Sulfonylbenzamide derivatives as BCL-2 inhibitors

Abstract

The present disclosure provides compounds having formula I, and pharma- ceutically acceptable salts and solvates thereof, wherein the variables are defined as described herein. The present disclosure further provides compounds of formula I for treating a disease, disorder, or condition responsive to Bcl-2 protein, particularly Bcl-2 WT and / or Bcl-2 G101V inhibition. JPEG2024504542000275.jpg76143

Description

[Technical Field]

[0001] The present disclosure provides Bcl-2 protein inhibitors and therapeutic methods for treating diseases, disorders, or conditions in which inhibition of Bcl-2 proteins is beneficial. [Background technology]

[0002] Apoptosis, the process of programmed cell death, is an important biological process for maintaining tissue homeostasis. Studies have shown that apoptosis is regulated during early embryonic development in mammals. Later in life, cell death is the default mechanism by which potentially dangerous cells, such as those with cancerous defects, are eliminated. Several apoptotic pathways are currently known. One of the major apoptotic pathways involves Bcl-2 family proteins, which are key regulators of the mitochondrial (also called "intrinsic") pathway of apoptosis. 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. Bcl-2 family proteins can be further classified into three subfamilies depending on the number of homologous domains contained in each protein and the biological activity of the protein (i.e., whether it has pro-apoptotic or anti-apoptotic functions).

[0003] The first subgroup of Bcl-2 proteins includes proteins that contain all four homology domains (i.e., BH1, BH2, BH3, and BH4). The general effect of such proteins is anti-apoptotic, i.e., preventing 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 this first subgroup. Proteins belonging to the second subgroup of Bcl-2 proteins contain three homology domains, BH1, BH2, and BH3, and have pro-apoptotic effects. Two major representative proteins of this second subgroup are Bax and Bak. The third subgroup of Bcl-2 proteins consists of proteins that contain only the BH3 domain, and members of this subgroup are usually referred to as "BH3-only proteins." Their biological effect on cells is pro-apoptotic. Bim, Bid, Bad, Bik, Noxa, Hrk, Bmf, and Puma are examples of proteins from this third subfamily. The exact mechanism by which Bcl-2 family proteins regulate cell death is not yet completely clear. One hypothesis for the regulation of cell death by Bcl-2 family proteins is that BH3-only proteins are further classified into "activators" (e.g., Bim and Bid proteins) or "sensitizers" (e.g., Bad, Bik, Noxa, Hrk, Bmf, and Puma proteins) depending on their regulatory function.

[0004] One of the keys to maintaining tissue homeostasis is achieving a balance of interactions among the three subgroups of Bcl-2 proteins in cells. Research has elucidated the mechanisms by which the pro- and anti-apoptotic subgroups of Bcl-2 family proteins interact, enabling cells to undergo programmed cell death. After receiving intracellular or extracellular signals, cells undergo post-translational or transcriptional activation of BH3-only proteins. BH3-only proteins are the primary inducers of the apoptotic cascade, one step of which is the activation of the pro-apoptotic proteins Bax and Bak in the mitochondrial membrane. After activating Bax and / or Bak, which are already anchored or translocated to the mitochondrial membrane, Bax and / or Bak oligomerize, triggering mitochondrial outer membrane permeabilization (MOMP), the release of cytochrome C, and downstream activation of effector caspases, ultimately leading to apoptosis. Some researchers hypothesize that BH3-only proteins, such as Puma, Bim, and Bid, are "activators" because they directly bind to the pro-apoptotic proteins Bax and Bak to initiate MOMP, whereas other BH3-only proteins, such as Bad, Bik, and Noxa, are "sensitizers" that indirectly induce Bax and Bak oligomerization by binding to anti-apoptotic proteins, such as Bcl-2, Bcl-xL, Bcl-w, and Mcl-1, thereby displacing and "liberating" the "activators," i.e., BH3-only proteins, which then bind to and activate pro-apoptotic proteins, such as Bax and Bak, inducing cell death. Other studies have suggested that anti-apoptotic proteins directly bind to or chelate Bax and Bak, and that all BH3-only proteins liberate Bax and Bak by modulating this interaction through binding to anti-apoptotic proteins, such as Bcl-2, Bcl-xL, Bcl-w, and Mcl-1.See Adams and Cory, Oncogene 26:1324-1337 (2007), and Willis et al., Science 315:856-859 (2007). Although the precise interplay between the regulation of apoptosis by anti- and pro-apoptotic Bcl-2 family proteins is still under investigation, there is a large body of scientific evidence indicating that compounds that inhibit the binding of BH3-only proteins to anti-apoptotic Bcl-2 family proteins promote apoptosis.

[0005] Dysregulation of apoptotic pathways is involved in the pathology of many important diseases, e.g., neurodegenerative conditions such as Alzheimer's disease (upregulated apoptosis), and proliferative diseases such as autoimmune and prothrombotic conditions (downregulated apoptosis).

[0006] Downregulated apoptosis (and more specifically, Bcl-2 family proteins) may be involved in 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 such dysregulation is that the altered cells survive; otherwise, these cells would undergo apoptosis under normal conditions. The recurrence of these defects associated with dysregulated proliferation is thought to be the starting point for cancerous evolution. Furthermore, studies have revealed that BH3-only proteins can act as tumor inhibitors when expressed in diseased animals.

