Sulfonamide macrocyclic derivatives and preparation methods and uses thereof

Abstract

The present invention provides a sulfonamide macrocyclic derivative and a preparation method and use thereof. The sulfonamide macrocyclic derivative is a compound having formula I and a pharmaceutically acceptable salt, tautomer, stereoisomer or solvate thereof, which is used to treat a disease, disorder or condition responsive to Bc1-2 protein inhibition, such as cancer.

Description

Technical Field

[0001] The present invention provides sulfonamide macrocyclic derivatives and preparation methods and uses thereof. Background Art

[0002] Apoptosis is a process of programmed cell death and an important biological process for tissue homeostasis. In mammals, it has been shown to regulate early embryonic development. In the later stages of life, cell death is a default mechanism by which potentially dangerous cells, such as cells carrying cancerous defects, are removed. Several apoptotic pathways are known, and one of the most important apoptotic pathways involves the Bcl-2 protein family, which are key regulators of the mitochondrial (also known as "intrinsic") apoptotic pathway. See Danial and Korsmeyer, Cell 116:205-219 (2004). The structural homology domains BH1, BH2, BH3 and BH4 are characteristic of Bcl-2 family proteins. The Bcl-2 protein family can be further divided into three subfamilies, depending on how many homology domains each protein contains and its biological activity, i.e., whether it has pro-apoptotic function or anti-apoptotic function.

[0003] The first subgroup of Bcl-2 proteins includes proteins that possess all four homeodomains: BH1, BH2, BH3, and BH4. Their general role is anti-apoptotic, meaning they protect cells from initiating the cell death process. Proteins such as Bcl-2, Bcl-w, Bcl-xL, Mcl-1, and Bfl-1 / A1 are members of the first subgroup. Proteins belonging to the second subgroup of Bcl-2 proteins contain three homeodomains: BH1, BH2, and BH3, and have pro-apoptotic effects. The two main representatives of the second subgroup are Bax and Bak. The third subgroup of Bcl-2 proteins consists of proteins that contain only the BH3 domain. Members of this subgroup are often referred to as "BH3-only proteins," and their biological role in cells is pro-apoptotic. Bim, Bid, Bad, Bik, Noxa, Hrk, Bmf, and Puma are examples of this third subfamily of proteins. The exact mechanisms by which Bcl-2 family proteins regulate cell death are not fully understood. In one hypothesis that Bcl-2 family proteins regulate cell death, "BH3-only proteins" are further classified according to their regulatory function as either "activator" (e.g., Bim and Bid) or "sensitizer" (e.g., Bad, Bik, Noxa, Hrk, Bmf, and Puma) proteins.

[0004] One of the keys to tissue homeostasis is achieving a balanced interaction between the three subgroups of Bcl-2 proteins in cells. Research has elucidated the mechanisms by which pro-apoptotic and anti-apoptotic subgroups of Bcl-2 family proteins interact to enable cells to undergo programmed cell death. Following intracellular or extracellular signals, translational or post-transcriptional activation of "BH3-only proteins" occurs. "BH3-only proteins" are the primary inducers of the apoptotic cascade, which includes, as a step, the activation of the pro-apoptotic proteins Bax and Bak on the mitochondrial membrane. Following activation of Bax and / or Bak, which have anchored to or migrated to the mitochondrial membrane, Bax and / or Bak oligomerize, leading to mitochondrial outer membrane permeabilization (MOMP), release of cytochrome c, and downstream activation of effector caspases, ultimately leading to apoptosis. Some researchers have hypothesized that certain BH3-only proteins, such as Puma, Bim, and Bid, are "activators" because these proteins directly bind to the pro-apoptotic proteins Bax and Bak to initiate MOMP, while other BH3-only proteins, such as Bad, Bik, and Noxa, are "sensitizers" that act by binding to anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL, Bcl-w, Mcl-1) and displacing and "releasing" "activator" "BH3-only proteins," which then bind and activate pro-apoptotic proteins, such as Bax and Bak, to induce cell death. Other studies have shown that anti-apoptotic proteins directly engage and sequester Bax and Bak, and that all BH3-only proteins mediate this interaction by binding to anti-apoptotic proteins, such as Bcl-2, Bcl-xL, Bcl-w, and Mcl-1, which leads to the release of Bax and Bak. See Adams and Cory, Oncogene 26:1324-1337 (2007) and Willis et al., Science 315:856-859 (2007). Although the exact interaction between anti-apoptotic and pro-apoptotic Bcl-2 family proteins in regulating apoptosis is still under investigation, there is a large body of scientific evidence that compounds that inhibit the binding of "BH3-only proteins" to anti-apoptotic Bcl-2 family proteins promote apoptosis.

[0005] Dysregulation of apoptotic pathways has been implicated in the pathology of many important diseases, such as neurodegenerative diseases (apoptosis upregulated), such as Alzheimer's disease; and proliferative diseases (apoptosis downregulated), such as cancer, autoimmune diseases, and prothrombotic disorders.

[0006] Downregulation of apoptosis (particularly the Bcl-2 family of proteins) may be associated with the development of cancerous malignancies. For example, studies have shown that the anti-apoptotic proteins Bcl-2 and Bcl-xL are overexpressed in many cancer cell types. See Zhang, Nature Reviews Drug Discovery 1:101 (2002); Kirkin et al., Biochimica et Biophysica Acta 1644:229-249 (2004); and Amundson et al., Cancer Research 60:6101-6110 (2000). The effect of this imbalance is to alter the survival of cells that would otherwise undergo apoptosis under normal circumstances. The repetition of these defects associated with unregulated proliferation is considered to be the starting point for the evolution of cancer. In addition, studies have shown that when expressed in diseased animals, "BH3-only proteins" can act as tumor suppressors.

[0007] These findings enable new strategies for drug discovery targeting cancer. If a small molecule that can mimic the effects of a "BH3-only protein" can enter cells and overcome the overexpression of anti-apoptotic proteins, it is possible to reset the apoptotic process. These findings provide a new strategy for drug discovery targeting cancer. If a small molecule that can mimic the effects of a "BH3-only protein" can enter cells and overcome the overexpression of anti-apoptotic proteins, it is possible to reset the apoptotic process. The advantage of this strategy is that it can alleviate the problem of drug resistance, which is often the result of apoptosis dysregulation (abnormal survival). Therapeutic strategies targeting Bcl-2 and Bcl-XL in cancer to restore cancer cell sensitivity and overcome cancer cell resistance to apoptosis are reviewed. See Adams et al., Science 281:1322 (1998) and Reed, Adv. Pharmacol. 41:501 (1997); Reed et al., J. Cell. Biochem. 60:23 (1996).

[0008] Platelets also contain essential apoptotic machinery, such as Bax, Bak, Bcl-xL, Bcl-2, cytochrome c, caspase-9, caspase-3, and APAF-1, to execute programmed cell death via the intrinsic apoptotic pathway. Although the production of circulating platelets is a normal physiological process, excessive or undesired platelet activation can cause or exacerbate many diseases. This suggests that therapeutic agents that inhibit anti-apoptotic proteins in platelets and reduce platelet numbers in mammals may be useful in treating prothrombotic conditions and diseases characterized by excessive or undesired platelet activation.

[0009] Small molecule "BH3-only protein" mimetics, such as ABT-737 and ABT-263, bind strongly to the anti-apoptotic Bcl-2 protein subset (including Bcl-2, Bcl-w, and Bcl-xL) and weakly to Mcl-1 and A1. These small molecules have been tested in animal studies and have demonstrated cytotoxic activity as single agents in certain xenograft models, and when used in combination, have enhanced the effects of many chemotherapeutic agents on other xenograft models. See Tse, C. et al., Cancer Res 68:3421-3428 (2008) and van Delft, MF et al., Cancer Cell 10:389-399 (2006). These in vivo studies suggest that inhibitors of anti-apoptotic Bcl-2 family proteins may be useful in treating diseases involving dysregulation of apoptotic pathways. ABT-199 (Venetoclax) is a potent Bcl-2 inhibitor that has been approved by the U.S. Food and Drug Administration for the treatment of chronic lymphocytic leukemia. See Cang et al., Journal of Hematology & Oncology 8:129 (2015) and Souers et al., Nature Medicine 19:202-208 (2013).

[0010] The natural expression levels of anti-apoptotic Bcl-2 family protein members vary in different cell types. For example, in young platelets, Bcl-xL protein is highly expressed and plays an important role in regulating platelet cell death (lifespan). In addition, in certain cancer cell types, the survival of cancer cells is attributed to the dysregulation of the apoptotic pathway caused by overexpression of one or more anti-apoptotic Bcl-2 protein family members. Given the important role of the Bcl-2 protein family in regulating apoptosis in cancerous and normal (i.e., non-cancerous) cells, and the recognized inter-cell type variability of Bcl-2 family protein expression, it is advantageous to have a small molecule inhibitor that selectively targets and preferably binds to one or a subgroup of anti-apoptotic Bcl-2 proteins, for example, an anti-apoptotic Bcl-2 family member that is overexpressed in a certain cancer type. Such selective compounds may also have certain advantages in clinical settings, for example, by flexibly selecting the dosing regimen, reducing the on-target toxicity in normal cells, for example, lymphopenia was observed in Bcl-2-deficient mice. See Nakayama, K. et al. PNAS 91: 3700-3704 (1994).

[0011] There is a need for small molecules that selectively inhibit the activity of a Bcl-2 protein or its isoforms for the treatment of hyperproliferative diseases such as cancer. Summary of the Invention

[0012] In one aspect, the present disclosure provides compounds represented by any one of the following formulae I, II, III, IV, V, VI, II-a, III-a, IV-a, Va and VI-a, as well as pharmaceutically acceptable salts, tautomers, stereoisomers and solvates thereof, such as hydrates, collectively referred to herein as “compounds of the present disclosure”.

[0013] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and one or more pharmaceutically acceptable carriers.

[0014] In another aspect, the present disclosure provides a method of inhibiting Bcl-2 proteins, such as Bcl-2, Bcl-w, Bcl-xL, Mcl-1, and Bfl-1 / A1, or any combination thereof, in a subject (e.g., a human), comprising administering to the subject (preferably, an effective amount) of at least one compound of the present disclosure.

[0015] In another aspect, the present disclosure provides methods for treating or preventing a disease, disorder or condition, e.g., a hyperproliferative disease, e.g., cancer, e.g., small cell lung cancer, non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphoid (or lymphocytic) leukemia (CLL) or acute lymphoblastic leukemia (ALL), in a subject responsive to inhibition of a Bcl-2 protein, e.g., Bcl-2 and / or Bcl-xL, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0016] In another aspect, the present disclosure provides for the use of a compound of the present disclosure as an inhibitor of one or more Bcl-2 proteins, such as Bcl-2 and / or Bcl-xL.

[0017] In another aspect, the present disclosure provides the use of a compound of the present disclosure as a Bcl-2 inhibitor.

[0018] In another aspect, the present disclosure provides the use of a compound of the present disclosure as a Bcl-xL inhibitor.

[0019] In another aspect, the present disclosure provides pharmaceutical compositions for treating a disease, disorder, or condition responsive to inhibition of a Bcl-2 protein (e.g., Bcl-2 and / or Bcl-xL), wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure, optionally in admixture with one or more pharmaceutically acceptable carriers.

[0020] In another aspect, the disclosure provides compounds for use in treating or preventing a disease, disorder, or condition (eg, a hyperproliferative disease, eg, cancer) in a subject (eg, a human).

[0021] In another aspect, the present disclosure provides a compound of the present disclosure for use in the preparation of a medicament for treating a disease, disorder or condition, such as a hyperproliferative disease, such as cancer, in a subject, such as a human.

[0022] In another aspect, the present disclosure provides kits comprising a compound of the present disclosure.

[0023] In another aspect, the present disclosure provides a kit comprising a compound of the present disclosure and a second therapeutic agent useful for treating a relevant disease, disorder, or condition, and a package insert comprising instructions for use in treating the disease, disorder, or condition.

[0024] In another aspect, the present disclosure provides a composition comprising: (a) a compound of the present disclosure; (b) a second therapeutically active agent; and (c) optionally an excipient and / or a pharmaceutically acceptable carrier.

[0025] Additional embodiments and advantages of the present disclosure will be explained in part in the following description and will be derived from the description, or can be understood through the practice of the present disclosure. The embodiments and advantages of the present disclosure will be realized and obtained by the elements and combinations particularly pointed out in the appended claims.

[0026] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Detailed Description of the Invention

[0028] The compounds of the present disclosure inhibit Bcl-2 proteins, such as Bcl-2 and / or Bcl-xL. Given this property, the compounds of the present disclosure can be used to treat or prevent diseases, disorders, or conditions that respond to inhibition of Bcl-2 proteins in a subject, such as hyperproliferative diseases, such as cancer. Cancers that respond to inhibition of Bcl-2 proteins include, but are not limited to, small cell lung cancer, NHL, AML, CLL, and ALL.

[0029] In one embodiment, the compound of the present disclosure is a compound having Formula I:

[0030]

[0031] or a pharmaceutically acceptable salt, tautomer, stereoisomer or solvate thereof, wherein:

[0032] Ring A is an aromatic ring;

[0033] Ring B is a heteroaromatic ring;

[0034] Ring C is a heterocycloalkane;

[0035] Ring D is a cycloalkene or a heterocycloalkane;

[0036] The E ring is an aromatic ring or a heteroaromatic ring;

[0037] Each R 1 are independently -NO2 or -N(R 1a )(CR 1b R 1c ) n1 R 1d ;

[0038] R 1a 、R 1b and R 1c are each independently H or alkyl;

[0039] Each R 1d is heterocycloalkyl, cycloalkyl, substituted heterocycloalkyl or substituted cycloalkyl, wherein the substituents in the substituted heterocycloalkyl and substituted cycloalkyl are independently selected from halogen, -OH and alkyl;

[0040] Each n1 is independently 0, 1, 2 or 3;

[0041] Each R 2 are independently halogen, -OH or alkyl;

[0042] Or, any two R 2 Together with the carbon atoms to which they are attached, they form cycloalkanes;

[0043] Each R 3 are independently halogen, -OH, -CN, alkyl, substituted alkyl, alkoxy, cycloalkyl, heterocycloalkyl, -N(R 2a R 2b )、-S(O)2R 2c 、-N(R 2d )S(O)2R 2e , wherein the substituent in the substituted alkyl group is selected from halogen and -OH;

[0044] R 2a 、R 2b 、R 2c 、R 2d and R 2e are each independently H or alkyl;

[0045] m1, m2 and m3 are each independently 0, 1, 2, 3 or 4;

[0046] -L 1 - is a single key,

[0047] -M 0 -Yes-N(R 3e )-;

[0048] -M 0a- is cycloalkylene or heterocycloalkylene;

[0049] -L 1a -Yes-(CR 3a R 3b ) n2 -;

[0050] -L 1b -Yes-(CR 3c R 3d ) n3 -;

[0051] R 3a 、R 3b 、R 3c 、R 3d and R 3e are each independently H or alkyl;

[0052] n2 and n3 are each independently 0, 1, 2 or 3;

[0053] -M 1 - is -O- or -C(=O)-;

[0054] -M 2 - is a single bond, -O- or a cycloalkylene group;

[0055] -M 3 - is a single bond or -O-;

[0056] -L 2 -Yes-(CR 4a R 4b ) n4 -;

[0057] -L 3 -Yes-(CR 4c R 4d ) n5 -;

[0058] R 4a 、R 4b 、R 4c and R 4d are each independently H or alkyl;

[0059] n4 and n5 are each independently 0, 1, 2 or 3;

[0060] -X- is -O-, -S- or -N(R 5a )-;

[0061] -Y- is a single bond or -(CR 5b R 5c )-;

[0062] R 5a 、R5b and R 5c are each independently H or alkyl;

[0063] In the definitions of heteroaryl, heterocycloalkane, heterocycloalkyl or heterocycloalkylene, the number of heteroatoms is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from N, O and S.

[0064] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): In ring A, the aromatic ring is preferably C6-C 12 The aromatic ring is more preferably a benzene ring.

[0065] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): In ring B, the heteroaromatic ring is preferably a 5-12 membered heteroaromatic ring, more preferably an 8-10 membered fused heteroaromatic ring. The number of heteroatoms is preferably two. The heteroatom is preferably N. The 8-10 membered fused heteroaromatic ring is preferably a pyrrolopyridine, (e.g. ).

[0066] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): In ring C, heterocycloalkane (referring to monocyclic heterocycloalkane or spiroheterocycloalkane), preferably 3-12 membered heterocycloalkane, more preferably 4-6 membered monocyclic heterocycloalkane or 6-10 membered spiroheterocycloalkane. The number of heteroatoms is preferably 1 or 2. The heteroatom is preferably N. The heterocycloalkane is preferably piperazine, 7-azaspiro[3.5]nonane or 2-azaspiro[3.3]heptane.

[0067] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments): In ring D, the cycloalkene is preferably a C3-C8 cycloalkene, more preferably cyclohexene.

[0068] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): In ring D, the heterocycloalkane is preferably a 3-12 membered heterocycloalkane, more preferably a 4-6 membered monocyclic heterocycloalkane. The number of heteroatoms is preferably 1 or 2, more preferably 1. The heteroatom is preferably N. The heterocycloalkane is preferably pyrrolidine or piperazine, more preferably pyrrolidine.

[0069] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): In ring E, the aromatic ring is preferably C6-C 12 The aromatic ring is more preferably a benzene ring.

[0070] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): In ring E, the heteroaromatic ring is preferably a 5-12 membered heteroaromatic ring, more preferably a 5-6 membered monocyclic heteroaromatic ring. The number of heteroatoms is preferably 1 or 2, the heteroatom is preferably N, and the heteroaromatic ring is preferably pyridine or pyrazole.

[0071] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): 1a 、R 1b and R 1c In the above, the alkyl groups are each independently preferably C1-C6 alkyl groups, more preferably C1-C3 alkyl groups (eg, methyl, ethyl, propyl or isopropyl).

[0072] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): 1d In the embodiment, the halogen is preferably F, Cl, Br or I, more preferably F.

[0073] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): 1d In the embodiment, the alkyl group is preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group (eg, methyl, ethyl, propyl or isopropyl), and even more preferably a methyl group.

[0074] In another embodiment, certain groups of the compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): 1d In the heterocycloalkyl group and the substituted heterocycloalkyl group, the heterocycloalkyl group is preferably a 3-12 membered heterocycloalkyl group, more preferably a 4-6 membered monocyclic heterocycloalkyl group. The number of heteroatoms is preferably 1 or 2, and the heteroatoms are preferably selected from N and O, more preferably O. The heterocycloalkyl group is preferably a dioxanyl group or a tetrahydropyranyl group, more preferably (For example, )or The substituents in the substituted heterocycloalkyl group are preferably selected from halogen. The number of substituents in the substituted heterocycloalkyl group is preferably 1. The substituted heterocycloalkyl group is preferably The carbon marked with "*" refers to an achiral carbon or a chiral carbon.

[0075] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): 1d In the cycloalkyl group, the cycloalkyl group is preferably a C3-C6 cycloalkyl group, more preferably a cyclohexyl group. The substituent group in the substituted cycloalkyl group is preferably selected from -OH and an alkyl group. The number of substituent groups in the substituted cycloalkyl group is preferably 2. The substituted cycloalkyl group is preferably (For example, ), wherein the carbon marked with "*" refers to an achiral carbon or a chiral carbon.

[0076] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): 2 In the embodiment, the halogen is preferably F, Cl, Br or I, more preferably F.

[0077] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): 2 In the embodiment, the alkyl group is preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group (eg, methyl, ethyl, propyl or isopropyl), and even more preferably a methyl group.

[0078] In another embodiment, certain groups of the compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): 2 When forming a cycloalkyl group together with the carbon atom to which they are attached, the cycloalkyl group is preferably a C3-C6 cycloalkyl group, more preferably a cyclobutyl group.

[0079] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): 3 In the embodiment, the halogen is preferably F, Cl, Br or I, more preferably F.

[0080] In another embodiment, certain groups of the compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): 3 In the alkyl group and the alkyl group in the substituted alkyl group, each independently is preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group (e.g., methyl, ethyl, propyl or isopropyl group). The substituent in the substituted alkyl group is preferably selected from -OH and F, and the number of substituents in the substituted alkyl group is preferably 1, 2 or 3. The substituted alkyl group is preferably -CF3,

[0081] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): 3 In the above, the alkoxy group is preferably a C1-C6 alkoxy group, more preferably a C1-C3 alkoxy group (eg, methoxy, ethoxy, propoxy or isopropoxy), even more preferably a methoxy group.

[0082] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): 3 In the cycloalkyl group, the cycloalkyl group is preferably a C3-C6 cycloalkyl group, more preferably a cyclopropyl group.

[0083] In another embodiment, certain groups of the compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): 3 In the embodiment, the heterocycloalkyl group is preferably a 3-12 membered heterocycloalkyl group, more preferably a 4-6 membered monocyclic heterocycloalkyl group. The number of heteroatoms is preferably 1. The heteroatom is preferably 0. The heterocycloalkyl group is preferably a tetrahydropyranyl group (e.g., ).

[0084] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): 2a 、R 2b 、R 2c 、R 2d and R 2e In the above, the alkyl group is preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group (eg, methyl, ethyl, propyl or isopropyl).

[0085] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): 1 -M, -M 0 - preferably linked to ring A.

[0086] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are defined as in any embodiment): 0a -, the cycloalkylene groups are each independently preferably C3-C6 cycloalkylene groups, more preferably cyclohexylene groups, and even more preferably (For example ), where -M 0a -The "j" end of the - is connected to the -L 1a -, -M 0a -The "k" end is connected to -L 1b -, the carbon marked with "*" refers to achiral carbon or chiral carbon.

[0087] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are defined as in any embodiment): 0a -, the heterocycloalkylene is preferably a 3-12 membered heterocycloalkylene, more preferably a 4-6 membered monocyclic heterocycloalkylene. The number of heteroatoms is preferably 1 or 2, and the heteroatoms are preferably selected from N and O. The heterocycloalkylene is preferably More preferred (For example )or Where -M 0a Connect the "j" end of - to -L 1a -, and its "k" end -M 0a -with-L 1b-, the carbon marked with "*" refers to an achiral carbon or a chiral carbon.

[0088] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): -M 2 -, cycloalkylene is preferably C3-C6 cycloalkylene, more preferably cyclopropylene or cyclobutene, even more preferably (For example, ), (For example, )or (For example, ), wherein a carbon marked with "*" refers to an achiral carbon or a chiral carbon.

[0089] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): 3a 、R 3b 、R 3c 、R 3d and R 3e In the above, the alkyl groups are each independently preferably C1-C6 alkyl groups, more preferably C1-C3 alkyl groups (eg, methyl, ethyl, propyl or isopropyl).

[0090] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): 4a 、R 4b 、R 4c and R 4d In the above, the alkyl groups are each independently preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group (eg, methyl, ethyl, propyl or isopropyl).

[0091] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): 5a 、R 5b and R 5c In the above, the alkyl groups are each independently preferably C1-C6 alkyl groups, more preferably C1-C3 alkyl groups (eg, methyl, ethyl, propyl or isopropyl).

[0092] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): 1 In, -N(R 1a )-C(R 1b R 1c ) n1 R 1d Preferably (For example ), (For example )or (For example ), wherein the carbon marked with "*" is an achiral carbon or a chiral carbon.

[0093] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): 3 In, -N(R 2a R 2b ) is preferably -NH2, -NH(CH3) or -N(CH3)2.

[0094] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): 3 Medium, -S(O)2R 2c Preferred is -S(O)2CH3.

[0095] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): 3 In, N(R 2d )S(O)2R 2e Preferred is -NHS(O)2CH3.

[0096] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): In -Y-, -(CR 5b R 5c )- is preferably -CH2-.

[0097] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any of the embodiments): Ring A is preferably a benzene ring.

[0098] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): Ring B is preferably pyrrolopyridine, (e.g. ).

[0099] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any of the embodiments): Ring C is preferably piperazine, 7-azaspiro[3.5]nonane or 2-azaspiro[3.3]heptane.

[0100] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any of the embodiments): Ring D is preferably cyclohexene, pyrrolidine, or piperazine.

[0101] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any of the embodiments): Ring E is a benzene ring, pyridine, or pyrazole.

[0102] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): each R 1 Preferably -NO2, (For example ), (For example )or (For example, ), wherein the carbon marked with "*" refers to an achiral carbon or a chiral carbon.

[0103] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are defined as in any embodiment): each R 2 Preferably, they are independently F, OH or methyl; or, two R 2 Any of the following, taken together with the carbon atom to which they are attached, form a cyclobutyl group.

[0104] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): each R 3 are independently F, Cl, -OH, -CN, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF3, -NH2, -NH(CH3), -N(CH3)2, -S(O)2CH3 or -N(H)S(O)2CH3.

[0105] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): -M 0 -Yes-NH-.

[0106] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): -M 0a - preferably cyclohexylene, dioxanyl or morpholinyl, more preferably (For example (For example )or Where -M 0a -The "j" end of the - is connected to the -L 1a -, -M 0a -The "k" end is connected to -L 1b -, and carbons marked with "*" refer to either achiral carbons or chiral carbons.

[0107] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): -L 1a -is-CH2-.

[0108] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): -L 1b - is -(CH2)0-, -CH2-, -(CH2)2- or -(CH2)3-.

[0109] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): -M 2 - is a single bond, -O-, cyclopropene or cyclobutene.

[0110] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments): -X- is -O-.

[0111] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are defined as in any embodiment): -Y- is a single bond or -CH2-.

[0112] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): 1 -middle, Preferred is -NH-(CH2)3-.

[0113] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): 1 -middle, Preferred More preferred Even more preferred (For example ), (For example The carbon marked with "*" refers to an achiral carbon or a chiral carbon.

[0114] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): -L 1 - is a single bond, -NH-(CH2)3, (For example ), (For example )or The carbon marked with "*" refers to an achiral carbon or a chiral carbon.

[0115] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): Preferably More preferably, Even more preferred

[0116] Best (For example ), (For example (For example ), (For example ), (For example )or (For example ), wherein the "a" end of ring A is connected to -L 1 -, the "b" end of ring A is connected to the S atom, and the carbon marked with "*" is an achiral carbon or a chiral carbon.

[0117] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): Preferably The "c" end of ring B is connected to M 3 , the "d" end of ring B is connected to the ring O atom.

[0118] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): Preferably The "c" end of ring B is connected to M 3 , the "d" end of ring B is connected to the ring O atom.

[0119] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): Preferably The "e" end of the C ring is connected to the phenyl group, and the "f" end of the C ring is connected to the D ring.

[0120] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): Preferably More preferably The "g" end of ring D is connected to ring C, the "h" end of ring D is connected to ring E, and the carbon marked with "*" refers to an achiral carbon or a chiral carbon.

[0121] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): This part is preferably More preferably

[0122] The "g" end of ring D is connected to ring C, the "h" end of ring D is connected to ring E, and the carbon marked with "*" refers to an achiral carbon or a chiral carbon.

[0123] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): Preferably or More preferably

[0124] The "g" end of ring D is connected to ring C, the "h" end of ring D is connected to ring E, and the carbon marked with "*" refers to an achiral carbon or a chiral carbon.

[0125] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): Preferably More preferably

[0126] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any embodiment): Preferably

[0127]

[0128] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): 1d 、R 1 、-M 0a -、-M 2 -and In the above, each chiral carbon is independently preferably in its S-configuration or R-configuration.

[0129] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment):1d 、R 1 、-M 0a -、-M 2 -and The carbons marked with a "*" are each independently a chiral carbon in its S-configuration.

[0130] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): 1d 、R 1 、-M 0a -、-M 2 -and Carbons marked with a "*" each independently represent a chiral carbon in its R-configuration.

[0131] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one embodiment): 1d 、R 1 、-M 0a -、-M 2 --or In the above, carbon atoms marked with "*" each independently refer to an achiral carbon.

[0132] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0133] Ring D is a cycloalkenyl group,

[0134] Each R 2 are independently alkyl,

[0135] Or, any two R 2 Together with the carbon atom to which they are attached they form a cycloalkyl group.

[0136] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0137] Ring D is a heterocycloalkyl group,

[0138] Each R 2 are independently halogen, -OH or alkyl.

[0139] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0140] Ring C is a monocyclic heterocycloalkane,

[0141] -Y-Yes-(CR 5b R 5c )-.

[0142] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0143] Ring C is a spiroheterocycloalkane,

[0144] -Y- is a single bond.

[0145] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0146] Ring C is a monocyclic heterocycloalkane,

[0147] -Y-Yes-(CR 5b R 5c )-,

[0148] Ring D is a cycloalkene.

[0149] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0150] Ring C is a spiroheterocycloalkyl group,

[0151] -Y- is a single bond,

[0152] Ring D is heterocycloalkyl.

[0153] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0154] -L 1 - is a single key,

[0155] -M 1 -Yes-O-.

[0156] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0157] -L 1 - is a single key,

[0158] -M 1 -Yes-O-,

[0159] -M 2 - is a single bond.

[0160] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0161] -L 1 - is a single key,

[0162] -M 1 -Yes-O-,

[0163] -M 2 - is a single key,

[0164] -M 3 - is a single bond.

[0165] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0166] -L 1 - is a single key,

[0167] -M 1 -Yes-O-,

[0168] -M 2 - is a single key,

[0169] -M 3 -Yes-O-.

[0170] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0171] -L 1 - is a single key,

[0172] -M 1 -Yes-O-,

[0173] -M 2 -Yes-O-.

[0174] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0175] -L 1 - is a single key,

[0176] -M 1 -Yes-O-,

[0177] -M 2 -Yes-O-,

[0178] -M 3 -Yes-O-.

[0179] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0180] -L 1 - is a single key,

[0181] -M 1 –Yes-O-,

[0182] -M 2 - is a cycloalkylene group.

[0183] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0184] -L 1 - is a single key,

[0185] -M 1 -Yes-O-,

[0186] -M 2 - is a cycloalkylene group,

[0187] -M 3 -Yes-O-.

[0188] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0189] -L 1 -yes

[0190] -M 1 -Yes-O-,

[0191] -M 2 - is a single key,

[0192] -M 3 - is a single bond.

[0193] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0194] -L 1 -yes

[0195] -M 2 - is a single bond or -O-,

[0196] -M 3 - is a single bond.

[0197] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0198] -L 1 -yes

[0199] -M 1 -Yes-O-,

[0200] -M 2 - is a single bond or -O-,

[0201] -M 3 - is a single bond.

[0202] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0203] -L 1 -yes

[0204] -M 1 -is -C(=O)-,

[0205] -M 2 - is a single key,

[0206] -M 3 - is a single bond.

