue was purified by reverse phase C18 flash chromatography (water:ACN:FA) to give I-40 (702 mg, 85.3%) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ 11.07(s,1H),8.25(s,formic acid,1H),7.69(d,1H),7.34(d,1H),7.26(dd,1H),5.08(dd,1H),4.00(t,2H),3.66(dd,2H),3.43(t, 4H),3.11-2.96(m,1H),2.95-2.79(m,1H),2.65-2.51(m,4H),2.50-2.44(m,4H),2.09-1.96(m,1H).;LCMS(ESI)m / z:[M+H] + =412.19.

[0273] Example 56. Preparation of intermediates The intermediates in Table B10 were prepared in a similar manner as described in Example 55 from the common intermediate 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione formate and the appropriate aldehyde. [Table 17]

[0274] Example 57. Preparation of 3-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]propanoic acid (I-41) [ka] Step 1: Preparation of tert-butyl 3-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]propanoate [ka] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione formate (5.0 g, 14.6 mmol) and tert-butyl 3-bromopropanoate (3.6 g 17.2 mmol) in DMF (50 mL) was added dropwise DIEA (2.8 g, 21.7 mmol) and the mixture was stirred at 70° C. for 6 h. The reaction mixture was concentrated and the residue was purified by reverse phase C18 flash chromatography (water:ACN) to give tert-butyl 3-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]propanoate (2.1 g, 30.6%) as a yellow solid. LCMS (ESI) m / z [M+H] + =471.

[0275] Step 2: Preparation of 3-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]propanoic acid (I-41) [ka] A solution of tert-butyl 3-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]propanoate (2.1 g, 4.5 mmol) in DCM (20 mL) and TFA (5 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase C18 flash chromatography (water:MeOH) to give 3-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]propanoic acid (I-41) (0.78 g, 42.2%) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ 12.03(br,1H),11.10(s,1H),7.68(d,J=8.5Hz,1H),7.35(d,J=1.7Hz,1H),7.27(dd,J=8.6,2.0Hz,1H),5.08(dd,J=12.8,5.4H z,1H),3.49-3.40(m,4H),2.96-2.80(m,1H),2.67-2.52(m,8H),2.44(t,J=6.9Hz,2H),2.07-1.97(m,1H).LCMS(ESI)m / z[M+H] + =415.10.

[0276] Example 58. Preparation of 5-(2-aminoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (I-44) [ka] Step 1: Preparation of tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)carbamate [ka] To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (1.0 g, 3.6 mmol) and 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide tert-butyl (0.98 g, 4.4 mmol) in DMF (10 mL) was added DIEA (0.94 g, 7.3 mmol) under nitrogen atmosphere. After stirring at 80° C. for 2 h, water was added followed by extraction with EtOAc three times. The combined organic layer was washed with water three times and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to dryness under reduced pressure and the residue was purified by reverse phase C18 flash chromatography (water:ACN) to give tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)carbamate (1.7 g, 94.4%) as a yellow oil. LCMS (ESI) m / z: [M+H] +=418.

[0277] Step 2: Preparation of 5-(2-aminoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; trifluoroacetate (I-44) [ka] To a stirred solution of (tert-butyl(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)carbamate (1.4 g, 3.4 mmol) in DCM (20 mL) was added TFA (5 mL) dropwise. After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography to give I-44 (750 mg, 51.2%) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 11.15(s,1H),8.04(br,3H),7.91(d,J=8.3Hz,1H),7.50(d,J=2.2Hz,1H),7.41(dd,J=8.3,2.3Hz,1H),5.14(dd,J=12.9,5.3Hz ,1H),4.38(t,J=4.9Hz,2H),3.35-3.23(m,2H),2.98-2.81(m,1H),2.66-2.54(m,2H),2.11-2.01(m,1H).LCMS(ESI)m / z:[M+H] + =418.10.

[0278] Example 59. Preparation of 4-(5-aminopent-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione trifluoroacetate (I-81) [ka] Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl trifluoromethanesulfonate [ka] To a stirred mixture of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindole-1,3-dione (2.00 g, 7.29 mmol) in DCM (21.0 mL) was added TEA (2.28 mL, 16.4 mmol) and pyridine (2.28 mL, 28.3 mmol). The reaction was cooled to 0° C., then trifline anhydride (3.09 g, 10.9 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 2 h. The resulting mixture was diluted with water and extracted three times with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was diluted with DCM (50 mL) and stirred at room temperature for 0.5 h. The resulting mixture was filtered and the filter cake was washed with DCM to give 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl trifluoromethanesulfonate (1.92 g, 58.3%) as an off-white solid. LCMS (ESI) m / z [M+H] + =407.