[0007] These findings allow the emergence of a new strategy for cancer-targeting drug development. If small molecules that can mimic the effects of BH3-only proteins can enter cells and overcome the overexpression of anti-apoptotic proteins, the apoptotic process can be reset. The advantage of such a strategy is that it can alleviate the problem of drug resistance, which is usually caused by apoptosis dysregulation (abnormal survival). Bcl-2 and Bcl-X in cancer L Therapeutic strategies for targeting apoptosis to restore cancer cell sensitivity and overcome cancer cell resistance to apoptosis have been outlined. 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 further contain apoptotic mechanisms, such as Bax, Bak, Bcl-xL, Bcl-2, cytochrome c, caspase-9, caspase-3, and APAF-1, necessary to execute programmed cell death via the intrinsic apoptotic pathway. While the production of circulating platelets is a normal physiological process, many diseases are caused or exacerbated by excessive or unwanted platelet activation. Therefore, it has become clear that therapeutic agents capable of inhibiting anti-apoptotic proteins in platelets and reducing platelet numbers in mammals could be used to treat prothrombotic conditions and diseases characterized by excessive or unwanted platelet activation.

[0009] Small molecules, i.e., BH3-only protein mimetics (e.g., ABT-737 and ABT-263), have high binding affinity to a subset of anti-apoptotic Bcl-2 proteins (including Bcl-2, Bcl-w, and Bcl-xL) but low binding affinity to Mcl-1 and A1. These small molecules have been tested in animal studies and have demonstrated cytotoxic activity as single agents in several xenograft models, and when used in combination, they enhanced the efficacy of many chemotherapeutic agents in other xenograft models. See Tse, C. et al., Cancer Res 68:3421-3428 (2008) and van Delft, M. F. et al., Cancer Cell 10:389-399 (2006). These in vivo studies demonstrate the potential efficacy of inhibitors of anti-apoptotic Bcl-2 family proteins in treating diseases associated with dysregulation of the apoptotic pathway. ABT-199 (Venetocrax) is an effective Bcl-2 inhibitor 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] Different cell types have different natural expression levels of anti-apoptotic Bcl-2 family protein members. For example, Bcl-xL protein is highly expressed in young platelets and plays an important role in regulating platelet cell death (lifespan). Furthermore, in some cancer cell types, cancer cell survival is due to dysregulation of the apoptotic pathway through overexpression of one or more anti-apoptotic Bcl-2 protein family members. Given the important role of Bcl-2 family proteins in regulating apoptosis in cancerous and normal (i.e., non-cancerous) cells, and the recognized cell-to-cell variability in Bcl-2 family protein expression, it would be advantageous to have small molecule inhibitors that selectively target and preferentially bind to one or more types or subsets of anti-apoptotic Bcl-2 proteins (e.g., bind to anti-apoptotic Bcl-2 family members that are overexpressed in a certain cancer type). Such selective compounds could also offer several advantages in the clinical setting by providing, for example, flexibility in administration options and reduced on-target toxic effects in normal cells; for example, a reduction in lymphocyte counts has been observed in Bcl-2-deficient mice. See Nakayama, K. et al. PNAS 91:3700-3704 (1994).

[0011] Mutations in drug-binding sites are a common mechanism by which malignant cells evade treatment. Venetoclax was approved in 2016, and current understanding of potential drug resistance mechanisms remains limited. To predict potential drug-resistant mutations, researchers have induced resistance to Venetoclax in cancer cells using mouse models. See, for example, Fresquet, V. et al., Blood 123, 4111-4119 (2014). This study discovered that mutation of phenylalanine 104 (human numbering), located within the BH3-binding groove of Bcl-2, to leucine (F104L) or cysteine ​​(F104C) conferred resistance to Venetoclax in lymphoma cell lines. Subsequent studies confirmed that these mutations can also confer resistance in human leukemia and lymphoma models, although these mutations have not yet been observed in patients. See, for example, Tahir, SK et al., BMC Cancer 17, 399 (2017).

[0012] Recently, a novel Bcl-2 mutation has been specifically described in patients receiving venetoclax treatment. See Blombery, P. et al., Cancer Discov. 9, 342-353 (2018). One such mutation, G101V, was present in patients with chronic lymphocytic leukemia (CLL) in clinical trials. These patients initially responded to treatment but showed CLL-type clinical progression after 19 to 42 months. The presence of the mutation in patient samples is a sign of clinical progression. The Bcl-2 G101V mutation reduced the drug's affinity for Bcl-2 by approximately 180-fold. However, Bcl-2 G101V maintains its affinity for the BH3 motif of proapoptotic proteins (e.g., BAX and BIM) and can therefore still function as an inhibitor of apoptosis. By selectively reducing affinity for venetoclax, the BCL-2 G101V mutation conferred resistance to the treatment.