[0207] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0208] -L 1 - is a single key,

[0209] -M 1 -Yes-O-,

[0210] -M 2 - is a single key,

[0211] -M 3 -Yes-O-,

[0212] Ring C is a monocyclic heterocycloalkyl group,

[0213] -Y-Yes-(CR 5b R 5c )-,

[0214] Ring D is a cycloalkene.

[0215] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0216] -L 1 - is a single key,

[0217] -M 1 -Yes-O-,

[0218] -M 2 - is a single key,

[0219] -M 3 - is a single key,

[0220] Ring C is a monocyclic heterocycloalkyl group,

[0221] -Y-Yes-(CR 5b R 5c )-,

[0222] Ring D is a cycloalkene.

[0223] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0224] -L 1 - is a single key,

[0225] -M 1 -Yes-O-,

[0226] -M 2 - is a single key,

[0227] -M 3 -Yes-O-,

[0228] Ring C is a spiroheterocycloalkane,

[0229] -Y- is a single bond,

[0230] Ring D is heterocycloalkyl.

[0231] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0232] -L 1 - is a single key,

[0233] -M 1 -Yes-O-,

[0234] -M 2 - is a single key,

[0235] -M 3 - is a single key,

[0236] Ring C is a spiroheterocycloalkyl group,

[0237] -Y- is a single bond,

[0238] Ring D is heterocycloalkyl.

[0239] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0240] -L 1 - is a single key,

[0241] -M1 -Yes-O-,

[0242] -M 2 -Yes-O-,

[0243] -M 3 -Yes-O-,

[0244] Ring C is a spiroheterocycloalkyl group,

[0245] -Y- is a single bond,

[0246] Ring D is heterocycloalkyl.

[0247] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0248] -L 1 - is a single key,

[0249] -M 1 -Yes-O-,

[0250] -M 2 - is a cycloalkylene group,

[0251] -M 3 -Yes-O-,

[0252] Ring C is a spiroheterocycloalkyl group,

[0253] -Y- is a single bond,

[0254] Ring D is heterocycloalkyl.

[0255] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0256] -L 1 -yes

[0257] -M 1 -Yes-O-,

[0258] -M 2 - is a single key,

[0259] -M 3 - is a single key,

[0260] Ring C is a monocyclic heterocycloalkyl group,

[0261] -Y-Yes-(CR 5b R 5c )-,

[0262] Ring D is cycloalkenyl.

[0263] In another embodiment, certain groups of compounds of the present disclosure are defined as follows (unspecified groups are as defined in any one of the embodiments):

[0264] -L 1 -yes

[0265] -M 1 - is -O- or -C(=O)-,

[0266] -M 2 - is a single bond or -O-,

[0267] -M 3 - is a single key,

[0268] Ring C is a monocyclic heterocycloalkyl group,

[0269] -Y-Yes-(CR 5b R 5c )-,

[0270] Ring D is cycloalkenyl.

[0271] In one embodiment, the compound of the present disclosure is a compound having Formula II:

[0272]

[0273] Among them, -X-, -Y-, ring C, ring D, ring E, R 1 、R 2 、R 3 、m1、m2、m3、-L 1 -、-L 2 -、-L 3 -、-M 1 -、-M 2 -and-M 3 -As defined in formula I.

[0274] In one embodiment, the compound of the present disclosure is a compound having Formula II-a:

[0275]

[0276] Among them, R 1 -N(R 1a )(CR 1b R 1c ) n1 R 1d ;

[0277] -X-, -Y-, Ring C, Ring D, Ring E, R 1a , R 1b , R 1c , R 1d,n1,R 2 , R 3 ,m1,m2,m3,-L 1 -, -L 2 -、-L 3 -、-M 1 -、-M 2 -and-M 3 -As defined in formula I.

[0278] In one embodiment, the compound of the present disclosure is a compound having Formula III:

[0279]

[0280] Among them, -X-, -Y-, ring C, ring D, ring E, R 1 、R 2 、R 3 、m1、m2、m3、-L 1 -、-L 2 -、-L 3 -、-M 1 -、-M 2 -and-M 3 -As defined in formula I.

[0281] In one embodiment, the compound of the present disclosure is a compound having Formula III-a:

[0282]

[0283] Among them, R 1 -N(R 1a )(CR 1b R 1c ) n1 R 1d ;

[0284] -X-, -Y-, Ring C, Ring D, Ring E, R 1a , R 1b , R 1c , R 1d ,n1,R 2 , R 3 ,m1,m2,m3,-L 1 -, -L 2 -、-L 3 -、-M 1 -、-M 2 -and-M 3 -As defined in formula I.

[0285] In one embodiment, the compound of the present disclosure is a compound having Formula IV:

[0286]

[0287] Among them, -X-, -Y-, ring C, ring D, ring E, R 1 、R 2 、R 3 、m1、m2、m3、-L 1 -、-L 2 -、-L 3 -、-M 1 -、-M 2 -and-M 3 - as defined in conjunction with Formula I.

[0288] In one embodiment, the compound of the present disclosure is a compound having Formula IV-a:

[0289]

[0290] Among them, -X-, -Y-, ring C, ring D, ring E, R 2 、R 3 、m2、m3、-L 1 -、-L 2 -、-L 3 -、-M 1 -、-M 2 -and-M 3 - as defined in conjunction with Formula I.

[0291] In one embodiment, the compound of the present disclosure is a compound having Formula V:

[0292]

[0293] Among them, -X-, -Y-, ring C, ring D, ring E, R 1 、R 2 、R 3 、m1、m2、m3、-L 1 -、-L 2 -、-L 3 -、-M 1 -、-M 2 -and-M 3 - as defined in conjunction with Formula I.

[0294] In one embodiment, the compound of the present disclosure is a compound having Formula Va:

[0295]

[0296] Among them, -X-, -Y-, ring C, ring D, ring E, R 2 、R 3 、m2、m3、-L 1 -、-L2 -、-L 3 -、-M 1 -、-M 2 -and-M 3 - as defined in conjunction with Formula I.

[0297] In one embodiment, the compound of the present disclosure is a compound having Formula VI:

[0298]

[0299] Among them, -X-, -Y-, ring C, ring D, ring E, R 1 、R 2 、R 3 、m1、m2、m3、-L 1 -、-L 2 -、-L 3 -、-M 1 -、-M 2 -and-M 3 - as defined in conjunction with Formula I.

[0300] In one embodiment, the compound of the present disclosure is a compound having Formula VI-a:

[0301]

[0302] Among them, -X-, -Y-, ring C, ring D, ring E, R 2 、R 3 、m2、m3、-L 1 -、-L 2 -、-L 3 -、-M 1 -、-M 2 -and-M 3 -As defined in formula I.

[0303] In another embodiment, the compound of the present disclosure is selected from one or more compounds of Table 1:

[0304] Table 1:

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323] , or a pharmaceutically acceptable salt, tautomer, stereoisomer or solvate thereof.

[0324] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0325] In one embodiment, the present disclosure provides a method of treating or preventing a hyperproliferative disease in a subject, such as a human, comprising administering a therapeutically effective amount of a compound of the present disclosure.

[0326] In some embodiments, the compounds of the present disclosure can be used to treat a "Bcl-2 protein-mediated disorder," such as a Bcl-2-mediated disorder and / or a Bcl-xL-mediated disorder. A Bcl-2 protein-mediated disorder is any pathological condition in which a Bcl-2 protein is known to play a role. In one embodiment, the Bcl-2-mediated disorder is a hyperproliferative disorder. In one embodiment, the Bcl-2-mediated disorder is cancer.

[0327] In one embodiment, the present disclosure provides a method of treating or preventing a hyperproliferative disease in a subject, such as a human, comprising administering a therapeutically effective amount of a compound of the present disclosure.

[0328] In another embodiment, the present disclosure provides a method for treating or preventing cancer in a subject, comprising administering a therapeutically effective amount of a compound of the present disclosure. Although not limited to a particular mechanism, in some embodiments, the compounds of the present disclosure may treat or prevent cancer by inhibiting Bcl-2 proteins, such as Bcl-2 and / or Bcl-xL. Examples of treatable cancers include, but are not limited to, any one or more of the cancers listed in Table 2:

[0329] Table 2:

[0330]

[0331]

[0332]

[0333]

[0334] In another embodiment, the cancer is breast cancer, cervical cancer, colon cancer, kidney cancer, liver cancer, head and neck cancer, skin cancer, pancreatic cancer, ovarian cancer, esophageal cancer, or prostate cancer.

[0335] In another embodiment, the cancer is a hematological malignancy, such as acute myeloid leukemia (AML), B- and T-acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or mantle cell lymphoma (MCL).

[0336] In another embodiment, the cancer is esophageal squamous cell carcinoma (ESCC), bladder cancer, or cervical cancer.

[0337] In another embodiment, the cancer is a leukemia, such as a leukemia selected from acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia (MLL). In another embodiment, the cancer is NUT-midline carcinoma. In another embodiment, the cancer is multiple myeloma. In another embodiment, the cancer is lung cancer, such as small cell lung cancer (SCLC). In another embodiment, the cancer is neuroblastoma. In another embodiment, the cancer is Burkitt's lymphoma. In another embodiment, the cancer is cervical cancer. In another embodiment, the cancer is esophageal cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer.

[0338] In another embodiment, the cancer is adrenocortical carcinoma, urothelial carcinoma of the bladder, invasive breast carcinoma, colorectal adenocarcinoma, diffuse large B-cell lymphoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, renal clear cell carcinoma, skin cutaneous melanoma, gastric adenocarcinoma, uterine carcinosarcoma, or uterine corpus endometrial carcinoma.

[0339] In another embodiment, the present disclosure provides a method for treating a subject in need of such treatment by administering a therapeutically effective amount of a compound of the present disclosure.

[0340] The compounds of the present invention may be administered to a subject in the form of a raw chemical in the absence of any other ingredients. The compounds of the present invention may also be administered to a subject as part of a pharmaceutical composition comprising the compound in combination with one or more suitable pharmaceutically acceptable carriers. Such carriers may be selected from pharmaceutically acceptable excipients and adjuvants. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" includes any standard pharmaceutical carrier, solvent, surfactant or carrier. Suitable pharmaceutically acceptable carriers include aqueous carriers and non-aqueous carriers. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.

[0341] Pharmaceutical compositions within the scope of the present disclosure include all compositions in which the compounds of the present disclosure are combined with one or more pharmaceutically acceptable carriers. In one embodiment, the compounds of the present disclosure are present in the composition in an amount effective to achieve their intended therapeutic purpose. Although individual needs may vary, it is within the technical scope of the art to determine the optimal range of the effective amount of each compound. Typically, the compounds of the present disclosure can be orally administered to mammals, such as humans, daily at a dose of about 0.0025 to about 1500 mg / kg of mammal body weight, or an equivalent amount of a pharmaceutically acceptable salt or solvate, to treat a specific disease. A useful oral dose of the compounds of the present disclosure administered to a mammal is about 0.0025 to about 50 mg / kg of mammal body weight, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. For intramuscular injection, the dose is typically about half of the oral dose.

[0342] A unit oral dose may contain from about 0.01 mg to about 1 g of a compound of the present disclosure, for example, from about 0.01 mg to about 500 mg, from about 0.01 mg to about 250 mg, from about 0.01 mg to about 100 mg, from 0.01 mg to about 50 mg, for example, from about 0.1 mg to about 10 mg of the compound. The unit dose may be administered once or more daily, for example, as one or more tablets or capsules, each containing from about 0.01 mg to about 1 g of the compound, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.

[0343] The compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be administered to any patient or subject who may experience the beneficial effects of the compounds of the present invention. Most important among such patients or subjects are mammals, such as humans and companion animals, although the present disclosure is not intended to be limited thereto. In one embodiment, the patient or subject is a human.

[0344] The compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be administered by any means that achieves its intended purpose. For example, administration can be by oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, intranasal, transmucosal, rectal, intravaginal or oral routes or by inhalation. The dosage and route of administration will vary according to the specific subject's circumstances and take into account factors such as age, sex, health and weight of the recipient, the condition or disorder to be treated, the type of concurrent treatment, if any, the frequency of treatment and the nature of the desired effect.

[0345] In one embodiment, the compounds of the present disclosure or pharmaceutical compositions comprising the compounds of the present disclosure can be administered orally. In another embodiment, the pharmaceutical compositions of the present disclosure can be administered orally and formulated as tablets, dragees, capsules, or oral liquid formulations. In one embodiment, the oral formulation comprises extruded multiparticulates containing the compounds of the present disclosure.

[0346] Alternatively, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered rectally and formulated as suppositories.

[0347] Alternatively, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds can be administered by injection.

[0348] Alternatively, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered transdermally.

[0349] Alternatively, a compound of the disclosure or a pharmaceutical composition comprising a compound of the disclosure may be administered by inhalation or by intranasal or transmucosal administration.

[0350] Alternatively, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds can be administered via the intravaginal route.

[0351] The pharmaceutical compositions of the present disclosure may contain about 0.01% to 99% by weight, e.g., about 0.25% to 75% by weight, e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70% or about 75% of a compound of the invention by weight.

[0352] The pharmaceutical compositions of the present disclosure are manufactured in a manner known per se according to the present disclosure, for example, by conventional mixing, granulating, dragee-coating, dissolving, extruding or lyophilizing processes. Thus, a pharmaceutical composition for oral use can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture and processing the granular mixture, adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.

[0353] Suitable excipients include fillers such as sugars (e.g., lactose, sucrose, mannitol, or sorbitol), cellulose preparations, calcium phosphates (e.g., tricalcium phosphate or dibasic calcium phosphate), and binders such as starch paste (using, for example, corn starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinyl pyrrolidone. If desired, one or more disintegrants may be added, such as the above-mentioned starches as well as carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

[0354] The auxiliary agent is normally flow regulator and lubricant, for example silicon dioxide, talcum, stearic acid or its salt (for example magnesium stearate or calcium stearate) and polyethylene glycol.Dragee core has the suitable coating of gastric juice resistance.For this purpose, concentrated sugar solution can be used, it can optionally comprise gum arabic, talcum, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.In order to produce the coating of gastric juice resistance, suitable cellulose preparation solution can be used, for example acetylcellulose phthalate or hydroxypropyl methylcellulose phthalate.Dye or pigment can be added in tablet or dragee coating, for example, for identifying or characterizing the combination of active compound dosage.

[0355] Examples of other pharmaceutical formulations that can be used orally include push-fit capsules made of gelatin or soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the compound in the form of granules, which can be mixed with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers, or extruded multigranules. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid, such as a fatty oil or liquid paraffin. In addition, stabilizers may be added.

[0356] Possible pharmaceutical preparations for rectal administration include, for example, suppositories consisting of a combination of one or more active compounds with a suppository base. Suitable suppository bases include natural and synthetic triglycerides and paraffin hydrocarbons, among others. Gelatin rectal capsules consisting of a combination of the active compound with a base material such as liquid triglycerides, polyethylene glycol or paraffin hydrocarbons may also be used.

[0357] Suitable formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form, such as water-soluble salts, alkaline solutions or acidic solutions. Alternatively, the suspension of the active compound can be prepared into an oily suspension. Suitable lipophilic solvents or carriers for, for example, suspensions can include fatty oils (such as sesame oil), synthetic fatty acid esters (such as ethyl oleate), triglycerides or polyethylene glycols such as polyethylene glycol-400 (PEG-400). Aqueous suspensions can include one or more substances to increase the viscosity of the suspension, including, for example, sodium carboxymethylcellulose, sorbitol and / or dextran. The suspension can optionally include a stabilizer.

[0358] In another embodiment, the disclosure provides a kit comprising a compound of the disclosure (or a pharmaceutical composition comprising a compound of the disclosure), which is packaged in a manner that is conducive to them being used to practice the disclosed method. In one embodiment, the kit includes a compound of the disclosure (or a pharmaceutical composition comprising a compound of the disclosure) packaged in a container such as a sealed bottle or a vessel, and a label is attached to the container or is included in the kit to describe the use of the compound or composition to implement the disclosed method. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit may also include a device suitable for administering the composition according to the intended route of administration.

[0359] In another embodiment, a compound of the present invention is co-administered to a subject with a second therapeutic agent. The second therapeutic agent is different from the compound of the present invention. The compound of the present invention and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect. In addition, the compound of the present invention and the second therapeutic agent can be administered as a single composition or as two separate compositions.

[0360] The second therapeutic agent is administered in an amount to provide its desired therapeutic effect.The effective dosage range of each second therapeutic agent is known in the art, and the second therapeutic agent is administered to an individual in need thereof within such a determined range.

[0361] The compounds of the present invention and the second therapeutic agent can be administered together as a single unit dose or separately as multiple unit doses, wherein the compounds of the present invention are administered before the second therapeutic agent, or vice versa. One or more doses of the compounds of the present invention and / or one or more doses of the second therapeutic agent can be administered. Thus, the compounds of the present invention can be used in combination with one or more second therapeutic agents, such as, but not limited to, anticancer agents.

[0362] In some embodiments, the second therapeutic agent is an epigenetic drug. As used herein, the term "epigenetic drug" refers to a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulators include histone lysine methyltransferase, histone arginine methyltransferase, histone demethylase, histone deacetylase, histone acetylase, and DNA methyltransferase. Histone deacetylase inhibitors include, but are not limited to, vorinostat.

[0363] In another embodiment, chemotherapeutic agents or other antiproliferative agents can be combined with the compounds of the present disclosure to treat proliferative diseases and cancer. Examples of therapies and anticancer agents that can be used in combination with the compounds of the present disclosure include surgery, radiotherapy (e.g., gamma ray, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioisotopes), endocrine therapy, biological response modifiers (e.g., interferons, interleukins, tumor necrosis factor (TNF), hyperthermia and cryotherapy, agents that mitigate any adverse reactions (e.g., antiemetics), and any other approved chemotherapeutic drugs.

[0364] Examples of anti-proliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; antiandrogens; gonadotropin agonists; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active agents; alkylating agents; retinoids, carotenoids, or tocopherols; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antimetabolites; platinum compounds; methionine aminopeptidase inhibitors; bisphosphonates; anti-proliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used to treat hematological malignancies; Flt-3 inhibitors; Hsp90 inhibitors; kinesin spindle protein inhibitors; MEK inhibitors; antitumor antibiotics; nitrosoureas; compounds that target / decrease the activity of a protein or lipid kinase; compounds that target / decrease the activity of a protein or lipid phosphatase, or any other anti-angiogenic compound.

[0365] Non-limiting exemplary aromatase inhibitors include, but are not limited to, steroids such as atamestane, exemestane, and formestane, and nonsteroidal such as aminoglutethimide, rosiglamide, pyridoglutethimide, trilostane, testosterone lactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole.

[0366] Non-limiting antiestrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Antiandrogens include, but are not limited to, bicalutamide. Gonadorelin agonists include, but are not limited to, abarelix acetate and goserelin acetate.

[0367] Exemplary topoisomerase I inhibitors include, but are not limited to, topotecan, gimatidecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148. Topoisomerase II inhibitors include, but are not limited to, anthracyclines such as doxorubicin, daunorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones such as mitoxantrone and losoxantrone; and podophyllotoxins such as etoposide and teniposide.

[0368] Microtubule active agents include microtubule stabilizers, microtubule destabilizing compounds, and tubulin polymerization inhibitors, including but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine, vinblastine sulfate, vincristine, and vincristine sulfate, and vinorelbine; discodermolides; colchicine, and epothilones and their derivatives.

[0369] Exemplary, non-limiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas, such as carmustine and lomustine.

[0370] Exemplary non-limiting cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives, such as celecoxib, rofecoxib, etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids, such as lumiracoxib.

[0371] Exemplary, non-limiting matrix metalloproteinase inhibitors ("MMP inhibitors") include collagen peptidomimetics and non-peptide mimetic inhibitors, tetracycline derivatives, batimastat, marimastat, prinostat, metastat, BMS-279251, BAY12-9566, TAA211, MMI270B, and AAJ996.

[0372] Exemplary, non-limiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and have anti-proliferative activity, such as sirolimus, everolimus, CCI-779, and ABT578.

[0373] Exemplary, non-limiting antimetabolites include 5-fluorouracil (5-FU), capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed.

[0374] Exemplary, non-limiting platinum compounds include carboplatin, cisplatin, cisplatinum, and oxaliplatin.

[0375] Exemplary, non-limiting methionine aminopeptidase inhibitors include bengamide or its derivatives and PPI-2458.

[0376] Exemplary, non-limiting bisphosphonates include etradinic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid.

[0377] Exemplary non-limiting anti-proliferative antibodies include trastuzumab, trastuzumab-DM1, cetuximab, bevacizumab, rituximab, PR064553 and 2C4. The term "antibody" is intended to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0378] Exemplary, non-limiting heparanase inhibitors include compounds that target, reduce or inhibit the degradation of heparan sulfate, such as PI-88 and OGT2115.

[0379] As used herein, the term "inhibitor of an oncogenic isoform of Ras," such as H-Ras, K-Ras, or N-Ras, refers to a compound that targets, decreases, or inhibits the oncogenic activity of Ras, for example, farnesyltransferase inhibitors such as L-744832, DK8G557, tipifarnib, and lonafarnib.

[0380] Exemplary, non-limiting telomerase inhibitors include compounds that target, decrease, or inhibit telomerase activity, such as compounds that inhibit the telomerase receptor, such as telomestatin.

[0381] Exemplary, non-limiting proteasome inhibitors include compounds that target, decrease, or inhibit proteasome activity, including but not limited to bortezolomide.

[0382] As used herein, the phrase "compounds for treating hematological malignancies" includes FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-beta-D-arabinofuranosine cytosine (ara-c) and busulfan; and ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase.

[0383] Exemplary, non-limiting Flt-3 inhibitors include PKC412, midostaurin, staurosporine derivatives, SU11248, and MLN518.

[0384] Exemplary non-limiting HSP90 inhibitors include compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; or compounds that degrade, target, reduce, or inhibit HSP90 client proteins through the ubiquitin proteosome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 are particularly compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors.

[0385] As used herein, the phrase "targets / decreases protein or lipid kinase activity; or protein or lipid phosphatase activity; or any other anti-angiogenic compound" includes protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, decrease or inhibit platelet-derived growth factor receptor (PDGFR) activity, such as compounds that target, decrease or inhibit PDGFR activity, such as N-phenyl-2-pyrimidinyl-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, decrease or inhibit fibroblast growth factor receptor (FGFR) activity; c) compounds that target, decrease or inhibit insulin-like growth factor receptor I (IGF-IR) activity, such as compounds that target, decrease or inhibit IGF-I R activity; d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family or ephrin B4 inhibitors; e) compounds that target, reduce or inhibit the activity of the Axl receptor tyrosine kinase family; f) compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase, such as imatinib; i) compounds that target, reduce or inhibit the activity of c-Abl family members, their gene fusion products (such as Bcr-Abl kinase) and mutants (such as N-phenyl-2-pyrimidinyl-amine derivatives), such as imatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; or dasatinib; j) compounds that target, decrease or inhibit the activity of protein kinase C (PKC) and Raf serine / threonine kinase family members, MEK, SRC, JAK, FAK, PDK1, PKB / Akt and Ras members / MAPK family members, and / or members of the cyclin-dependent kinase family (CDK), such as staurosporine derivatives disclosed in US Pat. No. 5,093,330, such as midostaurin; other examples of compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; imofosine; RO318220 and RO320432; GO6976; Isis 3521; LY333531 / LY379196; isoquinoline compounds; farnesyl transferase inhibitors; PD184352 or QAN697, or AT7519; k) compounds that target, decrease or inhibit protein-tyrosine kinase activity, such as imatinib mesylate or tyrosine kinases, such as Tyrphostin A23 / RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748;Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44(+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (adamantyl 4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoate; NSC 680410, adaphostin); 1) Compounds that target, decrease or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their mutants, such as CP 358774, ZD 1839, ZM105180; trastuzumab, cetuximab, gefitinib, erlotinib, OSI-774, Cl-1033, EKB-569, GW-2016, antibodies E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, and E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, decrease, or inhibit the activity of the c-Met receptor.

[0386] Exemplary compounds that target, decrease or inhibit protein or lipid phosphatase activity include inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or a derivative thereof.

[0387] Other anti-angiogenic compounds include compounds with an alternative mechanism of activity unrelated to protein or lipid kinase inhibition, such as thalidomide and TNP-470.

[0388] Additionally, non-limiting exemplary chemotherapeutic compounds, one or more of which can be used in combination with the compounds of the present disclosure, include: daunorubicin, doxorubicin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin, PKC412, 6-mercaptopurine (6-MP), fludarabine phosphate, octreotide, SOM230, FTY720, 6-thioguanine, cladribine, 6-mercaptopurine, pentostatin, hydroxyurea, 2-hydroxy-1H-isoindole-1,3-dione derivatives, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate, angiostatin, endostatin, Dermatostatin, anthranilamide, ZD4190, ZD6474, SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macugon; FLT-4 inhibitor, FLT-3 inhibitor, VEGFR-2 IgGI antibody, RPI4610, bevacizumab, pofibrem sodium, anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocortisone, cortisol, 17a-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, dexamethasone, fluocinolone acetonide, plant alkaloids, hormone compounds and / or antagonists, biological response modifiers, such as lymphokines or interferons, antisense oligonucleotides or oligonucleotide derivatives, shRNA and siRNA.

[0389] Other examples of second therapeutic agents, one or more of which may also be combined with a compound of the present disclosure, include, but are not limited to: treatments for Alzheimer's disease, such as donepezil and rivastigmine; treatments for Parkinson's disease, such as levodopa / carbidopa, entacapone, robinol, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; agents used to treat multiple sclerosis (MS), such as beta interferon (e.g., and ), glatiramer acetate, and mitoxantrone; asthma treatments such as albuterol and montelukast; agents used to treat schizophrenia, such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators, including immunosuppressants, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; Neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, or anti-Parkinson's disease agents; agents for treating cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, or statins; agents for treating liver diseases, such as corticosteroids, cholestyramine, interferons, antiviral agents; agents for treating blood diseases, such as corticosteroids, antileukemia agents, or growth factors; or agents for treating immunodeficiency diseases, such as immunoglobulin.

[0390] The preparation and administration of the aforementioned second therapeutically active agents, one or more of which can be used in combination with the compounds of the present disclosure, are described in the art.

[0391] definition

[0392] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0393] As used herein, the term "enantiomerically pure" or "enantiopure" refers to a sample of a chiral substance, all molecules of which (within the limits of detection) have the same sense of chirality. In one embodiment, the disclosed compounds having one or more chiral centers are enantiomerically pure.

[0394] As used herein, the term "enantiomerically enriched" or "enantioenriched" refers to a sample of chiral material having an enantiomeric excess of greater than 50%, e.g., about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, about 98% or more, or about 99% or more. An enantiomerically enriched compound can be enantiomerically pure. In one embodiment, a compound of the present disclosure having one or more chiral centers is enantiomerically enriched.

[0395] Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by a solid wedge-shaped bond. and dotted wedge key Indicates that the wavy line Indicates a wedge-shaped solid key or dotted wedge key and the relative configuration of the stereocenters is determined by straight solid bonds and straight dashed bonds When the compounds of the present disclosure contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, they include both E and Z geometric isomers. Likewise, all tautomeric forms are encompassed within the scope of the present invention.

[0396] Compounds of the present disclosure may have specific geometric or stereoisomeric forms. The present disclosure encompasses all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures, such as mixtures enriched in enantiomers or diastereomers, all of which are included within the scope of the present disclosure. Substituents such as alkyl groups may have additional asymmetric carbon atoms. All of these isomers and mixtures thereof are included within the scope of the present disclosure.

[0397] Optically active (R)- and (S)-isomers, or D and L isomers, can be prepared using chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is to be obtained, it can be obtained by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and cleavage of the auxiliary group to obtain the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), the compound is reacted with an appropriate optically active acid or base to form a diastereomeric salt, which is then subjected to diastereomeric resolution by conventional methods in the art to obtain the pure enantiomer. In addition, enantiomers and diastereomers are typically separated by chromatography using a chiral stationary phase and optionally combined with a chemical derivatization method (such as a carbamate produced from an amine).

[0398] As used herein, the term "solvate" as used herein is a combination, physical association and / or solvation of a compound of the present disclosure with a solvent molecule, such as a disolvate, a monosolvate, or a hemisolvate, wherein the ratio of solvent to compound of the present disclosure is about 2:1, about 1:1, or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" includes both solution-phase and separable solvates. The compounds of the present disclosure may exist as solvated forms with pharmaceutically acceptable solvents such as water, methanol, ethanol, and the like, and the present disclosure is intended to include both solvated and unsolvated forms of the compounds of the present disclosure.

[0399] In one embodiment, the solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates in which the solvent molecule is water. Solvates can generally act as pharmacological equivalents. The preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93 (3): 601-611 (2004) for a description of the preparation of a solvate of fluconazole with ethyl acetate and water. EC van Tonder et al., AAPS Pharm. Sci. Tech., 5 (1): Article 12 (2004) and AL Bingham et al., Chem. Commun. 603-604 (2001) for a description of the preparation of solvates, hemisolvates, hydrates and the like. A typical non-limiting method for preparing a solvate would include dissolving a compound of the present disclosure in a desired solvent (organic solvent, water or a mixture thereof) at a temperature above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods such as filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of solvent in solvate crystals.

[0400] As used herein, the terms "a" and "an" mean one or more.

[0401] As used herein, the term "about" includes ±10% of the stated number. Thus, "about 10" means 9 to 11.

[0402] As used herein, the terms "treat," "treating," "treatment," and the like refer to the elimination, reduction, or amelioration of a disease or condition, and / or symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require the complete elimination of the disease, condition, or symptoms associated therewith. The term "treat" and synonyms contemplate the administration of a therapeutically effective amount of a compound of the present disclosure to a subject in need of such treatment. Treatment can be symptomatic, for example, to suppress symptoms. It can be effective in the short term, can be carried out in the medium term, or can be a long-term treatment, for example, in the context of maintenance therapy.

[0403] As used herein, the terms "prevent," "preventing," and "prevention" refer to methods of preventing the onset of a disease or condition and / or its associated symptoms or preventing a subject from acquiring a disease. As used herein, "prevent," "preventing," and "prevention" also include delaying the onset of a disease and / or its associated symptoms and reducing the risk of a subject developing a disease. The terms "prevent," "preventing," and "prevention" may include "prophylactic treatment," which refers to reducing the likelihood that a subject will develop a disease or condition again or relapse of a previously controlled disease or condition, without, but at risk for, or be susceptible to a disease or condition or recurrence of a disease or condition.