[0279] Step 2: Preparation of tert-butyl N-[5-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]pent-4-yn-1-yl]carbamate [ka] To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl trifluoromethanesulfonate (1.60 g, 3.94 mmol) and tert-butyl N-(pent-4-yn-1-yl)carbamate (2.02 g, 11.3 mmol) in THF (40 mL) was added CuI (75.0 mg, 0.394 mmol), DIEA (6.86 mL, 53.1 mmol), and Pd(PPh3)2Cl2 (276 mg, 0.394 mmol). The resulting mixture was stirred at 70 °C for 1 h. The reaction was filtered and the filter cake was washed three times with EtOAc. The filtrate was concentrated under reduced pressure and the residue was dissolved in water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc) to give tert-butyl N-[5-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]pent-4-yn-1-yl]carbamate (1.12 g, 64.7%) as an off-white solid. LCMS (ESI) m / z: [M+H] + =440.

[0280] Step 3: Preparation of 4-(5-aminopent-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione trifluoroacetate (I-81) [ka] To a stirred solution of tert-butyl N-[5-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]pent-4-yn-1-yl]carbamate (1.10 g, 2.50 mmol) in dichloromethane (6 mL) was added TFA (3.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give I-81 (890 mg, 91.2%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 11.15(s,1H),7.97-7.73(m,6H),5.14(dd,1H),3.09-2.97(m,2H),2.96-2.84(m,1H),2. 67(t,3H),2.62-2.54(m,1H),2.12-2.02(m,1H),1.82-1.94(m,2H).LCMS(ESI)m / z:[M+H] + =340.12.

[0281] Example 60. Preparation of tert-butyl 4-[3-(prop-2-yn-1-yloxy)propyl]piperazine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (22.4 g, 0.09 mol) in THF (500 mL) was added NaH (4.4 g, 0.18 mol) in portions over 30 min at 0° C. Then, propargyl bromide (32.7 g, 0.27 mol) was added dropwise to the reaction at room temperature and the mixture was stirred for 12 h. The reaction mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated to dryness and the residue was purified by reverse flash C18 chromatography (water:ACN) to give tert-butyl 4-[3-(prop-2-yn-1-yloxy)propyl]piperazine-1-carboxylate (14.9 g, 57.6%) as an off-white solid. LCMS (ESI) m / z: [M+H] + =283.

[0282] Example 61. Preparation of intermediates The following compound in Table B11 was synthesized according to the protocol of Example 59 using 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione instead of 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl trifluoromethanesulfonate and the appropriate alkyne. [Table 18]

[0283] Example 62. Preparation of 3-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)propanoic acid formate [ka] To a stirred solution of 5-[2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (12.0 g, 33.9 mmol) and acrylic acid (4.9 g, 68.1 mmol), DIEA (8.8 g, 68.2 mmol) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the residue was purified by reverse flash C18 column chromatography (water:ACN:FA) to give 3-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)propanoic acid formate (1.8 g, 12.5%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 11.12(br,1H),8.28(s,1H),7.64(d,J=8.3Hz,1H),6.79(d,J=2.1Hz,1H),6.64(dd,J=8.3,2.1Hz,1H),5.06(dd,J=12.9,5.4Hz,1H),4.10(s ,4H),4.10(s,5H),2.95-2.81(m,1H),2.61-2.59(m,2H),2.57-2.54(m,1H),2.19(t,J=6.8Hz,2H),2.05-1.96(m,1H).LCMS(ESI)m / z:[M+H] + =427.15.