[0013] Therefore, there is a continuing need for small molecules that selectively inhibit the activity of one type or subset of Bcl-2 proteins (including wild-type and mutant variants) to treat hyperproliferative diseases, such as cancer. Summary of the Invention

[0014] In one aspect, the present disclosure provides compounds represented by any one of the following formulas, and pharmaceutically acceptable salts and solvates (e.g., hydrates) thereof, collectively referred to herein as "compounds of the present disclosure."

[0015] One embodiment of the present disclosure is a compound of formula I: [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: Ring X is a 5- or 6-membered ring containing one or more additional degrees of unsaturation; Each R 1 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 independently selected from the group consisting of haloalkyl and halogen; p is 0, 1 or 2; Ring Y is a 5- to 9-membered monocyclic or fused ring system containing at least one S and optionally containing one or more additional heteroatoms selected from O, N, or S, and containing one or more degrees of unsaturation; Each R 2 is (CH2) t independently selected from the group consisting of —R4, CONH-R4, NHC(O)-R4, NHR4, and (C≡C)-R4; Each R 4 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, aryl, C 3-10 heterocyclyl, heteroaryl, Each R4 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, halogen, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, OSO2CH3, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl), C 1-6 Alkoxy, OH, C 1-6 Alkyl-OH, C 2-6 Alkyl(OH)(C 3-6 cycloalkyl), C 1-6 Haloalkyl-OH, C 3-6 Cycloalkyl-OH, C 1-6 Alkyl-COOH, C 1-6 Alkyl-OC 1-6 Alkyl, CN, C 1-6 Alkyl-CN, C 1-6 Alkyl-NHC(O)-C 1-6 Alkyl and C 1-6 alkyl-C(O)NH—Ci_6 alkyl groups; q is 1 or 2; each t is 0, 1, 2, 3, 4, 5, or 6; Ring Z is a saturated 6-membered ring optionally containing one or more O; Each R 3 is C 1-6 Alkyl, C 1-6 selected from the group consisting of one or more of alkoxy and OH; and r is 0, 1 or 2.

[0016] One embodiment of the present disclosure is a compound wherein ring X is a 6-membered cyclohexenyl ring and the compound has formula Ix: [ka]

[0017] One embodiment of the present disclosure is a compound in which p is 2 and each R 1In one embodiment of the present disclosure, each R 1 C 1-6 One embodiment of the present disclosure is where each R 1 is methyl. One embodiment of the present disclosure includes wherein each methyl is located para to the indicated point of attachment of the piperazine-methylene to the compound of formula Ixi: [ka]

[0018] An embodiment of the present disclosure includes wherein ring Y is thiophene. An embodiment of the present disclosure includes wherein the S atom is located alpha to ring X and the compound is a compound of formula Iy: [ka]

[0019] An embodiment of the present disclosure includes where q is 1. An embodiment of the present disclosure includes where each R 2 But independently, (CH2) t An embodiment of the present disclosure includes when t is 0 and R 4 One embodiment of the present disclosure is a compound in which q is 1 and R 4 is substituted β-position to the depicted S in the depicted thiophene ring, and the compound has the formula Iyi: [ka]

[0020] One embodiment of the present disclosure is R 4 One embodiment of the present disclosure includes where R 4 An embodiment of the present disclosure includes where R 4 But C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, OH, C 1-6 Alkyl-OH and C 1-6One embodiment of the present disclosure includes R 4 But halogen, C 1-6 Alkyl-OH and C 1-6 One embodiment of the present disclosure includes ring Z being selected from substituted cyclohexyl and 1,4-dioxane. One embodiment of the present disclosure includes ring Z being substituted with one or more of a methyl and an OH group, and the substitution is at the para position to the point of attachment to the amino shown: [ka]

[0021] One embodiment of the present disclosure is the stereochemistry shown: [ka]

[0022] One embodiment of the present disclosure is the stereochemistry shown: [ka]

[0023] One embodiment of the present disclosure includes a compound selected from the group consisting of: [ka]

[0024] [ka]

[0025] [ka]

[0026] [ka]

[0027]

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[0028]

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[0029]

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[0030]

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[0031]

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[0032]

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[0033]

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[0034]

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[0035]

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[0036]

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[0037] [ka]

[0038] One embodiment of the present disclosure includes a compound of the present disclosure, the pharmaceutically acceptable salt form of which is a trifluoroacetate or formate salt.

[0039] One embodiment of the present disclosure includes a compound of the present disclosure, wherein at least one hydrogen atom is replaced with a deuterium atom.

[0040] One embodiment of the present disclosure includes a pharmaceutical composition, which comprises a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable vector.

[0041] One embodiment of the present disclosure includes a method of treating a patient, the method comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, to the patient, wherein the patient is suffering from a hyperproliferative disease. The method of the present disclosure includes wherein the hyperproliferative disease is cancer. The method of the present disclosure includes wherein the cancer is selected from one or more of the cancers in Table 2. The method of the present disclosure includes 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. The method of the present disclosure includes administering a therapeutically effective amount of a second therapeutic agent for treating the disease.

[0042] One embodiment of the present disclosure includes a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable vector. One embodiment of the present disclosure includes a pharmaceutical composition of the present disclosure, wherein the pharmaceutical composition is for treating a hyperproliferative disease. One embodiment of the present disclosure includes a pharmaceutical composition of the present disclosure, wherein the hyperproliferative disease is cancer. One embodiment of the present disclosure includes a pharmaceutical composition of the present disclosure, wherein the cancer is selected from one or more of the cancers in Table 2. One embodiment of the present disclosure includes a pharmaceutical composition of the present disclosure, 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.