[0404] As used herein, the term "therapeutically effective amount" or "effective dose" as used herein refers to an amount of active ingredient that is sufficient to be effectively delivered when administered by the methods of the present disclosure for the treatment of an active ingredient for a condition or disease of interest to an individual in need thereof. In the case of cancer or other proliferative diseases, a therapeutically effective amount of an agent can reduce (i.e., delay and preferably stop to some extent) unwanted cell proliferation; reduce the number of cancer cells; reduce tumor size; inhibit (i.e., delay and preferably stop to some extent) cancer cell infiltration into peripheral organs; inhibit (i.e., delay and preferably stop to some extent) tumor metastasis; inhibit tumor growth to some extent; regulate protein methylation in target cells; and / or alleviate one or more symptoms associated with cancer to some extent. Insofar as the compound or composition administered prevents growth and / or kills existing cancer cells, it can be cytostatic and / or cytotoxic.

[0405] The term "container" refers to any container and closure suitable for storing, transporting, dispensing and / or handling pharmaceutical products accordingly.

[0406] The term "insert" refers to the information that accompanies a drug product and provides a description of how to administer the product, as well as the safety and effectiveness data needed to allow physicians, pharmacists, and patients to make informed decisions about the product's use. The package insert is often considered the drug's "label."

[0407] In the present disclosure, the term "Bcl-2 protein" or "Bcl-2 protein family" refers to any one or more of the following proteins: Bax, Bak, Bid, Bcl-2, Bcl-xL, Mcl-1, Bcl-w, Bfl-1 / A1, Bim, Puma, Bad, Bik / Blk, Noxa, Bmf, Hrk / DP5, and Beclin-1. See Cold Spring Harb Perspect Biol 2013;5:a008714.

[0408] The term "disease" or "condition" or "disorder" refers to a disorder and / or abnormality that is generally considered a pathological condition or function and can manifest itself in the form of specific signs, symptoms, and / or malfunctions. The compounds of the present disclosure inhibit Bcl-2 proteins, such as Bcl-2 and / or Bcl-xL, and can be used to treat or prevent diseases, conditions, or disorders, such as hyperproliferative diseases, in which inhibition of Bcl-2 proteins provides a benefit.

[0409] The term "hyperproliferative disease" refers to any condition in an animal in which a localized population of proliferating cells is not controlled by the usual limits of normal growth. In one embodiment, the hyperproliferative disease is cancer.

[0410] Different expressions such as “X is selected from A, B or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C”, etc. have the same meaning, that is, X can be any one or more of A, B, C.

[0411] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1-3 hydrogen atoms, independently replaced by a corresponding number of substituents. It goes without saying that substituents are only present in their possible chemical positions. Those skilled in the art can determine whether substitution is possible or impossible by experiment or theory without undue effort. For example, a combination of an amino or hydroxyl group containing free hydrogen and a carbon atom containing an unsaturated bond (e.g., an olefin) may be unstable.

[0412] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0413] The term "pharmaceutically acceptable salt" refers to a salt formed by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.

[0414] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0415] The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0416] The term "alkylene" is a divalent group that is attached to the rest of the molecule by two single bonds, and the rest of the definition is the same as the term "alkyl".

[0417] The term "alkoxy" refers to a group R X -O-, R X is defined as the same as the term "alkyl". Alkoxy includes but is not limited to methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0418] The term "cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (eg, C3 to C6).

[0419] The term "spirocyclic cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (eg, C5 to C9), which is polycyclic (eg, 2 or 3) and shares one carbon atom between the rings.

[0420] The term "(monocyclic)cycloalkenyl" refers to a cyclic, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C5-C6), which has one or more (e.g., 1, 2 or 3) carbon-carbon sp2 double bonds, is monocyclic and does not have aromaticity.

[0421] The term "aryl" refers to a cyclic, aromatic, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C6 to C10), which is monocyclic or polycyclic (e.g., 2 or 3). When it is polycyclic, the monocyclic rings share two atoms and one bond.

[0422] The term "heterocycloalkyl" refers to a cyclic, saturated, monovalent group having a specified number of ring atoms (e.g., 3-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). The heterocycloalkyl group is attached to the rest of the molecule through a carbon atom or a heteroatom.

[0423] The term "spiroheterocycloalkyl" refers to a cyclic, saturated, monovalent group having a specified number of ring atoms (e.g., 7-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It is polycyclic (e.g., 2 or 3) with one carbon atom shared between the rings. A spiroheterocycloalkyl group is attached to the rest of the molecule through a ring containing heteroatoms or a ring without heteroatoms; a spiroheterocycloalkyl group is attached to the rest of the molecule through a carbon atom or a heteroatom.

[0424] The term "heteroaryl" refers to a cyclic, unsaturated, monovalent group with a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It is monocyclic or polycyclic, with two atoms and one bond shared between the rings, and is aromatic. A heteroaryl group is attached to the rest of the molecule through a carbon atom or a heteroatom; a heteroaryl group is attached to the rest of the molecule through a ring containing a heteroatom or a ring without a heteroatom.

[0425] General synthesis of compounds

[0426] The disclosed compounds can be prepared using methods known to those skilled in the art in view of the present disclosure. The solvents, temperatures and other reaction conditions provided in the present disclosure are exemplary and can be changed according to methods well known in the art. The disclosed compounds can be synthesized using suitable starting materials according to their specific structures and according to the methods described in the examples, or they can be synthesized using methods similar to those described in the examples. The starting materials for synthesizing the disclosed compounds can be prepared by known synthetic methods or similar methods described in the literature or obtained from commercial sources. The compounds of the present invention can be further resolved by methods well known in the art such as crystallization, chromatography, etc. to obtain the desired stereoisomers, and the resolution conditions are that those skilled in the art can easily obtain experiments in a conventional or limited manner.

[0427] In one embodiment, the present invention provides a method for preparing the disclosed compounds, comprising Scheme 1 or Scheme 2:

[0428] Scheme 1: The compound of formula IA is subjected to the following cyclization reaction to obtain a compound of formula I;

[0429]

[0430] Scheme 2: The compound of formula VII-A and the compound of formula VII-B undergo the following condensation reaction to obtain the compound of formula VII;

[0431]

[0432] Among them, -X-, ring A, ring B, ring C, ring D, ring E, R 1 , R 2 , R 3 ,m1,m2,m3,-L 1 -, -L 2 -、-L 3 -、-M 1 -、-M 2 -and-M 3 - as defined in conjunction with formula I.

[0433] In one embodiment, the present disclosure provides an intermediate having Formula IA for preparing the compounds of the present disclosure:

[0434]

[0435] Among them, -X-, -Y-, ring A, ring B, ring C, ring D, ring E, R 1 、R 2 、R 3 、m1、m2、m3、-L 1 -、-L 2 -、-L 3 -、-M 1 -、-M 2 -and-M 3 - as defined in conjunction with formula I.

[0436] In one embodiment, the present disclosure provides an intermediate having formula VII-A for preparing the compounds of the present disclosure:

[0437]

[0438] Among them, -X-, ring A, ring B, R 1 ,m1,-L 1 -, -L 2 -、-L 3 -、-M 1 -、-M 2 -and-M 3 - as defined in conjunction with formula I. DETAILED DESCRIPTION

[0439] The present invention will be further described by the following examples, but the present invention is not limited to the scope of the described examples. In the following examples, experimental methods without specific conditions are all based on conventional methods and conditions, or selected according to product instructions.

[0440] Example 1

[0441] (S)-35-(2-((S)-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-9-methyl-75-nitro-74-((((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide

[0442]

[0443] Step a:

[0444] (S)-5-(Hydroxymethyl)dihydrofuran-2(3H)-one

[0445]

[0446] Under N₂ protection, BH₃·THF (1.2 equiv., 44.3 mmol, 3.8 g) was added to a suspension of (S)-5-oxotetrahydrofuran-2-carboxylic acid (1.0 equiv., 36.9 mmol, 4.8 g) in THF (80 mL) in an ice-water bath. The reaction mixture was then stirred at 25°C for 4 hours. After completion of the reaction, MeOH was added at 0°C and the mixture was concentrated in vacuo to afford 4.28 g of the crude product, which was used in the next step without further purification.

[0447] Step b:

[0448] (S)-(5-Oxotetrahydrofuran-2-yl)methyl-4-methylbenzenesulfonate

[0449]

[0450] Under N₂ protection, 4-methylbenzenesulfonyl chloride (1.5 equiv., 55.3 mmol, 10.54 g) was added to a suspension of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (1.0 equiv., 36.9 mmol, 4.28 g) and pyridine (3.0 equiv., 111 mmol, 8.75 g) dissolved in DCM (80.0 mL) in an ice-water bath. The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, water was added to the resulting mixture, and the solution was extracted with ethyl acetate. The organic layer was washed with 0.5N HCl solution, H₂O, saturated NaHCO₃(aq), and brine. The combined organic layers were dried over anhydrous Na₂SO₄. After filtration and concentration, the residue was purified by silica gel column chromatography eluting with 0%-50% ethyl acetate in hexane to give the product as a light oil (6.3 g, 63.2% yield). MS (ESI) m / z 271.5 [M+H] + .

[0451] Step c:

[0452] (R)-Pentane-1,4-diol

[0453]

[0454] In an ice-water bath under N2 protection, LiAlH4 (4.0 equivalents, 29.6 mmol, 1.12 g) was added to a suspension of (S)-(5-oxotetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (1.0 equivalents, 7.4 mmol, 2 g) and tetrahydrofuran (30 mL). The reaction mixture was then stirred at 75 ° C overnight. After the reaction was completed, H2O (1.1 mL), 15% NaOH solution (1.1 mL) and water (3.3 mL) were added to the resulting mixture at 0 ° C and then filtered. The solution was diluted with ethyl acetate and washed with brine. The organic layer was separated and dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel column chromatography, eluting with 0 to 10% methanol in dichloromethane to obtain the product as a light oil (613 mg, 80% yield).

[0455] Step d:

[0456] (R)-5-((tert-Butyldiphenylsilyl)oxy)pentan-2-ol

[0457]

[0458] To a suspension of (R)-pentane-1,4-diol (1.0 equiv, 5.89 mmol, 613 mg) in DMF (10 mL) was added imidazole (1.0 equiv, 5.89 mmol, 401 mg) and tert-butylchlorodiphenylsilane (1.0 equiv, 5.89 mmol, 1.6 g) in an ice-water bath under N2 protection. The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated, and the residue was purified by silica gel column chromatography eluting with 0 to 20% ethyl acetate in hexane to give a light oily product (1.62 g, 80% yield). MS (ESI) m / z 343.6 [M+H] + .

[0459] Step e:

[0460] (R)-5-((tert-Butyldiphenylsilyl)oxy)pentan-2-yl methanesulfonate

[0461]

[0462] To a suspension of (R)-5-((tert-butyldiphenylsilyl)oxy)pentan-2-ol (1.0 equiv, 0.29 mmol, 100 mg) in DCM (10 mL) was added triethylamine (2.0 equiv, 0.58 mmol, 59.1 mg), methanesulfonyl chloride (1.2 equiv, 0.35 mmol, 40.1 mg) and N,N-dimethylpyridin-4-amine (0.6 equiv, 0.17 mmol, 21.4 mg) under N2 protection in an ice-water bath. The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was separated and dried over Na2SO4. After filtration and concentration, the residue was dried to give a light oily product (123 mg), which was used directly in the next step without further purification. MS (ESI) m / z 443.2 [M+H] + .

[0463] Step f:

[0464] (S)-3-((5-((tert-Butyldiphenylsilyl)oxy)pentan-2-yl)oxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H)-pyran-4-yl)methyl)amino)benzenesulfonamide

[0465]

[0466] A suspension of (R)-5-((tert-butyldiphenylsilyl)oxy)pentan-2-yl methanesulfonate (1.0 equiv, 0.29 mmol, 123 mg) and 3-hydroxy-N,N-bis(4-methoxybenzyl)- under N2 was added 5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1.0 equiv, 0.29 mmol, 167 mg) in acetonitrile (15 mL) and K2CO3 (3.0 equiv, 0.87 mmol, 121 mg) was added. The reaction mixture was then stirred at 80°C overnight. After completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated and dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel column chromatography eluting with 0% to 35% ethyl acetate in hexanes to give the product as a yellow oil (262 mg, 99% yield). MS (ESI) m / z 896.8 [M+H] + .

[0467] Step g:

[0468] (S)-3-((5-hydroxypentan-2-yl)oxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide

[0469]

[0470] Under N protection, to (S)-3-((5-((tert-butyldiphenylsilyl)oxy)pentan-2-yl)oxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1.0 equiv, 0.29 mmol, 261 mg) in THF (15 mL) was added TBAF (1.2 equiv, 0.35 mmol, 91 mg). The reaction mixture was then stirred at 25° C. for 2 hours. After completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated and dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel column chromatography eluting with 0% to 3.5% methanol in dichloromethane to give the product as a yellow solid (152 mg, 79% yield). MS (ESI) m / z 658.9 [M+H] + .

[0471] Step h:

[0472] (S)-4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl methanesulfonate

[0473]

[0474] Under N2 protection, to a suspension of (S)-3-((5-hydroxypentanyl-2-yl)oxy)-N,N-bis(4-methoxyphenyl)-5-nitro-4-(((tetrahydro-2H-pyran-4)-yl)methyl)amino)benzenesulfonamide (1.0 equiv, 0.23 mmol, 152 mg) in DCM (10 ml) in an ice-water bath were added triethylamine (2.0 equiv, 0.46 mmol, 46.8 mg), methanesulfonyl chloride (1.2 equiv, 0.27 mmol, 31.8 mg) and N,N-dimethylpyridin-4-amine (0.6 equiv, 0.14 mmol, 16.94 mg). The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated and dried over Na2SO4. After filtration and concentration, the residue was dried to obtain a light oily product (170 mg), which was used directly in the next step without further purification. MS (ESI) m / z 736.8 [M+H] + .

[0475] Step i:

[0476] Methyl (S)-2-((6-((4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)))methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate

[0477]

[0478] To a suspension of (S)-4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl methanesulfonate (1.0 equiv, 0.76 mmol, 559 mg), methyl 4-fluoro-2-((6-hydroxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.2 equiv, 0.91 mmol, 276 mg), and KCO (3.0 equiv, 2.28 mmol, 315 mg) in acetonitrile (15 mL) was added TBAI (1.0 equiv, 0.76 mmol, 281 mg) under N protection. The reaction mixture was then stirred at 80 ° C overnight. After completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated and dried over NaSO. After filtration and concentration, the residue was purified by silica gel column chromatography eluting with 0% to 50% ethyl acetate in hexane to give the product as a yellow solid (427 mg, 59.7% yield). MS (ESI) m / z 942.7 [M+H] + .

[0479] Step j:

[0480] Methyl 2-((6-(((S)-4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)))methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate

[0481]

[0482] To a suspension of (S)-methyl 2-((6-((4-(5-(N,N-bis(4-methoxyphenyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran))-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 equiv, 0.26 mmol, 244 mg) and (S)-2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (10.0 equiv, 2.59 mmol, 809 mg) in DMF (10 mL) was added NaCO (20.0 equiv, 5.18 mmol, 549 mg) under N. The reaction mixture was then stirred at 100° C. overnight. After the reaction was complete, the resulting mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated and dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel column chromatography using 0% to 50% ethyl acetate in hexane to give the product as a yellow solid (61.0 mg, 19.08% yield). MS (ESI) m / z 1235.2 [M+H] + .

[0483] Step k:

[0484] Methyl 4-(2-((S)-2-(2-Isopropylphenyl)pyrrol-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((S)-4-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)phenyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate

[0485]

[0486] Methyl 2-((6-(((S)-4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-))pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2)-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonyl-7-yl)benzoate (0.049 mmol, 61 mg) and TFA (10.0 equiv, 0.49 mmol, 56.3 mg) were added to the reaction flask. The reaction mixture was then stirred at 60 °C for 3 hours. After completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution. The organic layer was separated and dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel column chromatography, eluting with 0% to 7% methanol in dichloromethane to give the product as a yellow solid (18 mg, 36.6% yield). MS (ESI) m / z 994.9 [M+H] + .

[0487] Step 1:

[0488] 4-(2-((S)-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((S)-4)-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid

[0489]

[0490] Under N2 protection, methyl 4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((S)-4)-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.0 equiv, 0.018 mmol, 18 mg) was added to a suspension of THF (2 mL), H2O (2 mL) and MeOH (2 mL) with sodium hydroxide (2.0 equiv, 0.036 mmol, 1.45 mg). The reaction mixture was then stirred at 50°C for 3 hours. After completion of the reaction, the resulting mixture was diluted with water, washed with 1N HCl solution, and extracted with EA. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product as a yellow solid (17 mg), which was used in the next step without further purification. MS (ESI) m / z 980.9 [M+H]+ .

[0491] Step m:

[0492] (S)-35-(2-((S)-2-(2-Isopropylphenyl)pyrrol-1-yl)-7-azaspiro[3.5]nonan-7-yl)-9-methyl-75-nitro-74-((((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenyltridec-4-one-6,6-dioxide

[0493]

[0494] 4-(2-((S)-2-(2-Isopropylphenyl)pyrrol-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((S)-4-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid (1.0 eq, 0.017 mmol, 17 mg) and EDCI (2.0 eq, 0.035 mmol, 6.65 mg) were added to DMAP (2.0 eq, 0.035 mmol, 4.24 mg) dissolved in DCM (8 ml). The reaction mixture was then stirred at 30 °C overnight. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give a yellow solid product (1.2 mg, 7.19% yield over two steps). MS (ESI) m / z 962.9 [M+H] + .

[0495] Example 2

[0496] (S)-35-(2-((S)-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-12-methyl-75-nitro-74-((((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide

[0497]

[0498] Step a:

[0499] (S)-methyl 2-((6-((5-((tert-Butyldiphenylsilyl)oxy)pentan-2-yl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate

[0500]

[0501] To a suspension of methyl 4-fluoro-2-((6-hydroxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.0 equiv, 1.92 mmol, 580 mg) and (R)-5-((tert-butyldiphenylsilyl)oxy)pentan-2-yl methanesulfonate (1.0 equiv, 1.92 mmol, 807 mg) in acetonitrile (25 mL) was added KCO (3.0 equiv, 5.76 mmol, 796 mg) under N. The reaction mixture was then stirred at 30 ° C overnight. After completion of the reaction, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over NaSO, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with 0% to 33 ethyl acetate in hexane to give the following product as a yellow oil (454 mg, 37.7% yield). MS (ESI) m / z 627.8 [M+H] + .

[0502] Step b:

[0503] (S)-methyl 4-fluoro-2-((6-((5-hydroxypentan-2-yl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate

[0504]

[0505] To a suspension of (S)-methyl 2-((6-((5-((tert-butyldiphenylsilyl)oxy)pentan-2-yl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 equiv, 0.72 mmol, 454 mg) in THF (15 mL) was added TBAF (1.2 equiv, 0.87 mmol, 227 mg) under N protection. The reaction mixture was then stirred at 25° C. for 1 hour. After completion of the reaction, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with 0 to 3.5% methanol in dichloromethane to give the product as a yellow solid (232 mg, 82% yield). MS (ESI) m / z 389.2 [M+H] + .

[0506] Step c:

[0507] (S)-methyl 2-((6-((5-((tert-Butyldimethylsilyl)oxy)pentan-2-yl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate

[0508]

[0509] To a suspension of (S)-methyl 4-fluoro-2-((6-((5-hydroxypentan-2-yl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.0 eq, 0.60 mmol, 232 mg) and 1H-imidazole (1.3 eq, 0.78 mmol, 52.9 mg) in DCM (15 mL) was added tert-butylchlorodimethylsilane (1.2 eq, 0.72 mmol, 108 mg) under N protection. The reaction mixture was then stirred at 25 °C for 3 hours. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA was 0-33%) to give the product as a light oil (229 mg, 76% yield). MS (ESI) m / z 503.9 [M+H] + .

[0510] Step d:

[0511] (S)-methyl 2-((6-((5-((tert-Butyldimethylsilyl)oxy)pentan-2-yl)oxy)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate

[0512]

[0513] To a suspension of (S)-methyl 2-((6-((5-((tert-butyldimethylsilyl)oxy)pentan-2-yl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 equiv, 0.46 mmol, 229 mg), triethylamine (2.0 equiv, 0.91 mmol, 92 mg) and N,N-dimethylpyridin-4-amine (1.0 equiv, 0.46 mmol, 55.7 mg) in DCM (15 mL) was added 4-methylbenzenesulfonyl chloride (1.2 equiv, 0.55 equiv, 104 mg) under N protection. The reaction mixture was then stirred at 45 ° C overnight. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-11%) to give the product as a light oil (300 mg, 99% yield). MS (ESI) m / z 679.8 [M+Na] + .

[0514] Step e:

[0515] (S)-methyl 4-fluoro-2-((6-((5-hydroxynonan-2-yl)oxy)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate

[0516]

[0517] To a suspension of (S)-methyl 2-((6-((5-((tert-butyldimethylsilyl)oxy)pentan-2-yl)oxy)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 equiv, 0.46 mmol, 300 mg) in THF (15) was added TBAF (1.2 equiv, 0.55 mmol, 143 mg) under N protection. The reaction mixture was then stirred at 25°C for 2 hours. After completion of the reaction, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 3.3%) to give the product as a yellow solid (107 mg, 43.2% yield). MS (ESI) m / z 543.6 [M+H] + .

[0518] Step f:

[0519] (S)-methyl 4-fluoro-2-((6-((5-((methylsulfonyl)oxy)pentan-2-yl)oxy)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate

[0520]

[0521] Under N protection, to a suspension of methyl (S)-4-fluoro-2-((6-((5-hydroxynonan-2-yl)oxy)-1-methylbenzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.0 equiv, 0.20 mmol, 107 mg), triethylamine (2.0 equiv, 0.39 mmol, 39.9 mg) and N,N-dimethylpyridin-4-amine (0.6 equiv, 0.12 mmol, 14.46 mg) in DCM (10 mL) was added methanesulfonyl chloride (1.2 equiv, 0.24 mmol, 27.1 mg) in an ice-water bath. The reaction mixture was then stirred at 25° C. overnight. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product as a yellow oil (122 mg), which was used in the next step without further purification. MS (ESI) m / z 621.8 [M+H] + .

[0522] Step g:

[0523] (S)-methyl 2-((6-((5-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)))methyl)amino)phenoxy)pentan-2-yl)oxy)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate

[0524]

[0525] To a suspension of (S)-methyl 4-fluoro-2-((6-((5-((methylsulfonyl)oxy)pentyl-2-yl)oxy)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.0 equiv, 0.20 mmol, 122 mg), 3-hydroxy-N,N-bis(4-methoxyphenyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1.2 equiv, 0.24 mmol, 135 mg), and KCO (3.0 equiv, 0.59 mmol, 81 mg) in acetonitrile (15 mL) was added TBAI (0.5 equiv, 0.10 mmol, 36.3 mg) under N protection. The reaction mixture was then stirred at 80° C. overnight. After completion of the reaction, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-50%) to give the product as a yellow solid (180 mg, 84% yield). MS (ESI) m / z 1096.8 [M+H] + .

[0526] Step h:

[0527] Methyl 2-((6-(((S)-5-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)))methyl)amino)phenoxy)pentan-2-yl)oxy)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate

[0528]

[0529] To a suspension of (S)-methyl 2-((6-((5-(5-(N,N-bis(4-methoxyphenyl))sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran))-4-yl)methyl)amino)phenoxy)pentan-2-yl)oxy)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 equiv, 0.16 mmol, 180 mg) and (S)-2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (10.0 equiv, 1.64 mmol, 513 mg) in DMF (10 mL) was added NaCO (20.0 equiv, 3.28 mmol, 348 mg) under N protection. The reaction mixture was then stirred at 100° C. overnight. After the reaction was complete, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0-5%) to give the product as a yellow oil (120 mg, 52.6% yield). MS (ESI) m / z 1388.9 [M+H] + .

[0530] Step i:

[0531] Methyl 4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((S)-5-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentan-2-yl)oxy)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate

[0532]

[0533] To the reaction was added methyl 2-((6-(((S)-5-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-))pyran-4-yl)methyl)amino)phenoxy)pentan-2-yl)oxy)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate (1.0 eq, 0.086 mmol, 120 mg) and TFA (10.0 eq, 0.86 mmol, 99 mg). The reaction mixture was then stirred at 60 ° C for 3 hours. After completion of the reaction, the resulting mixture was evaporated, diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 6%) to give the product as a yellow solid (77 mg, 78% yield). MS (ESI) m / z 1149.0 [M+H] + .

[0534] Step j:

[0535] 4-(2-((S)-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((S)-5)-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentan-2-yl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid

[0536]

[0537] To a suspension of methyl 2-((6-(((S)-5-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-))pyran-4-yl)methyl)amino)phenoxy)pentan-2-yl)oxy)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate (1.0 equiv, 0.067 mmol, 77 mg) in THF (2 mL) and EtOH (2 mL) was added 2N NaOH solution (5 mL) under N2. The reaction mixture was then stirred at 80°C overnight. After completion of the reaction, the resulting mixture was diluted with water, washed with 1N HCl solution, and extracted with EA. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product as a yellow solid (65.7 mg), which was used in the next step without further purification. MS (ESI) m / z 980.9 [M+H] + .

[0538] Step k:

[0539] (S)-35-(2-((S)-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-12-methyl-75-nitro-74-((((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide

[0540]

[0541] To a solution of 4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((S)-5)-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentan-2-yl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid (1.0 eq, 0.067 mmol, 66 mg) and EDCI (2.0 eq, 0.14 mmol, 25.8 mg) in DCM (10 mL) was added DMAP (2.0 eq, 0.14 mmol, 16.45 mg). The reaction mixture was then stirred at 30° C. overnight. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give a yellow solid product (2.2 mg, 3.4% yield over two steps). MS (ESI) m / z 962.8 [M+H] + .

[0542] Example 3

[0543] (S)-35-(2-((R)-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-9-methyl-75-nitro-74-((((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide

[0544]

[0545] Step a:

[0546] tert-Butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate

[0547]

[0548] To a suspension of tert-butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate (1.0 equivalent, 20.91 mmol, 6.82 g) in dioxane (90 mL) and water (30 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.0 equivalent, 41.8 mmol, 7.03 g), PdCl2(dppf) (0.1 equivalent, 2.09 mmol, 1.53 g) and K2CO3 (3.0 equivalent, 62.7 mmol, 8.67 g) under N2 protection. The reaction mixture was then stirred at 100 ° C for 4 hours. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-20%) to give the product as a light oil (6 g, 99% yield). MS (ESI) m / z 310.3 [M+Na] + .

[0549] Step b:

[0550] tert-Butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate

[0551]

[0552] To a suspension of tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrole-1-carboxylate (1.0 eq, 20.88 mmol, 6 g) in MeOH (100 mL) was added Pd / C (0.9 eq, 18.79 mmol, 2 g). The reaction mixture was then stirred at 25 °C under H2 overnight. After completion of the reaction, the resulting mixture was filtered and concentrated in vacuo to give the crude product as an oil (6.04 g), which was used in the next step without further purification. MS (ESI) m / z 312.3 [M+Na] + .

[0553] Step c:

[0554] 2-(2-Isopropylphenyl)pyrrolidine

[0555]

[0556] To a suspension of tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (1.0 equiv, 20.9 mmol, 6.05 g) in DCM (5 mL) was added 2,2,2-trifluoroacetic acid (5.0 equiv, 105 mmol, 11.92 g). The reaction mixture was then stirred at 25°C for 30 minutes. After completion of the reaction, the resulting mixture was evaporated, washed with saturated NaHCO3 solution, and diluted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 3.96 g of crude product as a gray oil, which was used in the next step without further purification. MS (ESI) m / z 190.5 [M+H] + .

[0557] Step d:

[0558] tert-Butyl 2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0559]

[0560] To a suspension of 2-(2-isopropylphenyl)pyrrolidine (1.0 equiv, 20.9 mmol, 3.96 g) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (2.0 equiv, 41.8 mmol, 10.0 g) in DCE (100 mL) was added sodium triacetylborohydride (2.0 equiv, 41.8 mmol, 6.85 g), and the reaction mixture was stirred at 45 ° C for 3 hours. After completion of the reaction, the resulting mixture was washed with saturated NaHCO 3 solution and diluted with EA. The organic layer was separated, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range of 0 to 5%) to give the product as a yellow oil (8.3 g, 96% yield). MS (ESI) m / z 414.0 [M + H] + .

[0561] Step e:

[0562] (R)-2-(2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane

[0563]

[0564] To a suspension of (R)-tert-butyl 2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 equiv, 2.42 mmol, 1 g) in DCM (15 mL) was added 2,2,2-trifluoroacetic acid (5.0 equiv, 12.12 mmol, 1.38 g). The reaction mixture was then stirred at 25 °C for 30 min. After completion of the reaction, the resulting mixture was evaporated, washed with saturated NaHCO3 solution, and diluted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and NH3 in MeOH, NH3 in MeOH in the range of 0 to 10%) to give the product as a yellow oil (573 mg, 76% yield). MS (ESI) m / z 329.1 [M+H] + .

[0565] Step f:

[0566] 2-((6-(((S)-4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)))methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid methyl ester

[0567]

[0568] To a suspension of (S)-2-((6-((4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran))-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 equiv, 0.18 mmol, 173 mg) and (R)-2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (10.0 equiv, 1.84 mmol, 574 mg) in DMF (15 mL) under N was added NaCO (20.0 equiv, 3.67 mmol, 389 mg). The reaction mixture was then stirred at 100° C. overnight. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-50%) to give the product as a yellow solid (67 mg, 29.6% yield). MS (ESI) m / z 1235.2 [M+H] + .

[0569] Step g:

[0570] Methyl 4-(2-((R)-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonyl-7-yl)-2-((6-(((S)-4-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate

[0571]

[0572] To the reaction flask was added 2-((6-(((S)-4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)))methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid methyl ester (1.0 eq, 0.054 mmol, 67 mg) and TFA (10.0 eq, 0.54 mmol, 61.9 mg). The reaction mixture was then stirred at 60° C. under N2 for 5 h. After completion of the reaction, the resulting mixture was evaporated, diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated and purified by Na2 The mixture was dried over SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 6%) to give the product as a yellow solid (52 mg, 96% yield). MS (ESI) m / z 994.9 [M+H] + .

[0573] Step h:

[0574] 4-(2-((R)-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((S)-4)-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid

[0575]

[0576] To a suspension of methyl 4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((S)-4)-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.0 equiv, 0.052 mmol, 527 mg) in THF (2 mL) and MeOH (2 mL) was added 2N NaOH solution (3 mL) under N2 protection. The reaction mixture was then stirred at 50 °C for 3 h. After completion of the reaction, the resulting mixture was diluted with water, washed with 1N HCl solution, and extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 51.3 mg of crude product as a yellow solid, which was used in the next step without further purification. MS (ESI) m / z 980.9 [M+H] + .

