Potent and selective SMARCA2 decomposition chimeric molecules as cancer therapeutics

Abstract

Heterobifunctional compounds for the treatment of SMARCA4-deficient cancers are provided, the heterobifunctional compounds comprising a SMARCA2-binding moiety, a linker, and a ubiquitin ligase-binding moiety.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 266,068, filed December 28, 2021, which is incorporated by reference in its entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under award CA272945 from the National Institutes of Health. The Government has certain rights in this invention. [Background technology]

[0003] The switch / sucrose nonfermenting (SWI / SNF) complex is a multisubunit complex that regulates chromatin structure through the activity of two mutually exclusive helicase / ATPase catalytic subunits, SWI / SNF-related matrix-binding actin-dependent chromatin regulator subfamily A member 2 (SMARCA2) and SWI / SNF-related matrix-binding actin-dependent chromatin regulator subfamily A member 4 (SMARCA4). The core and regulatory subunits of SMARCA2 and SMARCA4 couple ATP hydrolysis to destabilization of histone-DNA contacts, thereby providing access points for transcription factors to cognate DNA elements that promote gene activation and repression.

[0004] SMARCA2 and SMARCA4 are highly homologous and are thought to have overlapping functions, but they have been reported to have different roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, whereas SMARCA2 inactivation is rare in tumor development. In fact, many types of cancer have been shown to be SMARCA4-associated, including cancers with SMARCA4 mutations or SMARCA4 deletions, such as non-small cell lung cancer.

[0005] SMARCA2 has been demonstrated to be a key gene in SMARCA4-deficient or SMARCA4-mutated cancer cells, as SMARCA4-deficient or SMARCA4-mutated cells are solely dependent on SMARCA2 activity. In these cells, SMARCA2 incorporation into the complex is increased to compensate for SMARCA4 deficiency. Therefore, SMARCA2 can be targeted in SMARCA4-deficient / mutated cancers. However, identifying selective inhibitors of SMARCA2 has been a challenge, as SMARCA2 and SMARCA4 have very similar bromodomains and ATPase domains. Therefore, selective inhibitors of SMARCA2 are needed. Summary of the Invention

[0006] In some embodiments, the compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof is provided, During the ceremony, D is a ubiquitin ligase binding moiety, L is a linker comprising a fluoro-phenyl or difluoro-phenyl substituted with one or more groups selected from the group consisting of piperazine groups, piperidine groups, methoxypropyl and methoxyethoxy groups; S is the SMARCA2 binding moiety.

[0007] In some embodiments, the compound of formula II: [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein: Q is selected from the group consisting of -CH2- and -C(=O)-; W is -CH-; V is [ka] and where the bond marked with an "*" is attached to W, R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen and fluoro; X is -O-, N(R 5a )-, [ka] is selected from the group consisting of where the bond marked with an "*" is either attached to Y or X is a bond; R 5a is selected from the group consisting of hydrogen and C1-C4 alkyl; Y is selected from the group consisting of C1-C8 alkylenyl and 3- to 8-membered heteroalkylenyl; or Y is a bond; Z is -O-, -N(R 5b )-, [ka] is selected from the group consisting of where the bond marked with an "*" is either attached to Y or Z is a bond; R 5b is selected from the group consisting of hydrogen and C1-C4 alkyl.

[0008] In some embodiments, the compound of formula III: [ka] or a pharma- ceutically acceptable salt or solvate thereof is provided.

[0009] In some embodiments, the compound of formula IV: [ka] or a pharma- ceutically acceptable salt or solvate thereof is provided.

[0010] In some embodiments, in the compound of Formula I-IV, or a pharma- ceutically acceptable salt or solvate thereof, Q is --C(.dbd.O)--.

[0011] In some embodiments, R 1 is fluoro and R 2 , R 3 , and R 4 is hydrogen.

[0012] In some embodiments, R 4 is fluoro and R 1 , R 2 , and R 3 is hydrogen.

[0013] In some embodiments, R 1 and R 2 is fluoro and R 3 and R 4 is hydrogen.

[0014] In some embodiments, R 1 and R 4 is fluoro and R 2 and R 3 is hydrogen.

[0015] In some embodiments, R 1 and R 3 is fluoro and R 2 and R 4 is hydrogen.

[0016] In some embodiments, R 3 and R 4 is fluoro and R 1 and R 2 is hydrogen.

[0017] In some embodiments, X is a bond. In some embodiments, X is -O-.

[0018] In some embodiments, Y is C1-C8 alkylenyl. In some embodiments, Y is selected from the group consisting of -CH2-, -CH2CH2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-. In some embodiments, Y is 3-8 membered heteroalkylenyl. In some embodiments, Y is selected from the group consisting of -CH2CH2OCH2CH2- and -CH2CH2OCH2CH2CH2-.

[0019] In some embodiments, Z is represented by -O-. In some embodiments, Z is represented by -N(R 5b )-.

[0020] In some embodiments, -ZYVW- is [ka] is selected from the group consisting of Here, the bond marked with "*" is attached to the SMARCA2 binding site.

[0021] In some embodiments, the compound is selected from the group consisting of: [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0022] In some embodiments, compounds of the disclosure have a DC potency of about 0.1 nM to about 300 nM, about 1 nM to about 200 nM, about 2 nM to about 150 nM, about 5 nM to about 120 nM, about 10 nM to about 100 nM, about 15 nM to about 80 nM, about 20 nM to about 70 nM, or about 30 nM to about 60 nM for SMARCA2.50 (the concentration at which 50% of the target protein is degraded).

[0023] In some embodiments, compounds of the disclosure have a DC activity against SMARCA2 of less than about 300 nM, less than about 200 nM, less than about 150 nM, less than about 120 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, or less than about 2 nM. 50 has.

[0024] In some embodiments, the compounds of the present disclosure have a D activity against SMARCA2 of about 60% to about 100%, about 65% to about 99%, about 70% to about 95%, or about 75% to about 90%. max (maximal degradation as a percentage of DMSO control).

[0025] In some embodiments, compounds of the disclosure have a D activity against SMARCA2 of about 60%, 65%, 67%, 70%, 72%, 75%, 77%, 80%, 82%, 85%, 87%, 90%, 92%, 95%, 97%, 98%, 99%, or 100%. max has.

[0026] In some embodiments, compounds of the disclosure have a DC potency of about 500 nM to about 100 μM, about 700 nM to about 90 μM, about 800 nM to about 80 μM, about 900 nM to about 70 μM, about 1 μM to about 60 μM, about 2 μM to about 50 μM, about 5 μM to about 25 μM, or about 10 μM to about 20 μM against SMARCA4. 50 has.

[0027] In some embodiments, compounds of the disclosure have a DC activity against SMARCA4 of greater than about 500 nM, greater than about 700 nM, greater than about 1 μM, greater than about 2 μM, greater than about 5 μM, greater than about 7 μM, or greater than about 10 μM. 50 has.

[0028] In some embodiments, compounds of the present disclosure have a D activity against SMARCA4 of about 10% to about 80%, about 15% to about 70%, about 20% to about 60%, or about 25% to about 50%. max has.

[0029] In some embodiments, compounds of the present disclosure have a D activity against SMARCA4 of less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 25%, or less than about 20%. max has.

[0030] In some embodiments, compounds of the disclosure have an IC of about 10 nM to about 50 μM, about 50 nM to about 20 μM, about 100 nM to about 10 μM, about 200 nM to about 8 μM, about 300 nM to about 5 μM, about 400 nM to about 2 μM, or about 500 nM to about 1 μM. 50 (the concentration at which 50% of cell proliferation is inhibited).

[0031] In some embodiments, compounds of the disclosure have an IC of about 900 nM to about 50 μM, about 1 μM to about 40 μM, about 2 μM to about 30 μM, about 5 μM to about 25 μM, or about 10 μM to about 20 μM in wild-type SMARCA4 cells. 50 has.

[0032] In some embodiments, compounds of the disclosure have an IC of greater than about 900 nM, greater than about 1 μM, greater than about 2 μM, greater than about 3 μM, greater than about 5 μM, greater than about 7 μM, or greater than about 10 μM in wild-type SMARCA4 cells. 50 has.

[0033] In some embodiments, compounds of the present disclosure exhibit an IC of about 50 nM to about 10 μM, about 75 nM to about 5 μM, about 100 nM to about 1 μM, about 125 nM to about 900 nM, about 150 nM to about 800 nM, about 175 nM to about 700 nM, about 200 nM to about 600 nM, or about 250 nM to about 500 nM in mutant SMARCA4 cells. 50 has.

[0034] In some embodiments, compounds of the disclosure have an IC of less than about 10 μM, less than about 5 μM, less than about 2 μM, less than about 1 μM, less than about 900 nM, less than about 800 nM, less than about 600 nM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, or less than about 2 nM, or less than about 1 nM in mutant SMARCA4 cells. 50 has.

[0035] In some embodiments, compounds of the present disclosure competitively inhibit the binding of pomalidomide to cereblon.

[0036] In some embodiments, compounds of the present disclosure competitively inhibit the binding of a SMARCA2 inhibitor to SMARCA2.

[0037] In some embodiments, compounds of the present disclosure inhibit the proliferation of SMARCA4 mutant cancer cells.

[0038] In some embodiments, compounds of the present disclosure do not inhibit the proliferation of SMARCA4 wild-type cells.

[0039] In some embodiments, a pharmaceutical composition is provided that includes a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable adjuvant, carrier, or vehicle.

[0040] In some embodiments, the pharmaceutical composition further comprises an additional pharma- ceutical active agent.

[0041] In some embodiments, the additional pharma- ceutically active agent is a hormone analog or anti-hormone, aromatase inhibitor, growth factor inhibitor, antimetabolite, antitumor antibiotic, platinum derivative, mitosis inhibitor, angiogenesis inhibitor, topoisomerase inhibitor, serine / threonine kinase inhibitor, tyrosine kinase inhibitor, PARP inhibitor, tubulin inhibitor, DNA synthesis inhibitor, protein-protein interaction inhibitor, MEK / ERK inhibitor, TRAIL inhibitor, BCR-ABL inhibitor, HDAC inhibitor, radiopharmaceutical, immune checkpoint inhibitor, ADCC enhancer, T cell engager, chemotherapeutic agent, or tumor vaccine.

[0042] In some embodiments, a method is provided for inducing degradation of SMARCA2 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0043] In some embodiments, the subject is afflicted with a SMARCA4 deficient malignant tumor.

[0044] In some embodiments, the SMARCA4-deficient malignancy comprises a SMARCA4-inactivating mutation or a SMARCA4 deletion.

[0045] In some embodiments, the SMARCA4 deletion is a truncation of the SMARCA4 gene.

[0046] In some embodiments, the SMARCA4 deficient malignancy is lung cancer, liver cancer, bladder cancer, breast cancer or colon cancer.

[0047] In some embodiments, the lung cancer is non-small cell lung cancer.

[0048] In some embodiments, a method of treating a SMARCA4-deficient malignant tumor in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0049] In some embodiments, a method of treating a tumor in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0050] In some embodiments, the tumor comprises an inactivating SMARCA4 mutation or a SMARCA4 deletion.

[0051] In some embodiments, the tumor is lung cancer, liver cancer, bladder cancer, breast cancer or colon cancer.

[0052] In some embodiments, the lung cancer is non-small cell lung cancer.

[0053] In some embodiments, the method further comprises administering a hormone analog or anti-hormone, an aromatase inhibitor, a growth factor inhibitor, an antimetabolite, an antitumor antibiotic, a platinum derivative, a mitosis inhibitor, an angiogenesis inhibitor, a topoisomerase inhibitor, a serine / threonine kinase inhibitor, a tyrosine kinase inhibitor, a PARP inhibitor, a tubulin inhibitor, a DNA synthesis inhibitor, a protein-protein interaction inhibitor, a MEK / ERK inhibitor, a TRAIL inhibitor, a BCR-ABL inhibitor, an HDAC inhibitor, a radiopharmaceutical, an immune checkpoint inhibitor, an ADCC enhancer, a T cell engager, a chemotherapeutic agent, or a tumor vaccine.

[0054] In some embodiments, a method of treating a condition or disease selected from a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition described herein.

[0055] In some embodiments, heterobifunctional compounds are provided that include two binding moieties connected by a linker, wherein the linker is [ka] is selected from the group consisting of Here, the bond marked with "*" is attached to the SMARCA2 binding site.

[0056] In some embodiments, the linker is [ka] is selected from Here, the bond marked with "*" is attached to the SMARCA2 binding site. [Brief description of the drawings]

[0057] [Figure 1] Schematic diagram of heterobifunctional compounds that interact with SMARCA2 protein and cereblon ubiquitin ligase. [Figure 2A] 1 shows the degradation profile of SMARCA2 by SMARCA2 PROTAC compound 101 and ACBI1 in different cell lines with wild-type SMARCA4. [Figure 2B] 1 shows the degradation profile of SMARCA4 by SMARCA2 PROTAC compound 101 and ACBI1 in different cell lines with wild-type SMARCA4. [Figure 3A] 1 shows colony assays stained with crystal violet after treatment of cell lines expressing wild-type SMARCA4 with DMSO or different concentrations of SMARCA2 PROTAC compounds 101 and ACBI1. [Figure 3B] 1 shows colony assays stained with crystal violet after treatment of mutant SMARCA4 expressing cell lines with DMSO or different concentrations of SMARCA2 PROTAC compounds 101 and ACBI1. [Figure 3C] A line graph of colonies of different wild-type SMARCA4 cell lines (dashed lines) and mutant SMARCA4 cell lines (solid lines) after treatment with ACBI1 is shown. [Figure 3D]1 shows line graphs of colonies of different wild-type SMARCA4 cell lines (dashed lines) and mutant SMARCA4 cell lines (solid lines) after treatment with SMARCA2 PROTAC compound 101. [Figure 4A] 1 shows a Western blot of SMARCA2 expression in H1792 cells (wild-type SMARCA4) and H1299 cells (mutated SMARCA4) treated with different concentrations of SMARCA2 PROTAC compound 103 for 72 or 96 hours. [Figure 4B] 1 shows a Western blot of SMARCA4 expression in H1792 and H1299 cells treated with different concentrations of SMARCA2 PROTAC compound 103 for 72 or 96 hours. [Figure 4C] Western blot of polybromo 1 (PBRM1) expression in H1792 and H1299 cells treated with different concentrations of SMARCA2 PROTAC compound 103 for 72 or 96 hours. [Figure 5A] 1 shows a Western blot of SMARCA2 expression in H1792 cells (wild-type SMARCA4) and H1299 cells (mutated SMARCA4) treated with different concentrations of SMARCA2 PROTAC compound 102 for 72 or 96 hours. [Figure 5B] 1 shows a Western blot of SMARCA4 expression in H1792 and H1299 cells treated with different concentrations of SMARCA2 PROTAC compound 102 for 72 or 96 hours. [Figure 5C] Western blot of polybromo 1 (PBRM1) expression in H1792 and H1299 cells treated with different concentrations of SMARCA2 PROTAC compound 102 for 72 or 96 hours. [Figure 6A] 1 shows Western blots of SMARCA2, SMARCA4, and PBRM1 expression in H1975 cells treated with different concentrations of Compound 104 and Compound 105. [Figure 6B]1 shows Western blots of SMARCA2, SMARCA4, and PBRM1 expression in H1975 cells treated with different concentrations of Compound 106, Compound 107, and Compound 108. [Figure 7] A shows immunohistochemistry images of SMARCA2 in H1299 xenograft tumors in female NCR nude mice treated intraperitoneally with vehicle or SMARCA2 degradation-inducing compound 101 (200 mg / kg). B shows quantification of SMARCA2 protein levels in mouse xenografts treated intraperitoneally with vehicle or SMARCA2 degradation-inducing compound 101 at a concentration of 200 mg / kg for 4 days, with tumor tissue harvested 24 hours after the last dose. [Figure 8] Shown are measurements of xenograft tumor growth in female NCR nude mice implanted with HCC515 lung cancer and then treated with vehicle control or daily intraperitoneal administration of SMARCA2 degradation-inducing compound 101 (12.5 mg / kg) for the indicated time periods. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] I. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0059] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as "one or more," and "at least one," may be used interchangeably herein. In certain embodiments, the term "a" or "an" means "one." In other embodiments, the term "a" or "an" includes "two or more" or "plural."

[0060] Furthermore, "and / or," as used herein, is deemed to specifically disclose each of the two specified features or components, with or without the other. Thus, the term "and / or" as used herein in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" (single), and "B" (single). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (single); B (single); and C (single).

[0061] The term "about" is used herein to mean approximately, roughly, around, or within a region thereof. When the term "about" is used in conjunction with a numerical range, the term identifies the range by extending the boundaries above and below the stated numerical values. In general, the term "about" allows a numerical value to be adjusted above or below the specified numerical value by a certain variability, for example, a variability of 10 percent above and below (high and low). In some embodiments of the present disclosure, the term "about" encompasses deviations from the recited value between 0.001% and 10%, inclusive of the endpoints. In some embodiments, the term "about" encompasses increases from the recited value between 0.001% and 10%, inclusive of the endpoints. In some embodiments, the term "about" encompasses decreases from the recited value between 0.001% and 10%, inclusive of the endpoints.

[0062] Units, prefixes, and symbols are shown in their International System of Units (SI) accepted form.

[0063] Numeric ranges are inclusive of the numbers defining the range. When a range of values ​​is recited, it is understood that each integer and each fractional part between the recited upper and lower limits of that range is also specifically disclosed, along with each subrange between those values.