[0043]

[0013] One embodiment of the present disclosure includes a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, for treating a hyperproliferative disease. One embodiment includes the hyperproliferative disease is cancer. One embodiment includes the cancer being selected from one or more of the cancers in Table 2. One embodiment includes the cancer being 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.

[0044]

[0013] An embodiment of the present disclosure includes the use of a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating a hyperproliferative disease.

[0014] An embodiment of the present disclosure includes the hyperproliferative disease being cancer.

[0015] An embodiment of the present disclosure includes the cancer being selected from one or more of the cancers in Table 2.

[0016] An embodiment of the present disclosure includes the cancer being 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.

[0045] One embodiment of the present disclosure includes a kit, the kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt or solvate thereof, to a patient suffering from a hyperproliferative disease. One embodiment of the present disclosure includes the hyperproliferative disease is cancer. One embodiment of the present disclosure includes the cancer being selected from one or more of the cancers in Table 2. One embodiment of the present disclosure includes the cancer being 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. One embodiment of the present disclosure includes one or more additional therapeutic agents.

[0046] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure and one or more pharmaceutically acceptable vectors.

[0047] In another aspect, the present disclosure provides a method of inhibiting a Bcl-2 protein, e.g., Bcl-2, Bcl-2 WT, Bcl-xL, Mcl-1, and Bfl-1 / A1, or any combination thereof, in a subject (e.g., a human), the method comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure. In one embodiment, the aspect provides a method of inhibiting Bcl-2 WT. In one embodiment, the aspect provides a method of inhibiting a G101V mutant.

[0048] In another aspect, the disclosure provides a method for treating or preventing a disease, disorder, or condition in a subject that is responsive to Bcl-2 protein, e.g., Bcl-2 WT and / or Bcl-2 G101V inhibition, wherein the disease, disorder, or condition is, for example, a hyperproliferative disease, e.g., cancer such as small cell lung cancer, non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphoid (or lymphocytic) leukemia (CLL), or acute lymphoblastic leukemia (ALL), the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure.

[0049] In another aspect, the present disclosure provides for the use of compounds of the present disclosure as inhibitors of one or more Bcl-2 proteins, for example, Bcl-2 WT and / or Bcl-2 G101V.

[0050] In another aspect, the present disclosure provides the use of the compounds of the present disclosure as inhibitors of Bcl-2 WT.

[0051] In another aspect, the present disclosure provides the use of compounds of the present disclosure as inhibitors of Bcl-2 G101V.

[0052] In another aspect, the present disclosure provides a pharmaceutical composition for treating a disease, disorder, or condition responsive to Bcl-2 protein, e.g., Bcl-2 WT and / or Bcl-2 G101V inhibition, 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 vectors.

[0053] In another aspect, the disclosure provides a compound of the disclosure for treating or preventing a disease, disorder, or condition in a subject (e.g., a human), wherein the disease, disorder, or condition is, for example, a hyperproliferative disease such as cancer.

[0054] In another aspect, the disclosure provides a compound of the disclosure for making a medicament for treating a disease, disorder, or condition in a subject (e.g., a human), wherein the disease, disorder, or condition is, for example, a hyperproliferative disease such as cancer.

[0055] In another aspect, the disclosure provides a kit, the kit comprising a compound of the disclosure.

[0056] In another aspect, the disclosure provides a kit comprising a compound of the disclosure and a second therapeutic agent for treating a disease, disorder, or condition in a subject, and a packaging insert comprising instructions for treating the disease, disorder, or condition.

[0057] In another aspect, the disclosure provides a composition, the composition comprising: (a) a compound of the disclosure; (b) a second therapeutically active agent; and (c) an optional excipient and / or pharmaceutically acceptable vector.

[0058] Additional embodiments and advantages of the disclosure will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0059] It should be understood that the foregoing description and the following detailed description are exemplary and explanatory only and are not restrictive of the present disclosure as claimed. DETAILED DESCRIPTION OF THE INVENTION

[0060] The compounds of the present disclosure inhibit Bcl-2 proteins, such as Bcl-2 WT and / or Bcl-2 G101V. The compounds of the present disclosure are intended to treat or prevent a disease, disorder, or condition in a subject that responds to Bcl-2 protein inhibition, such as a hyperproliferative disease, such as cancer. Cancers that respond to Bcl-2 protein inhibition include, but are not limited to, small cell lung cancer, NHL, AML, CLL, and ALL.

[0061] In one embodiment, the compounds of the present disclosure are compounds having formula I, including compounds of formula Ix, Ixi, Iy, and Iyi.

[0062] In this disclosure, the term "halogen" or "halogen", when used by itself or as part of another group, refers to -Cl, -F, -Br, or -I.

[0063] In this disclosure, the term "nitro," when used by itself or as part of another group, refers to --NO.sub.2.

[0064] In this disclosure, the term "cyano," when used by itself or as part of another group, refers to --CN.