[0577] Step i:

[0578] (S)-35-(2-((R)-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-9-methyl-75-nitro-74-((((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide

[0579]

[0580] To a suspension of 4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((S)-4)-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid (1.0 eq, 0.052 mmol, 51 mg) and EDCI (2.0 eq, 0.10 mmol, 19.95 mg) in DCM (8 mL) was added DMAP (2.0 eq, 0.10 mmol, 12.71 mg). The reaction mixture was then stirred at 30° C. overnight. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give the product 3.7 mg as a yellow solid, 7.39% (yield over two steps).1 HNMR(400MHz,DMSO)δ:11.38(s,1H),8.12(m,1H),8.00(m,1H),7.63–7.47(m,3H),7.39-7.36(m,1H),7.22-7.17(m, 4H),6.63(dd,J=9.0,2.0Hz,1H),6.28(s,1H),6.02(s,1H),4.68(m,2H),4.18(m,1H),3.83-3.80(m,2H),3.58-3.51 (m,1H),3.45–3.41(m,2H),3.31-3.14(m,4H),2.99(m,2H),2.92-2.91(m,2H),2.04-1.96(m,2H),1.76–1.73(m,6H) ,1.54-1.48(m,5H),1.42–1.39(m,2H),1.34(m,2H),1.30-1.29(m,4H),1.24(m,2H),1.19-1.14(m,9H).MS(ESI)m / z 963.0[M+H] + .

[0581] Example 4

[0582] (61R,62R)-96-(((((S)-1,4-dioxan-2-yl)methyl)amino)-15-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-95-nitro-31H-2,4,8-trioxa-10-thia-11-aza-3(5,6)-pyrrolo[2,3-b]pyridine-1(1,2),9(1,3)-diphenyl-6(1,2)-cyclopropanecyclododec-12-one-10,10-dioxide

[0583]

[0584] Step a:

[0585] E-(1R,2R)-cyclopropane-1,2-diacyl chloride

[0586]

[0587] E-(1R,2R)-cyclopropane-1,2-dicarboxylic acid (1.0 equivalent, 15.37 mmol, 2 g) and sulfurous dichloride (10.0 equivalent, 154 mmol, 18.29 g) were added to the reaction flask. The reaction mixture was then stirred at 85°C for 3 hours. After the reaction was complete, the resulting mixture was evaporated in vacuo to afford 2.57 g of the crude product as a white solid, which was used in the next step without further purification.

[0588] Step b:

[0589] P1: Bis((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)(1S,2S)-cyclopropane-1,2-dicarboxylate

[0590] P2: Bis((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)(1R,2R)-cyclopropane-1,2-dicarboxylate

[0591]

[0592] To a suspension of E-(1R,2R)-cyclopropane-1,2-diacyl chloride (1.0 equiv, 15.39 mmol, 2.57 g) in toluene (30 mL) was added (1R,2S,5R)-2-isopropyl-5-methylcyclohexan-1-ol (2.5 equiv, 38.5 mmol, 6.01 g) and pyridine (5.0 equiv, 77 mmol, 6.09 g) under an ice-water bath. The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was dissolved in water and diluted with EA. The organic layer was washed with 1N HCl solution, water, saturated NaHCO3 solution and brine, separated, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (PE and EA, EA range of 0 to 1%) to give 950 mg of product P1 as a white solid with a yield of 15.18% and 917 mg of P2 with a yield of 14.65%. The mixture solid was dissolved in warm methanol to give colorless needles, which were then recrystallized three times to give optically pure P1.

[0593] Step c:

[0594] ((1R,2R)-cyclopropane-1,2)dimethanol

[0595]

[0596] To a suspension of bis((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)(1R,2R)-cyclopropane-1,2-dicarboxylate (1.0 equiv, 2.26 mmol, 917 mg) in THF (30 mL) was added lithium aluminum (III) hydride (4.0 equiv, 9.02 mmol, 342 mg) under N2 with an ice-water bath. The reaction mixture was then stirred at 75°C overnight. After completion of the reaction, the resulting mixture was dissolved in water (2.3 mL), 15% NaOH solution (2.3 mL) and H2O (6.9 mL) at 0°C, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range of 0-10%) to give 176 mg of the product as a light oil in 76% yield.

[0597] Step d:

[0598] ((1R,2R)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanol

[0599]

[0600] To a suspension of ((1R,2R)-cyclopropane-1,2-diyl)dimethanol (1.0 equiv, 1.72 mmol, 176 mg) in DMF (15 mL) under N₂ in an ice-water bath were added tert-butylchlorodiphenylsilane (1.0 equiv, 1.72 mmol, 474 mg) and 1H-imidazole (1.0 equiv, 1.72 mmol, 117 mg). The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-25%) to afford 227 mg of the product as a light oil in a 38.7% yield.

[0601] Step e:

[0602] Methyl ((1R,2R)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanesulfonate

[0603]

[0604] To a suspension of ((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanol (1.0 equiv, 0.67 mmol, 228 mg), N,N-dimethylpyridin-4-amine (0.6 equiv, 0.40 mmol, 49.1 mg), and triethylamine (3.0 equiv, 2.0 mmol, 203 mg) in DCM (15 mL) was added methanesulfonyl chloride (1.2 equiv, 0.80 mmol, 92 mg). The reaction mixture was then stirred at 25°C for 3 hours. After completion of the reaction, the resulting mixture was diluted with DCM and washed with brine. The organic layer was separated, dried over NaSO, filtered, and concentrated in vacuo to afford 280 mg of the crude product as a yellow oil, which was used in the next step without further purification.

[0605] Step f:

[0606] 4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-(((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methoxy)-N,N-bis(4-methoxybenzyl)-5-nitrobenzenesulfonamide

[0607]

[0608] To a suspension of (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-hydroxy-N,N-bis(4-methoxyphenyl)-5-nitrobenzenesulfonamide (1.0 equiv, 0.488 mmol, 280 mg), ((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanesulfonate (1.4 equiv, 0.683 mmol, 286 mg), and KCO (3.0 equiv, 1.464 mmol, 202 mg) in ACN (15 mL) was added TBAI (0.5 equiv, 0.24 mmol, 90 mg). The reaction mixture was then stirred at 85° C. overnight. After completion of the reaction, the resulting mixture was evaporated, added with water, extracted with EA, and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-33%) to give 413 mg of the product in 94% yield as a yellow oil. MS (ESI) m / z 897.0 [M+H] + .

[0609] Step g:

[0610] 4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)methoxy)-N,N-bis(4-methoxybenzyl)-5-nitrobenzenesulfonamide

[0611]

[0612] To a suspension of 4-(((((S)-1,4-dioxan-2-yl)methyl)amino)-3-(((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-cyclopropyl)methoxy)-N,N-bis(4-methoxybenzyl)-5-nitrobenzenesulfonamide (1.0 eq., 0.461 mmol, 413 mg) in THF (15 mL) under N2 was added tetrabutylammonium fluoride (1.2 eq., 0.553 mmol, 145 mg). The reaction mixture was then stirred at 25°C for 3 h. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0-2%) to give 291 mg of the product in a 96% yield as a yellow solid. MS (ESI) m / z 658.8[M+H] + .

[0613] Step h:

[0614] Methyl ((1R,2R)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitrophenoxy)methyl)cyclopropyl)methanesulfonate

[0615]

[0616] To a suspension of 4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)methoxy)-N,N-bis(4-methoxybenzyl)-5-nitrobenzenesulfonamide (1.0 equiv, 0.44 mmol, 291 mg), N,N-dimethylpyridin-4-amine (0.6 equiv, 0.26 mmol, 32.4 mg), and triethylamine (3.0 equiv, 1.3 mmol) (134 mg) in DCM (15 mL) was added methanesulfonyl chloride (1.2 equiv, 0.53 mmol, 60.8 mg) in an ice-water bath. The reaction mixture was then stirred at 25° C. for 3 hours. After completion of the reaction, the resulting mixture was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give 326 mg of crude product as a yellow oil, which was used in the next step without further purification.

[0617] Step i:

[0618] Methyl 2-((6-(((1R,2R)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitrophenoxy)methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate

[0619]

[0620] To a suspension of ((1R,2R)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitrophenoxy)methyl)cyclopropyl)methanesulfonate (1.0 eq, 0.44 mmol, 326 mg), 4-fluoro-2-((6-hydroxy-1H-pyrrolo[2,3-b]pyridine)methyl-5-yl)oxy)benzoate (1.3 eq, 0.576 mmol, 174 mg) and K2CO3 (3.0 eq, 1.33 mmol, 184 mg) in acetonitrile (15 mL) was added TBAI (0.5 eq, 0.22 mmol, 82 mg). The reaction mixture was then stirred at 85° C. overnight. After the reaction was complete, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to yield the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH in the range of 0-5%) to give 229 mg of the product, a 54.9% yield, as a yellow solid. MS (ESI) m / z 942.9 [M+H]+.

[0621] Step j:

[0622] Methyl 2-((6-(((1R,2R)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitrophenoxy)methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate

[0623]

[0624] To a suspension of methyl 2-((6-(((1R,2R)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitrophenoxy)methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 equiv, 0.24 mmol, 229 mg) and (S)-2-(2-(2-isopropylphenyl)pyridin-1-yl)-7-azaspiro[3.5]nonane (10.0 equiv, 2.43 mmol, 760 mg) in DMF (15 mL) was added NaCO (20.0 equiv, 4.86 mmol, 515 mg) under N. The reaction mixture was then stirred at 100° C. overnight. After the reaction was complete, the resulting mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to yield the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH in the range of 0-2.5%) to yield 100 mg of the product in a 33.3% yield as a yellow solid. MS (ESI) m / z 1234.9 [M+H] + .

[0625] Step k:

[0626] Methyl 2-((6-(((1R,2R)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitro-5-sulfamoylphenoxy)))methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonyl-7-yl)benzoate

[0627] Methyl 2-((6-(((1R,2R)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitrophenoxy)methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonyl-7-yl)benzoate (1.0 eq, 0.081 mmol, 100 mg) and TFA (10.0 eq, 0.81 mmol, 92 mg) were added to the reaction flask. The reaction mixture was then stirred at 60 ° C under N2 for 40 minutes. After completion of the reaction, the resulting mixture was evaporated, diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0-6%) to give 42 mg of the product in a yield of 52.2% as a yellow solid. MS (ESI) m / z 995.0 [M+H] + .

[0628] Step 1:

[0629] 2-((6-(((1R,2R)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitro-5-sulfamoylphenoxy))methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid

[0630]

[0631] To a suspension of methyl 2-((6-(((1R,2R)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitro-5-sulfamoylphenoxy)))methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonyl-7-yl)benzoate (1.0 equiv, 0.433 mmol, 17.3 mg) in THF (2 mL) and EtOH (2 mL) was added sodium hydroxide (10.0 equiv, 0.433 mmol, 17.3 mg) under N2. The reaction mixture was then stirred at 50°C for 1 hour. After the reaction was complete, the resulting mixture was diluted with water, washed with 1N HCl solution, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 42 mg of the crude product as a yellow solid, which was used directly in the next step without further purification. MS (ESI) m / z 980.8 [M+H] + .

[0632] Step m:

[0633] (61R,62R)-96-(((((S)-1,4-dioxan-2-yl)methyl)amino)-15-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-95-nitro-31H-2,4,8-trioxa-10-thia-11-aza-3(5,6)-pyrrolo[2,3-b]pyridine-1(1,2),9(1,3)-diphenyl-6(1,2)-cyclopropanecyclododec-12-one-10,10-dioxide

[0634]

[0635] 2-((6-(((1R,2R)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitro-5-sulfamoylphenoxy))methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid (1.0 equiv, 0.043 mmol, 42 mg) and EDCI (2.0 equiv, 0.086 mmol, 16.43 mg) in DCM (8 mL) were added DMAP (2.0 equiv, 0.86 mmol, 10.47 mg). The reaction mixture was then stirred at 30° C. overnight. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give 3 mg of yellow solid product, 7.28% (two-step yield). 1HNMR (400 MHz, DMSO) δ: 11.14 (s, 1H), 7.93 (s, 1H), 7.59-7.50 (m, 3H), 7.22–7.05 (m, 6H), 6.62-6.60 (d, J = 8.6 Hz, 1H), 6.17 (s, 1H), 6.11 (s, 1H), 4.77-4.75 (m, 1H), 4.03–3.98 (m, 3H), 3.7 7–3.67(m,6H),3.64–3.54(m,4H),2.91-2.98(m,7H),2.19(m,1H),2.03–1.97(m,1H),1.80-1 .76(m,4H),1.50(m,3H),1.41–1.34(m,4H),1.13-1.18(m,8H),0.54-0.47(m,2H).MS(ESI)m / z 962.8[M+H]+.

[0636] Example 5

[0637] (61S,62S)-96-(((((S)-1,4-dioxan-2-yl)methyl)amino)-15-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-95-nitro-31H-2,4,8-trioxa-10-thia-11-aza-3(5,6)-pyrrolo[2,3-b]pyridine-1(1,2),9(1,3)-diphenyl-6(1,2)-cyclopropanecyclododec-12-one-10,10-dioxide

[0638]

[0639] Step a:

[0640] ((1S,2S)-cyclopropane-1,2-diyl)dimethanol

[0641]

[0642] In N 2下 To a suspension of bis((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)(1S,2S)-cyclopropane-1,2-dicarboxylate (1.0 equiv, 6.89 mmol, 2.8 g) in THF (30 mL) was added lithium aluminum(III) hydride (4.0 equiv, 27.5 mmol, 1.05 g) under an ice-water bath. The reaction mixture was then stirred at 75°C overnight. After completion of the reaction, the resulting mixture was dissolved in water (6.9 mL), 15% NaOH solution (6.9 mL) and H2O (21 mL) at 0°C, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0-10%) to give 774 mg of the product as a light oil in 110% yield.

[0643] Step b:

[0644] ((1S,2S)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanol

[0645]

[0646] To a suspension of ((1S,2S)-cyclopropane-1,2-diyl)dimethanol (1.0 equiv, 6.88 mmol, 703 mg) in DMF (15 mL) in an ice-water bath under N₂ was added tert-butylchlorodiphenylsilane (1.0 equiv, 6.88 mmol, 1.89 g) and 1H-imidazole (1.0 equiv, 6.88 mmol, 469 mg). The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-25%) to afford 668 mg of the product as a light oil in a 28.5% yield.

[0647] Step c:

[0648] ((1S,2S)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanesulfonate

[0649]

[0650] To a suspension of ((1S,2S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanol (1.0 equiv, 1.96 mmol, 668 mg), N,N-dimethylpyridin-4-amine (0.6 equiv, 1.18 mmol, 144 mg), and triethylamine (3.0 equiv, 5.88 mmol, 596 mg) in DCM (25 mL) was added methanesulfonyl chloride (1.2 equiv, 2.35 mmol, 270 mg) in an ice-water bath. The reaction mixture was then stirred at 25°C for 3 hours. After completion of the reaction, the resulting mixture was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to afford 821 mg of the crude product as a yellow oil, which was used in the next step without further purification.

[0651] Step d:

[0652] 4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-(((1S,2S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methoxy)-N,N-bis(4-methoxybenzyl)-5-nitrobenzenesulfonamide

[0653]

[0654] To a suspension of (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-hydroxy-N,N-bis(4-methoxyphenyl)-5-nitrobenzenesulfonamide (1.0 equiv, 1.63 mmol, 937 mg), ((1S,2S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanesulfonate (1.4 equiv, 2.29 mmol, 957 mg) and KCO (3.0 equiv, 4.90 mmol, 677 mg) in acetonitrile (25 mL) was added TBAI (0.5 equiv, 0.82 mmol, 302 mg). The reaction mixture was then stirred at 85° C. overnight. After completion of the reaction, the resulting mixture was evaporated, added with water, extracted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-33%) to give 1.2 g of the product in 82% yield as a yellow oil. MS (ESI) m / z 896.9 [M+H] + .

[0655] Step e:

[0656] 4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-N,N-bis(4-methoxybenzyl)-5-nitrobenzenesulfonamide

[0657]

[0658] To a suspension of 4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-(((1S,2S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-cyclopropyl)methoxy)-N,N-bis(4-methoxybenzyl)-5-nitrobenzenesulfonamide (1.0 eq, 1.34 mmol, 1.2 g) in THF (25 ml) was added tetrabutylammonium fluoride (1.2 eq, 1.61 mmol, 420 mg) under N2. The reaction mixture was then stirred at 25 ° C for 3 hours. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-33%) to give 865 mg of the product in a 98% yield as a yellow solid.

[0659] Step f:

[0660] Methyl ((1S,2S)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitrophenoxy)methyl)cyclopropyl)methanesulfonate

[0661]

[0662] To a suspension of 4-(((((S)-1,4-dioxan-2-yl)methyl)amino)-3-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-N,N-bis(4-methoxybenzyl)-5-nitrobenzenesulfonamide (1.0 equiv, 1.32 mmol, 865 mg), N,N-dimethylpyridin-4-amine (0.6 equiv, 0.79 mmol, 96 mg), and triethylamine (3.0 equiv, 3.95 mmol, 399 mg) in DCM (15 mL) was added methanesulfonyl chloride (1.2 equiv, 1.58 mmol, 181 mg). The reaction mixture was then stirred at 25° C. for 3 hours. After completion of the reaction, the resulting mixture was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to afford 968 mg of the crude product as a yellow oil, which was used in the next step without further purification.

[0663] Step g:

[0664] Methyl 2-((6-(((1S,2S)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitrophenoxy)methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate

[0665]

[0666] To a suspension of ((1S,2S)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-5-(N,N-bis(4-))methoxybenzyl)sulfamoyl)-3-nitrophenoxy)methyl)cyclopropyl)methanesulfonate (1.0 eq, 1.32 mmol, 970 mg), 4-fluoro-2-((6-hydroxy-1H-pyrrolo[2,3-b]pyridinyl)methyl-5-yl)oxy)benzoate (1.2 eq, 1.58 mmol, 478 mg) and K2CO3 (3.0 eq, 3.95 mmol, 547 mg) in acetonitrile (25 mL) was added TBAI (0.5 eq, 0.66 mmol, 243 mg) under N2. The reaction mixture was then stirred at 85°C overnight. After completion of the reaction, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 5%) to give 750 mg of the product in a 60.4% yield as a yellow solid. MS (ESI) m / z 942.7 [M+H] + .

[0667] Step h:

[0668] Methyl 2-((6-(((1S,2S)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitrophenoxy)methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate

[0669]

[0670] Under N2, methyl 2-((6-(((1S,2S)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitrophenoxy)methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 equiv, 0.32 mmol, 300 mg) and (S)-2-(2-(2-isopropylphenyl)pyridin-1-yl)-7-azaspiro[3.5]nonane (10.0 equiv, 3.18 mmol, 995 mg) were added Na2CO3 (20.0 equiv, 6.37 mmol, 675 mg) in DMF (15 mL). The reaction mixture was then stirred at 100°C overnight. After the reaction was complete, the resulting mixture was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH ranging from 0 to 2.5%) to give 140 mg of the product, a 35.6% yield, as a yellow solid. MS (ESI) m / z 1234.9 [M+H] + .

[0671] Step i:

[0672] Methyl 2-((6-(((1S,2S)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitro-5-sulfamoylphenoxy)))methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonyl-7-yl)benzoate

[0673]

[0674] To the reaction flask was added methyl 2-((6-(((1S,2S)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitrophenoxy)methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonyl-7-yl)benzoate (1.0 eq, 0.11 mmol, 140 mg) and TFA (10.0 eq, 1.13 mmol, 129 mg). The reaction mixture was then stirred at 60 ° C under N2 for 40 minutes. After completion of the reaction, the resulting mixture was evaporated, diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0-6%) to give 56 mg of the product in a 49.7% yield as a yellow solid. MS (ESI) m / z 995.1 [M+H] + .

[0675] Step j:

[0676] 2-((6-(((1S,2S)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitro-5-sulfamoylphenoxy))methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid

[0677]

[0678] Under N2 protection, methyl 2-((6-(((1S,2S)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitro))-5-sulfamoylphenoxy)methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonyl-7-yl)benzoate (1.0 equiv, 0.56 mmol, 22.5 mg) was added to a suspension of THF (2 mL) and EtOH (2 mL) with sodium hydroxide (10.0 equiv). The reaction mixture was then stirred at 50°C for 2 hours. After completion of the reaction, the resulting mixture was diluted with water, washed with 1N HCl solution, and extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 55.2 mg of crude yellow solid product, which was used in the next step without further purification. MS (ESI) m / z 981.1 [M+H] + .

[0679] Step k:

[0680] (61S,62S)-96-(((((S)-1,4-dioxan-2-yl)methyl)amino)-15-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-95-nitro-31H-2,4,8-trioxa-10-thia-11-aza-3(5,6)-pyrrolo[2,3-b]pyridine-1(1,2),9(1,3)-diphenyl-6(1,2)-cyclopropanecyclododec-12-one-10,10-dioxide

[0681]

[0682] To a suspension of 2-((6-(((1S,2S)-2-((2-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitro-5-sulfamoylphenoxy))methyl)cyclopropyl)methoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid (1.0 equiv, 0.056 mmol, 55 mg) and EDCI (2.0 equiv, 0.11 mmol, 21.5 mg) in DCM (8 mL) was added DMAP (2.0 equiv, 0.11 mmol, 13.7 mg). The reaction mixture was then stirred at 30° C. overnight. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give 7 mg of the product as a yellow solid, 13.0% (yield over two steps). 1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 8.26 (s, 1H), 7.91 (m, 1H), 7.56-7.49 (m, 3H), 7.23-7.19 (m, 5H), 7.01 (s, 1H), 6.62-6.64 (d, J = 8.7 Hz, 1H), 6.17-6.14 (m, 2H), 4.88-4.86 (m, 1H), 4.15 (m, 1H), 3.97–3.92(m,3H),3.80–3.64(m,6H),3.47(m,3H),3.02-2.94(m,7H),2.22(m,1H),2.05–1.97( m,1H),1.83-1.76(m,4H),1.51(m,3H),1.42-1.35(m,4H),1.23-1.13(m,8H),0.55–0.50(m,2H). MS(ESI)m / z 962.8[M+H]+.

[0683] Example 6

[0684] (S)-35-(6-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]hept-2-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[0685]

[0686] Step a:

[0687] (S)-tert-Butyl 6-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0688]

[0689] To a suspension of (S)-2-(2-isopropylphenyl)pyrrolidine (1.0 equiv, 3.17 mmol, 600 mg) and tert-butyl 6-oxo-2-azaspiro[3.3]hexane-2-carboxylate (2.0 equiv, 6.34 mmol, 1.34 g) in DCE (30 mL) was added sodium triacetylborohydride (2.0 equiv, 6.34 mmol, 1.04 g). The reaction mixture was then stirred at 45°C for 6 hours. After completion of the reaction, the residue was dissolved in saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0 to 25%) to afford 1.22 g of the product in 100% yield as a yellow oil. MS (ESI) m / z 401.5 [M+H] + .

[0690] Step b:

[0691] (S)-6-(2-(2-Isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane

[0692]

[0693] To the reaction flask was added tert-butyl (S)-6-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (1.0 equiv, 4.03 mmol, 1.55 g) and TFA (10.0 equiv, 40.3 mmol, 4.6 g). The reaction mixture was then stirred at 25°C for 30 minutes. After completion of the reaction, the resulting mixture was evaporated, diluted with ethyl acetate and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range from 0 to 10%) to give the product (920 mg, 80% yield) as a yellow oil. MS (ESI) m / z 301.4 [M+H] + .

[0694] Step c:

[0695] (S)-methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl))methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]hept-2-yl)benzoate

[0696]

[0697] To a suspension of methyl 2-((6-(4-(5-(N,N-bis(4-methoxyphenyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl))methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 eq, 0.32 mmol, 300 mg) and (S)-6-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane (10.0 eq, 3.32 mmol, 920 mg) in DMF (15 mL) was added NaCO (20.0 eq, 6.47 mmol, 685 mg) under N. The reaction mixture was then stirred at 100° C. overnight. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 2.5%) to give 80 mg of the product in a 20.8% yield as a yellow solid. MS (ESI) m / z 1193.5 [M+H] + .

[0698] Step d:

[0699] (S)-methyl 4-(6-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]hept-2-yl)-2-((6-(4-(3-)nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate

[0700]

[0701] To the reaction flask was added (S)-methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran))-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzoate (1.0 equiv, 0.067 mmol, 80 mg) and TFA (10.0 equiv, 0.67 mmol 76 mg). The reaction mixture was then stirred at 60 ° C under N2 for 40 minutes. After completion of the reaction, the resulting mixture was evaporated, diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 6%) to give the product 38 mg, 59.5% yield, as a yellow solid. MS (ESI) m / z 953.0 [M+H] + .

[0702] Step e:

[0703] (S)-4-(6-(2-(2-Isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]hept-2-yl)-2-((6-(4-(3-nitro)-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid

[0704]

[0705] To a suspension of (S)-methyl 4-(6-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]hept-2-yl)-2-((6-(4-(3-)nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.0 equiv, 0.04 mmol, 38 mg) in THF (2 mL) and EtOH (2 mL) under N2 was added sodium hydroxide (10.0 equiv, 0.40 mmol, 16.0 mg). The reaction mixture was then stirred at 50 °C for 2 h. After completion of the reaction, the resulting mixture was diluted with water, washed with 1N HCl solution, and extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 37.4 mg of crude product as a yellow solid, which was used directly in the next step. MS (ESI) m / z 939.0 [M+H] + .

[0706] Step f:

[0707] (S)-35-(6-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]hept-2-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[0708]

[0709] To a suspension of (S)-4-(6-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]hept-2-yl)-2-((6-(4-(3-nitro)-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid (1.0 eq, 0.039 mmol, 37 mg) and EDCI (2.0 eq, 0.079 mmol, 15.1 mg) in DCM (8 mL) was added DMAP (2.0 eq, 0.079 mmol, 9.64 mg). The reaction mixture was then stirred at 30 °C overnight. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give 5.6 mg as a yellow solid, 15.4% yield (yield over two steps). 1 H NMR (400MHz, DMSO) δ11.44(s,1H),8.14(s,1H),8.01(s,1H),7.66-7.64(m,1H),7.48–7.45(m,2H),7. 39(s,1H),7.21–7.07(m,4H),6.30(s,1H),6.02(dd,J=8.6,1.7Hz,1H),4.44(m,2H),4.19-4.16(m,2H) ,3.82-3.78(m,2H),3.62–3.55(m,3H),3.49-3.44(m,4H),3.25-3.19(m,3H),3.13-3.09(m,1H),2.16 –1.97(m,4H),1.90-1.85(m,2H),1.79–1.69(m,8H),1.53-1.46(m,3H),1.18-1.12(m,8H).MS(ESI)m / z 921.13[M+H] + .

[0710] Example 7

[0711] (S)-35-(2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[0712]

[0713] Step a:

[0714] (S)-2-(2-Methoxyphenyl)pyrrolidine

[0715]

[0716] To a suspension of (S)-2-(2-bromophenyl)pyrrolidine (1.0 equiv, 4.42 mmol, 1 g) and sodium methoxide (6.0 equiv, 26.5 mmol, 1.43 g) in methanol (20 mL) was added copper(I) bromide (0.5 equiv, 2.21 mmol, 317 mg). The reaction mixture was then stirred at 80°C for 16 hours. After completion of the reaction, the resulting mixture was concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0-6%) to afford 700 mg of an oil in 89% yield. MS (ESI) m / z 178.4 [M+H] + .

[0717] Step b:

[0718] (S)-tert-Butyl 2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0719]

[0720] To a suspension of (S)-2-(2-methoxyphenyl)pyrrolidine (1.0 equiv, 4.16 mmol, 738 mg) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (2.0 equiv, 8.33 mmol, 1.99 g) in DCE (30 mL) was added sodium triacetylborohydride (2.0 equiv, 8.33 mmol, 1.37 g). The reaction mixture was then stirred at 45°C for 6 hours. After completion of the reaction, the residue was dissolved in saturated NaHCO3 solution and extracted with DCM. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-20%) to give the product 1.67 g in 100% yield as a yellow oil. MS (ESI) m / z 401.9 [M+H] + .

[0721] Step c:

[0722] (S)-2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane

[0723]

[0724] To the reaction flask was added tert-butyl (S)-2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 equiv, 4.24 mmol, 1.7 g) and TFA (10.0 equiv, 42.4 mmol, 4.84 g). The reaction mixture was then stirred at 25°C for 30 minutes. After completion of the reaction, the resulting mixture was evaporated, diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 10%) to give 880 mg of the product in 69% yield as a yellow oil. MS (ESI) m / z 301.3 [M+H] + .

[0725] Step d:

[0726] (S)-methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl))methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate

[0727]

[0728] To a suspension of methyl 2-((6-(4-(5-(N,N-bis(4-methoxyphenyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl))methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 eq, 0.32 mmol, 300 mg) and (S)-2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (10.0 eq, 3.23 mmol, 971 mg) in DMF (15 ml) was added NaCO (20.0 eq, 6.47 mmol, 685 mg) under N2. The reaction mixture was then stirred at 100°C overnight. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 2.5%) to give the product 70 mg, 17.9% yield. MS (ESI) m / z 1208.6 [M+H] + .

[0729] Step e:

[0730] (S)-methyl 4-(2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonyl-7-yl)-2-((6-(4-(3-)nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate

[0731]

[0732] Under N protection, (S)-methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran))-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-methoxyphenyl)pyrrolidin-1-)yl)-7-azaspiro[3.5]nonan-7-yl)benzoate (1.0 equiv, 0.058 mmol, 70 mg) and TFA (10.0 equiv, 0.58 mmol, 66 mg) were added to the reaction flask. The reaction mixture was then stirred at 60° C. for 40 minutes. After completion of the reaction, the resulting mixture was evaporated, diluted with EA, and washed with saturated NaHCO solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0-6%) to give 20 mg of the product in a 35.7% yield as a yellow solid. MS (ESI) m / z 969.0 [M+H] + .

[0733] Step f:

[0734] (S)-4-(2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(4-(3-nitro)-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid

[0735]

[0736] To a suspension of (S)-methyl 4-(2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonyl-7-yl)-2-((6-(4-(3-)nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.0 eq, 0.02 mmol, 20 mg) in THF (2 mL) and EtOH (2 mL) was added sodium hydroxide (10.0 eq, 0.21 mmol, 8.26 mg) under N protection. The reaction mixture was then stirred at 50 ° C for 1 hour. After completion of the reaction, the resulting mixture was diluted with water, washed with 1N HCl solution, and extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 19 mg of a yellow solid, which was used directly in the next step. MS (ESI) m / z 955.0 [M+H] + .