[0064] The upper and lower limits of any range can be independently included or excluded from the range, and each range including either limit, both limits, or neither limit is included in the scope of the present disclosure. Thus, it is understood that the ranges recited herein are shorthand notations for all values ​​within the range, including the recited endpoints. For example, the range of 1 to 10 is understood to include any number, combination of numbers, or subranges from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0065] Any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in its respective measurement. In addition, all ranges disclosed herein are understood to encompass all subranges subsumed therein. For example, a range described as "1-10" shall be deemed to include all subranges between a minimum value of 1 and a maximum value of 10 (inclusive), i.e., starting from a minimum value of 1 or more, e.g., 1-6.1, and ending at a maximum value of 10 or less, e.g., 5.5-10.

[0066] Additionally, any document cited herein or referred to as "incorporated herein" is understood to be incorporated by reference in its entirety.

[0067] When a value is explicitly recited, it should be understood that values ​​that are approximately the same size or amount as the recited value are also within the scope of this disclosure.When a combination is disclosed, each subcombination of the elements of the combination is also specifically disclosed and is within the scope of this disclosure.On the other hand, when different elements or groups of elements are individually disclosed, their combinations are also disclosed.When any element of this disclosure is disclosed as having multiple alternatives, examples of the disclosure in which each alternative is excluded, alone or in any combination with other alternatives, are also disclosed herein, and two or more elements of the disclosure may have such an exclusion, and all combinations of elements with such exclusions are disclosed herein.

[0068] The term "heterobifunctional compound" as used herein refers to a chemical compound characterized by having different reactive groups at both ends of the compound. Each group of the compound may be connected via a linker. In some embodiments, the heterobifunctional compound is represented by Formula I DLS, where D is a degradation-inducing moiety capable of binding to ubiquitin ligase, L is a linker connecting D and S, and S is a moiety capable of binding to SMARCA2. In some embodiments, the heterobifunctional compound is represented by Formula II, III, IV, and / or V. The heterobifunctional compounds represented by Formula IV are collectively referred to as "compounds of the present disclosure."

[0069] The term “alkyl,” as used herein, by itself or as part of another group, refers to an alkyl group having 1 to 12 carbon atoms (i.e., C1-C 12 Alkyl) or a straight or branched chain aliphatic hydrocarbon containing the specified number of carbon atoms. In one embodiment, alkyl is C1-C 10 In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1-C3 alkyl, i.e., methyl, ethyl, propyl, or isopropyl. Non-limiting C1-C 12 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0070] The term "alkylenyl" as used herein by itself or as part of another group refers to a divalent form of an alkyl group. In one embodiment, alkylenyl is a C-C 12 The divalent form of alkyl, i.e., C1-C 12 In another embodiment, the alkylenyl is C-C 10 The divalent form of alkyl, i.e., C1-C 10In another embodiment, alkylenyl is a divalent form of C1-C8, i.e., C1-C8 alkylenyl. In another embodiment, alkylenyl is a divalent form of unsubstituted C1-C6 alkyl, i.e., C1-C6 alkylenyl. In another embodiment, alkylenyl is an unsubstituted C 1-4 A divalent form of alkyl is C1-C4 alkylenyl. Non-limiting examples of alkylenyl groups include -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2(CH2)2CH2-, -CH(CH2)3CH2-, and -CH2(CH2)4CH2-.

[0071] The term "heteroalkyl" by itself or as part of another group refers to an unsubstituted straight or branched chain aliphatic hydrocarbon containing 3 to 15 chain atoms (i.e., 3-15 membered heteroalkyl) or the specified number of carbon atoms, in which at least one -CH2- is replaced with at least one of -O-, -N(H)-, -N(C1-C4 alkyl)-, or -S-. The -O-, -N(H)-, -N(C1-C4 alkyl)-, or -S- may be independently placed at any position on the aliphatic hydrocarbon, so long as each of the -O-, -N(H)-, -N(C1-C4 alkyl)-, and -S- groups is separated by at least two -CH2- groups. In one embodiment, one -CH2- group is replaced with one -O- group. In another embodiment, two -CH2- groups are replaced with two -O- groups. In another embodiment, three -CH2- groups are replaced with three -O- groups. Non-limiting examples of heteroalkyl groups include -CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2N(H)CH2CH3, -CH2OCH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH2CH3.

[0072] The term "heteroalkylenyl," as used herein, by itself or as part of another group, refers to a divalent form of a heteroalkyl group. In one embodiment, a heteroalkylenyl is a 3-15 membered heteroalkylenyl. In another embodiment, a heteroalkylenyl is a 3-10 membered heteroalkylenyl. In another embodiment, a heteroalkylenyl is a 3-8 membered heteroalkylenyl. In another embodiment, a heteroalkylenyl is a 3-6 membered heteroalkylenyl. In another embodiment, a heteroalkylenyl is a 5 membered heteroalkylenyl. Non-limiting examples of heteroalkylenyl groups include -CH2OCH2-, -CH2OCH2CH2-, -CH2CHOCH2CH2-, -CH2CHOCH2CH2CH2-, -CH2CHOCH2CH2CH2-, and -CH2CHOCH2CH2OCH2CH2CH2-.

[0073] As used herein, the term "degradation-inducing moiety" refers to a compound that binds to a bromodomain protein and degrades the bromodomain protein with a measurable activity.

[0074] As used herein, the term "measurable activity" refers to the measurable degradation of a bromodomain protein between (i) a sample containing a compound of Formula I or Formula II, or a composition thereof, and the bromodomain protein, and (ii) an equivalent sample containing the bromodomain protein but not containing a compound of Formula I or Formula II, or a composition thereof.

[0075] The term "linker" refers to a molecule comprising a fluoro-phenyl or difluoro-phenyl substituted with one or more groups selected from piperazine, piperidine, methoxypropyl, and methoxyethoxy groups.

[0076] The term "ubiquitin ligase" refers to a family of proteins that transfer ubiquitin to specific substrate proteins, facilitating targeting of the substrate proteins for degradation. For example, E3 ubiquitin ligase proteins, alone or in combination with E2 ubiquitin-conjugating enzymes, attach ubiquitin to lysines on target proteins, thereby targeting the specific protein substrate for degradation by the proteasome. Thus, E3 ubiquitin ligases, alone or in complex with E2 ubiquitin-conjugating enzymes, are responsible for transferring ubiquitin to target proteins. In general, ubiquitin ligases are involved in polyubiquitination, whereby a second ubiquitin is attached to the first ubiquitin, and a third ubiquitin is attached to the second ubiquitin. Polyubiquitination marks proteins for degradation by the proteasome. However, some ubiquitination events are restricted to monoubiquitination, in which only one ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted for proteasomal degradation and can change their location or function in the cell, for example by binding to other proteins that contain domains that can bind ubiquitin.

[0077] As used herein, the term "ubiquitin ligase binding moiety" or "moiety capable of binding to ubiquitin ligase" refers to any molecular structure capable of binding to a ubiquitin ligase enzyme, including, but not limited to, thalidomide, pomalidomide, lenalidomide, CC-885, CC-122, CC-220, bBETI. Examples of ubiquitin ligase binding moieties are disclosed in Ito et al. Proc. Jpn. Acad. Ser B 96 (2020).

[0078] As used herein, the term "SMARCA2 binding moiety" or "moiety capable of binding to SMARCA2" refers to a compound that can bind to the SMARCA2 bromodomain and inhibit its function. SMARCA2 bromodomain inhibitors are used as ligands for the heterobifunctional compounds of the present disclosure.

[0079] The term "pharmaceutical composition" as used herein refers to a preparation in which the biological activity of the active ingredient, e.g., the compound of the present disclosure, is in a form such that it is effective, and does not contain additional components that are unacceptably toxic to the subject to which the composition is administered. Such compositions may be sterile. A "pharmaceutical composition" comprises a compound according to the present invention described herein, or a pharmaceutically acceptable salt thereof, having a desired degree of purity, in a physiologically acceptable carrier, excipient, or stabilizer. A pharmaceutically acceptable carrier, excipient, or stabilizer is non-toxic to a recipient at the dosage and concentration employed, and includes, but is not limited to, any auxiliary agent, carrier, excipient, flow agent, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier.

[0080] The term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts. These salts can be prepared in situ during the manufacturing process of the administration vehicle or dosage form, or by separately reacting the purified compound of the present invention in its organic base form with a suitable organic or inorganic acid and isolating the salt thus formed during subsequent purification. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J.Pharm.Sci.66:1-19).

[0081] Pharmaceutically acceptable salts of the subject compounds include conventional non-toxic salts or quaternary ammonium salts of the compounds obtained, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like.

[0082] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "pharmaceutically acceptable adjuvant," or "pharmaceutically acceptable vehicle" refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation, suitable for use in contact with the tissues or organs of human and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0083] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein to refer to a mammalian subject, such as, for example, a human subject.

[0084] As used herein, the terms "treat", "treated" and "treating" refer to both therapeutic and prophylactic or preventative measures aimed at preventing or slowing (alleviating) an undesirable physiological condition, disorder or disease, or obtaining a beneficial or desired clinical outcome. Thus, those in need of treatment also include those who have already been diagnosed with or are suspected of having a disorder. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; reduction in the extent of the condition, disorder or disease; a stabilized condition, disorder or disease (i.e., not worsening); a delay in the onset or slowing of the progression of the condition, disorder or disease; an improvement or remission (whether partial or complete) of the condition, disorder or disease state, whether detectable or undetectable; an improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or an improvement or amelioration of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to the expected survival in the absence of treatment.

[0085] The term "administering" as used herein refers to any manner of transporting, delivering, introducing, or conveying a therapeutic agent to a subject in need of treatment with that agent. Such modes of administration include oral, topical, and parenteral administration.

[0086] The term "parenteral administration" as used herein includes intravenous, intraperitoneal, intramuscular, intradermal, intranasal, subcutaneous, intraarterial, intracranial, intrathecal, intracapsular, intraorbital, intracardiac, intrahepatic, transtracheal, subcuticular, intra-articular, intrasynovial, subcapsular, subarachnoid, intraspinal, epidural, intrasternal, and intralesional injection and infusion.

[0087] The term "therapeutically effective amount" refers to an amount of a compound according to the present invention that provides a beneficial or desired therapeutic and / or prophylactic effect. For prophylactic use, beneficial or desired results may include one or more results, such as, for example, eliminating or reducing the risk of disease, reducing the severity, or delaying the onset or recurrence of disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes exhibited during the development of the disease. For therapeutic use, beneficial or desired results may include one or more results, such as, for example, reducing one or more symptoms and pathologies caused or associated with the disease, improving the quality of life of a person suffering from the disease, reducing the dose of other drugs required to treat the disease, increasing the effect of another drug, such as through targeting, delaying disease progression, and / or prolonging survival. An effective amount may be, for example, an amount sufficient to directly or indirectly achieve a prophylactic or therapeutic treatment. As understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Therefore, effective amount can be considered in the context of administering one or more therapeutic agents.Effective amount can be administered in one dose or divided into multiple doses, the sum of the multiple doses being an effective amount.For example, effective amount can be provided in two separate administrations over a period of time, the sum of which provides an effective amount of the formulation.

[0088] The term "tumor cell" or neoplastic cell and grammatical equivalents refer to the entire population of cells derived from a tumor, pre-neoplastic lesion, or neoplasm, including both non-tumorigenic cells, which constitute the majority of the tumor cell population, and tumorigenic stem cells. As used herein, the term "tumor cell" or "neoplastic cell" is modified by the term "non-tumorigenic" only when it refers to tumor cells that lack the ability to regenerate and differentiate, to distinguish tumor cells from tumor stem cells.

[0089] As used herein, the terms "tumor" and "neoplasm" refer to any mass of tissue resulting from excessive cell growth or proliferation, whether benign (non-neoplastic) or malignant (neoplastic), and include pre-neoplastic lesions.

[0090] The term "SMARCA4-deficient malignant tumor" or "SMARCA4-mutated malignant tumor" or "SMARCA4-deficient tumor" or "SMARCA4-mutated tumor" or "SMARCA4-deficient cell" or "SMARCA4-mutated cell" refers to a malignant tumor, tumor, or cell in which the SMARCA4 gene is deleted or mutated, or the SMARCA4 protein is functionally defective. Examples of SMARCA4-deficient or mutated tumors include lung cancer, particularly non-small cell lung cancer, liver cancer, bladder cancer, breast cancer, colon cancer, gastrointestinal cancer, melanoma, endometrial cancer, or sarcoma.

[0091] II. Heterobifunctional Compounds The present disclosure describes heterobifunctional compounds that recruit endogenous proteins to ubiquitin ligases for degradation and methods of their use.

[0092] In some embodiments, the present disclosure provides heterobifunctional or proteolysis-inducing chimeric molecule (PROTAC) compounds containing a ligand for a target protein of interest connected via a linker to a ligand for an E3 ubiquitin ligase.

[0093] In some embodiments, the disclosure provides a compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof: [ka] It comprises a portion capable of binding to a ubiquitin ligase (i.e., the degradation inducer "D"), a linker ("L"), and a portion capable of binding to a target protein, e.g., SMARCA2 ("S").

[0094] In some embodiments, the heterobifunctional compound has formula II: [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0095] In some embodiments, the heterobifunctional compound has formula III: [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0096] In some embodiments, the heterobifunctional compound has formula IV: [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0097] In some embodiments, the heterobifunctional compound has formula V: [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0098] In some embodiments, Q is selected from the group consisting of -CH2- and -C(=O)-, W is -CH2- and V is [ka] and where the bond marked with an "*" is attached to W, R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen and fluoro; X is -O-, N(R5a )-, [ka] is selected from the group consisting of where the bond marked with an "*" is either attached to Y or X is a bond; R 5a is selected from the group consisting of hydrogen and C1-C4 alkyl; Y is selected from the group consisting of C1-C8 alkylenyl and 3- to 8-membered heteroalkylenyl; or Y is a bond; Z is -O-, -N(R 5b )-, [ka] is selected from the group consisting of where the bond marked with an "*" is either attached to Y or Z is a bond; R 5b is selected from the group consisting of hydrogen and C1-C4 alkyl.

[0099] In some embodiments where the heterobifunctional compound has formula II, III, IV, or V, R 1 is fluoro and R 2 , R 3 , and R 4 In some embodiments where the heterobifunctional compound has formula II, III, IV, or V, R 4 is fluoro and R 1 , R 2 , and R 3 In some embodiments where the heterobifunctional compound has formula II, III, IV, or V, R 1 and R 2 is fluoro and R 3 and R 4 In some embodiments where the heterobifunctional compound has formula II, III, IV, or V, R1 and R 4 is fluoro and R 2 and R 3 In some embodiments where the heterobifunctional compound has formula II, III, IV, or V, R 1 and R 3 is fluoro and R 2 and R 4 In some embodiments where the heterobifunctional compound has formula II, III, IV, or V, R 3 and R 4 is fluoro and R 1 and R 2 is hydrogen.

[0100] In some embodiments where the heterobifunctional compound has formula II, III, IV, or V, X is a bond. In some embodiments where the heterobifunctional compound has formula II, III, IV, or V, X is -O-.

[0101] In some embodiments where the heterobifunctional compound has formula II, III, IV, or V, Y is C-C alkylenyl. In embodiments where Y is C-C alkylenyl, Y is selected from the group consisting of -CH-, -CHCH-, -CHCHCH-, and -CHCHCHCHCH-.

[0102] In some embodiments where the heterobifunctional compound has Formula II, III, IV, or V, Y is a 3-8 membered heteroalkylenyl. In embodiments where Y is a 3-8 membered heteroalkylenyl, Y is selected from the group consisting of -CH2CH2OCH2CH2- and -CH2CH2OCH2CH2CH2-.

[0103] In some embodiments where the heterobifunctional compound has formula II, III, IV, or V, Z is represented by -O-. In some embodiments where the heterobifunctional compound has formula II, III, IV, or V, Z is represented by -N(R 5b )-.

[0104] In some embodiments, the heterobifunctional compound has formula V, X is O, R1 is fluoride, and R2, R3, and R4 are each hydrogen ("Compound 101").

[0105] In some embodiments, the heterobifunctional compound has formula IV, where X is [ka] wherein Y is C alkylenyl and Z is O ("Compound 102").

[0106] In some embodiments, the heterobifunctional compound has formula III, wherein X is [ka] and Y is C1 alkylenyl and Z is [ka] ("Compound 103").

[0107] In some embodiments, the heterobifunctional compound has formula V, X is O, R1 and R2 are each fluoride, and R3 and R4 are each hydrogen ("Compound 104").

[0108] In some embodiments, the heterobifunctional compound has formula V, X is O, R1 and R4 are each fluoride, and R2 and R3 are each hydrogen ("Compound 105").

[0109] In some embodiments, the heterobifunctional compound has formula V, X is O, R1 and R3 are each fluoride, and R2 and R4 are each hydrogen ("Compound 106").

[0110] In some embodiments, the heterobifunctional compound has formula V, X is O, R3 and R4 are each fluoride, and R1 and R2 are each hydrogen ("Compound 107").

[0111] In some embodiments, the degradation-inducing moiety "D" binds to a ubiquitin ligase.

[0112] In some embodiments, moieties that bind to a ubiquitin ligase enzyme include, but are not limited to, thalidomide, pomalidomide, lenalidomide, CC-885, CC-122, or CC-220.