[0284] Example 63. Preparation of 5-[3-(2-aminoethoxy)azetidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione [ka] Step 1: Preparation of tert-butyl 3-(2-[[(benzyloxy)carbonyl]amino]ethoxy)azetidine-1-carboxylate [ka] To a solution of tert-butyl 3-(2-aminoethoxy)azetidine-1-carboxylate (10.2 g, 47.3 mmol) in THF (50.0 mL) was added benzyl chloroformate (8.07 g, 47.3 mmol), H2O (50.0 mL), and K2CO3 (19.61 g, 142 mmol). The resulting solution was stirred at room temperature for 3 h. The resulting mixture was extracted three times with EtOAc. The combined organic layers were washed three times with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc) to give tert-butyl 3-(2-[[(benzyloxy)carbonyl]amino]ethoxy)azetidine-1-carboxylate (4.23 g, 25.5%) as a colorless oil. LCMS (ESI) m / z: [M+H] += 351.

[0285] Step 2: Preparation of benzyl N-[2-(azetidin-3-yloxy)ethyl]carbamate [ka] To a stirred solution of tert-butyl 3-(2-[[(benzyloxy)carbonyl]amino]ethoxy)azetidine-1-carboxylate (4.23 g, 12.1 mmol) in DCM (10.0 mL) was added TFA (10.0 mL, 135 mmol). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase C18 flash chromatography (water:ACN:NH4HCO3) to give benzyl N-[2-(azetidin-3-yloxy)ethyl]carbamate (4.56 g) as a colorless oil. LCMS (ESI) m / z [M+H] + =251.

[0286] Step 3: Preparation of benzyl N-[2-([1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]azetidin-3-yl]oxy)ethyl]carbamate [ka] To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (3.30 g, 11.9 mmol) in DMF (45.0 mL) was added N-[2-(azetidin-3-yloxy)ethyl]benzyl carbamate (2.99 g, 11.9 mmol) and DIEA (4.63 g, 35.8 mmol). The resulting mixture was stirred for 2 h at 90° C. The reaction was quenched with water at room temperature. The resulting mixture was extracted three times with EtOAc. The combined organic layers were washed three times with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a pale yellow solid of N-[2-([1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]azetidin-3-yl]oxy)ethyl]benzylcarbamate (3.41 g). LCMS (ESI) m / z: [M+H] += 507.

[0287] Step 4: Preparation of 5-[3-(2-aminoethoxy)azetidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione [ka] To a stirred solution of benzyl N-[2-([1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]azetidin-3-yl]oxy)ethyl]carbamate (3.10 g, 6.12 mmol) in ACN (45.0 mL) was added Pd / C (1.55 g, 14.6 mmol). The resulting mixture was stirred at room temperature under hydrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse flash C18 column chromatography to give the title compound (391 mg, 17.2%) as a pale yellow solid. 1H NMR(300MHz,DMSO-d6)δ 8.45-8.25(d,1H),7.71-7.51(m,1H),7.44-7.25(m,1H),6.83(d,1H),6.69(dd,1H),5.12-4.99(m,1H),4.61-4.50(m,1H),4 .27(dd,2H),3.90(dd,2H),3.61-3.43(m,2H),2.98-2.69(m,3H),2.66-2.51(m,1H),2.10-1.95(m,1H);LCMS(ESI)m / z:[M+H] + =373.14.

[0288] Example 64. Preparation of 5-[2-([3-[(2-aminoethoxy)methyl]phenyl]methoxy)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione [ka] Step 1: Preparation of 2-[2-[(3-[[2-(oxan-2-yloxy)ethoxy]methyl]phenyl)methoxy]ethoxy]oxane [ka] To a solution of 2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-1-ol (9.50 g, 65.0 mmol) in anhydrous THF (75.0 mL) was added NaH (2.34 g, 97.5 mmol). The reaction mixture was stirred at 70° C. The THF solvent was evaporated. The crude material was dissolved in EtOAc, washed with water, washed with brine, and then dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 2-[2-[(3-[[2-(oxan-2-yloxy)ethoxy]methyl]phenyl)methoxy]ethoxy]oxane (13.9 g, 54.2%). LCMS (ESI) m / z: [M+H] + =395.

[0289] Step 2: Preparation of 2-([3-[(2-hydroxyethoxy)methyl]phenyl]methoxy)ethanol [ka] To a stirred solution of 2-[2-[(3-[[2-(oxan-2-yloxy)ethoxy]methyl]phenyl)methoxy]ethoxy]oxane (13.9 g, 35.2 mmol) in MeOH (15.0 mL) was added DCM (15.0 mL) and HCl (30.0 mL, 987 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. The residue was purified by reverse phase C18 flash chromatography to give 2-([3-[(2-hydroxyethoxy)methyl]phenyl]methoxy)ethanol (5.2 g, 65.2%) as a colorless oil. LCMS (ESI) m / z: [M+H] += 227.