[0065] In this disclosure, the term "hydroxy" when used by itself or as part of another group refers to --OH.

[0066] In this disclosure, the term "amino," when used by itself or as part of another group, refers to --NH.sub.2.

[0067] In this disclosure, the term "alkyl," when used by itself or as part of another group, refers to an unsubstituted straight or branched chain aliphatic hydrocarbon having 1 to 12 carbon atoms (i.e., C 1-12alkyl) or a specified number of carbon atoms, e.g., C1 alkyl such as methyl, C2 alkyl such as ethyl, C3 alkyl such as propyl or isopropyl, C4 alkyl such as methyl, ethyl, propyl or isopropyl 1-3 In one embodiment, the alkyl group is a straight chain C 1-6 In another embodiment, the alkyl group is a branched C 3-6 In another embodiment, the alkyl group is a straight chain C 1-4 In another embodiment, the alkyl group is a branched C 3-4 In another embodiment, the alkyl group is a straight or branched chain C 3-4 In another embodiment, the alkyl group is partially or fully deuterated, i.e., one or more hydrogen atoms of the alkyl group are replaced with deuterium atoms. 1-12 Alkyl groups include methyl, -CD3, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1-4 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, and isobutyl. 1-4 Groups include methyl, ethyl, propyl, isopropyl and t-butyl.

[0068] In this disclosure, the term "optionally substituted alkyl," when used by itself or as part of another group, refers to an alkyl that is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkoxy, amino, alkylamino, dialkylamino, and optionally substituted aryl. In one embodiment, an optionally substituted alkyl is substituted with two substituents. In another embodiment, an optionally substituted alkyl is substituted with one substituent. In another embodiment, an optionally substituted alkyl is unsubstituted. Non-limiting exemplary optionally substituted alkyl groups include -CHPh, -CHCHNO, -CHCHOH, -CHCHOCH, and -CHCHF.

[0069] In this disclosure, the term "cycloalkyl," when used by itself or as part of another group, refers to an unsubstituted saturated or partially unsaturated (e.g., containing one or two double bonds) cyclic aliphatic hydrocarbon, which contains 1 to 3 rings and 3 to 12 carbon atoms (i.e., C 3-12 In one embodiment, a cycloalkyl group has two rings. In one embodiment, a cycloalkyl group has one ring. In another embodiment, a cycloalkyl group has C 3-8 In another embodiment, the cycloalkyl group is C 3-6 In another embodiment, the cycloalkyl group is C 3-5 Cycloalkyl. The term "cycloalkyl" is intended to include groups in which the ring -CH2- is replaced with -C(=O)-. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decahydronaphthalene, adamantyl, cyclohexenyl, cyclopentenyl, cyclopentanone, spiro[3.3]heptane, and bicyclo[3.3.1]nonane.

[0070] In this disclosure, the term "optionally substituted cycloalkyl," when used by itself or as part of another group, refers to a cycloalkyl that is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, haloalkyl, and heterocyclyl. In one embodiment, the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent. In another embodiment, the optionally substituted cycloalkyl is unsubstituted.

[0071] In this disclosure, the term "haloalkyl," when used by itself or as part of another group, refers to an alkyl substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In one embodiment, the alkyl group is substituted with one, two, or three iodine and / or chlorine atoms. In another embodiment, the haloalkyl group is C 1-4 Non-limiting exemplary haloalkyls include fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.

[0072] In this disclosure, the term "alkoxy" when used by itself or as part of another group refers to an optionally substituted alkyl attached to a terminal oxygen atom. In one embodiment, an alkoxy group is a C 1-6 In another embodiment, the alkoxy group is a C bonded to a terminal oxygen atom. 1-4 Alkyl. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and t-butoxy.

[0073] In this disclosure, the term "aryl" when used by itself or as part of another group refers to an unsubstituted monocyclic or bicyclic aromatic ring system having 6 to 14 carbon atoms, i.e., C 6-14 "aryl" refers to aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthalene, phenanthryl, anthryl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl. In one embodiment, the aryl group is phenyl or naphthalene.

[0074] In this disclosure, the term "optionally substituted aryl," as used herein by itself or as part of another group, refers to an aryl that is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, haloalkyl, and heterocyclyl. In one embodiment, the optionally substituted aryl is an optionally substituted phenyl. In another embodiment, the optionally substituted phenyl has one substituent. In another embodiment, the optionally substituted phenyl is unsubstituted. Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, and 4-chlorophenyl.