[0737] Step g:

[0738] (S)-35-(2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[0739]

[0740] To a suspension of (S)-4-(2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(4-(3-nitro)-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid (1.0 eq, 0.02 mmol, 19 mg) and EDCI (2.0 eq, 0.04 mmol, 7.64 mg) in DCM (8 mL) was added DMAP (2.0 eq, 0.04 mmol, 4.87 mg). The reaction mixture was then stirred at 30 °C overnight. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give 1.5 mg of the product as a yellow solid, 8.1% (yield over two steps). MS (ESI) m / z 936.7 [M+H] + .

[0741] Example 8

[0742] (S)-35-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecane-4-

[0743] Ketone-6,6-dioxide

[0744]

[0745] Step a:

[0746] (S)-tert-Butyl 2-(2-(2-bromophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0747]

[0748] To a suspension of (S)-2-(2-bromophenyl)pyrrolidine (1.0 equiv, 22.11 mmol, 5 g) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (1.5 equiv, 33.2 mmol, 7.94 g) in DCE (30 mL) was added sodium triacetylborohydride (1.5 equiv, 33.2 mmol, 5.44 g). The reaction mixture was then stirred at 45° C. for 6 hours. After completion of the reaction, the residue was dissolved in saturated NaHCO 3 solution and extracted with DCM. The organic layer was separated, washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-20%) to give 9.1 g of the product in 92% yield as a yellow oil. MS (ESI) m / z 450.7 [M+H] + .

[0749] Step b:

[0750] (S)-tert-Butyl 2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0751]

[0752] Under N2 protection, to tert-butyl (S)-2-(2-(2-bromophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 equiv, 4.45 mmol, 2 g) suspended in dioxane (18.0 mL) and water (2.0 mL) were added PdCl2(dppf) (0.1 equiv, 0.45 mmol, 0.33 g), cyclopropylboronic acid (5.0 equiv, 22.3 mmol, 1.9 g) and K2CO3 (5.0 equiv, 22.3 mmol, 3.08 g). The reaction mixture was then stirred at 100°C for 16 hours. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-20%) to give 1.1 g of the product in a 60.2% yield as a yellow oil. MS (ESI) m / z 412.2 [M+H] + .

[0753] Step c:

[0754] (S)-2-(2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane

[0755]

[0756] To the reaction flask was added tert-butyl (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 equiv, 2.68 mmol, 1.1 g) and TFA (10.0 equiv, 26.8 mmol, 3.05 g). The reaction mixture was then stirred at 25° C. for 30 minutes. After completion of the reaction, the resulting mixture was evaporated, diluted with EA, and washed with saturated NaHCO 3 solution. The organic layer was separated, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and NH 3 in MeOH, NH 3 in MeOH ranging from 0 to 10) to give 800 mg of the product as a yellow oil in 96% yield. MS (ESI) m / z 311.4 [M+H] + .

[0757] Step d:

[0758] (S)-methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl))methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate

[0759]

[0760] To a suspension of methyl 2-((6-(4-(5-(N,N-bis(4-methoxyphenyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl))methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 eq, 0.32 mmol, 300 mg) and (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (10.0 eq, 3.23 mmol, 1.04 g) in DMF (15 mL) was added NaCO (20.0 eq, 6.47 mmol, 685 mg) under N protection. The reaction mixture was then stirred at 100 ° C overnight. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0-2.5%) to give 150 mg of the product in a 38.1% yield as a yellow solid. MS (ESI) m / z 1218.9 [M+H] + .

[0761] Step e:

[0762] Methyl (S)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(4-(3-)nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate

[0763]

[0764] To the reaction flask was added (S)-methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl))methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate (1.0 equiv, 0.12 mmol, 150 mg) and TFA (10.0 equiv, 1.23 mmol, 140 mg). The reaction mixture was then stirred at 60° C. under N for 40 minutes. After completion of the reaction, the resulting mixture was evaporated, diluted with EA, and washed with saturated NaHCO solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0-6%) to give 65 mg of the product in 54% yield as a yellow solid. MS (ESI) m / z 978.9 [M+H] + .

[0765] Step f:

[0766] (S)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(4-(3-nitro)-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid

[0767]

[0768] To a suspension of (S)-methyl 4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(4-(3-)nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.0 eq, 0.066 mmol, 65 mg) in THF (2 mL) and EtOH (2 mL) was added sodium hydroxide (10.0 eq, 0.66 mmol, 26.6 mg) under N2. The reaction mixture was then stirred at 50 °C for 1 hour. After completion of the reaction, the resulting mixture was diluted with water, washed with 1N HCl solution, and extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 64 mg of crude product as a yellow solid, which was used directly in the next step. MS (ESI) m / z 965.0 [M+H] + .

[0769] Step g:

[0770] (S)-35-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[0771]

[0772] To a suspension of (S)-methyl 4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(4-(3-)nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.0 equiv, 0.066 mmol, 64 mg) and EDCI (2.0 equiv, 0.13 mmol, 25.5 mg) in DCM (8 mL) was added DMAP (2.0 equiv, 0.13 mmol, 16.2 mg). The reaction mixture was then stirred at 30° C. overnight. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give 5.3 mg of product as a yellow solid, 8.4% (yield over two steps). 1H NMR (400MHz, DMSO) δ11.37(s,1H),8.08(s,1H),7.98(s,1H),7.54-7.50(m,3H),7.44(s,1H),7.16-7.14–7.04(m,3H ),6.95-6.93(m,1H),6.64-6.61(m,1H),6.27(s,1H),6.01(s,1H),4.47(m,2H),4.20-4.17(m,2H),3.83-3.79(m,2H ),3.48-3.45(m,2H),3.26–3.20(m,4H),3.13(m,1H),2.97-2.96(m,2H),2.89(m,2H),2.36–2.19(m,1H),2.07–1.74 (m,12H),1.55-1.51(m,4H),1.41–1.35(m,4H),1.21–1.15(m,2H),0.91-0.86(m,2H),0.65–0.55(m,2H).MS(ESI)m / z 946.8[M+H] + .

[0773] Example 9

[0774] (S)-35-(2-(2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[0775]

[0776] Step a:

[0777] (S)-tert-Butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate

[0778]

[0779] To a suspension of (S)-2-(2-bromophenyl)pyrrolidine (1.0 equiv, 4.42 mmol, 1 g) in DCM (15 mL) were added N,N-dimethylpyridin-4-amine (0.2 equiv, 0.88 mmol, 0.11 g), di-tert-butyl dicarbonate (1.2 equiv, 5.3 mmol, 1.16 g), and triethylamine (2.0 equiv, 8.84 mmol, 0.89 g). The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-10%) to afford 1.4 g of the product as a light oil in 97% yield.

[0780] Step b:

[0781] (S)-tert-Butyl 2-(2-((diphenylmethylene)amino)phenyl)pyrrolidine-1-carboxylate

[0782]

[0783] To a suspension of (S)-tert-butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate (1.0 equiv, 3.98 mmol, 1.3 g) and diphenylcarbamate (2.0 equiv, 7.97 mmol, 1.44 g) in dioxane (25 mL) was added Pd(dba) (0.1 equiv, 0.40 mmol, 0.36 g), Xantphos (0.3 equiv, 1.20 mmol, 0.92 g), and CsCO (3.0 equiv, 11.95 mmol, 3.9 g). The reaction mixture was then stirred at 110°C overnight. After completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over NaSO, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, 0-16% EA) to afford 1.8 g of the product in a 63.5% yield as a yellow oil. MS (ESI) m / z 427.4 [M+H] + .

[0784] Step c:

[0785] (S)-tert-Butyl 2-(2-aminophenyl)pyrrolidine-1-carboxylate

[0786]

[0787] To a suspension of (S)-tert-butyl 2-(2-((diphenylmethylene)amino)phenyl)pyrrolidine-1-carboxylate (1.0 equiv, 4.22 mmol, 1.8 g) in THF (10 mL) was added 0.5 N HCl (2.0 equiv, 8.44 mmol, 0.31 g). The reaction mixture was then stirred at 25° C. overnight. After completion of the reaction, the resulting mixture was dissolved in saturated NaHCO 3 solution and extracted with EA. The organic layer was separated, washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH ranging from 0 to 2%) to afford 225 mg of the product in a 20.3% yield as a yellow oil. MS (ESI) m / z 263.3 [M+H] + .

[0788] Step d:

[0789] (S)-tert-Butyl 2-(2-(dimethylamino)phenyl)pyrrolidine-1-carboxylate

[0790]

[0791] To a suspension of (S)-tert-butyl 2-(2-aminophenyl)pyrrolidine-1-carboxylate (1.0 equiv, 0.85 mmol, 224 mg) in MeOH (10 mL) were added HCHO (6.0 equiv, 5.12 mmol, 154 mg) and NaBH3CN (5.0 equiv, 4.27 mmol, 268 mg). The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was dissolved in saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH ranging from 0 to 3%) to afford 188 mg of the product in 76% yield as a yellow oil. MS (ESI) m / z 291.8 [M+H] + .

[0792] Step e:

[0793] (S)-N,N-Dimethyl-2-(pyrrolidin-2-yl)aniline

[0794]

[0795] To a suspension of (S)-tert-butyl 2-(2-(dimethylamino)phenyl)pyrrolidine-1-carboxylate (1.0 equiv, 0.65 mmol, 188 mg) in MeOH (5 mL) was added HCl (5 mL). The reaction mixture was then stirred at 25 ° C for 3 hours. After the reaction was complete, the resulting mixture was evaporated, NH3 in MeOH was added and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range of 0 to 10%) to give 63 mg of the product in 51.1% yield as a yellow oil. MS (ESI) m / z 191.3 [M + H] + .

[0796] Step f:

[0797] (S)-35-(2-(2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[0798]

[0799] To a suspension of 75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide (1.0 equiv, 0.018 mmol, 14 mg) and sodium triacetylborohydride (2.0 equiv, 0.036 mmol, 5.92 mg) in 1,2-dichloroethane (8 mL) was added (S)-N,N-dimethyl-2-(pyrrolidin-2-yl)aniline (2.0 equiv, 0.036 mmol, 6.88 mg). The reaction mixture was then stirred at 45°C overnight. After the reaction was complete, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give 1.7 mg of the product as a yellow solid, 9.9% (two-step yield). MS (ESI) m / z 949.8 [M+H] + .

[0800] Example 10

[0801] (S)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-35-(2-(2-(o-tolyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[0802]

[0803] Step a:

[0804] (S)-tert-Butyl 2-(2-(2-bromophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0805]

[0806] To a suspension of (S)-2-(2-bromophenyl)pyrrolidine (1.0 equiv, 4.42 mmol, 1 g) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (1.5 equiv, 33.2 mmol, 7.94 g) in DCE (30 mL) was added sodium triacetylborohydride (2 equiv, 8.84 mmol, 2.12 g). The reaction mixture was then stirred at 45°C for 6 hours. After completion of the reaction, the residue was dissolved in saturated NaHCO3 solution and extracted with DCM. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0 to 20%) to afford 1.99 g of the product in 100% yield as a yellow oil. MS (ESI) m / z 465.4 [M+H] + .

[0807] Step b:

[0808] (S)-tert-Butyl 2-(2-(o-Tolyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0809]

[0810] To a suspension of (S)-tert-butyl 2-(2-(2-bromophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 equiv, 3.34 mmol, 1.5 g) in dioxane (20.0 mL) and water (2.0 mL) was added PdCl(dppf) (0.1 equiv, 0.33 mmol, 0.24 g), 2,4,6-trimethyl-1,3,5,2,4,6-trioxazolidine (10.0 equiv, 33.4 mmol, 8.38 g), and KCO (10.0 equiv, 33.4 mmol, 4.61 g) under N2. The reaction mixture was then stirred at 100°C for 16 hours. After completion of the reaction, the resulting mixture was dissolved in saturated NaHCO solution, diluted with ethyl acetate, and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-20%) to give 900 mg of the product in a 70.1% yield as a yellow oil. MS (ESI) m / z 403.7 [M+H] + .

[0811] Step c:

[0812] (S)-2-(2-(o-Tolyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane

[0813]

[0814] To a vial was added tert-butyl (S)-2-(o-tolyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 equiv, 2.42 mmol, 930 mg) and TFA (10.0 equiv, 24.2 mmol, 2.76 g). The reaction mixture was then stirred at 25°C for 30 minutes. After completion of the reaction, the resulting mixture was evaporated, diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and NH3 in MeOH, NH3 in MeOH ranging from 0 to 10%) to give 688 mg of the product as a yellow oil in 100% yield. MS (ESI) m / z 301.2 [M+H] + .

[0815] Step d:

[0816] (S)-methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl))methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(o-tolyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate

[0817]

[0818] To a suspension of methyl 2-((6-(4-(5-(N,N-bis(4-methoxyphenyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl))methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 equiv, 0.27 mmol, 250 mg) and (S)-2-(2-(o-tolyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (9.0 equiv, 2.43 mmol, 690 mg) in DMF (15 ml) under N was added NaCO (20.0 equiv, 5.39 mmol, 571 mg). The reaction mixture was then stirred at 105 ° C overnight. After completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 2.5%) to give 60 mg of the product as a yellow solid, in an 18.7% yield. MS (ESI) m / z 1192.8 [M+H] + .

[0819] Step e:

[0820] (S)-methyl 2-((6-(4-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(o-methylphenyl)pyrrol-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate

[0821]

[0822] To the reaction flask was added (S)-methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran))-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(o-tolyl)pyrrolidin-1-)yl)-7-azaspiro[3.5]nonan-7-yl)benzoate (1.0 equiv, 0.05 mmol, 60 mg) and TFA (10.0 equiv, 0.5 mmol, 57.4 mg). The reaction mixture was then stirred at 60° C. under N for 40 minutes. After completion of the reaction, the resulting mixture was evaporated, diluted with EA, and washed with saturated NaHCO solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 6%) to give 27 mg of the product, a yield of 56.4%, as a yellow solid. MS (ESI) m / z 952.6 [M+H] + .

[0823] Step f:

[0824] (S)-2-((6-(4-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(o-methylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid

[0825]

[0826] To a suspension of (S)-methyl 2-((6-(4-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(o-methylphenyl)pyrrol-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate (1.0 equiv, 0.028 mmol, 27 mg) in THF (2 mL) and EtOH (2 mL) was added sodium hydroxide (10.0 equiv, 0.28 mmol, 11.3 mg) under N2. The reaction mixture was then stirred at 50 °C for 1 hour. After completion of the reaction, the resulting mixture was diluted with water, washed with 1N HCl solution, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 26 mg of crude product as a yellow solid, which was used directly in the next step. MS (ESI) m / z 938.6 [M+H] + .

[0827] Step g:

[0828] (S)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-35-(2-(2-(o-tolyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[0829]

[0830] To a suspension of (S)-2-((6-(4-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(o-methylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid (1.0 equiv, 0.028 mmol, 26 mg) and EDCI (2.0 equiv, 0.055 mmol, 10.6 mg) in DCM (8 mL) was added DMAP (2.0 equiv, 0.055 mmol, 6.7 mg). The reaction mixture was then stirred at 30° C. overnight. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give 3.1 mg of the product as a yellow solid, 12.2% (yield over two steps). 1H NMR (400 MHz, DMSO) δ 11.38 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.51-7.43 (m, 4H), 7.16-7.09 (m, 4H), 6.63-6.61 (m, 1H), 6.26 (s, 1H), 6.00 (s, 1H), 4.46 (m, 2H), 4.20-4.16 (m, 2H), 3.81-3.7 9(m,2H),3.48-3.44(m,2H),3.25-3.13(m,4H),2.97-2.88(m,4H),2.28(m,4H),2.01-1.93(m ,3H),1.81-1.76(m,6H),1.54-1.51(m,4H),1.41-1.34(m,6H),1.18–1.15(m,3H).MS(ESI)m / z 920.9[M+H]+.

[0831] Example 11

[0832] (S)-35-(2-(2-(2-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[0833]

[0834] To a suspension of 75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide (1.0 equiv, 0.026 mmol, 20 mg) and sodium triacetylborohydride (4.0 equiv, 0.10 mmol, 16.93 mg) in 1,2-dichloroethane (8 mL) was added (S)-2-(2-chlorophenyl)pyrrolidine (4.0 equiv, 0.10 mmol, 18.76 mg). The reaction mixture was then stirred at 50° C. overnight. After the reaction was complete, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give the product 7.7 mg as a yellow solid, 31.7%. 1 H NMR (400MHz, DMSO) δ11.43(s,1H),8.18(s,1H),8.02(s,1H),7.66-7.64(m,2H),7.49-7.47(m,1H),7.38–7.28 (m,3H),7.22-7.19(m,2H),6.63(d,J=8.0Hz,1H),6.30(s,1H),5.96(s,1H),4.45(m,2H),4.17–4.21(m,2H),3. 81-3.79(m,2H),3.49-3.46(m,2H),3.24-3.20(m,2H),3.12(m,1H),2.99-2.90(m,4H),2.22-2.20(m,1H),1.9 1(m,2H),1.79(m,7H),1.63-1.61(m,2H),1.54-1.51(m,3H),1.41-1.33(m,5H),1.23–1.13(m,4H).MS(ESI)m / z 940.9[M+H] + .

[0835] Example 12

[0836] (S)-35-(2-(2-(2-fluorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[0837]

[0838] To a suspension of 75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide (1.0 equiv, 0.026 mmol, 20 mg) and sodium triacetylborohydride (4.0 equiv, 0.10 mmol, 16.93 mg) in 1,2-dichloroethane (8 mL) was added (S)-2-(2-fluorophenyl)pyrrolidine (4.0 equiv, 0.10 mmol, 16.93 mg). The reaction mixture was then stirred at 50° C. overnight. After the reaction was complete, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give the product 10.1 mg as a yellow solid, 42.3%. 1H NMR (400MHz, DMSO) δ11.41(s,1H),8.14(s,1H),8.00(s,1H),7.70–7.45(m,3H),7.40(s,1H),7.30–7.00(m,4H ),6.62(d,J=8.7Hz,1H),6.28(s,1H),5.98(s,1H),4.56–4.38(m,2H),4.27–4.09(m,2H),3.82–3.77(m,2H),3 .47–3.45(m,2H),3.29–3.18(m,3H),3.05–2.94(m,2H),2.93–2.83(m,2H),2.26–2.11(m,1H),1.99–1.88(m,2 H),1.87–1.71(m,7H),1.70–1.49(m,6H),1.45–1.37(m,2H),1.37–1.27(m,3H),1.27–1.09(m,3H).MS(ESI)m / z 924.8[M+H] + .

[0839] Example 13

[0840] (S)-35-(2-(2-(2-(methylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[0841]

[0842] Step a:

[0843] (S)-Benzyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate

[0844]

[0845] To a suspension of (S)-2-(2-bromophenyl)pyrrolidine (1.0 equiv, 6.63 mmol, 1.5 g) in DCM (15 mL) were added benzyl chloroformate (1.2 equiv, 7.96 mmol, 1.36 g), N,N-dimethylpyridin-4-amine (0.2 equiv, 1.33 mmol, 0.16 g), and triethylamine (2.0 equiv, 13.3 mmol, 1.34 g). The reaction mixture was then stirred at 25°C overnight. Upon completion of the reaction, the resulting mixture was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-10%) to afford 2.33 g of the product in a 97% yield based on a light oil. MS (ESI) m / z 360.2 [M+H] + .

[0846] Step b:

[0847] (S)-Benzyl 2-(2-((diphenylmethylene)amino)phenyl)pyrrolidine-1-carboxylate

[0848]

[0849] To a suspension of (S)-benzyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate (1.0 equiv, 3.33 mmol, 1.2 g) and diphenylformamide (2.0 equiv, 6.66 mmol, 1.21 g) in dioxane (25 mL) was added Pd(dba) (0.1 equiv, 0.33 mmol, 0.31 g), Xantphos (0.3 equiv, 1.00 mmol, 0.58 g), and CsCO (3.0 equiv, 10.00 mmol, 3.26 g). The reaction mixture was then stirred at 100°C overnight. After completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over NaSO, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-16%) to afford 1.53 g of the product (100% yield) as a yellow oil. MS (ESI) m / z 461.5 [M+H] + .

[0850] Step c:

[0851] (S)-Benzyl 2-(2-aminophenyl)pyrrolidine-1-carboxylate

[0852]

[0853] To a suspension of (S)-benzyl 2-(2-((diphenylmethylene)amino)phenyl)pyrrolidine-1-carboxylate (1.0 equiv, 3.32 mmol, 1.53 g) in THF (10 mL) was added HCl (2.0 equiv, 6.64 mmol, 0.24 g). The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was dissolved in saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0 to 50%) to afford 547 mg of the product in 55.6% yield as a yellow oil. MS (ESI) m / z 297.3 [M+H] + .

[0854] Step d:

[0855] (S)-Benzyl 2-(2-((tert-Butoxycarbonyl)amino)phenyl)pyrrolidine-1-carboxylate

[0856]

[0857] To a suspension of (S)-benzyl 2-(2-aminophenyl)pyrrolidine-1-carboxylate (1.0 equiv, 1.85 mmol, 547 mg) in DCM (15 mL) were added N,N-dimethylpyridin-4-amine (0.2 equiv, 0.37 mmol, 225 mg), di-tert-butyl dicarbonate (1.2 equiv, 2.22 mmol, 483 mg), and triethylamine (2.0 equiv, 3.69 mmol, 374 mg). The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-10%) to afford 540 mg of the product in a 93.8% yield based on light oil. MS (ESI) m / z 419.4 [M+Na] + .

[0858] Step e:

[0859] (S)-Benzyl 2-(2-((tert-Butoxycarbonyl)(methyl)amino)phenyl)pyrrolidine-1-carboxylate

[0860]

[0861] To a suspension of (S)-2-(2-((tert-butoxycarbonyl)amino)phenyl)pyrrolidine-1-carboxylate (1.0 equiv, 0.25 mmol, 100 mg) in THF (15 mL) under N₂ in an ice-water bath were added iodomethane (1.5 equiv, 0.38 mmol, 53.7 mg) and sodium hydride (2.0 equiv, 0.50 mmol, 20.2 mg). The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was dissolved in water, diluted with ethyl acetate, and washed with brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-25%) to afford 88 mg of the product in 85% yield as a white solid. MS (ESI) m / z 411.4 [M+H] + .

[0862] Step f:

[0863] (S)-tert-Butyl methyl(2-(pyrrolidin-2-yl)phenyl)carbamate

[0864]

[0865] To a suspension of (S)-benzyl 2-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)pyrrolidine-1-carboxylate (1.0 equiv, 0.21 mmol, 88 mg) in MeOH (15 mL) was added Pd / C on carbon (0.4 equiv, 0.083 mmol, 88 mg). The reaction mixture was then stirred at 25°C overnight under H2. After completion of the reaction, the resulting mixture was filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0-10%) to afford 49 mg of the product as a light oil in 83% yield. MS (ESI) m / z 277.7 [M+H] + .

[0866] Step g:

[0867] tert-Butyl (S)-methyl(2-(1-(7-(7S-nitro-6,6-dioxo-4-oxo-7S-(((tetrahydro-2H-pyran-4-yl)methyl)amino))-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridin-3(1,2),7(1,3)-diphenylcyclotridec-35-yl)-7-azaspiro[3.5]nonan-2-yl)pyrrolidin-2-yl)phenyl)carbamate

[0868]

[0869] To a suspension of 75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino))-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide (1.0 equiv, 0.045 mmol, 35 mg) and (S)-tert-butyl methyl(2-(pyrrolidin-2-yl)phenyl)carbamate (4.0 equiv, 0.18 mmol, 49.9 mg) in 1,2-dichloroethane (8 mL) was added sodium triacetylborohydride (4.0 equiv, 0.18 mmol, 29.6 mg). The reaction mixture was then stirred at 50°C overnight. After the reaction was complete, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH ranging from 0 to 20%) to give 46 mg of the product in 98% yield as a yellow solid. MS (ESI) m / z 1035.9 [M+H] + .

[0870] Step h:

[0871] (S)-35-(2-(2-(2-(methylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino))-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[0872]

[0873] To a suspension of tert-butyl (S)-methyl(2-(1-(7-(7S-nitro-6,6-dioxo-4-oxo-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino))-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridin-3(1,2),7(1,3)-diphenylcyclotridec-35-yl)-7-azaspiro[3.5]non-2-yl)pyrrolidin-2-yl)phenyl)carbamate (1.0 equiv, 0.044 mmol, 46 mg) in DCM (8 mL) was added TFA (5.0 equiv, 0.22 mmol, 25.3 mg). The reaction mixture was then stirred at 25° C. for 3 hours. After completion of the reaction, the resulting mixture was evaporated, diluted with ethyl acetate and washed with saturated NaHCO solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give the product 12.1 mg, 29.1% yield, as a yellow solid. 1 H NMR (400MHz, DMSO) δ11.42(s,1H),8.17(s,1H),8.02(s,1H),7.63(s,1H),7.49(d,J=8.8Hz,1H),7.40(s,1H),7.19(s,1H) ,7.11–6.89(m,2H),6.62(dd,J=8.9,1.8Hz,1H),6.53–6.41(m,2H),6.29(s,1H),5.97(s,1H),4.55–4.39(m,2H),4.26–4.1 4(m,2H),3.88–3.75(m,2H),3.50–3.45(m,2H),3.25–3.19(m,2H),3.16–3.07(m,1H),3.00–2.94(m,2H),2.91–2.85(m,2H) ,2.71(s,3H),2.02–1.61(m,12H),1.58–1.44(m,4H),1.42–1.28(m,5H),1.25–1.20(m,2H),1.20–1.10(m,2H).MS(ESI)m / z 935.9[M+H] + .

[0874] Example 14

[0875] (S)-35-(2-(2-(2-(2-hydroxypropyl-2-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-((((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide

[0876]

[0877] Step a:

[0878] (S)-1-Benzyl-2-(2-bromophenyl)pyrrolidine

[0879]

[0880] To a suspension of (S)-2-(2-bromophenyl)pyrrolidine (1.0 equiv, 4.42 mmol, 1.0 g) in THF (15 mL) under argon and an ice-water bath was added sodium hydride (2.0 equiv, 8.84 mmol, 0.35 g), and the reaction mixture was stirred at 0°C for 1 hour. Bromomethylbenzene (2.0 equiv, 8.84 mmol, 1.51 g) was then added to the reaction mixture, and the mixture was stirred at 25°C overnight. After completion of the reaction, the mixture was dissolved in water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product. Purification by silica gel column chromatography (PE and EA, EA ranging from 0 to 20%) afforded 1.34 g of the product as a light oil in a 96% yield. MS (ESI) m / z 316.2 [M+H] + .

[0881] Step b:

[0882] (S)-2-(2-(1-Benzylpyrrolidin-2-yl)phenyl)propan-2-ol

[0883]

[0884] To a suspension of (S)-1-benzyl-2-(2-bromophenyl)pyrrolidine (1.0 equiv, 0.95 mmol, 300 mg) in THF (15 mL) was added 2.5 N butyllithium (2.0 equiv, 1.90 mmol, 122 mg) at −78° C. under argon, and the reaction mixture was stirred at −78° C. for 1 hour. Propan-2-one (2.0 equiv, 1.90 mmol, 110 mg) was then added to the reaction mixture, which was then stirred at 25° C. under argon overnight. After completion of the reaction, the resulting mixture was dissolved in water and extracted with EA. The organic layer was separated, washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-10%) to afford 60 mg of the product as a light oil in a 21.4% yield. MS (ESI) m / z 296.7 [M+H] + .

[0885] Step c:

[0886] (S)-2-(2-(Pyrrolidin-2-yl)phenyl)propan-2-ol

[0887]

[0888] To a suspension of (S)-2-(2-(1-benzylpyrrolidin-2-yl)phenyl)propan-2-ol (1.0 equiv, 0.20 mmol, 60 mg) in MeOH (15 mL) was added dihydroxy Pd / C (2.0 equiv, 0.40 mmol, 60 mg). The reaction mixture was then stirred at 25° C. overnight. After completion of the reaction, the resulting mixture was filtered and concentrated in vacuo to afford 41 mg of the crude product as a light oil, which was used directly in the next step. MS (ESI) m / z 206.1 [M+H] + .

[0889] Step d:

[0890] (S)-35-(2-(2-(2-(2-hydroxypropyl-2-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-((((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide

[0891]

[0892] To a suspension of 75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide (1.0 equiv, 0.05 mmol, 39 mg) and (S)-2-(2-(pyrrolidin-2-yl)phenyl)propan-2-ol (4.0 equiv, 0.20 mmol, 41.3 mg) in DCM (8 mL) was added sodium triacetylborohydride (4.0 equiv, 0.20 mmol, 33.0 mg). The reaction mixture was then stirred at 50° C. for 3 hours. After the reaction was complete, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product, which was purified by pre-HPLC to obtain 1.8 mg of the product in a 3.7% yield as a yellow solid. MS (ESI) m / z 964.7 [M+H] + .

[0893] Example 15

[0894] (S)-35-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,14-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[0895]

[0896] Step a:

[0897] 3-((5-bromopentyl)oxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide

[0898]

[0899] To a suspension of 3-hydroxy-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1.0 equiv, 1.75 mmol, 1.0 g) and 1,5-dibromopentane (5.0 equiv, 8.75 mmol, 2.0 g) in acetonitrile (30 mL) was added K2CO3 (3.0 equiv, 5.25 mmol, 0.73 g). The reaction mixture was then stirred at 30°C or 85°C overnight. After completion of the reaction, the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA ranging from 0 to 33%) to afford 1.2 g of the product in 95% yield as a yellow oil. MS (ESI) m / z 720.5 [M+H] + .

[0900] Step b:

[0901] Methyl 2-((6-((5-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)))phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate

[0902]

[0903] To a suspension of 3-((5-bromopentyl)oxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1.0 eq, 1.67 mmol, 1.2 g) and methyl 4-fluoro-2-((6-hydroxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.2 eq, 2.0 mmol, 0.6 g) in acetonitrile (15 mL) was added the mixture. K2CO3 (3.0 equivalents, 5.0 mmol, 0.69 g) was added to the solution. The reaction mixture was then stirred at 85°C overnight. After the reaction was complete, the resulting mixture was washed with ethyl acetate, the organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (PE and EA, EA 0-50%) to obtain 1.12 g of the product with a yield of 71.4% as a yellow solid. MS (ESI) m / z 942.9 [M+H] + .