[0113] In some embodiments, the ubiquitin ligase is selected from the group consisting of ubiquitin protein ligase E3A, mouse double minute 2 homolog (MDM2), anaphase promoting complex, ubiquitin protein ligase E3 component N-terminal residue recognition enzyme 5, suppressor of cytokine signaling / Cullin 5 / RING, ligand of numb-protein X1 (LNX1), HAKAI / Casitas B-cell lymphoma transforming sequence-like protein 1 (CBLL1); HECT domain and ankyrin repeat-containing E3 ubiquitin protein ligase 1, HECT domain E3 ubiquitin protein ligase 4; HECT, C2, and WW domain-containing E3 ubiquitin protein ligase 1 (HECW1); HECW2; HECT and RLD domain-containing E3 ubiquitin protein ligase family member 1 (HERC1), HERC2, HERC3, HERC4, HERC5, HERC6; HECT, UBA, and WWE domain-containing E3 ubiquitin protein ligase 1; itchy E3 ubiquitin protein ligase; neural progenitor cell expressed developmental down-regulated protein 4 (NEDD4); NEDD4-like peptidyl-prolyl cis-trans isomerase-like 2 (PPIL2); pre-mRNA processing factor 19 (PRPF19), an E3 of activated STAT1 SUMO protein ligase protein inhibitor (PIAS1), PIAS2, PIAS3, PIAS4, RAN-binding protein 2 (RANBP2), Ring finger protein 4, RING-box protein 1, SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1), SMURF2; STIP1 homologous and U-box-containing protein 1 (STUB1); TOP1-binding arginine / serine-rich protein (TOPORS), thyroid hormone receptor interactor 12 (TRIP12), ubiquitin-protein ligase E3A (UBE3A), UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, U-box domain containing 5 (UBOX5), von Hippel-Lindau tumor suppressor, WW domain-containing E3 ubiquitin protein ligase 1 (WWP1), WWP2, and PARKIN ligase. In some embodiments, the ubiquitin ligase is an E3 ubiquitin ligase.

[0114] In some embodiments, the linker (L) of the compounds of the present disclosure can be a fluoro-phenyl substituted with one or more groups selected from the group consisting of a piperazine group, a piperidine group, and a methoxyethoxy group. [ka] It is one of the Here, the bond marked with "*" is attached to the SMARCA2 binding site.

[0115] In some embodiments, without wishing to be bound by any theory, the linker moiety provides for targeted protein degradation by providing optimal proximity and orientation of the degradation-inducing moiety and the target protein binding moiety such that the target protein bound by the target protein binding moiety is in optimal proximity and orientation to the ubiquitin ligase bound by the ubiquitin ligase binding moiety, thereby allowing the target protein to be ubiquitinated by the ubiquitin ligase, thereby resulting in degradation of the target protein in the cellular ubiquitin-proteasome system.

[0116] In some embodiments, the target protein is SMARCA2 and one ligand is a SMARCA2 binding moiety.

[0117] In some embodiments, a target protein is any protein to which a target binding moiety can bind.

[0118] In some embodiments, when the heterobifunctional compound mediates heterodimerization of a ubiquitin ligase and a target protein, the target protein becomes ubiquitinated and degraded by the cellular proteasome.

[0119] In some embodiments, the heterobifunctional compound is [ka] and a linker selected from Combined with any target protein binding moiety and ubiquitin ligase binding moiety, where the bond marked with an "*" is attached to the target protein binding moiety. In some embodiments, without wishing to be bound by any theory, these linkers provide optimal proximity and orientation of the degradation-inducing moiety and the target protein-binding moiety to enable ubiquitination and degradation of the target protein.

[0120] In some embodiments, compounds of the disclosure have a DC potency of about 0.1 nM to about 300 nM, about 1 nM to about 200 nM, about 2 nM to about 150 nM, about 5 nM to about 120 nM, about 10 nM to about 100 nM, about 15 nM to about 80 nM, about 20 nM to about 70 nM, or about 30 nM to about 60 nM for SMARCA2. 50 In some embodiments, the compounds of the present disclosure have a DC of less than about 300 nM, less than about 200 nM, less than about 150 nM, less than about 120 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, or less than about 2 nM for SMARCA2. 50 has.

[0121] In some embodiments, compounds of the disclosure have a maximum observed degradation (D) as a percentage of DMSO control of about 60% to about 100%, about 65% to about 99%, about 70% to about 95%, about 75% to about 90%, or about 60%, 65%, 67%, 70%, 72%, 75%, 77%, 80%, 82%, 85%, 87%, 90%, 92%, 95%, 97%, 98%, 99%, or 100%, or a range between any of the aforementioned values. max In some embodiments, compounds of the present disclosure degrade SMARCA2 by greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 99% D.max to break down SMARCA2.

[0122] In some embodiments, compounds of the disclosure have a DC potency of about 500 nM to about 100 μM, about 700 nM to about 90 μM, about 800 nM to about 80 μM, about 900 nM to about 70 μM, about 1 μM to about 60 μM, about 2 μM to about 50 μM, about 5 μM to about 25 μM, or about 10 μM to about 20 μM against SMARCA4. 50 In some embodiments, compounds of the disclosure have a DC of greater than about 500 nM, greater than about 700 nM, greater than about 1 μM, greater than about 2 μM, greater than about 5 μM, greater than about 7 μM, or greater than about 10 μM for SMARCA4. 50 has.

[0123] In some embodiments, compounds of the present disclosure have a maximum observed degradation (D) as a percentage of DMSO control of about 10% to about 80%, about 15% to about 70%, about 20% to about 60%, or about 25% to about 50%. max In some embodiments, the compounds of the present disclosure degrade SMARCA4 with less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 25%, or less than about 20% D max So, let's disassemble the SMARCA4.

[0124] In some embodiments, compounds of the disclosure have an IC of about 10 nM to about 50 μM, about 50 nM to about 20 μM, about 100 nM to about 10 μM, about 200 nM to about 8 μM, about 300 nM to about 5 μM, about 400 nM to about 2 μM, or about 500 nM to about 1 μM. 50 (the concentration at which 50% of cell proliferation is inhibited).

[0125] In some embodiments, compounds of the disclosure have an IC of about 900 nM to about 50 μM, about 1 μM to about 40 μM, about 2 μM to about 30 μM, about 5 μM to about 25 μM, or about 10 μM to about 20 μM in wild-type SMARCA4 cells. 50In some embodiments, compounds of the disclosure have an IC of greater than about 900 nM, greater than about 1 μM, greater than about 2 μM, greater than about 3 μM, greater than about 5 μM, greater than about 7 μM, or greater than about 10 μM in wild-type SMARCA4 cells. 50 has.

[0126] In some embodiments, compounds of the present disclosure exhibit an IC of about 50 nM to about 10 μM, about 75 nM to about 5 μM, about 100 nM to about 1 μM, about 125 nM to about 900 nM, about 150 nM to about 800 nM, about 175 nM to about 700 nM, about 200 nM to about 600 nM, or about 250 nM to about 500 nM in mutant SMARCA4 cells. 50 In some embodiments, compounds of the disclosure have an IC of less than about 10 μM, less than about 5 μM, less than about 2 μM, less than about 1 μM, less than about 900 nM, less than about 800 nM, less than about 600 nM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, or less than about 2 nM, or less than about 1 nM in mutant SMARCA4 cells. 50 has.

[0127] In some embodiments, the compounds disclosed herein competitively inhibit the binding of pomalidomide to cereblon.In some embodiments, the compounds disclosed herein competitively inhibit the binding of SMARCA2 inhibitor to SMARCA2.In some embodiments, the compounds disclosed herein inhibit the proliferation of SMARCA4 mutant cells but do not inhibit the proliferation of SMARCA4 wild-type cells.

[0128] III.Synthesis method In some embodiments, the present disclosure is directed to methods for making a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof.

[0129] In some embodiments, the compounds of the present disclosure can be synthesized according to the methods described in the Examples herein or below.

[0130] In some embodiments, compounds of formula (II) can be synthesized as shown in Schemes 1-4. Compound 1 is mixed with compound a in the presence of potassium carbonate and dimethylformamide to form compound 2 (Scheme 1). [ka]

[0131] Compound 2 can be further reacted with compound b in the presence of sodium triacetoxyborohydride, N,N-diisopropylethylamine, and dimethylsulfoxide to form compound 3 (Scheme 2). [ka]

[0132] Compound 3 can be incubated with a mixture of hydrochloric acid and methanol and methanol to give compound 4 (Scheme 3). [ka]

[0133] When compound 4 is mixed with compound c in the presence of N,N-diisopropylethylamine and dimethylformamide, heterobifunctional compounds 101 and 104-108 shown in Scheme 4 can be formed. [ka]

[0134] In some embodiments, the compounds of the disclosure are produced with a purity of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or about 99.9%. In some embodiments, the compounds of the disclosure are produced with a purity of at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

[0135] IV. Pharmaceutical Compositions In some embodiments, the present disclosure is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. The heterobifunctional compounds of the present disclosure can be formulated into several different types of pharmaceutical compositions that contain a therapeutically effective amount of the heterobifunctional compound and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0136] In some embodiments, the compounds of the present disclosure, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle, are formulated for oral administration.

[0137] In some embodiments, the compound of the present disclosure or its pharma- ceutically acceptable salt or solvate and pharma- ceutically acceptable carrier, adjuvant or vehicle are formulated for parenteral administration. In some embodiments, the pharmaceutical composition for parenteral administration is for intravenous administration or subcutaneous administration. In some embodiments, the compound of the present disclosure or its pharma- ceutically acceptable salt or solvate formulated for parenteral administration comprises a surfactant. In some embodiments, the surfactant is a non-ionic surfactant, including but not limited to solutol, polysorbate, Cremophor® EL, ELP, or RH40, polyoxyethylene stearate, sorbitan fatty acid ester, polyoxyethylene alkyl ether, or polyoxyethylene nonylphenol ether.

[0138] In some embodiments, the compound of the present disclosure or its pharmaceutically acceptable salt or solvate is formulated for oral administration.In some embodiments, the compound of the present disclosure or its pharmaceutically acceptable salt or solvate is formulated as solid for oral administration.In some embodiments, the compound of the present disclosure or its pharmaceutically acceptable salt or solvate is formulated as liquid for oral administration.

[0139] In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof and a surfactant.In some embodiments, the composition comprises a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof and a non-ionic surfactant.In some embodiments, the non-ionic surfactant includes, but is not limited to, solutol, polysorbate, Cremophor® EL, ELP, or RH40, polyoxyethylene stearate, sorbitan fatty acid ester, polyoxyethylene alkyl ether, or polyoxyethylene nonylphenol ether.In some embodiments, the non-ionic surfactant is solutol, e.g., Kollophor® EL.

[0140] In some embodiments, the pharmaceutical composition comprises the compound of the present disclosure or its pharmaceutically acceptable salt or solvate and at least one metabolic stabilizer.In some embodiments, the pharmaceutical composition comprises the compound of the present disclosure or its pharmaceutically acceptable salt or solvate and an agent having CYP3A4 inhibitory activity.In some embodiments, the agent having CYP3A4 inhibitory activity is ritonavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, ceritinib, idelalisib, lonafarnib, tucatinib, clarithromycin, erythromycin, telithromycin, cobicistat, diltiazem, mifepristone, nefazodone, itraconazole, ketoconazole, levocetoconazole, posaconazole or voriconazole.In some embodiments, the pharmaceutical composition comprises the compound of the present disclosure or its pharmaceutically acceptable salt or solvate and ritonavir.

[0141] In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof and at least one metabolic stabilizer, wherein the compound is Compound 101, Compound 104, Compound 105, Compound 106, Compound 107, or Compound 108.

[0142] In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof, and does not comprise a metabolic stabilizer. In some embodiments, the pharmaceutical composition comprises compound 102 or compound 103, or a pharma- ceutically acceptable salt or solvate thereof, and does not comprise a metabolic stabilizer.

[0143] In some embodiments, the compounds of the present disclosure, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle, are formulated for administration with at least one additional pharma- ceutically active agent.

[0144] In some embodiments, the disclosed compound or a pharma- ceutically acceptable salt or solvate thereof and a pharma- ceutically acceptable carrier, adjuvant, or vehicle are formulated for simultaneous administration. In some embodiments, the disclosed compound or a pharma- ceutically acceptable salt or solvate thereof and a pharma- ceutically acceptable carrier, adjuvant, or vehicle are formulated for sequential administration.

[0145] In some embodiments, the pharmaceutical composition comprising the compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof is formulated for oral administration, and the second pharmaceutical composition comprising at least one additional agent is formulated for parenteral administration. In some embodiments, the pharmaceutical composition comprising the compound of formula I, formula II, formula III, formula IV, or formula V or a pharma- ceutically acceptable salt thereof is formulated for parenteral administration, and the second pharmaceutical composition comprising at least one additional agent is formulated for oral administration.

[0146] Compositions intended for oral use may contain one or more agents selected from the group consisting of inert, non-toxic, pharma- ceutically acceptable excipients suitable for tablet manufacture.Such excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as corn starch; binders such as starch; and lubricants such as magnesium stearate.Tablets may be uncoated or may be coated by known techniques for aesthetics or to delay the release of active ingredients.Oral formulations may also be provided as hard gelatin capsules in which active ingredients are mixed with inert diluents.

[0147] In some embodiments, the compounds described herein and / or additional therapeutic agent(s) are formulated by combining the components with a pharma- ceutically acceptable carrier, adjuvant, excipient or vehicle and formulated into oral dosage forms including, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0148] In some embodiments, pharmaceutical compositions for oral use can be prepared by mixing one or more solid excipients with the compounds described herein and / or additional therapeutic agent(s), optionally grinding the resulting mixture, and processing the mixture of granules, if desired, after adding suitable auxiliaries, to obtain tablets or dragee cores.

[0149] Suitable excipients are, inter alia, sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and the like; or others, such as fillers such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.

[0150] In some embodiments, dosage forms such as dragee cores and tablets are provided with one or more suitable coatings. In some embodiments, concentrated sugar solutions are used to coat dosage forms. Sugar solutions optionally contain additional components such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes and / or pigments are also optionally added to the coating for identification purposes. In addition, dyes and / or pigments are optionally used to characterize different combinations of active compound doses.

[0151] In some embodiments, a therapeutically effective amount of the disclosed compound or a pharma- ceutically acceptable salt or solvate thereof and / or additional therapeutic agent(s) described herein are formulated into other oral dosage forms. Unit dosage forms include physically discrete units suitable as unitary doses for a patient under treatment, each unit containing a predetermined amount of active agent calculated to produce a desired therapeutic effect, optionally with a suitable pharmaceutical carrier. The unit dosage form may be a single daily dose or multiple daily doses (e.g., about 1-4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose. Oral dosage forms include push-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. In some embodiments, the push-fit capsules contain the active ingredient mixed with one or more fillers. Fillers include, by way of example only, binders such as lactose, starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In some embodiments, the soft capsule contains one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added. In some embodiments, the stabilizer is a CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition is in a liquid dosage form suitable for oral administration. In some embodiments, the liquid formulation includes at least one of a buffer, an isotonicity agent, an inorganic salt, a surfactant, a metabolic stabilizer, or a combination thereof.

[0152] In some embodiments, the pharmaceutical composition is in a liquid dosage form suitable for parenteral administration. In some embodiments, the pharmaceutical composition is suitable for intravenous administration. In some embodiments, the pharmaceutical composition is suitable for intravenous infusion. In some embodiments, the pharmaceutical composition is suitable for injection. In some embodiments, the pharmaceutical composition is suitable for subcutaneous injection. In some embodiments, the composition for parenteral administration optionally further comprises one or more additional therapeutic agent(s). In some embodiments, the pharmaceutical composition for intravenous administration comprises at least one of a buffer, an isotonicity agent, an inorganic salt, a surfactant, a metabolic stabilizer, or a combination thereof.

[0153] In some embodiments, the buffer comprises a phosphate bicarbonate buffer.

[0154] In some embodiments, the inorganic salt comprises sodium chloride, calcium chloride, potassium chloride, magnesium chloride, sodium bicarbonate, monopotassium phosphate, or disodium phosphate.

[0155] In some embodiments, the tonicity agent is dextrose, glycerin, mannitol, potassium chloride, or sodium chloride.

[0156] In some embodiments, the surfactant is an anionic surfactant, a cationic surfactant, an amphoteric surfactant, or a non-ionic surfactant. In some embodiments, the anionic surfactant includes, but is not limited to, sodium lauryl sulfate and sodium docusate. In some embodiments, the cationic surfactant includes, but is not limited to, benzalkonium chloride, cetylpyridinium chloride, or a phosphatide. In some embodiments, the amphoteric surfactant includes, but is not limited to, a betaine, a sulfobetaine, an amino acid, or a phospholipid. In some embodiments, the non-ionic surfactant includes, but is not limited to, polysorbate, Solutol, Cremophor® EL, ELP, or RH40, polyoxyethylene stearate, sorbitan fatty acid ester, polyoxyethylene alkyl ether, or polyoxyethylene nonylphenol ether.

[0157] In some embodiments, the pharmaceutical compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable reservoir.

[0158] In some embodiments, the pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V or a pharma- ceutically acceptable salt thereof and at least one additional pharma- ceutical active agent can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination can be administered by intravenous injection, and one or more other therapeutic agents of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be injected intravenously.

[0159] V. Pharmaceuticals In some aspects, the present disclosure relates to the use of a compound of the present disclosure, or a pharma- ceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a tumor in a patient in need of said treatment.

[0160] In some embodiments, the medicament comprises a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof, and may optionally comprise one or more additional therapeutic agents. In some embodiments, the medicament is in a single dosage form or in separate dosage forms.