[0075] In this disclosure, the term "heterocyclyl," when used by itself or as part of another group, refers to unsubstituted saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic groups containing one, two, or three rings and having 3 to 14 ring members, i.e., 3- to 14-membered heterocyclyls, where at least one carbon atom in one of the rings is replaced with a heteroatom. The term "heterocyclyl" is intended to include cyclic ureidos such as imidazolidinyl-2-one, cyclic amides such as β-lactams, γ-lactams, δ-lactams, and ε-lactams, and cyclic urethanes such as oxazolidinyl-2-one. In one embodiment, a heterocyclyl group is a 4-, 5-, 6-, 7-, or 8-membered ring group containing one ring and one or two oxygen and / or nitrogen atoms. In one embodiment, a heterocyclyl group is a 5- or 6-membered ring group containing one ring and one or two nitrogen atoms. In one embodiment, a heterocyclyl group is an 8-, 9-, 10-, 11-, or 12-membered ring group containing two rings and one or two nitrogen atoms. In one embodiment, a heterocyclyl group is a 4- or 5-membered ring group containing one ring and one oxygen atom. A heterocyclyl can be optionally attached to the rest of the molecule through a carbon or nitrogen atom. Non-limiting exemplary heterocyclyl groups include 1,4-dioxane, 2-oxopyrrolidin-3-yl, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, 8-azabicyclo[3.2.1]octane (nortropane), 6-azaspiro[2.5]octane, 6-azaspiro[3.4]octane, indoline, indolin-2-one, and 1,3-dihydro-2H-benzo[d]imidazol-2-one.

[0076] In this disclosure, the term "optionally substituted heterocyclyl," as used herein by itself or as part of another group, refers to a heterocyclyl that is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, haloalkyl, and heterocyclyl.

[0077] In this disclosure, the term "alkylamino" when used by itself or as part of another group means -NHR 10 where R 10 is C 1-6 In one embodiment, R 10 is C 1-4 Non-limiting exemplary alkylamino groups include -N(H)CH3 and -N(H)CH2CH3.

[0078] In this disclosure, the term "dialkylamino" when used by itself or as part of another group means -NR 11a R 11b where R 11a and R 11b are each independently C 1-6 In one embodiment, R 11a and R 11b are each independently C 1-4 Non-limiting exemplary dialkylamino groups include -N(CH3)2 and -N(CH3)CH2CH(CH3)2.

[0079] In this disclosure, the term "(cycloalkyl)alkyl," when used by itself or as part of another group, refers to an alkyl substituted with one optionally substituted cycloalkyl group. In one embodiment, a (cycloalkyl)alkyl is an alkyl substituted with one optionally substituted C 3-6 Cycloalkyl-substituted C 1-4 It is alkyl.

[0080] In this disclosure, the term "(heterocyclo)alkyl" when used by itself or as part of another group refers to an alkyl substituted with one optionally substituted heterocyclyl. In one embodiment, a (heterocyclo)alkyl is a C substituted with one optionally substituted 4- to 6-membered heterocyclyl group. 1-4 Heterocyclyl can be attached to the alkyl group via a carbon or nitrogen atom. Non-limiting exemplary (heterocyclo)alkyl groups include: [ka]

[0081] In this disclosure, the term "heteroalkyl," when used by itself or as part of another group, refers to an unsubstituted straight- or branched-chain aliphatic hydrocarbon containing 6 to 12 chain atoms (i.e., a 6- to 12-membered heteroalkyl), or a specified number of chain atoms, wherein at least two -CH2- groups are independently replaced with -O-, -N(H)-, or -S-. The -O-, -N(H)-, or -S- groups may be independently located at any position within the aliphatic hydrocarbon chain, so long as each -O-, N(H)-, or S- group is separated by at least two -CH2- groups. In one embodiment, two -CH2- groups are replaced with two -O- groups. In another embodiment, three -CH2- groups are replaced with three -O- groups. Non-limiting exemplary heteroalkyl groups include -CH2CH2OCH2CH2OCH3, -CH2CH2OCH2CH2N(H)CH3, and -CH2CH2OCH2CH2OCH2CH2OCH2CH2OCH3.

[0082] The present disclosure encompasses any of the compounds of the present disclosure that are isotopically labeled (i.e., radiolabeled) by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, iodine, and chlorine, for example, 2 H (or deuterium (D)), 3 H, 11C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 Cl, e.g. 3 H, 11 C and 14 C. In one embodiment, compositions are provided in which substantially all atoms at a position in the compound of the present disclosure are replaced with atoms having different atomic masses or mass numbers. In another embodiment, compositions are provided in which a portion of atoms at a position in the compound of the present disclosure are replaced, i.e., a position in the compound of the present disclosure is enriched with atoms having different atomic masses or mass numbers. Isotopically labeled compounds of the present disclosure can be prepared by methods known in the art.

[0083] The compounds of the present disclosure may contain one or more asymmetric centers and thus can produce enantiomers, non-enantiomers, and other stereoisomeric forms. The present disclosure is intended to encompass the use of all such possible forms, including racemic and resolved forms, and mixtures thereof. In light of the present disclosure, single stereoisomers, e.g., enantiomers, can be isolated based on methods known in the art. When the compounds described herein contain an ethylenic double bond or other center of geometric asymmetry, they are intended to include both E and Z geometric isomers, unless otherwise specified. All tautomers are also intended to be encompassed by the present disclosure.

[0084] As used herein, the term "stereoisomer" or "stereoisomeric form" is a general term for all isomers of a single molecule that differ only with respect to the spatial orientation of their atoms. Stereoisomers include enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (non-enantiomers).

[0085] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom that is bonded to four different groups.

[0086] The terms "enantiomer" and "mirror" refer to a molecule that is optically active because it is not superimposable on its mirror image, where the enantiomer rotates the plane of polarized light in one direction while its mirror image rotates the plane of polarized light in the opposite direction.