[0904] Step c:

[0905] Methyl 2-((6-((5-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)))phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonyl-7-yl)benzoate

[0906]

[0907] To a suspension of methyl 2-((6-((5-(5-(N,N-bis(4-methoxyphenyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)))methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 equiv, 1.19 mmol, 1.12 g) and 2,2-dimethoxy-7-azaspiro[3.5]nonane (15.0 equiv, 17.83 mmol, 3.30 g) in DMF (10 ml) was added NaCO (25.0 equiv, 29.7 mmol, 3.15 g). The reaction mixture was then stirred at 105° C. overnight. After completion of the reaction, the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0 to 33%) to give 1.3 g of the product in 99% yield as a yellow solid. MS (ESI) m / z 1107.8 [M+H] + .

[0908] Step d:

[0909] Methyl 2-((6-((5-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate

[0910]

[0911] To the reaction flask was added methyl 2-((6-((5-(5-(N,N-bis(4-methoxyphenyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)benzoate (1.17 mmol, 1.3 g), TFA (10.0 equiv, 11.74 mmol, 1.34 g), and anisole (3.0 equiv, 3.52 mmol, 0.38 g). The reaction mixture was then stirred at 60° C. for 40 minutes. After completion of the reaction, the resulting mixture was evaporated, diluted with ethyl acetate, and washed with saturated NaHCO 3 solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 1.6%) to give 769 mg of the product in 80% yield as a yellow solid. MS (ESI) m / z 821.7 [M+H] + .

[0912] Step e:

[0913] 2-((6-((5-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoic acid

[0914]

[0915] To a suspension of methyl 2-((6-((5-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxo)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate in THF (8 mL) and EtOH (8 mL) was added 2N sodium hydroxide solution (5 mL) under N2. The reaction mixture was then stirred at 50 °C for 2 hours. After completion of the reaction, the resulting mixture was diluted with water, washed with 1N HCl solution, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH ranged from 0 to 5%) to give 334 mg of the product in a yield of 44.2% as a yellow solid. MS (ESI) m / z 807.8 [M+H] + .

[0916] Step f:

[0917] 75-Nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,14-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotetradec-4-one-6,6-dioxide

[0918]

[0919] To a suspension of 2-((6-((5-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoic acid (1.0 equiv, 0.41 mmol, 334 mg) and EDCI (2.0 equiv, 0.83 mmol, 159 mg) in DCM (8 mL) was added DMAP (2.0 equiv, 0.83 mmol, 101 mg). The reaction mixture was then stirred at 30° C. for 5 hours. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 3.5%) to give the product as a yellow solid (210 mg) in a 64.3% yield. MS (ESI) m / z 789.9 [M+H] + .

[0920] Step g:

[0921] (S)-35-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,14-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotetradec-4-one-6,6-dioxide

[0922]

[0923] A suspension of 75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,14-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotetradec-4-one-6,6-dioxide (1.0 equiv, 0.063 mmol, 50 mg) and (S)-2-(2-isopropylphenyl)pyrrolidine (4.0 equiv, 0.25 mmol, 48.0 mg) in DCE (8 mL) was added sodium acetylborohydride (4.0 equiv, 0.25 mmol, 41.6 mg). The reaction mixture was then stirred at 50° C. for 3 hours. After completion of the reaction, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give the product 17.3 mg, 28.4% yield, as a yellow solid. 1 H NMR(400MHz,DMSO)δ11.41(s,1H),8.13-7.99(m,2H),7.61–7.45(m,4H),7.29–7.06(m,4 H),6.60(d,J=7.6Hz,1H),6.30(s,1H),5.93(s,1H),4.33–4.15(m,4H),3.89–3.72(m,2H) ,3.43–3.41(m,2H),3.27–3.17(m,5H),2.98–2.82(m,4H),2.28–2.11(m,1H),1.89–1.62 (m,9H),1.58–1.42(m,6H),1.35(dd,J=15.4,8.8Hz,5H),1.26–1.09(m,10H).MS(ESI)m / z 962.8[M+H] + .

[0924] Example 16

[0925] (S)-35-(2-(2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenyltridec-4-one-6,6-dioxide

[0926]

[0927] Step a:

[0928] (S)-Benzyl 2-(2-(methylamino)phenyl)pyrrolidine-1-carboxylate

[0929]

[0930] To a suspension of (S)-benzyl 2-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)pyrrolidine-1-carboxylate (1.0 equiv, 0.41 mmol, 170 mg) in DCM (8 mL) was added TFA (5.0 equiv, 2.1 mmol, 236 mg). The reaction mixture was then stirred at 25° C. for 2 hours. After completion of the reaction, the resulting mixture was evaporated, diluted with ethyl acetate and washed with saturated NaHCO 3 solution. The organic layer was separated, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-33%) to afford product 113 in 88% yield as a light solid. MS (ESI) m / z 311.3 [M+H] + .

[0931] Step b:

[0932] (S)-Benzyl 2-(2-(dimethylamino)phenyl)pyrrolidine-1-carboxylate

[0933]

[0934] To a suspension of benzyl (S)-2-(2-(methylamino)phenyl)pyrrolidine-1-carboxylate (1.0 equiv, 0.36 mmol, 113 mg) in MeOH (8 mL) was added formaldehyde (6.0 equiv, 2.18 mmol, 177 mg) and NaCNBH4 (6.0 equiv, 2.18 mmol, 137 mg). The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was evaporated, diluted with ethyl acetate, and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-33%) to afford 100 mg of the product (85% yield) as a yellow solid. MS (ESI) m / z 325.8 [M+H] + .

[0935] Step c:

[0936] (S)-N,N-Dimethyl-2-(pyrrolidin-2-yl)aniline

[0937]

[0938] To a suspension of (S)-benzyl 2-(2-(dimethylamino)phenyl)pyrrolidine-1-carboxylate (1.0 equiv, 0.31 mmol, 100 mg) in MeOH (10 mL) was added 10% Pd / C / carbon (3.0 equiv, 0.94 mmol, 100 mg). The reaction mixture was then stirred at 25°C under H2 for 2 hours. After completion of the reaction, the resulting mixture was filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (DCM and NH3 in MeOH, NH3 in MeOH ranging from 0 to 10%) to afford 40 mg of the product in 68.2% yield as a light solid. MS (ESI) m / z 191.2 [M+H] + .

[0939] Step d:

[0940] (S)-35-(2-(2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenyltridec-4-one-6,6-dioxide

[0941]

[0942] To a suspension of 75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenyltridec-4-one-6,6-dioxide (1.0 equiv, 0.07 mmol, 55 mg) and (S)-N,N-dimethyl-2-(pyrrolidin-2-yl)aniline (3.0 equiv, 0.21 mmol, 40.5 mg) in DCE (8 mL) was added sodium triacetylborohydride (3.0 equiv, 0.21 mmol, 34.9 mg). The reaction mixture was then stirred at 50° C. for 3 hours. After the reaction was complete, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give 15.0 mg of the product in a yield of 22.3% as a yellow solid. 1HNMR(400MHz,DMSO)δ11.35(s,1H),8.18–7.83(m,2H),7.64–7.32(m,4H),7.31–7.01(m,4H),6 .61(d,J=8.8Hz,1H),6.24(s,1H),6.03(s,1H),4.55–4.37(m,2H),4.24–4.09(m,2H),3.86–3. 75(m,2H),3.47-3.44(m,2H),3.26–3.18(m,4H),3.00–2.92(m,2H),2.89–2.82(m,2H),2.58(s ,6H),2.37–2.23(m,1H),2.00–1.65(m,10H),1.55–1.46(m,3H),1.43–1.11(m,9H).MS(ESI)m / z 949.8[M+H] + .

[0943] Example 17

[0944] 35-(2-((5R)-2-(2-isopropylphenyl)-5-methylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenyltridec-4-one-6,6-dioxide

[0945]

[0946] Step a:

[0947] (R)-tert-Butyl 2-methyl-5-oxopyrrolidine-1-carboxylate

[0948]

[0949] To a suspension of (R)-5-methylpyrrolidin-2-one (1.0 equiv, 10.1 mmol, 1.0 g) in ACN (10 mL) were added N,N-dimethylpyridin-4-amine (1.0 equiv, 10.1 mmol, 1.23 g), triethylamine (3.0 equiv, 30.3 mmol, 3.06 g), and di-tert-butyl dicarbonate (1.5 equiv, 10.13 mmol, 3.3 g). The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was added to water, diluted with EA, and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0 to 33%) to afford 2.05 g of the product, a 102% yield, as a yellow oil. MS (ESI) m / z 222.1 [M+H] + .

[0950] Step b:

[0951] tert-Butyl (R)-(5-(2-isopropylphenyl)-5-oxopentan-2-yl)carbamate

[0952]

[0953] To a suspension of (R)-tert-butyl 2-methyl-5-oxopyrrolidine-1-carboxylate (1.0 equiv, 10.29 mmol, 2.05 g) in THF (60 mL) under argon at -78°C was added 2.5N butyl lithium (1.0 equiv, 10.29 mmol, 0.66 g), and the reaction mixture was stirred at -78°C for 30 minutes. A solution of 1-bromo-2-isopropylbenzene (1.5 equiv, 15.43 mmol, 3.07 g) in THF (20 mL) was then added to the reaction mixture, which was stirred at -78°C for 2 hours. After completion of the reaction, the resulting mixture was dissolved in saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0 to 11%) to give the product 1.28 g, 38.9% yield, as a light oil. MS (ESI) m / z 342.3 [M+H] + .

[0954] Step c:

[0955] (R)-4-Amino-1-(2-isopropylphenyl)pentan-1-one

[0956]

[0957] To a suspension of tert-butyl (R)-(5-(2-isopropylphenyl)-5-oxopentan-2-yl)carboxylate (1.0 equiv, 4.01 mmol, 1.28 g) in DCM (20 mL) was added TFA (5.0 equiv, 20.03 mmol, 2.28 g). The reaction mixture was then stirred at 25°C for 1 hour. After completion of the reaction, the resulting mixture was concentrated in vacuo to afford 0.88 g of the crude product as a light oil, which was used directly in the next step. MS (ESI) m / z 220.2 [M+H] + .

[0958] Step d:

[0959] (5R)-2-(2-Isopropylphenyl)-5-methylpyrrolidine

[0960]

[0961] To a suspension of (R)-4-amino-1-(2-isopropylphenyl)pentan-1-one (1.0 equiv, 4.01 mmol, 879 mg) in EtOH (20 mL) were added acetic acid (2.0 equiv, 8.02 mmol, 481 mg) and NaCNBH4 (2.0 equiv, 8.02 mmol, 504 mg). The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was dissolved in saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0 to 12.5%) to afford 607 mg of the product in 74.5% yield as a light oil. MS (ESI) m / z 204.5 [M+H] + .

[0962] Step e:

[0963] 35-(2-((5R)-2-(2-isopropylphenyl)-5-methylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenyltridec-4-one-6,6-dioxide

[0964]

[0965] To a suspension of 75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenyltridec-4-one-6,6-dioxide (1.0 equiv, 0.07 mmol, 55 mg) and (5R)-2-(2-isopropylphenyl)-5-methylpyrrolidine (4.0 equiv, 0.28 mmol, 57.7 mg) in DCE (8 mL) was added sodium triacetylborohydride (4.0 equiv, 0.28 mmol, 46.5 mg). The reaction mixture was then stirred at 50° C. overnight. After the reaction was complete, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give 27.4 mg of the product in a yield of 40.1% as a yellow solid. 1 H NMR (400MHz, DMSO) δ11.43(s,1H),11.31–11.19(m,1H),8.19(s,1H),8.03(s,1H),7.77–7.56(m,2H),7.52–7.44(m, 1H),7.37(s,1H),7.23–7.00(m,4H),6.63(d,J=8.7Hz,1H),6.30(s,1H),5.95(s,1H),4.57–4.35(m,2H),4.26–3.98 (m,3H),3.87–3.70(m,2H),3.50–3.44(m,2H),3.26–3.19(m,3H),3.03–2.96(m,2H),2.93–2.78(m,3H),2.18–2.00( m,1H),1.96–1.68(m,7H),1.69–1.58(m,1H),1.56–1.34(m,8H),1.33–1.26(m,2H),1.26–1.08(m,12H).MS(ESI)m / z 962.5[M+H] + .

[0966] Example 18

[0967] (S)-35-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,11,14-tetraoxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotetradecane-4-yl)

[0968] Ketone-6,6-dioxide

[0969]

[0970] Step a:

[0971] 3-(2-(2-bromoethoxy)ethoxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide

[0972]

[0973] To a suspension of 3-hydroxy-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1.0 equiv, 1.75 mmol, 1.0 g) and 1-bromo-2-(2-bromoethoxy)ethane (5.0 equiv, 8.75 mmol, 2.03 g) in acetonitrile (20 mL) was added KCO (3.0 equiv, 5.25 mmol, 0.73 g). The reaction mixture was then stirred at 85° C. for 3 hours. After completion of the reaction, the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over NaSO, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-50%) to afford 1.14 g of the product in a 90% yield as a yellow solid. MS (ESI) m / z 722.5 [M+H] + .

[0974] Step b:

[0975] Methyl 2-((6-(2-(2-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)))amino)phenoxy)ethoxy)ethoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate

[0976]

[0977] To a suspension of 3-(2-(2-bromoethoxy)ethoxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1.0 equiv, 1.58 mmol, 1.14 g) and methyl 4-fluoro-2-((6-hydroxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.2 equiv, 1.89 mmol, 0.57 g) in acetonitrile (20 mL) was added K2 CO3 ((3.0 equiv, 4.73 mmol, 0.65 g). The reaction mixture was then stirred at 85°C for 3 h. After completion of the reaction, the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA ranging from 0 to 33%) to give 562 mg of the product in a yield of 37.7% as a yellow solid. MS (ESI) m / z 944.9 [M+H] + .

[0978] Step c:

[0979] Methyl 2-((6-(2-(2-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)))amino)phenoxy)ethoxy)ethoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)benzoate

[0980]

[0981] To a suspension of methyl 2-((6-(2-(2-(5-(N,N-bis(4-methoxyphenyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)ethoxy)ethoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 equiv, 0.60 mmol, 562 mg) and 2,2-dimethoxy-7-azaspiro[3.5]nonane (15.0 equiv, 8.93 mmol, 1.65 g) in DMF (20 mL) was added Na2 CO3 (25.0 equiv., 14.88 mmol, 1.58 g). The reaction mixture was then stirred at 105°C overnight. After completion of the reaction, the resulting mixture was extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (PE and EA, EA ranging from 0 to 33%) to give 480 mg of the product in a 72.7% yield as a yellow solid. MS (ESI) m / z 1109.8 [M+H] + .

[0982] Step d:

[0983] Methyl 2-((6-(2-(2-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)ethoxy)ethoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate

[0984]

[0985] To the reaction flask was added methyl 2-((6-(2-(2-(5-(N,N-bis(4-methoxyphenyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)ethoxy)ethoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)benzoate (1.0 equiv, 0.43 mmol, 480 mg), TFA (10.0 equiv, 4.33 mmol, 493 mg) and anisole (3.0 equiv, 1.30 mmol, 140 mg). The reaction mixture was then stirred at 60° C. for 40 minutes. After completion of the reaction, the resulting mixture was evaporated, diluted with ethyl acetate and washed with saturated NaHCO 3 solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 5%) to give 320 mg of the product in 90% yield as a yellow solid. MS (ESI) m / z 823.8 [M+H] + .

[0986] Step e:

[0987] 2-((6-(2-(2-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)ethoxy)ethoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoic acid

[0988]

[0989] To a solution of methyl 2-((6-(2-(2-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)ethoxy)ethoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate (1.0 equiv, 0.39 mmol, 320 mg) in THF (8 mL) and EtOH (8 mL) was added 2N sodium hydroxide solution (5 mL). The reaction mixture was then stirred at 50° C. for 2 hours. After completion of the reaction, the resulting mixture was diluted with water, washed with 1N HCl solution, and extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 5%) to give 217 mg of the product in 69% yield as a yellow solid. MS (ESI) m / z 809.9 [M+H] + .

[0990] Step f:

[0991] 75-Nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,11,14-tetraoxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotetradec-4-one-6,6-dioxide

[0992]

[0993] To a suspension of 2-((6-(2-(2-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)ethoxy)ethoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7yl)benzoic acid (1.0 equiv, 0.27 mmol, 217 mg) and EDCI (2.0 equiv, 0.54 mmol, 103 mg) in DCM (8 mL) was added DMAP (2.0 equiv, 0.54 mmol, 65.6 mg). The reaction mixture was then stirred at 30° C. for 5 hours. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 3.5%) to give the product 150 mg, 70.7% yield, as a yellow solid. MS (ESI) m / z 791.6 [M+H] + .

[0994] Step g:

[0995] (S)-35-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,11,14-tetraoxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotetradec-4-one-6,6-dioxide

[0996]

[0997] To a suspension of 75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,11,14-tetraoxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotetradec-4-one-6,6-dioxide (1.0 equiv, 0.063 mmol, 50 mg) and (S)-2-(2-isopropylphenyl)pyrrolidine (4.0 equiv, 0.25 mmol, 48.0 mg) in DCE (8 mL) was added sodium triacetylborohydride (4.0 equiv, 0.25 mmol, 41.6 mg). The reaction mixture was then stirred at 50° C. for 3 hours. After the reaction was complete, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give 27.1 mg of the product in a yield of 44.5% as a yellow solid. 1 HNMR(400MHz,DMSO)δ11.42(s,1H),8.30–7.99(m,2H),7.65–7.47(m,4H),7.29–7.07(m,4H),6.65(dd,J =9.0,1.9Hz,1H),6.28(s,1H),6.05(s,1H),4.47–4.38(m,2H),4.33–4.23(m,2H),3.89–3.71(m,7H),3.5 1–3.44(m,2H),3.28–3.20(m,4H),3.05–2.95(m,2H),2.94–2.84(m,2H),2.32–2.11(m,1H),1.95–1.61(m ,5H),1.60–1.43(m,4H),1.42–1.27(m,5H),1.26–1.21(m,1H),1.16(dd,J=15.3,6.9Hz,9H).MS(ESI)m / z 964.8[M+H] + .

[0998] Example 19

[0999] 35-(2-(2-(4-Isopropylpyridin-3-yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,11,14-tetraoxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotetradec-4-one-6,6-dioxide

[1000]

[1001] Step a:

[1002] 3-Bromo-4-(prop-1-en-2-yl)pyridine

[1003]

[1004] To a suspension of 3,4-dibromopyridine (1.0 equiv, 2.11 mmol, 500 mg) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.3 equiv, 2.74 mmol, 461 mg) in dioxane (8 mL) and water (2.00 mL) was added Pd(pdf)2Cl2 (0.1 equiv, 0.21 mmol, 154 mg) and Na2CO3 (2.5 equiv, 5.28 mmol, 559 mg). The reaction mixture was then stirred at 100°C overnight under N2. After completion of the reaction, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA ranging from 0 to 10%) to afford 150 mg of the product as a light oil in a 35.9% yield. MS (ESI) m / z 198.0 [M+H] + .

[1005] Step b:

[1006] tert-Butyl 2-(4-(prop-1-en-2-yl)pyridin-3-yl)-1H-pyrrole-1-carboxylate

[1007]

[1008] To a suspension of 3-bromo-4-(prop-1-en-2-yl)pyridine (1.0 equiv, 0.76 mmol, 150 mg) and (1-tert-butoxycarbonyl-1H-pyrrol-2-yl)boronic acid (3.0 equiv, 2.27 mmol, 479 mg) in DMF (10 mL) and water (1.00 mL) were added PdCl(PPh) (0.1 equiv, 0.076 mmol, 53.2 mg) and KCO (5.0 equiv, 3.79 mmol, 523 mg). The reaction mixture was then stirred at 80°C overnight under N2. After completion of the reaction, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-10%) to afford 180 mg of the product as a yellow oil in 84% yield. MS (ESI) m / z 285.8 [M+H] + .

[1009] Step c:

[1010] 4-Isopropyl-3-(pyrrolidin-2-yl)pyridine

[1011]

[1012] To a suspension of tert-butyl 2-(4-(prop-1-en-2-yl)pyridin-3-yl)-1H-pyrrole-1-carboxylate (1.0 equiv, 0.63 mmol, 180 mg) in MeOH (20 mL) and concentrated hydrochloric acid (2.00 mL) was added platinum (IV) oxide (1.4 equiv, 0.88 mmol, 200 mg). The reaction mixture was then stirred at 25 ° C overnight under H2. After completion of the reaction, the residue was added to a saturated NaHCO3 solution, diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and NH3 in MeOH, NH3 in MeOH ranging from 0 to 10%) to give 33 mg of the product in a yield of 27.4% as a yellow oil.

[1013] Step d:

[1014] 35-(2-(2-(4-Isopropylpyridin-3-yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,11,14-tetraoxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotetradec-4-one-6,6-dioxide

[1015]

[1016] To a suspension of 75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide (1.0 equiv, 0.045 mmol, 35 mg) and 4-isopropyl-3-(pyrrolidin-2-yl)pyridine (4.0 equiv, 0.18 mmol, 34.4 mg) in DCE (8 mL) was added sodium triacetylborohydride (4.0 equiv, 0.18 mmol, 29.6 mg). The reaction mixture was then stirred at 50° C. overnight. After the reaction was complete, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give 12 mg of the product as a yellow solid in a 28% yield. 1 H NMR (400MHz, DMSO) δ11.44(s,1H),8.60(s,1H),8.37–8.26(m,1H),8.19(s,1H),8.02(s,1H),7.65(s,1H),7.49(d,J=8.8Hz,1H),7.39(s,1H),7.2 6–7.13(m,2H),6.63(dd,J=9.0,2.0Hz,1H),6.30(s,1H),5.97(s,1H),4. 65–4.37(m,2H),4.27–4.11(m,2H),3.81(dd,J=11.3,3.1Hz,2H),3.74–3 .56(m,1H),3.49–3.45(m,2H),3.31–3.29(m,1H),3.26–3.20(m,2H),3.1 7–3.09(m,1H),3.01–2.95(m,2H),2.93–2.87(m,2H),2.39–2.15(m,2H), 1.96–1.72(m,8H),1.70–1.60(m,1H),1.58–1.44(m,4H),1.43–1.37(m,2 H),1.35–1.30(m,2H),1.29–1.21(m,2H),1.20–1.11(m,8H).MS(ESI)m / z 949.9[M+H] + .

[1017] Example 20

[1018] 35-(2-(2-(3-cyclopropylpyridin-2-yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[1019]

[1020] Step a:

[1021] tert-Butyl (4-(3-cyclopropylpyridin-2-yl)-4-oxobutyl)carbamate

[1022]

[1023] To a suspension of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.0 equivalents, 2.70 mmol, 500 mg) in THF (60 mL) was added 2.5 N butyl lithium (1.1 equivalents, 2.97 mmol, 190 mg) at -78 ° C under argon, and the reaction mixture was stirred at -78 ° C for 30 minutes. Then, a solution of 2-bromo-3-cyclopropylpyridine (1.1 equivalents, 2.97 mmol, 588 mg) in THF (20 mL) was added to the reaction mixture under argon and stirred at -78 ° C for 2 hours. After the reaction was completed, the resulting mixture was dissolved with saturated NH4HCl solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (PE and EA, EA range of 0 to 12.5%) to give 498 mg of the product in a yield of 60.6% as a light oil. MS (ESI) m / z 305.3 [M+H] + .

[1024] Step b:

[1025] 4-Amino-1-(3-cyclopropylpyridin-2-yl)butan-1-one

[1026]

[1027] To a suspension of tert-butyl (4-(3-cyclopropylpyridin-2-yl)-4-oxobutyl)carbamate (1.0 equiv, 1.64 mmol, 498 mg) in DCM (20 mL) was added TFA (5.0 equiv, 8.18 mmol, 933 mg). The reaction mixture was then stirred at 25°C for 1 hour. After completion of the reaction, the resulting mixture was concentrated in vacuo to afford 334 mg of the crude product as a light oil, which was used directly in the next step.

[1028] Step c:

[1029] 3-Cyclopropyl-2-(pyrrolidin-2-yl)pyridine

[1030]

[1031] To a suspension of 4-amino-1-(3-cyclopropylpyridin-2-yl)butan-1-one (1.0 equiv, 1.64 mmol, 334 mg) in EtOH (20 mL) were added acetic acid (2.0 equiv, 3.27 mmol, 196 mg) and NaCNBH4 (2.0 equiv, 3.27 mmol, 206 mg). The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was dissolved in saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (DCM and NH3 in MeOH, NH3 in MeOH ranging from 0 to 10%) to afford 308 mg of the product as a light oil in 100% yield. MS (ESI) m / z 189.1 [M+H] + .

[1032] Step d:

[1033] 35-(2-(2-(3-cyclopropylpyridin-2-yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[1034]

[1035] To a suspension of 75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide (1.0 equiv, 0.045 mmol, 35 mg) and 3-cyclopropyl-2-(pyrrolidin-2-yl)pyridine (4.0 equiv, 0.18 mmol, 34.0 mg) in DCE (8 mL) was added sodium triacetylborohydride (4.0 equiv, 0.18 mmol, 29.6 mg). The reaction mixture was then stirred at 50° C. under N2 overnight. After the reaction was complete, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product, which was purified by pre-HPLC to obtain 12.2 mg of the product (28.5% yield) as a yellow solid. MS (ESI) m / z 947.9 [M+H] + .

[1036] Example 21

[1037] 35-(2-(2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[1038]

[1039] Step a:

[1040] 4-Bromo-1-isopropyl-3,5-dimethyl-1H-pyrazole

[1041]

[1042] To a suspension of 4-bromo-3,5-dimethyl-1H-pyrazole (1.0 equiv, 5.71 mmol, 1.0 g) in DMF (15 mL) at 0°C under N₂ was added sodium hydride (1.5 equiv, 8.57 mmol, 0.34 g). The reaction mixture was then stirred at 0°C under N₂ for 30 minutes. A solution of 2-iodopropane (1.1 equiv, 6.28 mmol, 1.07 g) in DMF (1 mL) was then added to the reaction mixture under N₂, and the mixture was stirred at 25°C overnight under N₂. After completion of the reaction, the resulting mixture was dissolved in ice water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA ranging from 0 to 12.5%) to afford 1.14 g of light oil in 92% yield. MS (ESI) m / z 217.0 [M+H] + .

[1043] Step b:

[1044] tert-Butyl (4-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-4-oxobutyl)carbamate

[1045]

[1046] Under argon, 2.5N butyl lithium (1.1 equiv, 2.97 mmol, 190 mg) was added to a suspension of 4-bromo-1-isopropyl-3,5-dimethyl-1H-pyrazole (1.0 equiv, 2.70 mmol, 586 mg) in THF (6 mL) at -78°C, and the reaction mixture was stirred at -78°C under Ar for 30 minutes. A solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.0 equiv, 2.70 mmol, 500 mg) in THF (2 mL) was then added to the reaction mixture under Ar, and the mixture was stirred at -78°C for 2 hours. After the reaction was complete, the resulting mixture was dissolved in saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0 to 50%) to give 768 mg of the product in 88% yield as a light oil. MS (ESI) m / z 346.4 [M+H] + .

[1047] Step c:

[1048] 4-Amino-1-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)butan-1-one

[1049]

[1050] A suspension of tert-butyl (4-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-4-oxobutyl)carbamate (1.0 equiv, 2.37 mmol, 768 mg) in DCM (20 mL) was added TFA (5.0 equiv, 11.87 mmol, 1.35 g). The reaction mixture was then stirred at 25 ° C for 30 minutes. After completion of the reaction, the resulting mixture was concentrated in vacuo to give 530 mg of crude product as a light oil, which was used directly in the next step. MS (ESI) m / z 224.6 [M + H] + .

[1051] Step d:

[1052] 1-Isopropyl-3,5-dimethyl-4-(pyrrolidin-2-yl)-1H-pyrazole

[1053]

[1054] To a suspension of 4-amino-1-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)butan-1-one (1.0 eq, 2.37 mmol, 530 mg) in ethanol (20 ml) was added acetic acid (2.0 eq, 4.75 mmol, 285 mg) and NaCNBH4 (2.0 eq, 4.75 mmol, 298 mg). The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was dissolved in saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and NH3 in MeOH, NH3 in MeOH ranging from 0 to 10%) to give 224 mg of the product as a light oil in a 45.5% yield. MS (ESI) m / z 208.2 [M+H] + .

[1055] Step e:

[1056] 35-(2-(2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[1057]

[1058] To a suspension of 75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide (1.0 equiv, 0.045 mmol, 35 mg) and 1-isopropyl-3,5-dimethyl-4-(pyridin-2-yl)-1H-pyrazole (4.0 equiv, 0.18 mmol, 37.5 mg) in DCE (8 mL) was added sodium triacetylborohydride (4.0 equiv, 0.18 mmol, 29.6 mg). The reaction mixture was then stirred at 50°C overnight. After the reaction was complete, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by pre-HPLC to afford 15.4 mg of the product in a 35.3% yield as a yellow solid. MS (ESI) m / z 966.8 [M+H] + .

[1059] Example 22

[1060] (S)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-35-(2-(2-(2-(tetrahydro-2H-pyran-4-yl))phenyl)pyridin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[1061]

[1062] Step a:

[1063] (S)-tert-Butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate

[1064]

[1065] To a suspension of (S)-2-(2-bromophenyl)pyrrolidine (1.0 equiv, 8.84 mmol, 2.0 g) in DCM (20 mL) were added N,N-dimethylpyridin-4-amine (0.1 equiv, 0.88 mmol, 0.11 g), triethylamine (2.0 equiv, 17.69 mmol, 1.79 g), and di-tert-butyl dicarbonate (1.2 equiv, 10.61 mmol, 2.32 g). The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the resulting mixture was dissolved in water and extracted with DCM. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0-10%) to afford 2.47 g of the product in 86% yield as a light oil. MS (ESI) m / z 348.1 [M+Na] + .

[1066] Step b:

[1067] (S)-tert-Butyl 2-(2-(3,6-dihydro-2H-pyran-4-yl)phenyl)pyrrolidine-1-carboxylate

[1068]

[1069] To a suspension of (S)-tert-butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate (1.0 equiv, 0.61 mmol, 200 mg) in dioxane (10 mL) and water (2.00 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 equiv, 0.92 mmol, 193 mg), PdCl2(dppf) (0.1 equiv, 0.06 mmol, 44.9 mg) and K2CO3 (2.5 equiv, 1.53 mmol, 212 mg). The reaction mixture was then stirred at 110°C under N2 overnight. After completion of the reaction, the resulting mixture was dissolved in water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0 to 25%) to give 187 mg of product as a light oil, a yield of 93%. MS (ESI) m / z 352.3 [M+Na] + .