[0290] Step 3: Preparation of ethyl 2-[[3-([2-[(4-methylbenzenesulfonyl)oxy]ethoxy]methyl)phenyl]methoxy]4-methylbenzenesulfonate [ka] To a stirred solution of 2-([3-[(2-hydroxyethoxy)methyl]phenyl]methoxy)ethanol (5.20 g, 23.0 mmol) in DCM (80.0 mL) was added DMAP (421 mg, 3.45 mmol), TEA (9.30 g, 91.9 mmol), and p-toluenesulfonyl chloride (13.1 g, 68.9 mmol) at 0° C. The resulting mixture was stirred for 2 h at 0° C. The resulting mixture was stirred for an additional 5 h at room temperature. The residue was purified by silica gel column chromatography (petroleum ether / THF) to give ethyl 2-[[3-([2-[(4-methylbenzenesulfonyl)oxy]ethoxy]methyl)phenyl]methoxy]4-methylbenzenesulfonate (10.3 g, 83.4%) as a light yellow oil. LCMS (ESI) m / z: [M+H] + =535.

[0291] Step 4: Preparation of tert-butyl N-(tert-butoxycarbonyl)-N-(2-[[3-([2-[(4-methylbenzenesulfonyl)oxy]ethoxy]methyl)phenyl]methoxy]ethyl)carbamate [ka] To a solution of ethyl 2-[[3-([2-[(4-methylbenzenesulfonyl)oxy]ethoxy]methyl)phenyl]methoxy]4-methylbenzenesulfonate (10.3 g, 19.2 mmol) in DMF (80.0 mL) was added tert-butyl N-(tert-butoxycarbonyl)carbamate (4.58 g, 21.1 mmol) and K2CO3 (3.97 g, 28.8 mmol). The reaction mixture was stirred at 60° C. for 9 h. The reaction mixture was then cooled to room temperature and poured into 50 mL of EtOAc. The EtOAc layer was then washed three times with 1N aqueous HCl and once with brine. The EtOAc layer was dried over MgSO4, filtered, and the solvent was removed by rotary evaporation. The crude product was purified by silica gel flash chromatography (hexanes:EtOAc) to give tert-butyl N-(tert-butoxycarbonyl)-N-(2-[[3-([2-[(4-methylbenzenesulfonyl)oxy]ethoxy]methyl)phenyl]methoxy]ethyl)carbamate (1.69 g, 15.2%) as a colorless oil. LCMS (ESI) m / z: [M+H] += 580.

[0292] Step 5: Preparation of tert-butyl N-(tert-butoxycarbonyl)-N-[2-([3-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethoxy)methyl]phenyl]methoxy)ethyl]carbamate [ka] To a solution of tert-butyl N-(tert-butoxycarbonyl)-N-(2-[[3-([2-[(4-methylbenzenesulfonyl)oxy]ethoxy]methyl)phenyl]methoxy]ethyl)carbamate (800 mg, 1.38 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (799 mg, 2.91 mmol) in DMF (20.0 mL) was added Na2CO3 (439 mg, 4.14 mmol). The resulting mixture was stirred at 80° C. for 5 h. The residue was purified by reverse phase C18 flash chromatography (water:MeOH) to give tert-butyl N-(tert-butoxycarbonyl)-N-[2-([3-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethoxy)methyl]phenyl]methoxy)ethyl]carbamate (920 mg, 97.8%) as a colorless solid. LCMS (ESI) m / z[M+H] + =682.

[0293] Step 6: Preparation of 5-[2-([3-[(2-aminoethoxy)methyl]phenyl]methoxy)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione [ka] To a solution of tert-butyl N-(tert-butoxycarbonyl)-N-[2-([3-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethoxy)methyl]phenyl]methoxy)ethyl]carbamate (920 mg) in DCM was added TFA (5.00 mL). The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash chromatography to give the title compound (510 mg) as a pale yellow solid. 1H NMR(300MHz,DMSO-d6)δ 8.40(s,1H),7.85(d,1H),7.48(d,1H),7.42-7.24(m,5H),5.13(dd,1H),4.58(s,2H),4.50(s,2H),4.43-4.34( m,2H),3.83(t,2H),3.54(t,2H),2.96-2.82(m,3H),2.66-2.46(m,2H),2.12-1.98(m,1H);LCMS(ESI)m / z:[M+H] + =482.18.