[0087] The term "racemic" refers to a mixture of equal parts of enantiomers, devoid of optical activity.

[0088] The term "absolute configuration" refers to the arrangement in space of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

[0089] Unless otherwise noted, the stereochemical terminology and conventions used herein correspond to those set forth in Pure & Appl. Chem 68:2193 (1996).

[0090] The term "enantiomeric excess" or "ee" refers to a measure of the amount of one enantiomer present relative to another. For a mixture of R and S enantiomers, enantiomeric excess is defined as |RS|*100, where R and S are the corresponding mole or weight fractions of the enantiomers in the mixture, such that R+S=1. Knowing the optical rotation of a chiral substance, enantiomeric excess can be calculated by subtracting ([α] obs / [α] max )*100, where [α] obs is the optical rotation of the enantiomeric mixture, while [α] max is the optical rotation of the pure enantiomer. Enantiomeric excess can be determined using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography, or polarimetry.

[0091] The terms "enantiomerically pure" or "enantiomerically pure" refer to a sample of chiral material in which all molecules (within the limits of detection) have the same chiral meaning. In one embodiment, compounds of the present disclosure having one or more chiral centers are enantiomerically pure.

[0092] The terms "enantiomerically enriched" or "enantiomerically enriched" refer to a sample of chiral material having an enantiomeric excess of greater than 50%, e.g., about 60% or greater, about 70% or greater, about 80% or greater, about 90% or greater, about 95% or greater, about 98% or greater, or about 99% or greater. An enantiomerically enriched compound may be an enantiomerically pure compound. In one embodiment, a compound of the present disclosure having one or more chiral centers is enantiomerically enriched.

[0093] The term "a" or "an" refers to one or more.

[0094] As used herein, the term "about" includes the recited number plus or minus 10%. Thus, "about 10" refers to 9 to 11.

[0095] The present disclosure encompasses the preparation and use of salts (including non-toxic pharmaceutically acceptable salts) of the compounds of the present disclosure. Examples of pharmaceutically acceptable addition salts include inorganic acid addition salts, organic acid addition salts, and base salts. Pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salts, potassium salts, and cesium salts; alkaline earth metal salts such as calcium salts and magnesium salts; organic amine salts such as triethylamine salts, pyridine salts, methylpyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, and N,N'-dibenzylethylenediamine salts; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, and sulfate; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, and formate; sulfonate salts such as methanesulfonate, benzenesulfonate, and p-toluenesulfonate; and amino acid salts such as arginine salts, aspartate, and glutamate. As used herein, the term "pharmaceutically acceptable salt" refers to any salt of a compound of the present disclosure that is physiologically acceptable in a target patient (e.g., a mammal such as a human), for example, a salt obtained by reaction with an acid or base.

[0096] Acid addition salts can be formed by mixing a solution of certain compounds of the present disclosure with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, etc. Base salts can be formed by mixing a solution of a compound of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, etc.

[0097] The present disclosure encompasses the preparation and use of solvates of the disclosed compounds. Solvates typically do not significantly alter the physiological activity or toxicity of the compound and can therefore function as pharmacological equivalents. As used herein, the term "solvate" refers to a combination, physical association, and / or solvation of a compound of the present disclosure with solvent molecules, e.g., a disolvate, a monosolvate, or a hemisolvate, wherein the ratio of solvent molecules to the compound of the present disclosure is about 2:1, about 1:1, or about 1:2, respectively. Such physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses solution-phase and isolatable solvates. The disclosed compounds may exist in solvated forms with pharmaceutically acceptable solvents such as water, methanol, ethanol, and the present disclosure is intended to encompass both solvated and unsolvated forms of the disclosed compounds.

[0098] 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 function 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), which describes the preparation of a solvate of fluconazole with ethyl acetate and water. The preparation of similar solvates, hemisolvates, hydrates, etc. is described in EC van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004) and A.L. Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting method for preparing solvates involves dissolving a compound of the present disclosure in a desired solvent (organic solvent, water, or a mixture thereof) at a temperature of 20° C. to about 25° C., cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods (e.g., filtration). Analytical techniques, such as infrared spectroscopy, may be used to confirm the presence of solvent in the solvate crystals.

[0099] Because the compounds of the present disclosure are inhibitors of Bcl-2 proteins, e.g., Bcl-2 WT and / or Bcl-2 G101V, many diseases, conditions, or disorders mediated by Bcl-2 proteins can be treated or prevented by administering these compounds to a subject. As such, the present disclosure generally relates to methods for treating or preventing a disease, condition, or disorder responsive to Bcl-2 protein, e.g., Bcl-2 WT and / or Bcl-2 G101V inhibition, in an animal suffering from or at risk for the disease, condition, or disorder, comprising administering to the animal a therapeutically effective amount of one or more compounds of the present disclosure.

[0100] The present disclosure further relates to a method of inhibiting Bcl-2 protein in an animal (e.g., a human) in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one compound of the present disclosure.

[0101] The present disclosure further relates to a method of inhibiting Bcl-2 in an animal (e.g., a human) in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one compound of the present disclosure.