[1070] Step c:

[1071] (S)-tert-Butyl 2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)pyrrolidine-1-carboxylate

[1072]

[1073] To a suspension of S)-tert-butyl 2-(2-(3,6-dihydro-2H-pyran-4-yl)phenyl)pyrrolidine-1-carboxylate (1.0 equiv, 0.57 mmol, 187 mg) in MeOH (20.0 mL) was added Pd / C (3.3 equiv, 1.88 mmol, 200 mg). The reaction mixture was then stirred at 25 ° C overnight under H2. After completion of the reaction, the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 188 mg of crude product as a light oil, which was used directly in the next step. MS (ESI) m / z 354.3 [M+Na] + .

[1074] Step d:

[1075] (S)-2-(2-(Tetrahydro-2H-pyran-4-yl)phenyl)pyrrolidine

[1076]

[1077] To a suspension of tert-butyl (S)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)pyrrolidine-1-carboxylate (1.0 equiv, 0.57 mmol, 188 mg) in DCM (20 mL) was added TFA (5.0 equiv, 2.84 mmol, 323 mg). The reaction mixture was then stirred at 25° C. for 1 hour. After completion of the reaction, the resulting mixture was added with NH 3 in methanol and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (DCM and NH 3 in methanol, NH 3 in methanol ranging from 0 to 10%) to afford 130 mg of the product as a light solid in 99% yield. MS (ESI) m / z 232.2 [M+H] + .

[1078] Step e:

[1079] (S)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-35-(2-(2-(2-(tetrahydro-2H-pyran-4-yl))phenyl)pyridin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[1080]

[1081] To 75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide (1.0 equiv, 0.052 mmol, 40 mg) and (S)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)pyrrolidine (4.0 equiv, 0.21 mmol, 47.8 mg) in DCE (8 mL) was added sodium triacetylborohydride (4.0 equiv, 0.21 mmol, 33.9 mg) and the reaction mixture was stirred at 50°C overnight. After the reaction was complete, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give 8.9 mg of the product in a 17.4% yield as a yellow solid. 1H NMR (400 MHz, DMSO) δ 11.42 (s, 1H), 8.31–8.05 (m, 1H), 7.99 (s, 1H), 7.58–7.46 (m, 2H), 7.41 (s, 1H), 7.30–6.99 (m, 5H), 6.62 (d, J = 8.9, 1.7 Hz, 1H), 6.28 (s, 1H), 5.99 (s, 1H), 4.59–4.36 (m, 2H), 4.26–4.13 (m, 2H), 4.01–3.88 (m, 2H), 3.86– 3.74(m,2H),3.48–3.45(m,2H),3.42–3.40(m,1H),3.25–3.10(m,4H),3.01–2.93(m,2H),2.92-2.83(m,2H),2.32–2.1 3(m,1H),1.97–1.88(m,3H),1.85–1.61(m,10H),1.56–1.45(m,7H),1.42–1.28(m,6H),1.21–1.13(m,2H).MS(ESI)m / z 991.2[M+H] + .

[1082] Example 23

[1083] (S)-2-(1-(7-(7S-nitro-6,6-dioxide-4-oxo-7S-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridin-3(1,2),7(1,3)-diphenylcyclotridec-3S-yl)-7-azaspiro[3.5]nonan-2-yl)pyrrolidin-2-yl)benzonitrile

[1084]

[1085] Step a:

[1086] To a suspension of 75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide (1.0 eq, 0.13 mmol, 100 mg) and (S)-2-(2-bromophenyl)pyrrolidine (4.0 eq, 0.52 mmol, 117 mg) in DCE (8 mL) was added sodium triacetylborohydride (4.0 eq, 0.52 mmol, 85 mg). The reaction mixture was then stirred at 50° C. overnight. After the reaction was complete, the residue was added to a saturated NaHCO solution, diluted with ethyl acetate, and washed with brine. The organic layer was separated, dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH ranging from 0 to 1.6%) to give 82 mg of the product as a yellow solid in a 64.5% yield. MS (ESI) m / z 984.5 [M+H] + .

[1087] Step b:

[1088] To a suspension of (S)-35-(2-(2-(2-bromophenyl)pyridin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecan-4-one-6,6-dioxide (1.0 equiv, 0.083 mmol, 82 mg) in DMF (15 mL) were added dicyanozinc (5.0 equiv, 0.42 mmol, 48.9 mg) and Pd(Ph3P)4 (0.1 equiv, 8.33 μmol, 9.62 mg). The reaction mixture was then stirred at 140°C under N2 for 5 hours. After completion of the reaction, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by pre-HPLC to afford 2.7 mg of the product (3.48% yield) as a yellow solid. 1 HNMR(400MHz,DMSO)δ11.36(s,1H),7.93(s,1H),7.78–7.59(m,4H),7.57–7.35(m,3H),7.26–7.03(m,1H),6.61(d,J=7.7Hz,1H),6.2 4(s,1H),6.04(s,1H),4.62–4.34(m,2H),4.23–4.12(m,2H),3.83–3.77(m,2H),3.70–3.62(m,1H),3.46–3.45(m,1H),3.24–3.19(m, 2H),3.13–3.08(m,1H),3.06–3.01(m,1H),2.99–2.93(m,2H),2.91–2.83(m,2H),2.41–2.31(m,1H),2.29–2.17(m,1H),2.00–1.90(m ,2H),1.87–1.69(m,7H),1.65–1.57(m,2H),1.54–1.48(m,3H),1.46–1.39(m,2H),1.38–1.30(m,2H),1.21–1.11(m,3H).MS(ESI)m / z 931.9[M+H] + .

[1089] Example 24

[1090] 74-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)(methyl)amino)-35-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridec-4-one-6,6-dioxide

[1091]

[1092] Step a:

[1093] 2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenol

[1094]

[1095] To a suspension of 2-fluoro-3-nitrophenol (1.0 equiv, 9.55 mmol, 1.5 g) in DMSO (30 mL) was added DIPEA (3.0 equiv, 28.6 mmol, 3.7 g) and (1r,4r)-4-(aminomethyl)-1-methylcyclohexan-1-ol hydrochloride (1.2 equiv, 11.46 mmol, 2.06 g). The reaction mixture was then stirred at 80°C overnight under N2. After completion of the reaction, the residue was dissolved in water, diluted with ethyl acetate, and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH ranging from 0 to 5%) to afford 2.28 g of the product in 85% yield as a red solid. MS (ESI) m / z 281.6 [M+H] + .

[1096] Step b:

[1097] 5-Bromo-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenol

[1098]

[1099] To a suspension of 2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenol (1.0 equiv, 8.10 mmol, 2.27 g) in dioxane (8 mL) was added dibromide monoxide (1.1 equiv, 8.91 mmol, 1.42 g). The reaction mixture was then stirred at 25°C overnight. After completion of the reaction, the residue was dissolved in water, diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 5%) to give the product 1.3 g, 44.7% yield, as a red solid. MS (ESI) m / z 359.2 [M+H] + .

[1100] Step c:

[1101] 5-(Benzylthio)-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenol

[1102]

[1103] To a suspension of 5-bromo-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenol (1.0 equiv, 3.62 mmol, 1.3 g) in dioxane (15 ml) was added benzylmercaptan (1.5 equiv, 5.43 mmol, 0.67 g), DIPEA (3.0 equiv, 10.86 mmol, 1.4 g), Pd2(dba)3 (0.1 equiv, 0.36 mmol, 0.33 g), and yellow phosphorus (0.2 equiv, 0.72 mmol, 0.42 g) under argon. The reaction mixture was then stirred at 110°C overnight. After completion of the reaction, the residue was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0 to 33%) to give 1.3 g of the product in 89% yield as a red solid. MS (ESI) m / z 403.8 [M+H] + .

[1104] Step d:

[1105] 5-(Benzylthio)-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzoate

[1106]

[1107] To a suspension of 5-(benzylthio)-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenol (1.0 equiv, 2.98 mmol, 1.2 g) in DCM (30 mL) was added benzoyl chloride (1.2 equiv, 3.58 mmol, 0.50 g) and triethylamine (1.5 equiv, 4.47 mmol, 0.45 g) in an ice-water bath. The reaction mixture was then stirred at 0°C for 1 hour. After completion of the reaction, the residue was dissolved in water and extracted with DCM. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0 to 25%) to give 1.15 g of the product in a 76% yield as a red solid. MS (ESI) m / z 507.7 [M+H] + .

[1108] Step e:

[1109] 5-(Chlorosulfonyl)-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzoate

[1110]

[1111] To a suspension of 5-(benzylthio)-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzoic acid benzoate (1.0 equiv, 2.27 mmol, 1.15 g) in acetonitrile (20 mL) was added 1-chloropyrrolidine-2,5-dione (3.0 equiv, 6.81 mmol, 0.91 g) and 2N hydrogen chloride (3.0 equiv, 6.81 mmol, 0.25 g) in an ice-water bath. The reaction mixture was then stirred at 0°C for 2 hours. After completion of the reaction, the residue was dissolved in water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 1.10 g of the crude product as a red solid, which was used directly in the next step. MS (ESI) m / z 483.2 [M+H] + .

[1112] Step f:

[1113] 5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzoate

[1114]

[1115] To a suspension of 5-(chlorosulfonyl)-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenylbenzoate (1.0 eq, 2.28 mmol, 1.1 g) in DCM (20 mL) in an ice-water bath was added bis(4-methoxybenzyl)amine (2.5 eq, 5.69 mmol, 1.47 g). The reaction mixture was then stirred at 25 ° C. under N2 for 4 hours. After completion of the reaction, the residue was dissolved in water and extracted with DCM. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range from 0 to 5%) to give the product 1.6 g, 100% yield, as a red solid. MS (ESI) m / z 704.5 [M+H] + .

[1116] Step g:

[1117] 3-Hydroxy-4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-N,N-bis(4-methoxybenzyl)-5-nitrobenzenesulfonamide

[1118]

[1119] To a suspension of 5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzoate (1.0 equiv., 2.13 mmol, 1.5 g) in THF (20 mL) was added lithium aluminum (III) hydride (1.2 equiv., 2.56 mmol, 0.10 g) in an ice-water bath. The reaction mixture was then stirred at 0° C. under N2 for 1 hour. After completion, the residue was dissolved in water (2.1 mL), 15% NaOH solution (2.1 mL), and water (6.3 mL) in that order, and then extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH ranging from 0 to 2%) to give 1.25 g of the product in a 98% yield as a red solid. MS (ESI) m / z 600.6 [M+H] + .

[1120] Step h:

[1121] 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-N,N-bis(4-methoxybenzyl)-3-nitro-5-(4-((tetrahydro-2H-)pyran-2-yl)oxy)butoxy)benzenesulfonamide

[1122]

[1123] To a suspension of 3-hydroxy-4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-N,N-bis(4-methoxybenzyl)-5-nitrobenzenesulfonamide (1.0 equiv, 2.08 mmol, 1.25 g) in ACN (20 mL) in an ice-water bath were added 2-(4-bromobutoxy)tetrahydro-2H-pyran (1.2 equiv, 2.5 mmol, 0.59 g) and KCO (2.0 equiv, 4.17 mmol, 0.58 g). The reaction mixture was then stirred at 0°C under N for 1 hour. After completion of the reaction, the residue was dissolved in water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 2%) to give the product 1.44 g, a yield of 91%, as a red solid. MS (ESI) m / z 778.7 [M+H] + .

[1124] Step i:

[1125] 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)(methyl)amino)-N,N-bis(4-methoxybenzyl)-3-nitro-5-(4-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)benzenesulfonamide

[1126]

[1127] To a suspension of 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-N,N-bis(4-methoxybenzyl)-3-nitro-5-(4-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)benzenesulfonamide (1.0 eq., 1.59 mmol, 1.2 g) in DMF (20 ml) was added sodium hydride (1.5 eq., 2.38 mmol, 0.10 g) under argon in an ice-water bath. The reaction mixture was then stirred at 0°C for 30 minutes under argon. Methyl iodide (1.5 eq., 2.38 mmol, 0.34 g) was then added to the mixture, and the mixture was stirred at 25°C for 1 hour. After completion of the reaction, the residue was dissolved in ice water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH ranging from 0 to 2%) to give the product 946 mg in 77% yield as a red solid.

[1128] Step j:

[1129] 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)(methyl)amino)-3-(4-hydroxybutoxy)-N,N-bis(4-methoxybenzyl)-5-nitrobenzenesulfonamide

[1130]

[1131] To a suspension of 4-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)(methyl)amino)-N,N-bis(4-methoxybenzyl)-3-nitro-5-(4)-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)benzenesulfonamide (1.0 equiv, 1.23 mmol, 946 mg) in MeOH (8 ml) was added PPTS (1.0 equiv, 1.23 mmol, 309 mg) in an ice-water bath. The reaction mixture was then stirred at 50°C under N2 for 3 hours. After completion of the reaction, the residue was dissolved in water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 2%) to give 585 mg of the product in a 69.4% yield as a red solid. MS (ESI) m / z 686.9 [M+H] + .

[1132] Step k:

[1133] Butyl 4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)(methyl)amino)-3-nitrophenoxy)methanesulfonate

[1134]

[1135] To a suspension of 4-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)(methyl)amino)-3-(4-hydroxybutoxy)-N,N-bis(4-methoxybenzyl)-5-nitrobenzenesulfonamide (1.0 equiv, 0.88 mmol, 600 mg) in DCM (18 mL) was added methanesulfonyl chloride (1.2 equiv, 1.05 mmol, 120 mg) and triethylamine (2.0 equiv, 1.75 mmol, 177 mg) in an ice-water bath. The reaction mixture was then stirred at 0°C under N2 for 3 hours. After completion of the reaction, the residue was taken up in ice water and extracted with DCM. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 668 mg of the crude product as a red solid, which was used directly in the next step. MS (ESI) m / z 764.6 [M+H] + .

[1136] Step 1:

[1137] Methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl))(methyl)amino)-3-nitrophenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate

[1138]

[1139] To a suspension of butyl 4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)(methyl)amino)-3-nitrophenoxy)methanesulfonate (1.0 equiv, 0.87 mmol, 668 mg) in ACN (25 mL) was added methyl 4-fluoro-2-((6-hydroxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.2 equiv, 1.05 mmol, 317 mg), K2 CO3 (3.0 eq, 2.62 mmol, 363 mg) and tetrabutylammonium iodide (0.5 eq, 0.44 mmol, 161 mg). The reaction mixture was then stirred at 75 ° C overnight under N2. After the reaction was complete, the residue was poured into ice water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0 to 33%) to give 263 mg of the product in a 31% yield as a red solid. MS (ESI) m / z 970.8 [M + H] + .

[1140] Step m:

[1141] Methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl))(methyl)amino)-3-nitrophenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonyl-7-yl)benzoate

[1142]

[1143] To a suspension of methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl))(methyl)amino)-3-nitrophenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 equiv, 0.27 mmol, 263 mg) in DMF (15 mL) was added 2,2-dimethoxy-7-azaspiro[3.5]nonane (15 equiv, 4.07 mmol, 753 mg) and Na2CO3 (25.0 equiv, 6.78 mmol, 718 mg). The reaction mixture was then stirred at 105 ° C under N2 overnight. After completion of the reaction, the residue was poured into ice water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 1.6%) to give 143 mg of the product in a 46.5% yield as a red solid. MS (ESI) m / z 1135.9 [M+H] + .

[1144] Step n:

[1145] Methyl 2-((6-(4-(2-(methyl(((1r,4r)-4-methyl-4-(2,2,2-trifluoroacetyl)cyclohexyl)methyl)amino)-3-nitro-5-sulfamoylphenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonyl-7-yl)benzoate

[1146]

[1147] To the reaction flask was added methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl))(methyl)amino)-3-nitrophenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonyl-7-yl)benzoate (1.0 equiv, 1.125 mmol, 142 mg), TFA (5.0 equiv, 0.625 mmol, 71.3 mg) and anisole (1.0 equiv, 0.125 mmol, 13.53 mg). The reaction mixture was then stirred at 60° C. under N2 for 40 minutes. After completion of the reaction, the resulting mixture was evaporated, diluted with ethyl acetate and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 5%) to give 60 mg of the product in 50.8% yield as a yellow solid. MS (ESI) m / z 945.9 [M+H] + .

[1148] Step o:

[1149] 2-((6-(4-(2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)(methyl)amino)-3-nitro-5-sulfamoylphenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoic acid

[1150]

[1151] To a suspension of methyl 2-((6-(4-(2-(methyl(((1r,4r)-4-methyl-4-(2,2,2-trifluoroacetyl)cyclohexyl)methyl)amino)-3-nitro-5)-sulfamoylphenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonyl-7-yl)benzoate (1.0 eq, 0.063 mmol, 60 mg) in THF (8 mL) and MeOH (8 mL) was added 2N sodium hydroxide (1.0 eq, 0.063 mmol, 2.54 mg) under N2. The reaction mixture was then stirred at 50 °C for 3 h under N2. After completion of the reaction, the resulting mixture was diluted with water, washed with 1N HCl solution, and extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 53.0 mg of crude product as a yellow solid, which was used directly in the next step. MS (ESI) m / z 835.6 [M+H] + .

[1152] Step p:

[1153] 74-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)(methyl)amino)-75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecyl-4-one-6,6-dioxide

[1154]

[1155] To a suspension of 2-((6-(4-(2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)(methyl)amino)-3-nitro-5-sulfamoylphenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoic acid (1.0 equiv, 0.06 mmol, 50 mg) and EDCI (1.5 equiv, 0.09 mmol, 17.2 mg) in DCM (8 mL) was added DMAP (2.0 equiv, 0.12 mmol, 14.63 mg). The reaction mixture was then stirred at 30° C. under N2 overnight. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 5%) to give the product 20 mg as a yellow solid in a 40.9% yield. MS (ESI) m / z 817.6 [M+H] + .

[1156] Step q:

[1157] 74-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)(methyl)amino)-35-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecyl-4-one-6,6-dioxide

[1158]

[1159] 74-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)(methyl)amino)-75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecyl-4-one-6,6-dioxide (1.0 equiv, 0.024 mmol, 20 mg) and (S)-2-(2-isopropylphenyl)pyrrolidine (4 To a suspension of 1,000 mmol (0.05 equiv, 0.098 mmol, 18.54 mg) in DCE (8 mL) was added sodium triacetylborohydride (4.0 equiv, 0.098 mmol, 16.05 mg). The reaction mixture was then stirred at 50°C overnight. After completion of the reaction, the residue was added to a saturated NaHCO solution, diluted with ethyl acetate, and washed with brine. The organic layer was separated, dried over NaSO, filtered, and concentrated in vacuo to afford the crude product, which was purified by pre-HPLC to afford 1.6 mg of product as a yellow solid in a 6.6% yield. 1 H NMR (400MHz, DMSO) δ11.38(s,1H),7.70–7.42(m,4H),7.41–7.04(m,5H),6.73–6.53(m,1H),6.26(s,1H),6.04 (s,1H),4.59–4.32(m,2H),4.31–4.12(m,2H),3.89–3.74(m,1H),3.28–3.24(m,2H),2.98–2.92(m,2H),2.88–2 .82(m,2H),2.79–2.72(m,2H),2.65(s,3H),2.35–2.21(m,1H),2.04–1.88(m,5H),1.84–1.70(m,4H),1.46–1.4 0(m,4H),1.38–1.32(m,5H),1.26–1.22(m,5H),1.21–1.17(m,3H),1.14–1.06(m,6H),1.02(s,3H).MS(ESI)m / z 991.1[M+H] + .

[1160] Example 25

[1161] 74-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-35-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenyltridecyl-4-one-6,6-dioxide

[1162]

[1163] Step a:

[1164] 3-(4-Bromobutoxy)-4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-N,N-bis(4-methoxybenzyl)-5-nitrobenzenesulfonamide

[1165]

[1166] To a suspension of 3-hydroxy-4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-N,N-bis(4-methoxybenzyl)-5-nitrobenzenesulfonamide (1.0 equiv, 0.84 mmol, 502 mg) in acetonitrile (20 mL) was added 1,4-dibromobutane (1.5 equiv, 1.26 mmol, 271 mg) and K2CO3 (2.0 equiv, 1.67 mmol, 231 mg). The reaction mixture was then stirred at 80 °C under N2 for 5 hours. After completion of the reaction, the residue was dissolved in water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range from 0 to 5%) to give 379 mg of the product in a 61.6% yield as a red solid. MS (ESI) m / z 734.3 [M+H] + .

[1167] Step b:

[1168] Methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino))-3-nitrophenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate

[1169]

[1170] To a suspension of 3-(4-bromobutoxy)-4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-N,N-bis(4-methoxybenzyl)-5-nitrobenzenesulfonamide (1.0 equiv, 0.52 mmol, 379 mg) in acetonitrile (25 mL) was added methyl 4-fluoro-2-((6-hydroxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.2 equiv, 0.62 mmol, 187 mg) and K2CO3 (3.0 equiv, 1.55 mmol, 214 mg). The reaction mixture was then stirred at 75°C overnight under N2. After completion of the reaction, the residue was poured into ice water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE and EA, EA range 0 to 33%) to give 360 ​​mg of the product in 73% yield as a red solid. MS (ESI) m / z 956.7 [M+H] + .

[1171] Step c:

[1172] Methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino))-3-nitrophenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)benzoate

[1173]

[1174] To a suspension of methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino))-3-nitrophenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.0 eq, 0.38 mmol, 360 mg) in DMF (15 ml) was added 2,2-dimethoxy-7-azaspiro[3.5]nonane (15 eq, 5.65 mmol, 1.05 g) and Na2CO3 (25.0 eq, 9.41 mmol, 998 mg). The reaction mixture was then stirred at 105°C under N2 overnight. After completion of the reaction, the residue was poured into ice water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 1.6%) to give 319 mg of the product in 76% yield as a red solid. MS (ESI) m / z 1121.7 [M+H] + .

[1175] Step d:

[1176] Methyl 2-((6-(4-(2-((((1r,4r)-4-methyl-4-(2,2,2-trifluoroacetoxy)cyclohexyl)methyl)amino)-3-nitro-5-sulfamoylphenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonyl-7-yl)benzoate

[1177]

[1178] To the reaction flask was added methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino))-3-nitrophenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)benzoate (1.0 equiv, 0.28 mmol, 319 mg), TFA (5.0 equiv, 1.42 mmol, 162 mg), and anisole (1.0 equiv, 0.28 mmol, 30.8 mg). The reaction mixture was then stirred at 60° C. under N2 for 40 minutes. After completion of the reaction, the resulting mixture was evaporated, diluted with ethyl acetate, and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 5%) to give the product 265 mg in 100% yield as a yellow solid. MS (ESI) m / z 931.9 [M+H] + .

[1179] Step e:

[1180] 2-((6-(4-(2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitro-5-sulfamoylphenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoic acid

[1181]

[1182] To a suspension of methyl 2-((6-(4-(2-((((1r,4r)-4-methyl-4-(2,2,2-trifluoroacetoxy)cyclohexyl)methyl)amino)-3-nitro-5-sulfamoylphenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonyl-7-yl)benzoate (1.0 eq, 0.29 mmol, 265 mg) in THF (8 mL) and MeOH (8 mL) was added 2N sodium hydroxide (1.0 eq, 0.29 mmol, 11.39 mg) under N2. The reaction mixture was then stirred at 50 ° C for 3 hours under N2. After completion of the reaction, the resulting mixture was diluted with water, washed with 1N HCl solution, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 234.0 mg of crude product as a yellow solid, which was used directly in the next step. MS (ESI) m / z 821.6 [M+H]+ .

[1183] Step f:

[1184] 74-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenyltridecyl-4-one-6,6-dioxide

[1185]

[1186] To a suspension of 2-((6-(4-(2-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitro-5-sulfamoylphenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoic acid (1.0 equiv, 0.285 mmol, 234 mg) and EDCI (1.5 equiv, 0.43 mmol, 82 mg) in DCM (8 mL) was added DMAP (2.0 equiv, 0.57 mmol, 69.6 mg). The reaction mixture was then stirred at 30° C. under N2 overnight. After completion of the reaction, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM and MeOH, MeOH range 0 to 5%) to give the product as a yellow solid (20 mg) in 8.74% yield. MS (ESI) m / z 803.7 [M+H] + .

[1187] Step g:

[1188] 74-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-35-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenyltridecyl-4-one-6,6-dioxide

[1189]

[1190] To a suspension of 74-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-75-nitro-35-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenyltridecyl-4-one-6,6-dioxide (1.0 equiv, 0.025 mmol, 20 mg) and (S)-2-(2-isopropylphenyl)pyridine (4.0 equiv, 0.10 mmol, 18.86 mg) in DCE (8 mL) was added sodium triacetylborohydride (4.0 equiv, 0.10 mmol, 16.34 mg). The reaction mixture was then stirred at 50° C. overnight. After the reaction was complete, the residue was added to a saturated NaHCO solution, diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over NaSO, filtered and concentrated in vacuo to give a crude product, which was purified by pre-HPLC to give 2.6 mg of the product as a yellow solid in a 10.7% yield. 1 H NMR (400MHz, DMSO) δ11.36(s,1H),8.11–7.83(m,1H),7.55–7.41(m,4H),7.40–7.36(m,1H),7.24–7.18(m,2H),7.1 7–7.06(m,3H),6.64–6.57(m,1H),6.23(s,1H),6.04(s,1H),4.92–4.77(m,1H),4.58–4.32(m,2H),4.20–4.10(m,2H ),3.93(s,1H),3.62–3.50(m,4H),3.00–2.91(m,2H),2.90–2.81(m,2H),2.37–2.28(m,1H),2.02–1.92(m,5H),1.84 –1.75(m,4H),1.51–1.46(m,4H),1.39–1.35(m,5H),1.27–1.23(m,8H),1.17–1.14(m,6H),1.03(s,3H).MS(ESI)m / z 976.8[M+H] + .

[1191] Example 26

[1192] 35-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenyltridecyl-4-one-6,6-dioxide

[1193]

[1194] Step a:

[1195] 3-(4-Bromobutoxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide

[1196]

[1197] In a 100 mL round-bottom flask, 3-hydroxy-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (0.2 g, 0.350 mmol, 1.0 equiv), 1,4-dibromobutane (0.755 g, 3.50 mmol, 10 equiv), and KCO (0.145 g, 1.050 mmol, 3 equiv) were dissolved in acetonitrile (15 mL) under argon to produce a yellow suspension. The reaction mixture was stirred at 70°C for 2 hours. Saturated NaCl (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was added to a silica gel column for chromatography and eluted with ethyl acetate / hexane from 0% to 50% to obtain 3-(4-bromobutoxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (0.24 g, yield 97%) as a yellow oil. Mass spectrum m / z (ESI): 706.2 (M+H) + .

[1198] Step b:

[1199] Methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino))phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate

[1200]

[1201] In a 100 mL round-bottom flask, 3-(4-bromobutoxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (0.24 g, 0.340 mmol, 1.0 equiv), methyl 4-fluoro-2-((6-hydroxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (0.205 g, 0.679 mmol, 2.0 equiv), and KCO (0.235 g, 1.698 mmol, 5.0 equiv) were dissolved in acetonitrile (15 mL) under argon to give a yellow suspension. The reaction mixture was stirred at 70°C for 16 hours. Saturated NaCl (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was added to a silica gel column chromatography and eluted with 0% to 50% ethyl acetate / hexane to obtain methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)))sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (0.15 g, 47.6%) as a yellow oil. Mass spectrum m / z (ESI): 928.3 (M+H). + .

[1202] Step c:

[1203] Methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino))phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonyl-7-yl)benzoate

[1204]

[1205] In a 100 mL round-bottom flask, methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino))phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (0.14 g, 0.151 mmol, 1.0 equiv), 2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (0.471 g, 1.509 mmol, 10 equiv), and sodium carbonate (0.320 g, 3.02 mmol, 20 equiv) were dissolved in DMF (10 ml) under argon to give a yellow suspension. The reaction mixture was stirred at 100° C. for 48 hours. H2O (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (40 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane from 0% to 4% to obtain methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl))sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonyl-7-yl)benzoate (0.047 g, 25.5%) as a yellow oil. Mass spectrum m / z (ESI): 1220.6 (M+H). + .

[1206] Step d:

[1207] Methyl 4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(4-(3-nitro-5-)sulfamoyl-2-((((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate

[1208]

[1209] In a 50 mL round-bottom flask, under argon, methyl 2-((6-(4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino))phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonyl-7-yl)benzoate (0.047 g, 0.039 mmol, 1.0 equiv) was dissolved in TFA (10 ml) to give a yellow solution. The reaction mixture was stirred at 60° C. for 4 hours. The crude product was added to a silica gel column for chromatography and eluted with 0% to 10% methanol / dichloromethane to obtain methyl 4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(4-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy))-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (0.037 g, 98%) as a yellow oil. Mass spectrum m / z (ESI): 980.5 (M+H). + .

[1210] Step e:

[1211] 4-(2-(2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(4-(3-nitro-5-sulfamoyl)-2-((((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid

[1212]

[1213] In a 100 mL round-bottom flask, methyl 4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(4-(3-nitro-5-)sulfamoyl-2-((((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (0.037 g, 0.038 mmol, 1.0 equiv) and NaOH (1.510 mg, 0.038 mmol, 1.0 equiv) were dissolved in THF (2.0 ml), MeOH (2.0 ml), and water (2.0 ml) under argon to form a yellow solution. The reaction mixture was stirred at 50° C. for 2 hours. 1M HCl (4 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford 4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(4-(3-nitro-5-sulfamoyl)-2-((((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid (0.036 g, 99%). Mass spectrum m / z (ESI) 966.4 (M+H) + .

[1214] Step f:

[1215] 35-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran)-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecyl-4-one-6,6-dioxide

[1216]

[1217] In a 100 mL round-bottom flask, 4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(4-(3-nitro-5-sulfamoyl)-2-((((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)butoxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid (0.036 g, 0.037 mmol, 1.0 equiv), DMAP (0.014 g, 0.112 mmol, 3.0 equiv) and EDC (0.021 g, 0.112 mmol, 3.0 equiv) were dissolved in DCM (30 ml) under argon to give a yellow solution. The reaction mixture was stirred at 30° C. for 10 hours. Saturated NaCl (30 mL) was added to the reaction mixture, followed by extraction with dichloromethane (40 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give 35-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-75-nitro-74-(((tetrahydro-2H-pyran)-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecyl-4-one-6,6-dioxide (2.9 mg, 8.2%). Mass spectrum m / z (ESI): 948.4 (M+H) + .