[0161] In some embodiments, the present disclosure relates to the use of the compound of the present disclosure or its pharmaceutically acceptable salt or solvate in the manufacture of a medicament for the treatment of tumor.In some embodiments, the medicament comprising the compound of the present disclosure or its pharmaceutically acceptable salt or solvate and at least one additional therapeutic agent is administered simultaneously.In some embodiments, the medicament comprising the compound of the present disclosure or its pharmaceutically acceptable salt or solvate and at least one additional therapeutic agent is administered separately.In some embodiments, the medicament comprising the compound of the present disclosure or its pharmaceutically acceptable salt or solvate and at least one additional therapeutic agent is administered sequentially.

[0162] VII. Treatment method In some embodiments, the present disclosure provides methods of using an effective amount of a compound of the present disclosure, or a pharma- ceutically acceptable salt or solvate thereof, for the treatment or amelioration of a disease or condition, such as cancer, e.g., SMARCA4-deficient cancer, including lung cancer, liver cancer, bladder cancer, breast cancer, or colon cancer.

[0163] In some embodiments, a method of treating a condition or disease is provided by administering a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof to a subject in need thereof. In some embodiments, the method of treatment comprises administering a therapeutically effective amount of a composition comprising a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof and at least one additional pharma- ceutical active agent. In some embodiments, the method of treatment comprises administering a therapeutically effective amount of a composition comprising a compound of the present disclosure or a pharma- ceutical acceptable salt or solvate thereof, an excipient, and at least one additional pharma- ceutical active agent. In some embodiments, the method of treatment comprises administering a therapeutically effective amount of a composition comprising a compound of the present disclosure or a pharma- ceutical acceptable salt or solvate thereof, an excipient, and a metabolic stabilizer. In some embodiments, the method of treatment comprises administering a therapeutically effective amount of a composition comprising a compound of the present disclosure or a pharma- ceutical acceptable salt or solvate thereof, an excipient, and an agent having CYP3A4 inhibitory activity. In some embodiments, the agent having CYP3A4 inhibitory activity is ritonavir.

[0164] In some embodiments, the method of treatment comprises administering a therapeutically effective amount of a composition comprising a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof and a surfactant. In some embodiments, the surfactant is an anionic surfactant, a cationic surfactant, an amphoteric surfactant, or a non-ionic surfactant. In some embodiments, the method of treatment comprises administering a therapeutically effective amount of a composition comprising a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof and an anionic surfactant, a cationic surfactant, an amphoteric surfactant, or a non-ionic surfactant. In some embodiments, the anionic surfactant includes, but is not limited to, sodium lauryl sulfate and sodium docusate. In some embodiments, the cationic surfactant includes, but is not limited to, benzalkonium chloride, cetylpyridinium chloride, or phosphatides. In some embodiments, the amphoteric surfactant includes, but is not limited to, betaine, sulfobetaine, amino acid, or phospholipid. In some embodiments, non-ionic surfactants include, but are not limited to, polysorbates, Solutol, Cremophor® EL, ELP, or RH40, polyoxyethylene stearates, sorbitan fatty acid esters, polyoxyethylene alkyl ethers, or polyoxyethylene nonylphenol ethers.

[0165] In some embodiments, the method of treatment comprises administering a therapeutically effective amount of a composition comprising a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof and a non-ionic surfactant. In some embodiments, the method of treatment comprises administering a therapeutically effective amount of a composition comprising a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof and solutol. In some embodiments, the method of treatment comprises administering a therapeutically effective amount of a composition comprising a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof, solutol, and ritonavir.

[0166] In some embodiments, the disease or condition can be treated by the degradation of SMARCA2 in cancer.In some embodiments, the disease treated by the compound of the present disclosure or its pharmaceutically acceptable salt or solvate is chronic autoimmune disorder, inflammatory condition, proliferation disorder, sepsis, or viral infection.In some embodiments, the compound of the present disclosure or its pharmaceutically acceptable salt or solvate reduces the proliferation of undesirable cells by inducing the apoptosis of cells.

[0167] In some embodiments, a composition comprising a compound of any of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle, for treating a disease or condition dependent on altered activity of the SWI / SNF complex.

[0168] In some embodiments, the disease / condition / cancer treated by the compound of formula I, formula II, formula III, formula IV, or formula V or its pharma- ceutically acceptable salt is a disease / condition / cancer defined as exhibiting one or more of the following: impaired or lost function of BAF complex subunits, including but not limited to, SMARCB1, ARID1A, ARID1B, ARID2, PBRM1, and SMARCA4, due to either inactivating mutations in the genes or loss of their expression by alternative mechanisms other than inactivating mutations; impaired or lost function of SMARCA4, due to either inactivating mutations in the SMARCA4 gene or loss of SMARCA4 expression by alternative mechanisms other than inactivating mutations. In some embodiments, the disease / condition / cancer is defined as exhibiting SMARCA4 deletion. In some embodiments, the SMARCA4 deletion is a heterozygous or homozygous SMARCA4 gene truncation.

[0169] In some embodiments, inactivating mutations affecting SMARCA4 function include heterozygous or homozygous nonsense or insertion / deletion (e.g., frameshift) mutations resulting in loss of protein or activity; and / or homozygous missense mutations resulting in heterozygosity that inactivates the function of the protein; and / or changes in gene expression levels; and / or changes in protein levels; and / or changes in protein function.

[0170] In some embodiments, the cancer has a mutation in SMARCA4 and / or exhibits loss of SMARCA4 function, but retains a functional copy of the SMARCA2 gene and / or expression of a functional SMARCA2 protein.

[0171] In some embodiments, the disease or condition is head and neck cancer, e.g., cancer of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, middle ear, larynx, hypopharynx, salivary glands; lung cancer, e.g., non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchoalveolar epithelial), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, mixed oat cell carcinoma); mediastinal neoplasms, e.g., neurogenic tumors (including neurofibroma, neurilemmoma, malignant schwannoma, neurosarcoma, ganglioneuroma, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (spermatozoa, sarcoidosis ... epithelioma, teratoma, non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangioleiomyoma); gastrointestinal (Gl) cancers, e.g., cancer of the esophagus, stomach (gastric cancer), pancreas, liver, biliary tract, gallbladder, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus), colorectal cancer, gastrointestinal stromal tumors, Hepatocellular carcinoma (HCC), hepatoblastoma, cholangiocarcinoma, cholangiocellular carcinoma, hepatic cystadenocarcinoma, angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma; cancer of the genitourinary system (kidney, e.g., renal pelvis), renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), adrenal gland, ureter, bladder, urethra, testis, testicular cancer; gynecological cancer, e.g., ovarian, fallopian tube, peritoneal, cervical, vulvar, vaginal, uterine cancer; breast cancer, e.g., breast adenocarcinoma (invasive ductal carcinoma, colloid breast carcinoma, invasive lobular carcinoma, tubular carcinoma of the breast, adenoid cystic carcinoma, papillary carcinoma, medullary carcinoma, mucinous carcinoma), hormone receptor positive breast cancer (estro gen receptor positive breast cancer, progesterone receptor positive breast cancer), Her2 positive breast cancer, triple negative breast cancer, Paget's disease of the breast; cancers of the endocrine system, e.g. cancers of the endocrine glands, thyroid (thyroid cancer / tumor; papillary, follicular, anaplastic, medullary), parathyroid (parathyroid carcinoma), adrenal cortex (adrenocortical carcinoma / tumor), pituitary (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, carotid body, islet cell tumor, paraganglia, pancreatic endocrine tumors (PET; non-functioning PET, gastrinoma, insulinoma, glucagonoma, somatostatinoma, carcinoid tumor);Sarcomas of soft tissues, e.g. fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumor of the pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic Schwannoma, gastrointestinal autonomic nerve tumor, neuroblastoma Neuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymal tumor, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor; sarcomas of bone, e.g., myeloma, reticulum cell sarcoma, chondrosarcoma (including intraskeletal, peripheral, clear cell, and mesenchymal chondrosarcoma), osteosarcoma, Ewing's tumor, malignant giant cell tumor, histiocytoma, fibrosarcoma , chordoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma; mesothelioma: e.g. pleural mesothelioma, peritoneal mesothelioma; cancer of the skin, e.g. basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentigo, nodular, intraocular melanoma), actinic keratosis, eyelid cancer; neoplasms of the central nervous system and brain, e.g. , astrocytoma (cerebral, cerebellar, diffuse, fibrous, anaplastic, pilocytic, protoplasmic, round cell), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, ganglioneuroma, neuroblastoma, retinoblastoma, schwannoma (e.g., acoustic neuroma), spinal axis tumor;Lymphomas and leukemias, including B-cell non-Hodgkin's lymphoma (NHL), small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt's lymphoma (BL), T-cell non-Hodgkin's lymphoma (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (ATLL) ), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), T-cell lymphoblastic lymphoma (T-LBL), adult T-cell lymphoma, B-cell lymphoblastic lymphoma (B-LB) L), Cytoma, Chronic B-cell lymphocytic leukemia (B-CLL), Chronic T-cell lymphocytic leukemia (T-CLL), B-cell small lymphocytic lymphoma (B-SLL), Cutaneous T-cell lymphoma (CTLC), Primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte predominant HD (NLPHD), nodular sclerosing HD (NSHD), mixed cellularity HD (MCHD), lymphocyte-rich classical HD, lymphopenic HD (LDHD)), large granular lymphocyte leukemia (LGL), chronic myeloid leukemia (CML), acute myeloid / myelocytic leukemia (AML), acute lymphoblastic leukemia (AML), The cancer may be myeloblastic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous / myelocytic leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML); or cancer of unknown primary site (CUP). The listed cancers are meant to include the primary tumor and any metastatic tumors derived therefrom.;

[0172] In some embodiments, the cancer treated by the disclosed compound or its pharma- ceutically acceptable salt or solvate is lung cancer, liver cancer, bladder cancer, breast cancer or colon cancer. In some embodiments, the cancer is non-small cell lung cancer.

[0173] VII. Combination Therapy In some embodiments, a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharma- ceutically acceptable salt thereof, is administered to a subject prior to, after, or together with at least one other pharma- ceutically active agent.

[0174] In some embodiments, the pharmacologically active agent used in combination with a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharma- ceutically acceptable salt thereof, can be selected from any one or more of the following: hormones, hormone analogs, and antihormones (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide); aromatase inhibitors (e.g., anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane); LHRH agonists and antagonists (e.g., goserelin acetate, salts, leuprolide; inhibitors of growth factors and / or their corresponding receptors (growth factors, e.g., platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, e.g., HER2, HER3, HER4) and hepatocyte growth factor (HGF), etc. and / or their corresponding receptors); antimetabolites (e.g., antifolates, e.g., methotrexate, raltitrexed, pyrimidine analogues, e.g., 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogues, capecitabine and gemcitabine, purine and adenosine analogues, e.g., mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (arabinose), C), fludarabine); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, Doxil (pegylated liposomal doxorubicin hydrochloride, Myoset (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin);Alkylating agents (e.g., estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas, such as carmustine and lomustine, thiotepa); mitotic inhibitors (e.g., vinca alkaloids, such as vinblastine, vindesine, vinorelbine and vincristine; and taxanes, such as paclitaxel, docetaxel, and the like); angiogenic agents. biosynthesis inhibitors (e.g., tasquinimod); tubulin inhibitors; DNA synthesis inhibitors; PARP inhibitors; topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone); serine / threonine kinase inhibitors (e.g., PDK1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, CRaf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors) , PI3K inhibitors, PI3Ka inhibitors, dual mTOR / PI3K inhibitors, STK33 inhibitors, AKT inhibitors, PLK1 inhibitors, CDK inhibitors, Aurora kinase inhibitors); tyrosine kinase inhibitors (e.g., cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, PTK2 / FAK inhibitors); protein-protein interaction inhibitors (e.g., IAP activators, Mcl-1, MDM2 / MDMX); MEK inhibitors; ERK inhibitors toxic agents;FLT3 inhibitors;BRD4 inhibitors;IGF-1R inhibitors;TRAILR2 agonists;Bcl-xL inhibitors;Bcl-2 inhibitors;ErbB receptor inhibitors;BCR-ABL inhibitors;ABL inhibitors;Src inhibitors;rapamycin analogues (e.g., everolimus, temsirolimus, ridaforolimus, sirolimus);androgen synthesis inhibitors;androgen receptor inhibitors;DNMT inhibitors;HDAC inhibitors;ANG1 / 2 inhibitors;CYP17 inhibitors;radiopharmaceuticals;Immunotherapeutic agents, such as immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3 binding molecules / immunoglobulins, such as ipilimumab, nivolumab, pembrolizumab, etc.), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g., anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), T cell engagers (e.g., bispecific T cell engagers (BiTE®), e.g., CD3xBCMA, CD3xCD33, CD3xCD19, PSMAxCD3), tumor vaccines; and various chemotherapeutic agents, such as amifostine, anagrelide, clodronate, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer.

[0175] In some embodiments, when two or more pharma- ceutically active agents are used in a combination treatment regimen, they may be administered via the same or different routes of administration, substantially simultaneously (i.e., simultaneously, together) or at different times (e.g., sequentially, consecutively, alternating, consecutively, or according to any other type of alternating regimen).

[0176] In some embodiments, when pharma- ceutical active agents are administered simultaneously via the same route of administration, they can be administered as different pharmaceutical compositions or as part of a combined pharmaceutical composition.When two or more pharma-ceutical active agents are used as part of a combined treatment regimen, each of the pharma-ceutical active agents can be administered in the same amount and according to the same regimen as when the pharma-ceutical active agent is used alone.

[0177] In some embodiments, when a compound of the disclosure and at least one additional therapeutic agent are administered sequentially, they are administered to the patient at two different time points separated by 16 minutes or more, e.g., 18 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 70 minutes, 80 minutes, or 90 minutes, 2 hours, 5 hours, 8 hours, 12 hours, 16 hours, 24 hours; 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days; or 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks.

[0178] In some embodiments, when the compound of the present disclosure and at least one additional therapeutic agent are co-administered to a patient, they are administered simultaneously or nearly simultaneously. For example, the compound of the present disclosure or a pharma- ceutically acceptable salt thereof and at least one additional therapeutic agent are administered "nearly simultaneously" if they are administered within about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minute of each other.

[0179] In some embodiments, the compound of the present disclosure and the at least one additional therapeutic agent are administered with a break that is a drug holiday following administration of the compound of the present disclosure and the at least one additional therapeutic agent, which can be at least one day.

[0180] VIII. Kit In some embodiments, a kit is provided that includes a pharmaceutical composition or dosage form that includes a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof and one or more pharma- ceutically acceptable carriers, excipients, and / or vehicles. In some embodiments, a kit is provided that includes a first pharmaceutical composition or dosage form that includes a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof and one or more pharma- ceutically acceptable carriers, excipients, and / or vehicles, and optionally a second pharmaceutical composition or dosage form that includes another pharma- ceutical active agent and one or more pharma- ceutical acceptable carriers, excipients, and / or vehicles.

[0181] In some embodiments, the kit contains a pharmaceutical or combination of pharmaceuticals packaged in a manner that facilitates use for practicing the methods of the present disclosure.

[0182] In some embodiments, the kit further comprises instructions regarding the pharmaceutical composition or methods of administration of the composition, and tools for preparation and administration of the pharmaceutical composition, e.g., via a parenteral route. EXAMPLES

[0183] Example 1 - Preparation of Compound 101 General procedure for the preparation of compound a: [ka] To a solution of compound a_1 (100 g, 487 mmol, 1.00 equiv) in DCM (750 mL) was added Et3N (148 g, 1.46 mol, 203 mL, 3.00 equiv) and TsCl (139 g, 731 mmol, 1.50 equiv) and the mixture was stirred at 25 °C for 1 h (Scheme 5).

[0184] LCMS showed the reactant was completely consumed. The mixture was diluted with H2O (500 mL) and then extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.

[0185] The crude product was triturated with MTBE / n-heptane (3:1, 80.0 mL) for 30 min at 0° C. The mixture was filtered, and the cake was collected and dried in vacuum to give compound a (171 g, 430 mmol, 88.3% yield, 90.4% purity) as a white solid. LCMS:Rt=0.916 min, m / z:260(M+H-Boc) + . HPLC: Rt = 2.98 min. 1 HNMR: (400MHz, CDCl3) δ7.81(d,J=8.4Hz,2H),7.35(d,J=8.0Hz,2H),4.16~4.14(m,2H),3.63~3.61(m,2H) ,3.45~3.43(m,2H),3.24~3.20(m,2H),3.14~3.10(m,1H),2.44(s,3H),1.44(s,9H).

[0186] General procedure for the preparation of compound 6 [ka] To a solution of compound a (35.0 g, 250 mmol, 1.00 equiv.) and compound 5 (98.7 g, 275 mmol, 1.10 equiv.) in DMF (350 mL), K2CO3 (86.3 g, 624 mmol, 2.50 equiv.) was added and the mixture was stirred at 90 °C for 2 h (Scheme 6). LCMS showed the reaction mixture was completely consumed. The mixture was diluted with H2O (1.00 L) and then extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was triturated with n-heptane for 30 min to give compound 6 (72.0 g, 219 mmol, 87.7% yield, 99.6% purity) as a light yellow solid. LCMS:R t =0.870min, m / z=228.2(M-56) HPLC:R t =2.73 minutes 1 HNMR: (400MHz, CDCl3) δ9.87~9.86(m,1H),7.64~7.60(m,2H),7.10(t,J=8.0Hz,1H),4.89(s,1H),4.29~4 .27(m,2H),3.89~3.87(m,2H),3.63~3.61(m,2H),3.35~3.34(m,2H),1.44(s,9H).