[0294] Example 65. Preparation of intermediates The following compounds in Table B12 were prepared using the procedure of Example 64 using the appropriate substituted phenol. [Table 19]

[0295] Example 66. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(5-(piperazin-1-yl)pent-1-yn-1-yl)isoindoline-1,3-dione trifluoroacetic acid [ka] Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(5-hydroxypent-1-yn-1-yl)isoindoline-1,3-dione [ka] To a stirred solution of 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (5.0 g, 14.8 mmol), Pd(PPh3)2Cl2 (2.1 g, 3.0 mmol), and copper(I) iodide (0.56 g, 3.0 mmol) in THF (40 mL) was added dropwise DIEA (19.2 g, 148 mmol) and pent-4-yn-1-ol (3.7 g, 44.5 mmol) at room temperature. The resulting mixture was stirred for 4 h at 50° C. The resulting mixture was filtered and the filter cake was washed three times with THF. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc) to give 2-(2,6-dioxopiperidin-3-yl)-5-(5-hydroxypent-1-yn-1-yl)isoindoline-1,3-dione (1.9 g, 37.6%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =341.

[0296] Step 2: Preparation of 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pent-4-ynal [ka] To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-(5-hydroxypent-1-yn-1-yl)isoindoline-1,3-dione (4.0 g, 11.7 mmol) in DCM (40 mL) was added PCC (5.1 g, 23.5 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 8 h. The mixture was filtered and the filter cake was washed three times with DCM. The filtrate was concentrated under reduced pressure to give 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pent-4-ynal (3.6 g, 89.8%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =339.

[0297] Step 3: Preparation of tert-butyl 4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pent-4-yn-1-yl)piperazine-1-carboxylate [ka] To a stirred mixture of 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pent-4-ynal (3.6 g, 10.6 mmol) and tert-butyl piperazine-1-carboxylate (1.98 g, 10.6 mmol) in MeOH (35.0 mL) was added NaBH3CN (2.7 g, 42.6 mmol) in portions at room temperature. The mixture was stirred for 3 h at room temperature. The resulting mixture was added to aqueous NH4Cl and extracted three times with EtOAc. The combined organic layers were washed twice with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH) to give tert-butyl 4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pent-4-yn-1-yl)piperazine-1-carboxylate (2.1 g, 38.9%) as a yellow semi-solid. LCMS (ESI) m / z: [M+H] + =509.

[0298] Step 4: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(5-(piperazin-1-yl)pent-1-yn-1-yl)isoindoline-1,3-dione trifluoroacetic acid [ka] To a stirred solution of tert-butyl 4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pent-4-yn-1-yl)piperazine-1-carboxylate (1.2 g, 2.4 mmol) in DCM (20 mL) was added TFA (5 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase C18 flash chromatography with the following conditions: column (water:ACN:TFA) to give the title compound (0.80 g, 66.7%) as a light yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 11.16(s,1H),9.01(br,2H),7.96-7.85(m,3H),5.17(dd,J=12.8,5.4Hz,1H),4.49(br,3H),3.08(br,3H),2.90(ddd,J=1 6.9,13.9,5.3Hz,1H),2.66-2.57(m,4H),2.56-2.53(m,4H),2.12-2.03(m,1H),1.98-1.85(m,1H)..LCMS(ESI)m / z:[M+H] + =409.40.

[0299] Example 67. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-[[5-(piperazin-1-yl)pentyl]oxy]isoindole-1,3-dione [ka] Step 1: Preparation of 5-[4-(1,3-dioxolan-2-yl)butoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione [ka] To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (3.00 g, 10.9 mmol) and 2-(4-bromobutyl)-1,3-dioxolane (2.74 g, 13.1 mmol) in DMF (25.0 mL) was added KHCO3 (2.19 g, 21.9 mmol) and KI (272 mg, 1.64 mmol) in portions under air at 60° C. The residue was purified by reverse-phase C18 flash chromatography (water:ACN) to give 5-[4-(1,3-dioxolan-2-yl)butoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (2.4 g, 54.5%) as an off-white solid. LCMS(ESI)m / z:[M+H] + =403.