[1218] Example 27

[1219] (R)-35-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-9-methyl-75 - Nitro-74-((((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenyltridecyl-4-one-6,6-dioxide

[1220]

[1221]

[1222] Step a:

[1223] (R)-5-(Hydroxymethyl)dihydrofuran-2(3H)-one

[1224]

[1225] In a 500 mL three-necked round-bottom flask, (R)-5-oxotetrahydrofuran-2-carboxylic acid (5 g, 38.4 mmol, 1.0 equiv) was dissolved in THF (80 ml) under argon to give a colorless solution. The reaction mixture was cooled to 0°C with an ice / water bath. BH3.THF (3.961 g, 46.1 mmol, 1.2 equiv) was added dropwise to the reaction mixture over 10 minutes. The reaction mixture was stirred at room temperature for 6 hours. MeOH (50 mL) was added dropwise to the reaction mixture over 10 minutes. The reaction mixture was concentrated to give (R)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (4.46 g, 100%). Mass spectrum m / z (ESI): 117.1 (M+H) + .

[1226] Step b:

[1227] (R)-(5-Oxotetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate

[1228]

[1229] In a 250 mL round-bottom flask, (R)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (4.46 g, 38.4 mmol, 1.0 equiv) and pyridine (9.11 g, 115 mmol, 3.0 equiv) were dissolved in DCM (100 mL) under argon to give a yellow solution. The reaction mixture was cooled to 0°C using an ice / water bath. TsCl (10.98 g, 57.6 mmol, 1.5 equiv) was added to the reaction mixture in one portion. The reaction mixture was stirred at room temperature for 16 hours. 1 M HCl (50 mL) was added to the reaction mixture, which was then extracted with dichloromethane (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column chromatography and eluted with ethyl acetate / hexane from 0% to 50% to obtain (R)-(5-oxotetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (4.84 g, 46.6%) as a white solid. Mass spectrum m / z (ESI) 271.1 (M+H) + .

[1230] Step c:

[1231] (S)-Pentane-1,4-diol

[1232]

[1233] In a 250 mL round-bottom flask, (R)-(5-oxotetrahydrofuran-2-yl)methyl-4-methylbenzenesulfonate (2 g, 7.40 mmol, 1.0 equiv) was dissolved in THF (30 ml) under argon to give a suspension. LAH (1.123 g, 29.6 mmol, 4.0 equiv) was added to the reaction mixture in one portion. The reaction mixture was stirred at 70°C for 16 hours. The crude product was added to a silica gel column chromatography and eluted with methanol / dichloromethane from 0% to 10% to give (S)-pentane-1,4-diol (0.568 g, 73.7%) as a yellow oil. Mass spectrum m / z (ESI) 105.1 (M+H) + .

[1234] Step d:

[1235] (S)-5-((tert-Butyldiphenylsilyl)oxy)pentan-2-ol

[1236]

[1237] In a 100 mL round-bottom flask, (S)-pentane-1,4-diol (0.568 g, 5.45 mmol, 1.0 equiv) and imidazole (0.371 g, 5.45 mmol, 1.0 equiv) were dissolved in DMF (10 mL) under argon to give a colorless solution. The reaction mixture was cooled to 0°C using an ice / water bath. TBDPS-Cl (1.499 g, 5.45 mmol, 1.0 equiv) was added in one portion to the reaction mixture. The reaction mixture was stirred at room temperature for 16 hours. Saturated NaCl (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (60 mL x 2). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was added to a silica gel column chromatography and eluted with ethyl acetate / hexane from 0% to 20% to give (S)-5-((tert-butyldiphenylsilyl)oxy)pentan-2-ol (1.37 g, 73.3%) as a colorless oil. Mass spectrum m / z (ESI): 343.2 (M+H) + .

[1238] Step e:

[1239] (S)-5-((tert-Butyldiphenylsilyl)oxy)pentan-2-yl methanesulfonate

[1240]

[1241] In a 100 mL round-bottom flask, (S)-5-((tert-butyldiphenylsilyl)oxy)pentan-2-ol (1.37 g, 4.00 mmol, 1.0 equiv), TEA (0.809 g, 8.00 mmol, 2.0 equiv), and DMAP (0.098 g, 0.800 mmol, 0.2 equiv) were dissolved in DCM (30 mL) under argon to yield a solution. The reaction mixture was cooled to 0°C using an ice / water bath. MsCl (0.550 g, 4.80 mmol, 1.2 equiv) was added dropwise to the reaction mixture over 5 minutes. The reaction mixture was stirred at room temperature for 1 hour. H2O (30 mL) was added to the reaction mixture, which was then extracted with dichloromethane (40 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated to give (S)-5-((tert-butyldiphenylsilyl)oxy)pentan-2-yl methanesulfonate (1.68 g, 100%). Mass spectrum m / z (ESI) 421.2 (M+H) + .

[1242] Step f:

[1243] (R)-3-((5-((tert-Butyldiphenylsilyl)oxy)pentan-2-yl)oxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H)-pyran-4-yl)methyl)amino)benzenesulfonamide

[1244]

[1245] In a 100 mL round-bottom flask, 3-hydroxy-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (0.54 g, 0.945 mmol, 1.0 equiv), (S)-5-((tert-butyldiphenylsilyl)oxy)pentan-2-yl methanesulfonate (0.477 g, 1.134 mmol, 1.2 equiv), and KCO (0.392 g, 2.83 mmol, 3.0 equiv) were dissolved in acetonitrile (30 mL) under argon to give a brown suspension. The reaction mixture was stirred at 75°C for 16 hours. Saturated NaCl (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (40 mL x 2). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was subjected to silica gel column chromatography and eluted with ethyl acetate / hexane from 0% to 30% to obtain (R)-3-((5-((tert-butyldiphenylsilyl)oxy)pentan-2-yl)oxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H)-pyran-4-yl)methyl)amino)benzenesulfonamide (0.59 g, 69.7%) as a yellow oil. Mass spectrum m / z (ESI): 896.4 (M+H). + .

[1246] Step g:

[1247] (R)-3-((5-hydroxypentan-2-yl)oxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide

[1248]

[1249] In a 100 mL round-bottom flask, (R)-3-((5-((tert-butyldiphenylsilyl)oxy)pentan-2-yl)oxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (0.59 g, 0.658 mmol, 1.0 equiv) and TBAF (0.258 g, 0.987 mmol, 1.5 equiv) were dissolved in THF (20 mL) under argon to give a yellow solution. The reaction mixture was stirred at room temperature for 1 hour. Saturated NaCl (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL x 2). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was subjected to silica gel column chromatography and eluted with methanol / dichloromethane from 0% to 5% to obtain (R)-3-((5-hydroxypentan-2-yl)oxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (0.378 g, 87%) as a yellow oil. Mass spectrum m / z (ESI): 658.3 (M+H). + .

[1250] Step h: (R)-pentyl 4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)methanesulfonate

[1251]

[1252] In a 100 mL round-bottom flask, (R)-3-((5-hydroxypentan-2-yl)oxy)-N,N-bis(4-methoxybenzyl)-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (0.378 g, 0.575 mmol, 1.0 equiv), TEA (0.116 g, 1.149 mmol, 2.0 equiv), and DMAP (0.014 g, 0.115 mmol, 0.2 equiv) were added to DCM (20 mL) under argon to give a yellow solution. The reaction mixture was cooled to 0° C. using an ice / water bath. MsCl (0.079 g, 0.690 mmol, 1.2 equiv) was added dropwise to the reaction mixture over 5 minutes. The reaction mixture was stirred at room temperature for 1 hour. Saturated NaCl (30 mL) was added to the reaction mixture, which was then extracted with dichloromethane (40 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give (R)-4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl methanesulfonate (0.423 g, 100%). Mass spectrum m / z (ESI): 736.3 (M+H) + .

[1253] Step i: (R)-methyl 2-((6-((4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate

[1254]

[1255] In a 100 mL round-bottom flask, (R)-pentyl 4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)methanesulfonate (0.423 g, 0.575 mmol, 1.0 equiv), methyl 4-fluoro-2-((6-hydroxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (0.226 g, 0.747 mmol, 1.3 equiv), TBAI (0.064 g, 0.172 mmol, 0.3 equiv), and KCO (0.397 g, 2.87 mmol, 5.0 equiv) were dissolved in MeCN (15 mL) under argon to produce a yellow suspension. The reaction mixture was stirred at 75° C. for 16 hours. Saturated NaCl (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane 0% to 50% to give (R)-2-((6-((4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid methyl ester (0.2 g, 36.9%) as a yellow oil. Mass spectrum m / z (ESI): 942.3 (M+H) + .

[1256] Step j:

[1257] Methyl 2-((6-(((R)-4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)))methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate

[1258]

[1259] In a 100 mL round-bottom flask, (R)-methyl 2-((6-((4-(5-(N,N-bis(4-methoxyphenyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (0.2 g, 0.212 mmol, 1.0 equiv), (S)-2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (0.663 g, 2.123 mmol, 10.0 equiv) and Na2CO3 (0.450 g, 4.25 mmol, 20 equiv) were dissolved in DMF (10 ml) under argon to give a yellow suspension. The reaction mixture was stirred at 100° C. for 24 hours. H 2 O (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL×2). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated. The crude product was added to a silica gel column chromatography and eluted with methanol / dichloromethane from 0% to 4% to obtain methyl 2-((6-(((R)-4-(5-(N,N-bis))(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonyl-7-yl)benzoate (0.06 g, 22.89%) as a yellow oil. Mass spectrum m / z (ESI): 1234.6 (M+H). + .

[1260] Step k:

[1261] Methyl 4-(2-((S)-2-(2-Isopropylphenyl)pyridin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((R)-4-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate

[1262]

[1263] In a 100 mL round-bottom flask, methyl 2-((6-(((R)-4-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-nitro-2-(((tetrahydro-2H-pyran-4-yl)))methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate (0.06 g, 0.049 mmol, 1.0 equiv) was dissolved in TFA (20 ml) under argon to give a yellow solution. The reaction mixture was stirred at 60° C. for 4 hours. The crude product was subjected to silica gel column chromatography and eluted with methanol / dichloromethane from 0% to 10% to give methyl 4-(2-((S)-2-(2-isopropylphenyl)pyridin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((R)-4-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (0.043 g, 89%) as a yellow oil. Mass spectrum m / z (ESI): 994.5 (M+H) + .

[1264] Step 1:

[1265] 4-(2-((S)-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((R)-4)-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid

[1266]

[1267] In a 100 mL round-bottom flask, under argon, methyl 4-(2-((S)-2-(2-isopropylphenyl)pyridin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((R)-4-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (0.043 g, 0.043 mmol, 1.0 equiv) and NaOH (1.730 mg, 0.043 mmol, 1.0 equiv) were dissolved in THF (2.000 ml), MeOH (2.000 ml) and water (2 ml) to give a yellow solution. The reaction mixture was stirred at 50° C. for 2 hours. 1M HCl (4 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford 4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((R)-4)-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid (0.042 g, 99%). Mass spectrum m / z (ESI): 980.5 (M+H). + .

[1268] Step m:

[1269] (R)-35-(2-((S)-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-9-methyl-75-nitro-74-((((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecyl-4-one-6,6-dioxide

[1270]

[1271] In a 100 mL round-bottom flask, 4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((R)-4)-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid (0.042 g, 0.043 mmol, 1.0 equiv), DMAP (0.016 g, 0.129 mmol, 3.0 equiv), and EDC (0.025 g, 0.129 mmol, 3.0 equiv) were dissolved in DCM (30 ml) under argon to give a yellow solution. The reaction mixture was stirred at 30° C. for 10 hours. Saturated NaCl (30 mL) was added to the reaction mixture, followed by extraction with dichloromethane (40 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give 4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((6-(((R)-4)-(3-nitro-5-sulfamoyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenoxy)pentyl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoic acid (10.1 mg, 24.5%). 1 H NMR(400MHz,DMSO)δ11.35(s,1H),8.14–7.87(m,2H),7.64–7.44(m,3H),7.39(s,1H),7 .18(d,J=25.2Hz,5H),6.62(d,J=8.1Hz,1H),6.27(s,1H),6.02(s,1H),4.73–4.51(m,2H ),4.19(s,1H),3.81(d,J=8.1Hz,2H),2.98–2.88(m,5H),2.26–2.11(m,2H),2.04–1.95 (m,2H),1.92–1.63(m,10H),1.59–1.46(m,6H),1.43–1.29(m,9H),1.19–1.08(m,9H).MS m / z(ESI)962.4(M+H) + .

[1272] Example 28

[1273] (R)-35-(2-((S)-2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-12-methyl-75-nitro-74-((((tetrahydro-2H-pyran-4-yl)methyl)amino)-11H-2,8,13-trioxa-6-thia-5-aza-1(5,6)-pyrrolo[2,3-b]pyridine-3(1,2),7(1,3)-diphenylcyclotridecyl-4-one-6,6-dioxide

[1274]

[1275] Step a:

[1276] (R)-methyl 2-((6-((5-((tert-Butyldiphenylsilyl)oxy)pentan-2-yl)oxy)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate

[1277]

[1278] In a 100 mL round-bottom flask, methyl 4-fluoro-2-((6-hydroxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (0.6 g, 1.985 mmol, 1.0 equiv), (S)-5-((tert-butyldiphenylsilyl)oxy)pentan-2-yl methanesulfonate (1.085 g, 2.58 mmol, 1.3 equiv), and KCO (0.823 g, 5.96 mmol, 3.0 equiv) were dissolved in acetonitrile (40 mL) and DMF (10 mL) under argon to form a suspension. The reaction mixture was stirred at 80°C for 48 hours. H2O (60 mL) was added to the reaction mixture, followe...

Claims

1. A compound having a structure shown in Formula I: or a pharmaceutically acceptable salt thereof, wherein: The compound of the structure shown in Formula I is the following compound Ring C is piperazine, 7-azaspiro[3.5]nonyl or 2-azaspiro[3.3]heptyl; Ring D is cyclohexenyl, pyrrole or piperazine; Ring E is a benzene ring, pyridine or pyrazole; R 1 are independently -NO2 or -N(R 1a )(CR 1b R 1c ) n1 R 1d ; R 1a , R 1b and R 1c Each independently is H or C1-C6 alkyl; R 1d is a 4-6 membered monocyclic heterocycloalkyl, cyclohexyl, substituted 4-6 membered monocyclic heterocycloalkyl or substituted cyclohexyl, wherein the substituents in the substituted heterocycloalkyl and substituted cyclohexyl are independently selected from halogen, -OH and C1-C6 alkyl; the 4-6 membered monocyclic heterocycloalkyl is dioxanyl or tetrahydropyranyl; n1 is independently 0, 1, 2 or 3; R 2 are independently halogen, -OH or C1-C6 alkyl; Or, any two R 2 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkanes; R 3 are independently halogen, -OH, -CN, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered monocyclic heterocycloalkyl, -N(R 2a R 2b )、-S(O)2R 2c 、-N(R 2d )S(O)2R 2e , wherein the substituent in the "substituted alkyl" is selected from halogen and -OH, the heteroatom in the 4-6 membered monocyclic heterocycloalkyl is O, and the number of heteroatoms is 1; R 2a , R 2b , R 2c , R 2d and R 2e Each independently is H or C1-C6 alkyl; m2 and m3 are each independently 0, 1, 2, 3 or 4; -L1- is a single bond, -M 0 -Yes-N(R 3e )-; -M 0a - is cyclohexylene or 4-6 membered monocyclic heterocycloalkylene, wherein the 4-6 membered monocyclic heterocycloalkylene is -L 1a -Yes-(CR 3a R 3b ) n2 -; -L 1b -Yes-(CR 3c R 3d ) n3 -; R 3a , R 3b , R 3c , R 3d and R 3e Each independently is H or C1-C6 alkyl; n2 and n3 are each independently 0, 1, 2 or 3; -M 1 - is -O- or -C(=O)-; -M 2 - is a single bond, -O- or C3-C6 cycloalkylene; the C3-C6 cycloalkylene is cyclopropylene or cyclobutylene; -M 3 - is a single bond or -O-; -L 2 -Yes-(CR 4a R 4b ) n4 -; -L 3 -Yes-(CR 4c R 4d ) n5 -; R 4a , R 4b , R 4c and R 4d Each independently is H or C1-C6 alkyl; n4 and n5 are each independently 0, 1, 2 or 3; -X- is -O-; -Y- is a single bond or -(CR 5b R 5c )-; R 5a , R 5b and R 5c Each is independently H or C1-C6 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: In R 1a , R 1b and R 1c In which, the C1-C6 alkyl groups are each independently C1-C3 alkyl groups; and / or, in R 1d In the formula (a), halogen is F, Cl, Br or I; and / or, in R 1d wherein the C1-C6 alkyl group is a C1-C3 alkyl group; and / or, in R 1d wherein the substituents in the substituted heterocycloalkyl are selected from halogen; and / or, in R 1d In the substituted cyclohexyl group, the substituent is selected from -OH and C1-C6 alkyl; and / or, in R 1d In the substituted cyclohexyl group, the number of substituents is 2; and / or, in R 2 In the formula (a), halogen is F, Cl, Br or I; and / or, in R 2 wherein the C1-C6 alkyl group is a C1-C3 alkyl group; And / or, when any two R 2 When together with the carbon atom to which they are attached form a C3-C6 cycloalkane, the C3-C6 cycloalkane is a cyclobutane; and / or, in R 3 In the formula (a), halogen is F, Cl, Br or I; and / or, in R 3 In the above formula (A), the alkyl group and the alkyl group in the substituted alkyl group are each independently a C1-C3 alkyl group; and / or, in R 1d wherein the substituent in the substituted alkyl is selected from -OH and F; and / or, in R 1d In the substituted alkyl group, the number of substituents is 1, 2 or 3; and / or, in R 3 In which C1-C6 alkoxy is C1-C3 alkoxy; and / or, in R 3 In, the C3-C6 cycloalkyl group is a cyclopropyl group; and / or, in R 2a , R 2b , R 2c , R 2d and R 2e wherein the C1-C6 alkyl group is a C1-C3 alkyl group; and / or, in -L 1 -M, -M 0 - connected to ring A; and / or, in R 3a , R 3b , R 3c , R 3d and R 3e In which, the C1-C6 alkyl groups are each independently C1-C3 alkyl groups; and / or, in R 4a , R 4b , R 4c and R 4d In which, the C1-C6 alkyl groups are each independently C1-C3 alkyl groups; and / or, in R 5a , R 5b and R 5c In the above, the C1-C6 alkyl groups are each independently C1-C3 alkyl groups.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: In R 1d In, halogen is F; and / or, in R 1d In which, the C1-C6 alkyl group is a methyl group; and / or, in R 2 In, halogen is F; and / or, in R 2 In which, the C1-C6 alkyl group is a methyl group; and / or, in R 3 In, halogen is F; and / or, in R 3 In the above, the C1-C6 alkoxy group is a methoxy group.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: In R 1d In the case of a substituted 4-6 membered monocyclic heterocycloalkyl group, The carbon marked with "*" refers to achiral carbon or chiral carbon; and / or, in R 1d In the case where the substituted C3-C6 cycloalkyl group is The carbon marked with "*" refers to achiral carbon or chiral carbon; and / or, in R 1d In the above, the substituted C1-C6 alkyl group is -CF3, and / or, in R 3 In the 4-6 membered monocyclic heterocycloalkyl group, tetrahydropyranyl is; and / or, in -M 0a -, cyclohexylene is Where -M 0a -The "j" end of the - is connected to -L 1a -, -M 0a -The "k" terminal is connected to -L 1b -, the carbon marked with "*" refers to achiral carbon or chiral carbon; and / or, in -M 2 -, C3-C6 cycloalkylene is The carbon marked with "*" refers to achiral carbon or chiral carbon.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein In R 1d In the present invention, the 4-6 membered monocyclic heterocycloalkyl group is in, Carbons marked with "*" refer to achiral carbons or chiral carbons; and / or, in R 3 In the present invention, the 4-6 membered monocyclic heterocycloalkyl group is and / or, in -M 0a -, the 4-6 membered monocyclic heterocyclic ring is Where -M 0a Connect the "j" end of - to -L 1a -, -M 0a The "k" terminal of - is connected to -L 1b -, and the carbon marked with "*" refers to an achiral carbon or a chiral carbon.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein: In R 1d In the present invention, the 4-6 membered monocyclic heterocycloalkyl group is and / or, in R 1d In the case of a substituted 4-6 membered monocyclic heterocycloalkyl group, and / or, in R 1d In the case of cyclohexyl, the substituted cyclohexyl group is and / or, in -M 0a -, cyclohexylene is Where -M 0a -The "j" end of -L 1a - connected, -M 0a -The "k" end of -L 1b - connected; and / or, in -M 0a -, the 4-6 membered monocyclic heterocyclic ring is Where -M 0a -The "j" end of the - is connected to -L 1a -, -M 0a -The "k" terminal is connected to -L 1b -; and / or, in -M 2 -, C3-C6 cycloalkylene is 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: In R 1 In, -N(R 1a )-C(R 1b R 1c ) n1 R 1d for The carbon marked with "*" is an achiral carbon or a chiral carbon; and / or, in R 3 In, -N(R 2a R 2b ) is -NH2, -NH(CH3) or -N(CH3)2; and / or, in R 3 Medium, -S(O)2R 2c is -S(O)2CH3; and / or, in -Y-, -(CR 5b R 5c )-is -CH2-.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein: In R 1 In, -N(R 1a )-C(R 1b R 1c ) n1 R 1d for 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Each R 1 Yes-NO2, and / or, each R 2 are independently F, OH or methyl; or, any two R 2 Together with the carbon atom to which they are attached they form a cyclobutyl group; and / or, each R 3 are independently F, -Cl, -OH, -CN, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF3, -NH2, -NH(CH3), -N(CH3)2, -S(O)2CH3 or -N(H)S(O)2CH3; and / or, -M 0 - is -NH-; and / or, -M 0a -yes Where -M 0a -The "j" end of the - is connected to -L 1a -, -M 0a -The "k" terminal is connected to -L 1b -; and / or, -L 1a - is -CH2-; and / or, -L 1b - is -(CH2)0-, -CH2-, -(CH2)2- or -(CH2)3-; And / or, -Y- is a single bond or -CH2-.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: -L 1 - is a single bond, -NH-(CH2)3-, 11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: yes 12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: This section yes The "e" end of ring C is connected to the phenyl group, and the "f" end of ring C is connected to the D ring; and / or, yes wherein the "g" end of ring D is connected to ring C, the "h" end of ring D is connected to ring E, and carbons marked with "*" refer to achiral carbons or chiral carbons; and / or yes 13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein: yes wherein the "g" end of ring D is connected to ring C, the "h" end of ring D is connected to ring E, and carbons marked with "*" refer to achiral carbons or chiral carbons; and / or, yes 14. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein: yes Wherein the "g" end of ring D is connected to ring C, the "h" end of ring D is connected to ring E, and the carbon marked with "*" refers to an achiral carbon or a chiral carbon.

15. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein: Said yes The "a" end of ring A is connected to -L 1 -, the "b" end of ring A is connected to the S atom, and the carbon marked with "*" is an achiral carbon or a chiral carbon.

16. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein: Said yes The "a" end of ring A is connected to -L 1 -, the "b" end of ring A is connected to the S atom.

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: yes The "g" end of ring D is connected to ring C, and the "h" end of ring D is connected to ring E.

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein: yes The "g" end of ring D is connected to ring C, and the "h" end of ring D is connected to ring E.

19. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein: yes The "g" end of ring D is connected to ring C, and the "h" end of ring D is connected to ring E.

20. The compound or pharmaceutically acceptable salt thereof according to any one of claims 4-5, 7-8 and 12-16, wherein: In R 1d , R 1 , -M 0a -、-M 2 -and In the above, the carbons marked with "*" each independently refer to a chiral carbon present in its S-configuration, a chiral carbon present in its R-configuration, or an achiral carbon.

21. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from one of the following options: Option 1: Ring D is cyclohexenyl, and Each R 2 are independently C1-C3 alkyl, Or, any two R 2 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkanes; Option 2: Ring D is pyrrole or piperazine, and Each R 2 are independently halogen, -OH or alkyl; Option 3: Ring C is piperazine, and -Y- is -(CR 5b R 5c )-; Option 4: Ring C is 7-azaspiro[3.5]nonyl or 2-azaspiro[3.3]heptyl, and -Y- is a single bond; Option 5: Ring C is piperazine, -Y-Yes-(CR 5b R 5c )-,and Ring D is cyclohexenyl; Option 6: Ring C is 7-azaspiro[3.5]nonyl or 2-azaspiro[3.3]heptyl, -Y- is a single bond, and Ring D is pyrrole or piperazine; Option 7: -L 1 - is a single bond, and -M 1 -Yes-O-; Option 8: -L 1 - is a single key, -M 1 - is -O-, and -M 2 - is a single bond; Option 9: -L 1 - is a single key, -M 1 -Yes-O-, -M 2 - is a single bond, and -M 3 - is a single bond; Option 10: -L 1 - is a single key, -M 1 -Yes-O-, -M 2 - is a single bond, and -M 3 -Yes-O-; Option 11: -L 1 - is a single key, -M 1 - is -O-, and -M 2 -Yes-O-; Option 12: -L 1 - is a single key, -M 1 -Yes-O-, -M 2 -is-O-, and -M 3 -Yes-O-; Option 13: -L 1 - is a single key, -M 1 -is-O-, and -M 2 - is C3-C6 cycloalkylene; Option 14: -L 1 - is a single key, -M 1 -Yes-O-, -M 2 - is cyclopropylene or cyclobutylene, and -M 3 -Yes-O-; Option 15: -L 1 -yes -M 1 -Yes-O-, -M 2 - is a single bond, and -M 3 - is a single bond; Option 16: -L 1 -yes -M 2 - is a single bond or -O-, and -M 3 - is a single bond; Option 17: -L 1 -yes -M 1 -Yes-O-, -M 2 - is a single bond or -O-, and -M 3 - is a single bond; Option 18: -L 1 -yes -M 1 - is -C(=O)-, -M 2 - is a single bond, and -M 3 - is a single bond; Option 19: -L 1 - is a single key, -M 1 -Yes-O-, -M 2 - is a single key, -M 3 - is a single key, Ring C is piperazine, -Y-Yes-(CR 5b R 5c )-,and Ring D is cyclohexenyl; Option 20: -L 1 - is a single key, -M 1 -Yes-O-, -M 2 - is a single key, -M 3 -Yes-O-, Ring C is 7-azaspiro[3.5]nonanyl or 2-azaspiro[3.3]heptyl, -Y- is a single bond, and Ring D is pyrrole or piperazine; Option 21: -L 1 - is a single key, -M 1 -Yes-O-, -M 2 - is a single key, -M 3 - is a single key, Ring C is 7-azaspiro[3.5]nonanyl or 2-azaspiro[3.3]heptyl, -Y- is a single bond, and Ring D is pyrrole or piperazine; Option 22: -L 1 - is a single key, -M 1 -Yes-O-, -M 2 -Yes-O-, -M 3 -Yes-O-, Ring C is 7-azaspiro[3.5]nonanyl or 2-azaspiro[3.3]heptyl, -Y- is a single bond, and Ring D is pyrrole or piperazine; Option 23: -L 1 - is a single key, -M 1 -Yes-O-, -M 2 - is cyclopropylene or cyclobutylene, -M 3 -Yes-O-, Ring C is 7-azaspiro[3.5]nonanyl or 2-azaspiro[3.3]heptyl, -Y- is a single bond, and Ring D is pyrrole or piperazine; Option 24: -L 1 -yes -M 1 -Yes-O-, -M 2 - is a single key, -M 3 - is a single key, Ring C is piperazine, -Y-Yes-(CR 5b R 5c )-,and Ring D is cyclohexenyl; Option 25: -L 1 -yes -M 1 - is -O- or -C(=O)-, -M 2 - is a single bond or -O-, -M 3 - is a single key, Ring C is piperazine, -Y-Yes-(CR 5b R 5c )-,and Ring D is a C3-C6 cycloalkene.

22. A compound or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the following compounds:

23. A method for preparing a compound as described in any one of claims 1 to 22, comprising Scheme 1 or Scheme 2: The compound of formula IA is subjected to the following cyclization reaction to obtain a compound of formula I; Scheme 2: The compound of formula VII-A and the compound of formula VII-B undergo the following condensation reaction to obtain the compound of formula VII; in, -X-, Ring A, Ring B, Ring C, Ring D, Ring E, R 1 , R 2 , R 3 , m 1 , m 2 , m 3 , -L 1 -, -L 2 -、-L 3 -、-M 1 -、-M 2 -and-M 3 - as defined in any one of claims 1 to 19.

24. Compounds of Formula IA or Formula VII-A: in, -X-, Ring A, Ring B, Ring C, Ring D, Ring E, R 1 , R 2 , R 3 , m 1 , m 2 , m 3 , -L 1 -, -L 2 -、-L 3 -、-M 1 -、-M 2 -and-M 3 - as defined in any one of claims 1 to 19.

25. A pharmaceutical composition comprising the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

26. Use of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 18 in the preparation of a medicament for treating a hyperproliferative disease.

27. The use according to claim 26, wherein the hyperproliferative disease is cancer, and the cancer is selected from: Lymphoma, leukemia, liver cancer, adenocarcinoma, adenoma, melanoma, breast cancer, pituitary tumor, rhabdomyoma, sarcoma, gastric cancer, squamous cell carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, uterine cancer, vaginal cancer, lung cancer, Watson's tumor, glioma, meningioma, astrocytoma, plasmacytoma, pharyngeal cancer, fibroma, germ cell tumor, soft tissue sarcoma, stromal cell tumor, genitourinary cancer, blastoma.

28. The use according to claim 27, wherein the sarcoma is liposarcoma or rhabdomyosarcoma.

29. The use according to claim 27, wherein the rhabdomyoma is rhabdomyosarcoma.

30. The use according to claim 26, wherein the hyperproliferative disease is cancer, and the cancer is chronic lymphocytic leukemia.

31. The use according to claim 30, wherein the chronic lymphocytic leukemia is B-cell chronic lymphocytic leukemia.

32. The use of claim 27, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer and breast cancer.

33. The use according to any one of claims 26 to 32, further comprising administering a therapeutically effective amount of a second therapeutic agent useful for treating the disease.

34. A kit comprising a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and instructions for administering the compound or pharmaceutically acceptable salt thereof to a patient suffering from a hyperproliferative disease, wherein the hyperproliferative disease is as defined in any one of claims 27 to 30.

35. The kit of claim 34, further comprising one or more additional therapeutic agents.

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