[0187] General procedure for the preparation of compound 7 [ka] To a solution of compound b (42.3 g, 137 mmol, 1.00 equiv, HCl) in DMSO (450 mL), DIEA (17.7 g, 137 mmol, 23.9 mL, 1.00 equiv) was added and stirred at 20° C. for 0.5 h (Scheme 7). Compound 6 (45.0 g, 137 mmol, 1.00 equiv) and NaBH(OAc)3 (58.3 g, 275 mmol, 2.00 equiv) were then added to the mixture. The mixture was stirred at 20° C. for 12 h. LCMS showed that the reaction mixture was completely consumed. The mixture was diluted with H2O (100 mL) and then extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 0 / 1, Rf = 0.20) to give compound 7 (57.0 g, 96.9 mmol, yield 70.5%, purity 99.1%) as a yellow solid. LCMS:R t =1.02 min, m / z=583.3(M+1) HPLC:R t =3.68 minutes 1 HNMR: (400MHz, DMSO-d6) δ14.10(s,1H),7.91(dd,J=1.6Hz,J=8.4Hz,1H),7.51(s,1H),7.25~7.21 (m,1H),7.18~7.11(m,2H),7.08~7.06(m,1H),6.90~6.86(m,2H),6.78(t, J=5.6Hz,1H),6.24(s,2H),4.16~4.13(m,2H),3.74~3.72(m,2H),3.50(s ,2H),3.45(t,J=6.4Hz,2H),3.11~3.07(m,5H),2.58(m,4H),1.36(s,9H).

[0188] General procedure for the preparation of compound 8 [ka] To a solution of compound 7 (57.0 g, 97.8 mmol, 1.00 equiv) in MeOH (250 mL), HCl / MeOH (4 M, 244.6 mL, 10.0 equiv) was added and the mixture was stirred at 15° C. for 12 h (Scheme 8). LCMS showed the reaction mixture was completely consumed. The mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE for 1 h to give compound 8 (52.0 g, 80.3 mmol, 81.8% yield, 91.1% purity, 3HCl) as a yellow solid. LCMS:R t =1.01 min, m / z=483.2(M+1) 1 HNMR: (400MHz, MeOD-d4) δ7.71(s,1H),7.65(dd,J=1.2Hz,J=8.0Hz,1H),7.51(dd,J=2.0Hz,J=11.6Hz ,1H),7.45~7.41(m,2H),7.26(t,J=8.8Hz,1H),7.03~7.06(m,2H),4.45(s,2 H),4.31~4.29(m,2H),3.97~3.93(m,4H),3.82(t,J=5.2Hz,2H),3.64~3.58( m,3H),3.55~3.52(m,1H),3.48~3.42(m,2H),3.35(s,2H),3.18~3.15(m,2H).

[0189] General procedure for the preparation of compound 101 [ka] To a solution of compound 8 (30.0 g, 50.8 mmol, 1.00 equiv, 3HCl) in DMF (300 mL), DIEA (39.4 g, 305 mmol, 6.00 equiv) and compound c (14.0 g, 50.8 mmol, 1.00 equiv) were added (Scheme 9). The mixture was stirred at 90° C. for 12 h. LCMS showed that the reaction mixture was completely consumed. The mixture was diluted with H2O (1.00 L) and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine (500 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=3 / 1 to 0 / 1 and dichloromethane / methyl alcohol=50 / 1, Rf=0.38). The crude product was then triturated with ACN at 15° C. for 30 min to give compound 101 (8.6 g, 11.7 mmol, 23.0% yield, 96.1% purity) as a yellow solid. A total of 5 g of compound 101 was produced with a purity of 95%. LCMS:R t =0.996 min, m / z=739.3(M+1) HPLC:R t =3.29 minutes 1 HNMR: (400MHz, CDCl3) δ13.77(s,1H),9.84(s,1H),7.59~7.57(m,1H),7.47(t,J=8.0Hz,1H)7 .28~7.25(m,2H),7.11~6.99(m,5H),6.91~6.87(m,2H),6.54(t,J=5.6 Hz,1H),4.97~4.88(m,3H),4.25~4.23(m,2H),3.83(t,J=5.2Hz,,2H), 3.62~3.59(m,1H),3.49~3.43(m,3H),3.15(s,4H),2.96~2.68(m,7H).

[0190] Example 2 - Preparation of Compound 104 General procedure for the preparation of compound 9 [ka] To a solution of compound a (2.50 g, 6.96 mmol, 1.10 equiv) and compound 9 (1.00 g, 6.33 mmol, 1.00 equiv) in DMF (25.0 mL) was added K2CO3 (2.19 g, 15.8 mmol, 2.50 equiv) and the mixture was stirred at 90 °C for 16 h (Scheme 10).

[0191] LCMS showed the reaction mixture was completely consumed. The mixture was diluted with H2O (100 mL) and then extracted with EtOAc (70.0 mL x 3). The combined organic layers were washed with brine (70.0 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 10 (2.20 g, 6.25 mmol, 98.8% yield, 98.1% purity) as a yellow oil, which was used directly in the next step. LCMS:Rt=0.898 min, m / z:246(M+H-Boc) + . HPLC: Rt = 2.88 min. 1 HNMR: (400MHz, CDCl3) δ9.85(t,J=1.6Hz,1H),7.46(d,J=8.4Hz,2H),4.86(brs,1H),4.45~4.43(m ,2H),3.81~3.79(m,2H),3.58~3.56(m,2H),3.31~3.29(m,2H),1.44(s,9H).

[0192] General procedure for the preparation of compound 11 [ka] To a solution of compound b (891 mg, 2.90 mmol, 1.00 equiv, HCl) in DMSO (15.0 mL), DIPEA (374 mg, 2.90 mmol, 504 μL, 1.00 equiv) was added and the mixture was stirred at 20° C. for 15 min (Scheme 11). Then, compound 10 (1.00 g, 2.90 mmol, 1.00 equiv) and NaBH(OAc)3 (1.23 g, 5.79 mmol, 2.00 equiv) were added and the mixture was stirred at 20° C. for 12 h. LCMS showed that the reaction mixture was completely consumed. The mixture was quenched with aqueous NaHCO3 (saturated, 12.0 mL), then H2O (60.0 mL) was added and the resulting mixture was extracted with EtOAc (40.0 mL×3). The combined organic layers were washed with brine (50.0 mL×2) and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 2) to give compound 11 (880 mg, 1.42 mmol, yield 49.1%, purity 97.0%) as a yellow solid. LCMS: Rt=1.05 min, m / z: 601 (M+H) + . HPLC: Rt = 3.67 min. 1 HNMR: (400MHz, CDCl3) δ13.7(s,1H),7.53(d,J=7.6Hz,1H),7.27~7.21(m,2H),6.99(d,J=8.0Hz,1H),6.89~6.83(m,3H),4.90~4.84(m,3H),4 .23~4.21(m,2H),3.73~3.71(m,2H),3.54~3.46(m,4H),3.27~3.26(m,2H),3.12(brs,4H),2.60(brs,4H),1.39(s,9H).

[0193] General procedure for the preparation of compound 12 [ka] To a solution of compound 11 (880 mg, 1.42 mmol, 1.00 equiv) in MeOH (10.0 mL) was added HCl / MeOH (4 M, 3.66 mL, 10.0 equiv) at 20° C., and the mixture was stirred at 20° C. for 12 h (Scheme 12). LCMS showed the reaction mixture was completely consumed. The mixture was concentrated under reduced pressure to give a residue, which was then triturated with MTBE (15.0 mL) at 20° C. for 30 min. The mixture was filtered, and the cake was collected and dried in vacuum to give compound 12 (300 mg, 0.49 mmol, 33.4% yield, 98.6% purity) as a light yellow solid. LCMS: Rt=0.966 min, m / z: 501 (M+H) + . HPLC: Rt = 3.19 min. 1 HNMR: (400MHz, DMSO-d6) δ12.3(s,1H),8.09(brs,3H),7.61~7.56(m,5H),7.38(t,J=7.2Hz,1H),7.11(d,J=8.0Hz,1H),6.97(t,J=7.2Hz,1 H),4.36(brs,2H),4.32~4.30(m,2H),4.77~4.75(m,4H),3.68~3.66(m,2H),3.61~3.42(m,8H),3.96~3.92(m,2H).

[0194] General procedure for the preparation of compound 104 [ka] A solution of compound 12 (300 mg, 492 μmol, 1.00 equiv, 3HCl), compound c (136 mg, 492 μmol, 1.00 equiv) and DIPEA (381 mg, 2.95 μmol, 514 uL, 6.00 equiv) in DMF (3.00 mL) was stirred at 100° C. for 14 h (Scheme 13).

[0195] LCMS showed the reaction mixture was completely consumed. The mixture was filtered and purified by preparative HPLC (column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 38%~68%, 10min) to give compound 104 (114mg, 145.52μmol, yield 29.59%, purity 96.6%) as a yellow solid. A total amount of 10mg of compound 104 was produced. LCMS: Rt=1.00 min, m / z: 757 (M+H) + . HPLC: Rt = 3.47 min. 1 HNMR: (400MHz, CDCl3) δ13.7(s,1H),9.25(s,1H),7.58~7.56(m,1H),7.49~7.45(m,1H),7.27~7.25(m,2H),7.09~7.03(m,2H),6.93~6.87(m,4H),6.49(t,J=5. 6Hz,1H), 4.95~4.89(m,3H),4.32~4.30(m,2H),3.85~3.78(m,4H),3.55~3.45(m,4H),3.15(s,4H),2.90~2.65(m,7H),2.13~2.09(m,1H).

[0196] Example 3 - Preparation of Compound 105 General procedure for the preparation of compound 14 [ka] To a solution of compound a (2.73 g, 7.59 mmol, 1.20 equiv) in DMF (35.0 mL), compound 13 (1.00 g, 6.33 mmol, 1.00 equiv) and K2CO3 (2.19 g, 15.8 mmol, 2.50 equiv) were added, and the mixture was stirred at 90 °C for 16 h (Scheme 14). LCMS showed the reaction mixture was completely consumed. The reaction mixture was diluted with H2O (60.0 mL) and extracted with EtOAc (30.0 mL x 2). The combined organic layers were washed with brine (80.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5:1 to 0:1) to give compound 14 (1.00 g, 2.88 mmol, 45.6% yield, 99.5% purity) as a yellow oil. LCMS:R t = 0.993 min, m / z = 246.2 (M-Boc+1) HPLC:R t =2.99 minutes 1 HNMR: (400MHz, CDCl3) δ10.2(s,1H),7.60~7.65(m,1H),6.86~6.90(m,1H),4.87(s,1H),4.29(t,J=4.8Hz ,2H),3.88(t,J=4.4Hz,2H),3.62(t,J=5.2Hz,2H),3.34~3.35(m,2H),1.45(s,9H).

[0197] General procedure for the preparation of compound 15 [ka] To a solution of compound b (891 mg, 2.90 mmol, 1.00 equiv, HCl) in DMSO (5.00 mL), DIPEA (374 mg, 2.90 mmol, 504 μL, 1.00 equiv) was added and the mixture was stirred at 25 °C for 15 min (Scheme 15). Then, to the mixture, a solution of compound 14 (1.00 g, 2.90 mmol, 1.00 equiv) in DMSO (5.00 mL) and NaBH(OAc)3 (1.23 g, 5.79 mmol, 2.00 equiv) was added and the mixture was stirred at 25 °C for 16 h. LCMS showed that the reaction mixture was completely consumed. The reaction mixture was adjusted to pH = 7-8 with NaHCO3, diluted with H2O (30.0 mL), and extracted with EtOAc (20.0 mL x 2). The combined organic layers were washed with brine (50.0 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=3:1 to 0:1) to give compound 15 (900 mg, 1.43 mmol, 49.3% yield, 95.3% purity) as a yellow solid. LCMS:R t =1.04 min, m / z=601.3(M+1) HPLC:R t =3.55 minutes 1 HNMR: (400MHz, CDCl3) δ7.58(dd,J=8.0,1.2Hz,1H),7.29~7.32(m,2H),7.02~7.07(m,2H),6.89~6.93(m,1H),6.75~6.80(m,1H),4.93(s,1H),4.81(s,2H),4.2 2(t,J=4.4Hz,2H),3.85(t,J=4.8Hz,2H),3.66(s,2H),3.63(t,J=5.2Hz,2H),3.34~3.36(m,2H),3.17(s,4H),2.69(s,4H),1.45(s,9H).

[0198] General procedure for the preparation of compound 16 [ka] To a solution of compound 15 (900 mg, 1.50 mmol, 1.00 equiv) in MeOH (10.0 mL), HCl / MeOH (4 M, 3.75 mL, 10.0 equiv) was added and the mixture was stirred at 20° C. for 16 h (Scheme 16). LCMS showed the reaction mixture was completely consumed. The reaction mixture was concentrated under reduced pressure to remove MeOH. The crude product was triturated with MTBE (5 V) at 20° C. for 30 min and filtered to give compound 16 (860 mg, 1.38 mmol, 92.4% yield, 98.2% purity, 3HCl) as a light yellow solid. LCMS:R t =0.994 min, m / z=501.2(M+1) HPLC:R t =3.22 minutes 1 HNMR: (400MHz, DMSO-d6) δ12.2(s,1H),8.20(s,3H),7.58~7.62(m,3H),7.38(t,J=7.6Hz,1H),7.20(d,J=8.0Hz,1H),7.15(d,J=8.0Hz,1H) ,6.97(t,J=7.6Hz,1H),4.39(s,2H),4.30~4.32(m,2H),3.69~3.84(m,7H),3.39~3.50(m,7H),2.94~2.98(m,2H).

[0199] General procedure for the preparation of compound 105 [ka] To a solution of compound 16 (300 mg, 492 μmol, 1.00 equiv, 3HCl) in DMF (3.00 mL), DIPEA (381 mg, 2.95 mmol, 514 μL, 6.00 equiv) and compound c (136 mg, 492 μmol, 1.00 equiv) (Scheme 17) were added. The mixture was stirred at 95 °C for 16 h. LCMS showed that the reaction mixture was completely consumed. The reaction mixture was filtered and purified by preparative HPLC (neutral conditions: column: Waters Xbridge C18 150*50 mm*10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 39%-69%, 10 min) to give compound 105 (105 mg, 138 μmol, yield 28.1%, purity 99.7%) as a yellow solid. A total of 10 mg of compound 105 was produced with a purity of 95%. LCMS:R t =0.994 min, m / z=757.3(M+1) HPLC:R t =3.380 minutes 1 HNMR: (400MHz, CDCl3) δ13.7(s,1H),10.1(s,1H),7.58(d,J=8.0Hz,1H),7.47(t,J=8.0Hz,1H),7.28(s,2H),7.06(dd,J=16 .4,7.2Hz,2H),7.00(t,J=7.2Hz,1H),6.88~6.92(m,2H),6.84(t,J=7.6Hz,1H),6.55(t,J=5.3Hz,1H) ,4.87~4.92(m,3H),4.23~4.31(m,2H),3.91(t,J=4.0Hz,2H),3.84(t,J=5.2Hz,2H),3.72(d,J=12.8H z,1H),3.57(d,J=12.8Hz,1H),3.45~3.49(m,2H),3.16(s,4H),2.68~2.96(m,7H),2.10~2.15(m,1H).

[0200] Example 4 - Preparation of Compound 106 General procedure for the preparation of compound 18 [ka] To a solution of compound a (2.73 g, 7.60 mmol, 1.20 equiv.) and compound 17 (1.00 g, 6.33 mmol, 1.00 equiv.) in DMF (25.0 mL), K2CO3 (2.19 g, 15.8 mmol, 2.50 equiv.) (Scheme 18) was added and the mixture was stirred at 90 °C for 16 h (Scheme 15). LCMS showed the reaction mixture was completely consumed. The mixture was diluted with H2O (100 mL) and then extracted with EtOAc (70.0 mL x 3). The combined organic layer was washed with brine (70.0 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 18 (2.20 g, 6.20 mmol, 98.0% yield, 97.4% purity) as a yellow oil, which was used directly in the next step. LCMS:Rt=0.893min, m / z:246(M+H-Boc) + . HPLC: Rt = 2.84 min. 1 HNMR: 400MHz, CDCl3) δ10.1(d,J=2.8Hz,1H),7.53(dd,J=10.4,6.4Hz,1H),7.76(dd,J=11.2,6.0Hz,1H),4.91(brs, 1H), 4.24~4.22(m,2H),3.86~3.84(m,2H),3.60~3.58(m,2H),3.32~3.30(m,2H),1.44(s,9H).