[0300] Step 2: Preparation of 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]pentanal [ka] A solution of 5-[4-(1,3-dioxolan-2-yl)butoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (2.40 g, 5.96 mmol) and HCl in 1,4-dioxane (4N, 12.0 mL, 48 mmol) and 1,4-dioxane (12.0 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification to give 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]pentanal (1.92 g, 89.8%) as an off-white solid. LCMS (ESI) m / z: [M+H] + =359.

[0301] Step 3: Preparation of tert-butyl 4-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]pentyl)piperazine-1-carboxylate [ka] To a stirred solution of 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]pentanal (1.89 g, 5.27 mmol) and tert-butyl piperazine-1-carboxylate (0.98 g, 5.27 mmol) in DMF (20.0 mL) was added NaBH(OAc)3 (2.24 g, 10.5 mmol) in portions at room temperature. The residue was purified by reversed-phase C18 flash chromatography (water:ACN) to give tert-butyl 4-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]pentyl)piperazine-1-carboxylate (1.46 g, 52.4%) as an off-white solid. LCMS (ESI) m / z: [M+H] + =529.

[0302] Step 4: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-[[5-(piperazin-1-yl)pentyl]oxy]isoindole-1,3-dione [ka] A solution of tert-butyl 4-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]pentyl)piperazine-1-carboxylate (1.40 g, 2.65 mmol) and TFA (5.00 mL, 67.3 mmol) in DCM was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash chromatography (water:ACN) to give 2-(2,6-dioxopiperidin-3-yl)-5-[[5-(piperazin-1-yl)pentyl]oxy]isoindole-1,3-dione (724 mg, 63.8%) as a white solid. 1H NMR(300MHz,DMSO-d6)δ 11.81(s,1H),11.12(s,1H),9.75(s,2H),7.85(d,1H),7.46-7.32(m,2H),5.12(dd,1H),4.20(t,2H),3.66(s,1H),3.48(s,2H),3.40-3.30 (m,1H),3.15(d,2H),2.99-2.81(m,1H),2.67-2.52(m,1H),2.13-1.98(m,1H),1.88-1.71(m,4H),1.56-1.40(m,2H).LCMS(ESI)m / z:[M+H] + =429.15.

[0303] Example 68. Preparation of N-[[3-([[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]oxy]methyl)bicyclo[1.1.1]pentan-1-yl]methyl]-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethoxy)ethoxy]propanamide (Compound 1) [ka] To a stirred mixture of 2-(6-amino-5-[[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]methoxy]pyridazin-3-yl)phenol (10.00 mg, 0.032 mmol) and 3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethoxy)ethoxy]propanoic acid (13.9 mg, 0.032 mmol) in DMF (2.00 mL) was added EDCI (12.3 mg, 0.064 mmol), HOBT (8.65 mg, 0.064 mmol), and DIEA (12.4 mg, 0.096 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The crude product was purified by preparative HPLC (water:ACN:FA) to give compound 1 (7.6 mg, 32.0%) as a white solid. 1H NMR(300MHz,DMSO-d6)δ 14.34(s,1H),11.12(s,1H),7.92(dd,J=8.3,1.6Hz,1H),7.85-7.75(m,2H),7.57(s,1H),7.44(d,J=2.3Hz, 1H),7.35(dd,J=8.3,2.3Hz,1H),7.30-7.19(m,1H),6.94-6.83(m,2H),6.55(s,2H),5.12(dd,J=12.9,5.3Hz ,1H),4.30(d,J=4.2Hz,4H),3.77(t,J=4.4Hz,2H),3.63-3.54(m,4H),3.54-3.47(m,2H),3.16(d,J=5.7Hz,2 H),2.96-2.82(m,1H),2.66-2.53(m,2H),2.31(t,2H),2.11-1.98(m,1H),1.70(s,6H).LCMS(ESI)m / z:[M+H] + =729.35.

[0304] Example 69. Preparation of 2-(6-amino-5-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy)pyridazin-3-yl)phenol hydrochloride [ka] To a stirred solution of tert-butyl (3-(2-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (150, 0.364 mmol) in 1,4-dioxane (3.00 mL) was added HCl (gas) in 1,4-dioxane (3.00 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. This afforded 2-(6-amino-5-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy)pyridazin-3-yl)phenol hydrochloride (100 mg, 88.0%) as a pale yellow solid. LCMS (ESI) m / z: [M+H] + =313.

[0305] Example 70. Preparation of Compounds The compounds in Table C1 were prepared following the scheme protocol of Example 68 using the appropriate amine and carboxylic acid. [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4] [Table 20-5] [Table 20-6] [Table 20-7] [Table 20-8] [Table 20-9]

[0306] Example 71. Preparation of N1-(3-(2-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)-N4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)succinamide (Compound 42) [ka] To a stirred mixture of 3-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]propanoic acid (10.0 mg, 0.019 mmol) and 2-(6-amino-5-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy)pyridazin-3-yl)phenol hydrochloride (5.89 mg, 0.019 mmol) in DMF (1.00 mL) was added HATU (8.60 mg, 0.023 mmol) and DIPEA (7.31 mg, 0.057 mmol) at room temperature under a nitrogen atmosphere. The mixture solution was purified by preparative HPLC to give compound 42 (8.7 mg, 54.8%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 14.45(s,1H),9.06(s,1H),8.64(t,J=6.0Hz,1H),8.39(s,1H),8.05(dd,J=8.4,1.6Hz,1H),7 .94(d,J=9.3Hz,1H),7.67(s,1H),7.54-7.41(m,4H),7.38-7.26(m,1H),7.03-6.92(m,2H),6. 52(s,2H),5.20(s,1H),4.63-4.39(m,4H),4.38-4.23(m,3H),3.71(d,J=7.3Hz,2H),2.52(s,4 H),2.49-2.23(m,3H),2.18-2.04(m,3H),2.00-1.89(m,7H),0.99(s,9H).LCMS(ESI)m / z[M+H] + =825.10.

[0307] Example 72. Preparation of Compounds The compounds in Table C2 were prepared following the scheme protocol of Example 71 using the appropriate amine and carboxylic acid. [Table 21-1] [Table 21-2] [Table 21-3]

[0308] Example 73. Preparation of Compounds The compounds in Table C3 were prepared following the scheme protocol in Example 22 using the appropriate amine and carboxylic acid. [Table 22-1] [Table 22-2] [Table 22-3] [Table 22-4] [Table 22-5] [Table 22-6] [Table 22-7] [Table 22-8] [Table 22-9] [Table 22-10] [Table 22-11] [Table 22-12]

[0309] Example 74. Degradation of BRM and BRG1 by the compounds of the present invention This example demonstrates the ability of compounds of the disclosure to degrade HiBit-BRM or HiBit-BRG1 fusion proteins in a cell-based degradation assay.

[0310] Procedure: A stable HeLa cell line expressing HiBiT-BRM was generated. On day 0, 5000 cells were seeded in 40 μL of medium into each well of a 384-well cell culture plate. On day 1, cells were treated with 120 nL of DMSO or 120 nL of 3-fold serial DMSO diluted compounds (10 points in duplicate with 30 μM as the final highest dose). Plates were then incubated for 24 hours in a standard tissue culture incubator and equilibrated at room temperature for 15 minutes. Nano-Glo HiBiT Lytic Detection System (Promega N3050) reagent was freshly prepared and 20 ul was added to each well. Upon addition of this LgBit-containing reagent, HiBiT and LgBiT proteins associate to form the light-emitting NanoBiT luciferase. Plates were shaken for 10 minutes at room temperature and bioluminescence was read using an EnVision plate reader (PerkinElmer).

[0311] To measure the degradation of BRG1, we generated a stable HeLa cell line expressing HiBit-BRG1 and LgBit, and then followed the same protocol as above.

[0312] The decomposition percentage was calculated using the following formula: Decomposition percentage = 100% - 100% x (Lum Sample -Lum LC ) / (Lum HC -Lum LC ) were used to calculate the IC. Cells treated with DMSO were used as the high control (HC) and standard treated cells with 2 μM of a known BRM / BRG1 degrader were used as the low control (LC). The data were fitted to a four-parameter nonlinear curve fit to calculate the IC, as shown in Table 3. 50 (μm) values ​​were calculated.

[0313] Results: As shown in Table 2 below, the compounds of the present invention degraded both BRM and BRG1. [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4]

[0314] Other embodiments All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. In the event that a term in this application is found to be defined differently in a document incorporated herein by reference, the definition provided herein shall serve as the definition of that term.