[0201] General procedure for the preparation of compound 19 [ka] To a solution of compound b (1.78 g, 5.79 mmol, 1.00 equiv, HCl) in DMSO (10.0 mL), DIPEA (748.50 mg, 5.79 mmol, 1.01 mL, 1.00 equiv) was added and the mixture was stirred at 20° C. for 15 min (Scheme 19). Then, to the mixture, a solution of compound 18 (2.00 g, 5.79 mmol, 1.0 equiv) in DMSO (10.0 mL) and NaBH(OAc)3 (2.45 g, 11.58 mmol, 2.00 equiv) was added and the mixture was stirred at 25° C. for 15 h. LCMS showed that the reaction mixture was completely consumed. The reaction mixture was diluted with EtOAc (30.0 mL) and adjusted to pH = 7-8 with aqueous NaHCO3 (saturated, 30 mL), then H2O (60.0 mL) was added and extracted with EtOAc (30.0 mL x 2). The combined organic layers were washed with brine (30.0 mL x 3), filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 2) to give compound 19 (1.50 g, 2.45 mmol, 42.3% yield, 98.2% purity) as a yellow solid. LCMS: Rt=1.03 min, m / z: 601 (M+H) + . HPLC: Rt = 3.56 min. 1 HNMR: (400MHz, CDCl3) δ13.7(s,1H),7.59(dd,J=8.0,1.6Hz,1H),7.33~7.27(m,2H),7.15(dd,J=11.6 ,6.8Hz,1H),7.06(dd,J=8.0,1.2Hz,1H),6.93~6.89(m,1H),6.73(dd,J=10.8, 6.8Hz,1H),4.92(s,1H),4.79(s,2H),4.19~4.16(m,2H),3.86~3.84(m,2H),3. 63~3.59(m,4H),3.37~3.34(m,2H),3.18(brs,4H),2.69(brs,4H),1.45(s,9H).

[0202] General procedure for the preparation of compound 20 [ka] To a solution of compound 19 (1.40 g, 2.33 mmol, 1.00 equiv) in MeOH (14.0 mL) was added HCl / MeOH (4 M, 5.83 mL, 10.0 equiv) at 20° C., and the mixture was stirred at 20° C. for 12 h (Scheme 20). LCMS showed the reaction mixture was completely consumed. The mixture was concentrated under reduced pressure to give a residue, which was then triturated with MTBE (15.0 mL) at 20° C. for 30 min. The mixture was filtered, and the cake was collected and dried in vacuum to give compound 20 (1.34 g, 2.16 mmol, 92.8% yield, 98.5% purity) as a light yellow solid. LCMS: Rt=1.00 min, m / z: 501 (M+H) + . HPLC: Rt = 3.17 min. 1 HNMR: (400MHz, MeOH-d4) δ7.71(brs,1H),7.65~7.63(m,1H),7.58~7.53(m,1H),7.46~7.42(m,1H),7.20~7.15(m,1H),7.07~7.03(m,2H),4.47( brs,2H),4.32~4.30(m,2H),4.96~4.94(m,4H),3.82~3.80(m,2H),3.72~3.58(m,5H),3.35(s,1H),3.17~3.15(m,2H).

[0203] General procedure for the preparation of compound 106 [ka] A solution of compound 20 (300 mg, 492 umol, 1.00 equiv, 3HCl), compound c (136 mg, 492 μmol, 1.00 equiv) and DIPEA (381 mg, 2.95 mmol, 514 μL, 6.00 equiv) in DMF (3.00 mL) was stirred at 100° C. for 14 hours (Scheme 21).

[0204] LCMS showed that the reaction mixture was completely consumed. The mixture was filtered and purified by preparative HPLC (column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 38%~68%, 10min) to give compound 106 (120mg, 157μmol, yield 31.9%, purity 99.0%) as a yellow solid. A total amount of 10mg of compound 106 was produced. LCMS: Rt=1.00 min, m / z: 757 (M+H) + . HPLC: Rt = 3.37 min. 1 HNMR: (400MHz, CDCl3) δ13.7(s,1H),9.83(s,1H),7.58(d,J=7.6Hz,1H),7.47(t,J=7.6Hz,1H),7.29~7 .26(m,2H),7.09~7.03(m,2H),6.92~6.88(m,2H),6.78~6.74(m,1H),6.54(t,J= 5.2Hz,3H),4.91~4.86(m,3H),4.21~4.20(m,2H),3.95~3.82(m,4H),3.66~3.63 (m,1H),3.54~3.44(m,3H),3.16(brs,4H),2.92~2.70(m,7H),2.13~2.09(m,1H).

[0205] Example 5 - Preparation of Compound 107 General procedure for the preparation of compound 22 [ka] To a solution of compound a (2.50 g, 6.96 mmol, 1.10 equiv) in DMF (25.0 mL) was added compound 21 (1.00 g, 6.33 mmol, 1.00 equiv) and K2CO3 (2.19 g, 15.8 mmol, 2.50 equiv) (Scheme 22). The mixture was stirred at 90 °C for 16 h (Scheme 19). HPLC showed that the reaction mixture was completely consumed. The reaction mixture was diluted with H2O (50.0 mL) and extracted with EtOAc (30.0 mL x 2). The combined organic layers were washed with brine (60.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5:1 to 1:1) to give compound 22 (1.90 g, 5.42 mmol, 85.7% yield, 98.5% purity) as a yellow oil. LCMS:R t =0.896 min, m / z=245.9 (M-Boc) HPLC:R t =2.889 minutes 1 HNMR: (400MHz, CDCl3) δ10.2(s,1H),6.53(d,J=10.8Hz,2H),4.88(s,1H),4.17(t,J=4.4Hz,2H),3 .84(t,J=4.4Hz,2H),3.61(t,J=5.2Hz,2H),3.33~3.38(m,2H),1.45(s,9H).

[0206] General procedure for the preparation of compound 23 [ka] To a solution of compound b (1.69 g, 5.50 mmol, 1.00 equiv, HCl) in DMSO (10.0 mL), DIPEA (711 mg, 5.50 mmol, 958 μL, 1.00 equiv) was added and the mixture was stirred at 20 °C for 15 min (Scheme 23). Then, to the mixture, a solution of compound 22 (1.90 g, 5.50 mmol, 1.00 equiv) in DMSO (10.0 mL) and NaBH(OAc)3 (2.33 g, 11.0 mmol, 2.00 equiv) was added and the mixture was stirred at 20 °C for 16 h. LCMS showed that the reaction mixture was completely consumed. The reaction mixture was adjusted to pH = 7-8 with NaHCO3, diluted with H2O (60.0 mL), and extracted with EtOAc (30.0 mL x 2). The combined organic layers were washed with brine (60.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3:1 to 0:1) to give compound 23 (1.90 g, 3.08 mmol, yield 55.9%, purity 97.3%) as a yellow solid. LCMS:R t =1.02 min, m / z=601.3(M+1) HPLC:R t =3.58 minutes 1 HNMR: (400MHz, CDCl3) δ13.8(s,1H),7.57(dd,J=8.0,1.2Hz,1H),7.28~7.30(m,2H),7.04~7.0 6(m,1H),6.89~6.93(m,1H),6.52(d,J=9.2Hz,2H),4.94(s,1H),4.81(s ,2H),4.10(t,J=4.4Hz,2H),3.82(t,J=4.8Hz,2H),3.74(s,2H),3.61(t ,J=5.2Hz,2H),3.35~3.36(m,2H),3.16(s,4H),2.70(s,4H),1.46(s,9H)

[0207] General procedure for the preparation of compound 24 [ka] To a solution of compound 23 (1.90 g, 3.16 mmol, 1.00 equiv) in MeOH (20.0 mL) was added HCl / MeOH (4 M, 7.91 mL, 10.0 equiv) (Scheme 24). The mixture was stirred at 20° C. for 16 h. LCMS showed the reaction mixture was completely consumed. The reaction mixture was concentrated under reduced pressure to remove MeOH. The crude product was triturated with MTBE (5 V) at 20° C. for 30 min and filtered to give compound 24 (1.70 g, 2.73 mmol, 86.3% yield, 97.9% purity, 3HCl) as a light yellow solid. LCMS:R t =0.977min, m / z=501.2(M+1) HPLC:R t =3.196 minutes 1 HNMR: (400MHz, MeOH-d4) δ7.73(s,1H),7.65(dd,J=8.0,1.6Hz,1H),7.42~7.46(m,1H),7.03~7.07(m,2H),6.84(d,J=9.6Hz,2H),4.52(s,2H),4.26(t,J=4.4Hz,2H), 3.97(s,1H),3.91(t,J=4.4Hz,2H),3.79(t,J=4.8Hz,2H),3.73(s,2H),3.60~3.63(m,2H),3.43(s,2H),3.35(s,1H),3.16(t,J=4.8Hz,2H).

[0208] General procedure for the preparation of compound 107 [ka] To a solution of compound 24 (300 mg, 492 μmol, 1.00 equiv, 3HCl) in DMF (3.00 mL), DIPEA (381 mg, 2.95 mmol, 514 μL, 6.00 equiv) and compound c (136 mg, 492 μmol, 1.00 equiv) were added (Scheme 25). The mixture was stirred at 95 °C for 16 h. LCMS (EW15912-251-P1A) showed that the reaction mixture was completely consumed. The reaction mixture was filtered and purified by preparative HPLC (neutral conditions: column: Waters Xbridge C18 150*50 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 38%-68%, 10 min) to give compound 107 (100 mg, 132 μmol, 26.9% yield) as a yellow solid. A total of 10 mg of compound 107 was produced with a purity of 95%. LCMS:R t =1.01 min, m / z=757.3(M+1) HPLC:R t =3.40 minutes 1 HNMR: (400MHz, CDCl3) δ13.8(s,1H),10.1(s,1H),7.58(d,J=7.2Hz,1H),7.47(t,J=8.0Hz,1H),7.29(s,1H) ),7.25(s,1H),7.09(d,J=7.2Hz,1H),7.04(d,J=8.4Hz,1H),6.89~6.92(m,2H),6.51 ~6.57(m,3H),4.88~4.92(m,3H),4.13(t,J=3.6Hz,2H),3.75~3.89(m,5H),3.61(d,J =13.2Hz,1H),3.44~3.48(m,2H),3.18(s,4H),2.70~2.93(m,7H),2.08~2.12(m,1H).

[0209] Example 6 - Preparation of Compound 108 General procedure for the preparation of compound 2A [ka] A mixture of compound 1A (20.0 g, 98.5 mmol, 1.00 equiv), compound d (18.3 g, 296 mmol, 16.5 mL, 3.00 equiv) (Scheme 23), and TsOH (339 mg, 1.97 mmol, 0.02 equiv) in toluene (200 mL) was degassed, purged with N2 three times, and stirred at 110 °C under N2 atmosphere for 23 h (Scheme 26). TLC (PE: EtOAc = 10: 1, R1 R f =0.57, P1 R f =0.51), indicating that compound 1A remained, and one new spot was detected. The reaction mixture was cooled to room temperature and purified by silica pad with EtOAc to give compound 2A (10.8 g, 43.4 mmol, 99.2% purity) as a yellow liquid. LCMS:R t =0.920 min, m / z=280 (M+Na) + HPLC:R t =2.44 minutes 1 HNMR: (400MHz, DMSO-d6) δ7.70~7.66(m,1H),7.37(dd,J=9.6,1.6Hz,1H),7.21(dd,J=8.4,1.6Hz,1H),5.74(s,1H),4.0~3.94(m,4H).

[0210] General procedure for the preparation of compound 3A [ka] To a solution of compound 2A (2.00, 8.11 mmol, 1.00 equiv), compound e (3.40 g, 12.2 mmol, 1.50 equiv) and Et3N (2.46 g, 24.3 mmol, 3.39 mL, 3.00 equiv) in DMF (20 mL), CuI (309 mg, 1.62 mmol, 0.20 equiv) and Pd(PPh3)4 (2.81 g, 2.43 mmol, 0.30 equiv) were added, degassed and purged with N2 three times, and then the mixture was stirred at 100° C. under N2 atmosphere for 12 hours (Scheme 27). LC-MS showed that the reaction mixture was completely consumed. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1) and further purified by reverse-phase HPLC (0.1% NH3·H2O) to give compound 3A (583 mg, 1.28 mmol, 15.8% yield, 97.9% purity) as a yellow oil. LCMS:R t =0.912 min, m / z=446(M+H) + HPLC:R t =2.02 minutes 1 HNMR: (400MHz, CDCl3) δ7.41~7.18(m,13H),5.82(s,1H),4.37(s,2H),4.13~4.05(m,4H),3.73(t,J=6.0Hz,2H),3.67(s,4H),2.77(t,J=6.0Hz,2H).

[0211] General procedure for the preparation of compound 4A [ka] To a solution of compound 3A (473 mg, 1.06 mmol, 1.00 equiv) in CF3CH2OH (5.00 mL), Pd / C (400 mg, 10% purity) was added, degassed and purged with H2 three times, and then the mixture was stirred under H2 atmosphere at 40°C for 12 h (Scheme 25). LC-MS showed that the reaction mixture was completely consumed. The reaction mixture was filtered, the cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to give compound 4A (290 mg, crude) as a yellow oil. LCMS:R t =0.818 min, m / z=270(M+H) + HPLC:R t =1.72 minutes 1 HNMR: (400MHz, CDCl3) δ7.23~7.14(m,3H),5.78(s,1H),4.14~4.01(m,4H),3.47~3.43(m,2H),2.84(t,J=6.8Hz,2H),2.74(t,J=7.6Hz,2H),1.93~1.86(m,2H).

[0212] General procedure for the preparation of compound 5A [ka] A solution of compound 4A (284 mg, 1.05 mmol, 1.00 equiv), compound c (291 mg, 1.05 mmol, 1.00 equiv), DIPEA (409 mg, 3.16 mmol, 551 μL, 3.00 equiv) in DMF (3.00 mL) was stirred at 100° C. for 14 h (Scheme 26). LC-MS showed the reaction mixture was completely consumed. EtOAc (10 mL) and H2O (10 mL) were added, the resulting mixture was extracted with 20 mL of EtOAc (10 mL×2), and the combined organic layers were washed with 20 mL of brine (10 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=5 / 1 to 1 / 1 and 2% DCM) to give compound 5A (290 mg, 552 μmol, 52.3% yield) as a yellow solid. LCMS:R t =0.973min, m / z=526(M+H) + HPLC:R t =2.60 minutes 1 HNMR: (400MHz, CDCl 3) δ8.58(s,1H),7.51~7.47(m,1H),7.20~7.09(m,4H),6.93(t,J=8.4Hz,1H),6.53(t,J=5.2Hz,1H),5.76(s,1H),4.91~4.87(m, Contains THF.

[0213] General procedure for the preparation of compound 6A [ka] To a solution of compound 5A (145 mg, 276 μmol, 1.00 equiv) in THF (1.00 mL), HCl (0.5 M, 1.00 mL) was added and the mixture was stirred at 40° C. for 1 h (Scheme 27). LC-MS showed that the reaction mixture was completely consumed. The mixture was adjusted to pH=8 with aqueous NaHCO3 (saturated), and then EtOAc (10 mL) and H2O (10 mL) were added. The resulting mixture was extracted with 20 mL of EtOAc (10 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 6A (103 mg, 200 μmol, 72.6% yield, 93.7% purity) as a yellow solid.

[0214] General procedure for the preparation of compound 108 [ka] To a solution of compound b (65.8 mg, 214 μmol, 1.00 equiv, HCl) in DMSO (1.00 mL), DIPEA (27.6 mg, 214 μmol, 37.26 μL, 1.00 equiv) was added and the mixture was stirred at 20° C. for 15 min (Scheme 28). Compound 6A (103 mg, 214 μmol, 1.00 equiv) and NaBH(OAc)3 (90.7 mg, 428 μmol, 2.00 equiv) were then added and the mixture was stirred at 25° C. for 14 h. LC-MS showed that 51.9% of the desired mass was detected. The reaction mixture was filtered and purified by preparative HPLC (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 40%~70%, 9 min) to give compound 108 (28.0 mg, yield 27.8%) as a yellow solid. LCMS:R t =1.02 min, m / z=737(M+H) + HPLC:R t =3.93 minutes 1 HNMR: (400MHz, CDCl3) δ13.7(s,1H),9.53(s,1H),7.57(d,J=7.6Hz,1H),7.50~7.47(m,1H),7.28~7. 24(m,2H),7.20~7.16(m,1H),7.09(d,J=6.8Hz,1H),7.05~7.00(m,3H),6.93~9 .86(m,2H),6.54(t,J=5.6Hz,1H),5.03(s,2H),4.94~4.90(m,1H),3.68~3.46 (m,8H),3.15(s,4H),2.77~2.66(m,9H),2.14~2.09(m,1H),1.94~1.90(m,2H).

[0215] Example 7 - Preparation of Compound 102 General procedure for the preparation of compound 26 [ka] To a solution of compound 25 (1.00 g, 7.04 mmol, 763 uL) in CH3CN (20.0 mL) was added Et3N (1.42 g, 14.0 mmol, 1.96 mL) and tert-butyl piperazine-1-carboxylate (1.57 g, 8.44 mmol) (Scheme 32). The mixture was stirred at 80 °C for 10 h. TLC (petroleum ether: ethyl acetate = 5:1) showed some starting material remained, and a major spot (Rf = 0.25) was formed. The reaction mixture was filtered and the filtrate was concentrated to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 5 / 1) to give compound 26 (0.80 g, 2.59 mmol, 36.8% yield) as a light yellow oil.

[0216] LCMS:R t =0.963min, m / z=253.1(M+H) +

[0217] General procedure for the preparation of compound 27 [ka] To a solution of compound 26 (1.00 g, 3.24 mmol) in DMSO (10.0 mL) was added 2-(6-amino-5-piperazin-1-yl-pyridazin-3-yl)phenol (967 mg, 3.57 mmol, HCl salt), NaBH(OAc)3 (824 mg, 3.89 mmol) and Et3N (656 mg, 6.49 mmol, 902 uL) (Scheme 33). The mixture was stirred at 20 °C for 12 h. TLC (petroleum ether:ethyl acetate = 1:1, P1: Rf = 0.25) showed starting material remained and some new spots were detected. The reaction mixture was diluted with H2O (30 mL) and then extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (10 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give compound 27 (450 mg, 784 umol, yield 24.2%, purity 98.3%) as a white solid.

[0218] LCMS:R t =0.805min, m / z=564.4(M+H) +

[0219] General procedure for the preparation of compound 28 [ka] To a solution of compound 27 (400 mg, 709 umol) in MeOH (4.00 mL) was added HCl / MeOH (4M, 4.00 mL) (Scheme 34). The mixture was then stirred at 20° C. for 1 h. The mixture was concentrated under reduced pressure to give a residue. The mixture was suspended in DCM (10 mL) and then the pH was adjusted to 8-9 with saturated NaHCO3 solution. The mixture was then extracted with DCM (20.0 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 28 (300 mg, 628 umol, 88.5% yield, 97.1% purity) as a white solid.

[0220] LCMS:R t =1.033min, m / z=464.1(M+H) +

[0221] 1 HNMR: (400MHz, DMSO-d6)

[0222] δ14.4-14.2(m,1H),8.0-7.9(m,1H),7.51(s,1H),7.30-7.21(m,1H),7.09-7.03(m,2H),7.01-6.9 5(m,1H),6.95-6.82(m,2H),6.24(s,2H),3.49(s,2H),3.11(s,4H),3.02-2.98(m,8H),2.58(s,5H)

[0223] General procedure for the preparation of compound 102 [ka] To a solution of compound 28 (203 mg, 431 umol) in DMF (2.00 mL), compound f (200 mg, 431 umol) (Scheme 35), Et3N (43.6 mg, 431 umol, 60.0 uL) were added. The mixture was stirred at 20° C. for 2 hours. The mixture was purified by preparative HPLC (neutral conditions) to give compound 102 (15.0 mg, 18.0 umol, 4.18% yield, 91.8% purity) as a white solid.

[0224] LCMS:R t =0.702 min, m / z=764.3(M+H) +

[0225] HPLC:R t =1.160 minutes, purity=95.9%

[0226] 1 HNMR: (400MHz, CDCl3)

[0227] δ14.1-13.4(m,1H),8.42-8.39(m,1H),7.88-7.76(m,1H),7.58-7.46(m,1H),7.48(m ,1H),7.32-7.30(m,1H),7.28-7.27(m,1H),7.25-7.22(m,1H),7.18-7.08(m,3H),7. 06-6.89(m,2H),4.98-4.94(m,1H),4.82(s,2H),4.42(s,2H),3.54(s,2H),3.25-3.1 8(m,8H),3.06-3.01(m,2H),2.94-2.76(m,7H),2.73-2.55(m,4H),2.17-2.08(m,1H)

[0228] FNMR: (400MHz, CDCl3)

[0229] SFC:Rt=0.555 minutes

[0230] Example 8 - Preparation of Compound 103 General procedure for the preparation of compound 30 [ka] To a solution of compound 29 (4.00 g, 16.0 mmol, 1.00 equiv) in DMSO (40.0 mL) was added IBX (6.74 g, 24.1 mmol, 1.50 equiv) (Scheme 36). The mixture was stirred at 15 °C for 2 h. LCMS showed that compound 29 was completely consumed, and one major peak with the desired mass was detected. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, crude compound 30 (3.70 g, crude) as a colorless oil, which was used in the next step without further purification.

[0231] LCMS:R t =0.993min, m / z=464.2(M+1)

[0232] 1HNMR: (400MHz, CDCl3)

[0233] δ9.67(s,H),7.39~7.31(m,5H),5.14(s,2H),4.08~4.05(m,2H),3.07~3.01(m,2H),2.48~2.41(m,1H),1.91(m,2H),1.64~1.54(m,2H)

[0234] General procedure for the preparation of compound 31 [ka] To a solution of compound 30 (3.70 g, 14.9 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (2.93 g, 15.7 mmol, 1.05 equiv) in (40.0 mL) was added HOAc (898 mg, 14.9 mmol, 856 uL, 1.00 equiv) and NaBH(OAc)3 (4.76 g, 22.4 mmol, 1.50 equiv) (Scheme 37). The mixture was stirred at 15 °C for 12 h. LCMS showed that compound 30 was completely consumed, and one major peak with the desired mass was detected. The mixture was diluted with HO (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue which afforded compound 31 (6.00 g, crude) as a white solid.

[0235] LCMS:R t =0.798 min, m / z=418.2(M+1)

[0236] 1 HNMR: (400MHz, CDCl3)

[0237] δ7.39~7.30(m,5H),5.13(s,2H),4.18(s,2H),3.41(d,J=4.8Hz,4H),2.77(m,2H),2.34(d,J=4. 8Hz,4H),2.17(t,J=7.2Hz,2H),1.77~1.74(m,2H),1.46(s,9H),1.27(m,1H),1.17~1.07(m,2H)

[0238] General procedure for the preparation of compound 32 [ka] To a solution of compound 31 (4.00 g, 9.58 mmol, 1.00 equiv) in MeOH (40.0 mL) was added Pd / C (0.40 g, 958 umol, 10.0% purity, 0.10 equiv) under N2 (Scheme 38). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 15°C for 2 h. TLC (petroleum ether:ethyl acetate=1:1) showed that reactant 1 was completely consumed, and one major new spot with more polarity was detected. The mixture was filtered, and the filter cake was washed with MeOH (100 ml) and concentrated under reduced pressure to give compound 32 (2.20 g, crude) as a grey solid.

[0239] 1 HNMR: (400MHz, CDCl3)

[0240] δ3.41(d,J=4.8Hz,4H),3.10~3.07(m,2H),2.63~2.51(m,2H),2.33(d,J=4.8Hz,4H),2.16(t,J =7.2Hz,2H),2.05(s,1H),1.75~1.72(m,2H),1.65~1.58(m,1H),1.46(s,9H),1.15~1.05(m,2H)

[0241] General procedure for the preparation of compound 33 [ka] To a solution of compound 32 (2.20 g, 7.76 mmol, 1.00 equiv) and 3,4-difluorobenzaldehyde (1.16 g, 8.15 mmol, 884 uL, 1.05 equiv) in DMF (20.0 mL) was added Et3N (1.18 g, 11.6 mmol, 1.62 mL, 1.50 equiv) (Scheme 39). The mixture was stirred at 90 °C for 4 h. LCMS showed that compound 32 was completely consumed, and one major peak with the desired mass was detected. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1, Rf = 0.40) to give compound 33 (2.30 g, 4.82 mmol, yield 62.0%, purity 84.9%) as a yellow solid.

[0242] LCMS:R t =0.799 min, m / z=406.2(M+1)

[0243] HPLC:R t =1.535 minutes

[0244] 1 HNMR: (400MHz, CDCl3)

[0245] δ9.81~9.80(m,1H),7.56~7.48(m,2H),6.99~6.96(m,1H),3.70~3.67(m,2H),3.43(m,4H),2.85~2.79(m,2H), 2.36(m,4H),2.23(t,J=7.2Hz,2H),1.88(t,J=12.4Hz,2H),1.74~1.68(m,1H),1.47(s,9H),1.40~1.36(m,2H)

[0246] General procedure for the preparation of compound 34 [ka] To a solution of compound 33 (1.00 g, 2.47 mmol, 1.00 equiv.) and 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol hydrochloride (704 mg, 2.59 mmol, 1.05 equiv.) in DMSO (10.0 mL) was added NaBH(OAc)3 (1.05 g, 4.94 mmol, 2.00 equiv.) (Scheme 40). The mixture was stirred at 15 °C for 12 h. LCMS showed that compound 33 was completely consumed, and one major peak with the desired mass was detected. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was triturated with PE (10.0 mL) for 15 min. The mixture was then filtered, and the filter cake was washed with petroleum ether (3 mL×2) to give compound 34 (1.00 g, 1.37 mmol, 55.3% yield, 90.3% purity) as a yellow solid.

[0247] LCMS:R t =0.741 min, m / z=661.3(M+1)

[0248] 1 HNMR: (400MHz, CDCl3)

[0249] δ13.7(s,1H),7.59~7.57(m,1H),7.32~7.28(m,2H),7.06~7.00(m,3H),6.94~6.89(m,2H),4.85(s,2H),3.54(s,2H),3.45(m,6H) ,3.17(s,3H),2.69~2.64(m,6H),2.40(s,4H),2.28~2.26(m,2H),1.89~1.87(m,2H),1.66(m,1H),1.47(s,9H),1.40~1.36(m,2H)

[0250] General procedure for the preparation of compound 35 [ka] A solution of compound 34 (500 mg, 756 umol, 1.00 equiv) in HCl / EtOAc (5.00 mL) was stirred at 15° C. for 2 h (Scheme 41). LCMS showed that compound 34 was completely consumed, and one major peak with the desired mass was detected. The mixture was concentrated under reduced pressure to give a residue, giving compound 35 (400 mg, crude, HCl) as a yellow solid.

[0251] LCMS:R t =0.711 min, m / z=561.3(M+1)

[0252] 1 HNMR: (400MHz, CDCl3)

[0253] δ12.7(s,1H),10.2(s,2H),7.59~7.57(m,1H),7.32~7.28(m,2H),7.06~7.00(m,3H),6.94~6.89(m,2H),4.85(s,2H),3.54(s,2H) ,3.45(m,6H),3.17(s,3H),2.69~2.64(m,6H),2.40(s,4H),2.28~2.26(m,2H),1.89~1.87(m,2H),1.66(m,1H),1.40~1.36(m,2H)

[0254] General procedure for the preparation of compound 103 [ka] To a solution of compound 35 (200 mg, 335 umol, 1.00 equiv, HCl) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (97.1 mg, 352 umol, 1.05 equiv) in DMF (2.00 mL) was added DIEA (216 mg, 1.67 mmol, 292 uL, 5.00 equiv) (Scheme 42). The mixture was stirred at 90° C. for 12 h. LCMS showed that compound 35 was completely consumed, and one major peak with the desired mass was detected. The mixture was diluted with H2O (20.0 mL) and extracted with ethyl acetate (20.0 mL×2). The combined organic layers were washed with brine (10.0 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 48%~78%, 11min) to give compound 103 (50.0mg, 59.5umol, yield 17.8%, purity 97.3%) as a yellow solid.

[0255] LCMS:R t =1.061 min, m / z=817.0(M+1)

[0256] HPLC:R t =2.611 minutes

[0257] 1 HNMR (400MHz, CDCl3)

[0258] FNMR:

[0259] δ13.7(s,1H),8.20(s,1H),7.70(t,J=8.4Hz,2H),7.60~7.58(m,1H),7.33(s,2H), 7.31~7.29(m,2H),4.97~4.93(m,1H),4.82(s,2H),3.55(s,2H),3.46~3.40(m,6H), 3.18(s,4H),2.92~2.77(m,3H),2.74~2.72(m,1H),2.71~2.66(m,5H),2.61(s,4H), 2.33(t,J=6.8Hz,2H),2.18~2.09(m,1H),1.89(t,J=12.4Hz,2H),1.53~1.40(m,3H)

[0260] Table 1 identifies the compounds disclosed in Examples 1-8. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0261] Example 9 - SMARCA2 Degradation in Wild-Type and Mutant SMARCA4 Cell Lines Using SMARCA2 PROTAC Compound 101 Cell lines (H1975, H1792, H2122, and H441) with wild-type SMARCA4 were treated with DMSO or 0.001, 0.01, 0.1, 1, or 10 μM ACBI1 (a degrader of SMARCA2, SMARCA4, and polybromo-associated BAF complex PBRM1) or compound 101, and the expression levels of SMARCA2 (Figure 2A) and SMARCA4 (Figure 2B) were detected by Western blot. Both ACBI1 and compound 101 degraded SMARCA2 and SMARCA4 when used at increasing concentrations. However, compound 101 selectively degraded SMARCA2 over SMARCA4 by more than 100-fold over ACBI1 (Tables 2 and 3 and Figures 2A and 2B). Table 2 shows the results for SMARCA2, and Table 3 shows the results for SMARCA4. [Table 2] [Table 3]

[0262] The data show that both compounds have D max (maximal degradation observed as a percentage of DMSO control) (Figure 2A, Table 2). On the other hand, only ACBI1 degraded SMARCA4 at 97–99% D max Compound 101 D max is either not measurable or has a D of 38% to 50%. max Compound 101 degraded SMARCA4 at 100 nm (Figure 2B, Table 3), confirming the selectivity of compound 101 for SMARCA2. Furthermore, in wild-type SMARCA4 cells, compound 101 showed DC 50 SMARCA4-specific DCs were significantly higher than those of the control group (Table 2). 50 was greater than 10 μM (Table 3).

[0263] Example 10 - SMARCA2 PROTAC compound 101 specifically reduces cell proliferation in SMARCA4 mutant cell lines Cell lines with wild-type SMARCA4 (HCC44, H2122, H1792, and H1975) and cell lines with mutant SMARCA4 (H1693, HCC515, H322, and H1299) were seeded at appropriate dilutions and allowed to form colonies for approximately 1-3 weeks. Cells were treated with ACBI1 or compound 101 at concentrations of 0.001, 0.01, 0.1, 1, and 10 μM. Colonies were fixed with glutaraldehyde (6% v / v), stained with crystal violet (0.5% w / v), and the percent area of ​​colonies was determined (Figures 3A and 3B). Inhibition of colony growth was more pronounced in cell lines with wild-type SMARCA4 after treatment with ACBI1 than with compound 101 (Figure 3A). In mutant SMARCA4 cell lines, more pronounced colony growth inhibition was observed with both ACBI1 and compound 101 (Figure 3B). ACBI1 inhibited wild-type and mutant SMARCA4 cells (Figure 3C), whereas compound 101 selectively inhibited SMARCA4 mutant cells (Figure 3D).

[0264] Cell lines with wild-type SMARCA4 (HCC44, H2122, H1792, H1975, H441, H2228, HCC827, HCC2279, and HOP62) and mutant SMARCA4 (H1693, HCC515, H322, H1299, A549, HCC366, H2023, H2126, H1793, H838, and H2935) were analyzed using the D max , D.C. 50 , and I.C. 50 (the concentration that inhibits 50% of cell proliferation) was further tested.

[0265] Compound 101 showed a D of 82%-99% (Table 4) in wild-type SMARCA4 cells and 81%-99% (Table 5) in mutant SMARCA4 cells. max Furthermore, the DC of compound 101 on SMARCA2 degradation was 50was 32 nM to 292 nM in wild-type SMARCA4 cells (Table 4) and 8 nM to 113 nM in mutant SMARCA4 cells (Table 4).

[0266] Compound 101 showed a D of 38%–79% in wild-type SMARCA4 cells. max The DC of compound 101 degraded SMARCA4 (Table 4). 50 ranged from 560 nM to greater than 10 μM in these cells (Table 4).

[0267] IC of compound 101 in wild-type SMARCA4 cells 50 The IC of compound 101 in mutant SMARCA4 cells was 0.97 μM to 10 μM (Table 4). 50 ranged from 0.93 nM to greater than 10 μM (Table 5). These data confirmed that compound 101 selectively inhibited cell proliferation in mutant SMARCA4 cell lines. [Table 4] [Table 5]

[0268] Example 11 -SMARCA2 PROTAC Compound 103 Cell lines with wild-type SMARCA4 (H1792) and mutant SMARCA4 (H1299) were treated with DMSO or 0.001, 0.01, 0.1, 1, or 10 μM of compound 103 for 72 or 96 hours and analyzed by Western blot for the expression of SMARCA2, SMARCA4, and PBRM1 (Figures 4A, 4B, and 4C). Compound 103 efficiently degraded SMARCA2 (Figure 4A) and reduced the expression of SMARCA4 (Figure 4B) in H1792 cells, but did not significantly affect the expression of PBRM1 (Figure 4C). Compared with compound 101, compound 103 significantly inhibited SMARCA2 expression at 100 nM in both H1792 and H1299 cells (Figure 4A). At this concentration, compound 101 achieved a maximum of 50% inhibition in SMARCA4 mutant cells and approximately less than 10% inhibition in wild-type SMARCA4 cells (see Figure 3D).

[0269] Example 12 - SMARCA2 PROTAC Compound 102 Cell lines with wild-type SMARCA4 (H1792) and mutant SMARCA4 (H1299) were treated with DMSO or 0.001, 0.01, 0.1, 1, or 10 μM of compound 102 for 72 or 96 h and analyzed by Western blot for the expression of SMARCA2, SMARCA4, and PBRM1 (Figures 5A, 5B, and 5C). Compound 102 efficiently degraded SMARCA2 (Figure 5A) and reduced the expression of SMARCA4 (Figure 5B), but did not significantly affect the expression of PBRM1 (Figure 5C). Compared with compound 101, compound 102 significantly inhibited SMARCA2 expression at 100 nM in both H1792 and H1299 cells (Figure 5A). At this concentration, compound 101 achieved a maximum of 50% inhibition in SMARCA4 mutant cells and approximately less than 10% inhibition in wild-type SMARCA4 cells (see Figure 3D).

[0270] Example 13 - SMARCA2 PROTAC Compounds 104, 105, 106, 107, and 108 A cell line (H1975) with wild-type SMARCA4 was treated with DMSO or 0.001, 0.01, 0.1, 1, or 10 μM of compounds 104, 105, 106, 107, or 108 and analyzed by Western blot for the expression of SMARCA2, SMARCA4, and PBRM1 (Figures 6A and 6B). Compounds 104-108 efficiently degraded SMARCA2, but not SMARCA4 or PBRM1 (Figures 6A and B).