[0315] While the invention has been described in connection with specific embodiments thereof, it will be understood that the invention is capable of further modifications, and this application is intended to cover any variations, uses, or adaptations of the invention which generally follow the principles of the invention and include departures from the present disclosure which come within known or customary practice within the art to which the invention pertains, and may be applied to the essential features set forth herein above, and which fall within the scope of the claims.

[0316] Other embodiments are within the scope of the claims.

Claims

1. A compound having the structure of Formula I, [Formula 1] During the ceremony, X is halo; X １ is absent, O or NR １ and k is 0, 1, 2, or 3; n is 0, 1, or 2; R １ is H or optionally substituted C １ -C ６ is alkyl, L １ is optionally substituted C １ -C ６ Alkylene, optionally substituted C ２ -C ６ Alkenylene, or optionally substituted C ２ -C ６ is alkynylene, L ２ is absent or optionally substituted C １ -C ６ Alkylene, optionally substituted C １ -C ２０ Heteroalkylene or optionally substituted C ２ -C ９ is a heterocyclylene, Each L ３ is independently an optionally substituted C １ -C ２０ Heteroalkylene, optionally substituted C ３ -C １０ Carbocyclylene, optionally substituted C ３ -C １０ Carbocyclylene-C １ -C ６ Alkylene, optionally substituted C ２ -C ９ Heterocyclylene, optionally substituted C ２ -C ９ Heterocyclylene-C １ -C ６Alkylene, optionally substituted C ６ -C １０ Arylene, optionally substituted C ６ -C １０ Arylene-C １ -C ６ Alkylene, optionally substituted C ２ -C ６ Alkynylene, O, or NR １ and D is a decomposition moiety, said decomposition moiety being [chemical 2] is a ubiquitin ligase binding moiety selected from the group consisting of A compound wherein A 2 is a bond between the degradable moiety and a linker, and R A1 , R A2 , R A3 , R A4 , and R A5 are hydrogen; or a pharma- ceutically acceptable salt thereof.

2. X １ The compound of claim 1 , or a pharma- ceutically acceptable salt thereof, wherein:

3. X １ is O or NR １ 2. The compound of claim 1, wherein:

4. L １ is optionally substituted C １ -C ６ 4. The compound of claim 3, or a pharma- ceutically acceptable salt thereof, which is alkylene.

5. L ２ is optionally substituted C １ -C ６ 5. The compound of claim 4, or a pharma- ceutically acceptable salt thereof, which is alkylene.

6. L ２ but, [C3] 5. The compound of claim 4, which is: or a pharma- ceutically acceptable salt thereof.

7. 7. The compound of claim 6, wherein n is 1 or 2, or a pharma- ceutically acceptable salt thereof.

8. At least one L ３ but, [C4] 7. The compound of claim 6, which is: or a pharma- ceutically acceptable salt thereof.

9. A compound selected from the group consisting of compounds 1 to 105 in Table 1 below, or a pharma- ceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

10. The compound is a BRG1 IC ５０ and BRM IC ５０ The compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein the ratio of

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

12. A drug for treating a BAF complex-associated disorder, comprising a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof.

13. The method of claim 12, wherein the BAF complex-associated disorder is cancer or a viral infection.

14. A drug for treating a disorder associated with a loss-of-function mutation in BRG1, comprising the compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof.

15. The method of claim 14, wherein the disorder associated with a loss-of-function mutation of BRG1 is cancer.

16. A drug for treating cancer, comprising the compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof.

17. The drug of claim 16, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary site, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal and gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenal cortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

18. The method of claim 16, 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, or penile cancer.

19. 18. The method of claim 17, wherein the agent is administered in combination with an anti-cancer therapy, the anti-cancer therapy being a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiation therapy, hyperthermia, or photocoagulation.

20. 20. The agent of claim 19, wherein the anti-cancer therapy is a chemotherapeutic or cytotoxic agent that is an antimetabolite, an antimitotic, an antitumor antibiotic, an asparagine-specific enzyme, a bisphosphonate, an anti-neoplastic agent, an alkylating agent, a DNA repair enzyme inhibitor, a histone deacetylase inhibitor, a corticosteroid, a demethylating agent, an immunomodulatory agent, a Janus-related kinase inhibitor, a phosphinositide 3-kinase inhibitor, a proteasome inhibitor, or a tyrosine kinase inhibitor.

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