[0271] Example 14 - Immunohistochemistry to visualize SMARCA2 degradation in vivo NCR nude mice were intraperitoneally injected with vehicle or SMARCA2 degradation-inducing compound 101 (200 mg / kg) once a day for 4 consecutive days. Tumor tissues were harvested 24 hours after the last dose and formalin-fixed for 24 hours, paraffin-embedded, sectioned, and stained according to standard procedures. Briefly, endogenous peroxidase was inactivated by 3% hydrogen peroxide. Nonspecific signals were blocked using 3% BSA, 10% goat serum in 0.1% Triton X-100. After antigen retrieval with citrate buffer, slides were stained overnight at 4°C using SMARCA2 antibody (Cell Signaling, D9E8B1:2000). After overnight incubation, slides were washed and incubated with secondary antibody (HRP-polymer, Biocare Medical) for 30 minutes at room temperature. Slides were washed three times and stained with DAB substrate (ThermoFisher Scientific). Slides were then counterstained with hematoxylin and mounted with mounting medium. Slides were imaged with a Vectra microscope, and the signal intensity and percentage of SMARCA2 positive cells were quantified using Vectra 3.0.7 software.

[0272] A significant decrease in SMARCA2 was observed in NCR nude mice treated with compound 101 compared to vehicle controls (Figure 7A), with the percentage of SMARCA2-positive cells decreasing by more than 50% after compound 101 treatment (Figure 7B).

[0273] Example 15 - In vivo antitumor efficacy study in female NCR nude mice using HCC515 lung cancer xenograft model Approximately 1 × 10 7 HCC515 cells were injected into each mouse. Tumors were monitored by visual inspection and palpation every two weeks. When tumors reached 100 mm 3 When the average volume of 1000 mg / kg of SMARCA2 degradation inducer was reached, the mice were randomly assigned to a control group and a SMARCA2 degradation inducer group. The treatment cohorts were as follows: vehicle was 15% Solutol in water with 12.5 mg / kg of ritonavir added as a metabolic stabilizer. In the vehicle group, 10 animals were intraperitoneally injected with vehicle. In the treatment group, 10 animals were intraperitoneally injected with 12.5 mg / kg of SMARCA2 degradation inducer compound 101 in 15% Solutol in water with 12.5 mg / kg of ritonavir added as a metabolic stabilizer once a day.

[0274] Tumor diameter and volume were determined based on caliper measurements of tumor length and height using the formula: tumor volume = (longest diameter x shortest diameter). 2 Tumor volumes and body weights were measured three times a week.

[0275] A significant reduction in tumor volume was observed in mice treated with compound 101 versus vehicle control mice, demonstrating the efficacy of SMARCA2 degrader in blocking tumor growth in vivo (Figure 8).

[0276] It is understood that the Detailed Description section is intended to be used to interpret the claims, and not the Summary and Abstract sections, which may set forth one or more, but not all, exemplary aspects of the disclosure as contemplated by the inventor(s), and thus are not intended to limit the scope of the invention and the appended claims in any way.

[0277] The present invention has been described above using functional building blocks that illustrate the implementation of certain functions and their relationships. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternative boundaries may be defined so long as the specified functions and their relationships are appropriately implemented.

[0278] The foregoing description of the specific embodiments fully reveals the general nature of the present invention, and those skilled in the art can easily modify and / or adapt such specific embodiments to various applications by applying knowledge within the art without undue experimentation and without departing from the general outline of the present invention. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the terms or phrases used herein are for the purpose of description, not of limitation, and that the terms or phrases used herein will be interpreted by those skilled in the art in light of the teachings and guidance.

[0279] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0280] The claims of this application are distinct from those of the parent application or other related applications. Accordingly, the applicants revoke any disclaimer of claims made in the parent application or any prior application related to this application. The examiner is therefore advised that it may be necessary to reconsider any such prior disclaimers and any references made to avoid them. Furthermore, the examiner is also advised that any disclaimers made in this application should not be read into or against the parent application.

Claims

1. Compounds of Formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof (In the formula, D is a ubiquitin ligase binding moiety; L is a linker comprising a fluoro-phenyl or difluoro-phenyl substituted with one or more groups selected from the group consisting of piperazine groups, piperidine groups, methoxypropyl and methoxyethoxy groups; S is the SMARCA2 binding moiety).

2. Compound of Formula II: 【Chemistry 2】 or a pharma- ceutically acceptable salt or solvate thereof, Q is selected from the group consisting of -CH2- and -C(=O)-; W is -CH ２ - and V is, 【Chemistry 3】 and where the bond marked with an "*" is attached to W, R １ , R ２ , R ３ , and R ４ is independently selected from the group consisting of hydrogen and fluoro; X is -O-, N(R ５ａ ) -, 【Chemistry 4】 is selected from the group consisting of where the bond marked with an "*" is attached to Y, or X is a bond; R ５ａ is hydrogen and C １ -C ４ is selected from the group consisting of alkyl, Y is C １ -C ８ selected from the group consisting of alkylenyl and 3- to 8-membered heteroalkylenyl; Y is a bond; Z is -O-, -N(R ５ｂ ) -, 【Chemistry 5】 is selected from the group consisting of where the bond marked with an "*" is attached to Y, or Z is a bond; R ５ｂ is hydrogen and C １ -C ４ (selected from the group consisting of alkyl).

3. Formula III: 【Chemistry 6】 3. The compound of claim 2, or a pharma- ceutically acceptable salt or solvate thereof.

4. Formula IV: 【Chemistry 7】 3. The compound of claim 2, or a pharma- ceutically acceptable salt or solvate thereof.

5. The compound according to any one of claims 2 to 4, wherein Q is -C(=O)-, or a pharma- ceutically acceptable salt or solvate thereof.

6. R １ is fluoro, R ２ , R ３ , and R ４ The compound according to any one of claims 2 to 5, or a pharma- ceutically acceptable salt or solvate thereof, wherein is hydrogen.

7. R ４ is fluoro, R １ , R ２ , and R ３ The compound according to any one of claims 2 to 5, or a pharma- ceutically acceptable salt or solvate thereof, wherein is hydrogen.

8. R １ and R ２ is fluoro, R ３ and R ４ The compound according to any one of claims 2 to 5, or a pharma- ceutically acceptable salt or solvate thereof, wherein is hydrogen.

9. R １ and R ４ is fluoro, R ２ and R ３ The compound according to any one of claims 2 to 5, or a pharma- ceutically acceptable salt or solvate thereof, wherein is hydrogen.

10. R １ and R ３ is fluoro, R ２ and R ４ The compound according to any one of claims 2 to 5, or a pharma- ceutically acceptable salt or solvate thereof, wherein is hydrogen.

11. R ３ and R ４ is fluoro, R １ and R ２ The compound according to any one of claims 2 to 5, or a pharma- ceutically acceptable salt or solvate thereof, wherein is hydrogen.

12. 12. The compound according to any one of claims 2 to 11, or a pharma- ceutically acceptable salt or solvate thereof, wherein X is a bond.

13. The compound according to any one of claims 2 to 11, or a pharma- ceutically acceptable salt or solvate thereof, wherein X is -O-.

14. Y is C １ -C ８ 14. The compound according to any one of claims 2 to 13, or a pharma- ceutically acceptable salt or solvate thereof, which is alkylenyl.

15. Y is -CH ２ --, --CH ２ CH ２ --, --CH ２ CH ２ CH ２ - and -CH ２ CH ２ CH ２ CH ２ 15. The compound of claim 14, selected from the group consisting of: - or a pharma- ceutically acceptable salt or solvate thereof.

16. The compound according to any one of claims 2 to 13, or a pharma- ceutically acceptable salt or solvate thereof, wherein Y is 3-8 membered heteroalkylenyl.

17. Y is -CH ２ CH ２ OCH ２ CH ２ - and -CH ２ CH ２ OCH ２ CH ２ CH ２ 17. The compound of claim 16, selected from the group consisting of: - or a pharma- ceutically acceptable salt or solvate thereof.

18. The compound according to any one of claims 2 to 17, wherein Z is represented by -O-, or a pharma- ceutically acceptable salt or solvate thereof.

19. Z is -N(R ５ｂ 18. The compound according to any one of claims 2 to 17, wherein the compound is represented by the formula:

20. -Z-Y-V-W-, 【Chemistry 8】 is selected from the group consisting of A compound according to any one of claims 2 to 19, wherein the bond marked with an "*" is attached to a SMARCA2 binding moiety.

21. The compound according to any one of claims 1 to 20, wherein the compound is selected from the group consisting of: 【Chemistry 9-1】 【Chemistry 9-2】 or a pharma- ceutically acceptable salt or solvate thereof.

22. The compound has a DC potency of about 0.1 nM to about 300 nM, about 1 nM to about 200 nM, about 2 nM to about 150 nM, about 5 nM to about 120 nM, about 10 nM to about 100 nM, about 15 nM to about 80 nM, about 20 nM to about 70 nM, or about 30 nM to about 60 nM for SMARCA2. ５０ The compound according to any one of claims 1 to 21, having a concentration at which 50% of the target protein is degraded.

23. The compound has a DC activity against SMARCA2 of less than about 300 nM, less than about 200 nM, less than about 150 nM, less than about 120 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, or less than about 2 nM. ５０ The compound according to any one of claims 1 to 21, having the formula:

24. The compound has a D of about 60% to about 100%, about 65% to about 99%, about 70% to about 95%, or about 75% to about 90% for SMARCA2. ｍａｘ 22. The compound of any one of claims 1 to 21, having a maximum degradation as a percentage of DMSO control.

25. The compound has a D of about 60%, 65%, 67%, 70%, 72%, 75%, 77%, 80%, 82%, 85%, 87%, 90%, 92%, 95%, 97%, 98%, 99%, or 100% against SMARCA2. ｍａｘ The compound according to any one of claims 1 to 21, having the formula:

26. The compound has a DC potency of about 500 nM to about 100 μM, about 700 nM to about 90 μM, about 800 nM to about 80 μM, about 900 nM to about 70 μM, about 1 μM to about 60 μM, about 2 μM to about 50 μM, about 5 μM to about 25 μM, or about 10 μM to about 20 μM against SMARCA4. ５０ The compound according to any one of claims 1 to 21, having the formula:

27. The compound has a DC activity against SMARCA4 of greater than about 500 nM, greater than about 700 nM, greater than about 1 μM, greater than about 2 μM, greater than about 5 μM, greater than about 7 μM, or greater than about 10 μM ５０ The compound according to any one of claims 1 to 21, having the formula:

28. The compound has a D of about 10% to about 80%, about 15% to about 70%, about 20% to about 60%, or about 25% to about 50% relative to SMARCA4. ｍａｘ The compound according to any one of claims 1 to 21, having the formula:

29. The compound has a D of less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 25%, or less than about 20% relative to SMARCA4. ｍａｘ The compound according to any one of claims 1 to 21, having the formula:

30. The compound has an IC of about 10 nM to about 50 μM, about 50 nM to about 20 μM, about 100 nM to about 10 μM, about 200 nM to about 8 μM, about 300 nM to about 5 μM, about 400 nM to about 2 μM, or about 500 nM to about 1 μM. ５０ (a concentration at which 50% of cell proliferation is inhibited)

31. The compound has an IC50 of about 900 nM to about 50 μM, about 1 μM to about 40 μM, about 2 μM to about 30 μM, about 5 μM to about 25 μM, or about 10 μM to about 20 μM in wild-type SMARCA4 cells. ５０ The compound according to any one of claims 1 to 21, having the formula:

32. The compound has an IC50 of greater than about 900 nM, greater than about 1 μM, greater than about 2 μM, greater than about 3 μM, greater than about 5 μM, greater than about 7 μM, or greater than about 10 μM in wild-type SMARCA4 cells. ５０ The compound according to any one of claims 1 to 21, having the formula:

33. The compound has an IC50 of about 50 nM to about 10 μM, about 75 nM to about 5 μM, about 100 nM to about 1 μM, about 125 nM to about 900 nM, about 150 nM to about 800 nM, about 175 nM to about 700 nM, about 200 nM to about 600 nM, or about 250 nM to about 500 nM in mutant SMARCA4 cells. ５０ The compound according to any one of claims 1 to 21, having the formula:

34. The compound has an IC of less than about 10 μM, less than about 5 μM, less than about 2 μM, less than about 1 μM, less than about 900 nM, less than about 800 nM, less than about 600 nM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, or less than about 2 nM, or less than about 1 nM in mutant SMARCA4 cells. ５０ The compound according to any one of claims 1 to 21, having the formula:

35. 35. The compound of any one of claims 1 to 34, wherein the compound competitively inhibits the binding of pomalidomide to cereblon.

36. The compound according to any one of claims 1 to 35, wherein the compound competitively inhibits the binding of a SMARCA2 inhibitor to SMARCA2.

37. The compound according to any one of claims 1 to 36, wherein the compound inhibits the proliferation of SMARCA4 mutant cancer cells.

38. The compound according to any one of claims 1 to 37, wherein said compound does not inhibit the proliferation of SMARCA4 wild-type cells.

39. 39. A pharmaceutical composition comprising a compound according to any one of claims 1 to 38 or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable adjuvant, carrier, or vehicle.

40. 40. The pharmaceutical composition of claim 39, further comprising a surfactant.

41. 41. The pharmaceutical composition of claim 39 or 40, further comprising an agent having CYP3A4 inhibitory activity.

42. 42. The pharmaceutical composition of claim 41, wherein the compound is compound 101, compound 104, compound 105, compound 106, compound 107, or compound 108.

43. 42. The pharmaceutical composition of claim 39 or 41, wherein the composition does not include an agent having CYP3A4 inhibitory activity.

44. 44. The pharmaceutical composition of claim 43, wherein the compound is compound 102 or compound 103.

45. 45. The pharmaceutical composition of any one of claims 39 to 44, further comprising an additional pharma- ceutically active agent.

46. 46. ​​The pharmaceutical composition of claim 45, wherein the additional pharma- ceutical active agent is a hormone analog or antihormone, aromatase inhibitor, growth factor inhibitor, antimetabolite, antitumor antibiotic, platinum derivative, mitosis inhibitor, angiogenesis inhibitor, topoisomerase inhibitor, serine / threonine kinase inhibitor, tyrosine kinase inhibitor, PARP inhibitor, tubulin inhibitor, DNA synthesis inhibitor, protein-protein interaction inhibitor, MEK / ERK inhibitor, TRAIL inhibitor, BCR-ABL inhibitor, HDAC inhibitor, radiopharmaceutical, immune checkpoint inhibitor, ADCC enhancer, T cell engager, chemotherapeutic agent, or tumor vaccine.

47. A method of inducing degradation of SMARCA2 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described in any one of claims 39 to 46.

48. 48. The method of claim 47, wherein the subject is suffering from a SMARCA4 deficient malignant tumor.

49. The method of claim 48, wherein the SMARCA4-deficient malignant tumor comprises a SMARCA4-inactivating mutation or a SMARCA4 deletion.

50. 50. The method of claim 49, wherein the SMARCA4 deletion is a SMARCA4 gene truncation.

51. The method according to any one of claims 47 to 50, wherein the SMARCA4 deficient malignant tumor is lung cancer, liver cancer, bladder cancer, breast cancer or colon cancer.

52. 52. The method of claim 51, wherein the lung cancer is non-small cell lung cancer.

53. A method of treating a SMARCA4-deficient malignant tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to any one of claims 39 to 46.

54. The method of claim 53, wherein the SMARCA4-deficient malignant tumor comprises a SMARCA4-inactivating mutation or a SMARCA4 deletion.

55. 55. The method of claim 54, wherein the SMARCA4 deletion is a SMARCA4 gene truncation.

56. The method according to any one of claims 53 to 55, wherein the SMARCA4 deficient malignant tumor is lung cancer, liver cancer, bladder cancer, breast cancer or colon cancer.

57. 57. The method of claim 56, wherein the lung cancer is non-small cell lung cancer.

58. A method of treating a tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to any one of claims 39 to 46.

59. 59. The method of claim 58, wherein the tumor comprises an inactivating SMARCA4 mutation or a SMARCA4 deletion.

60. 60. The method of claim 58 or 59, wherein the tumor is lung cancer, liver cancer, bladder cancer, breast cancer or colon cancer.

61. 61. The method of claim 60, wherein the lung cancer is non-small cell lung cancer.

62. 62. The method of any one of claims 47-61, wherein the method further comprises administering a hormone analog or antihormonal, aromatase inhibitor, growth factor inhibitor, antimetabolite, antitumor antibiotic, platinum derivative, mitosis inhibitor, angiogenesis inhibitor, topoisomerase inhibitor, serine / threonine kinase inhibitor, tyrosine kinase inhibitor, PARP inhibitor, tubulin inhibitor, DNA synthesis inhibitor, protein-protein interaction inhibitor, MEK / ERK inhibitor, TRAIL inhibitor, BCR-ABL inhibitor, HDAC inhibitor, radiopharmaceutical, immune checkpoint inhibitor, ADCC enhancer, T cell engager, chemotherapeutic agent, or tumor vaccine.

63. 50. A method of treating a condition or disease selected from a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of claims 39-46.

64. A heterobifunctional compound comprising two binding moieties connected by a linker, said linker comprising 【Chemistry 10】 is selected from the group consisting of wherein the bond marked with "*" is attached to one of the two linking moieties, said heterobifunctional compound.

65. The linker is 【Chemistry 11】 is selected from 65. The heterobifunctional compound of claim 64, wherein the bond marked with an "*" is attached to one of the two linking moieties.

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