[0102] The present disclosure further relates to a method of inhibiting Bcl-2 WT in an animal (e.g., a human) in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one compound of the present disclosure.

[0103] The present disclosure further relates to a method of inhibiting Bcl-2 G101V in an animal (eg, a human) in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one compound of the present disclosure.

[0104] As used herein, the term "treatment" means eliminating, alleviating, or ameliorating a disease or condition and / or symptoms associated with the disease and / or condition. Although not excluded, treatment of a disease or condition does not require complete elimination of the disease or condition and / or symptoms associated with the disease or condition. Synonyms for the term "treatment" include administering a therapeutically effective amount of a compound of the present disclosure to a subject in need of such treatment. Treatment can be symptomatic, e.g., to inhibit symptoms. Treatment can be effective in the short term and can be administered over the medium term, or it can be long-term treatment, e.g., in the context of maintenance therapy.

[0105] As used herein, the term "prevention" refers to a method of preventing the onset of a disease or condition and / or its associated symptoms, or barring a subject from acquiring a disease. As used herein, "prevention" further includes delaying the onset of a disease or condition and / or its associated symptoms, reducing a subject's risk of acquiring a disease. The term "prevention" may also include "prophylactic treatment," which refers to reducing the likelihood of a disease or condition recurring, or a previously controlled disease recurring, in a subject who has not recurred to the disease or condition but is at risk of recurrence, or is susceptible to recurrence of the disease or condition, or has experienced a recurrence of the disease or condition.

[0106] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount of an active ingredient sufficient, when administered by the methods of the present disclosure, to effectively deliver the active ingredient to an individual in need thereof to treat a target condition or disease. In the case of cancer or other proliferative disorders, a therapeutically effective amount of an agent can reduce (i.e., slow to some extent and preferably stop) unwanted cell proliferation, reduce the number of cancer cells, reduce tumor size, inhibit (i.e., slow to some extent and preferably stop) cancer cell invasion into surrounding organs, inhibit (i.e., slow to some extent and preferably stop) tumor metastasis, inhibit tumor growth to some extent, modulate protein methylation in target cells, and / or alleviate to some extent one or more symptoms associated with cancer. To the extent that an administered compound or composition prevents the growth of and / or kills existing cancer cells, it may be cytoinhibitory and / or cytotoxic.

[0107] The term "container" refers to any container and closure suitable for storing, transporting, dispensing and / or handling a pharmaceutical agent.

[0108] The term "packaging insert" refers to the information that accompanies a drug product, providing instructions on how to administer the product and the necessary safety and effectiveness data to enable physicians, pharmacists, and patients to make informed decisions about the product's use. The packaging insert is typically considered the drug's "label."

[0109] In the present disclosure, the term "Bcl-2 protein" or "Bcl-2 family protein" refers to any one or more of the following proteins: Bax, Bak, Bid, Bcl-2, Bcl-xL, Mcl-1, Bcl-w or Bcl-2 WT, Bcl-2 G101V, Bfl-1 / A1, Bim, Puma, Bad, Bik / Blk, Noxa, Bmf, Hrk / DP5, and Beclin-1.

[0110] The terms "disease" or "condition" or "disorder" refer to disorders and / or abnormalities that are generally considered pathological conditions or functions and may be manifested in the form of specific symptoms, symptoms, and / or dysfunctions. The compounds of the present disclosure inhibit Bcl-2 proteins, e.g., Bcl-2 WT and / or Bcl-2 G101V, and can be used to treat and prevent diseases, conditions, or disorders, e.g., hyperproliferative diseases, in which inhibition of Bcl-2 proteins provides a benefit.

[0111] The term "hyperproliferative disease" refers to any condition in an animal in which a localized population of proliferating cells is not governed by the usual limits of normal proliferation. In one embodiment, the hyperproliferative disease is cancer.

[0112] In some examples, compounds of the present disclosure can be used to treat a "Bcl-2 protein-mediated disorder," e.g., a Bcl-2-mediated disorder, a Bcl-2 WT-mediated disorder, and / or a Bcl-2 G101V-mediated disorder. A Bcl-2 protein-mediated disorder is any pathological condition in which Bcl-2 protein is known to play a role. In one embodiment, the Bcl-2-mediated disorder is a hyperproliferative disease. In one embodiment, the Bcl-2-mediated disorder is cancer.

[0113] In one embodiment, compounds of the present disclosure have a Bcl-2 WT and / or Bcl-2 G101V IC of less than about 10 μM. 50 In another embodiment, compounds of the present disclosure have a Bcl-2 WT and / or Bcl-2 G101V IC of less than about 5 μM. 50 In another embodiment, compounds of the present disclosure have a Bcl-2 WT and / or Bcl-2 G101V IC of less than about 1 μM. 50 In another embodiment, compounds of the present disclosure have a Bcl-2 WT and / or Bcl-2 G101V IC of less than about 0.5 μM. 50 In another embodiment, compounds of the present disclosure have a Bcl-2 WT and / or Bcl-2 G101V IC of less than about 0.1 μM. 50 In another embodiment, compounds of the present disclosure have a Bcl-2 WT and / or Bcl-2 G101V IC of less than about 0.05 μM. 50 In another embodiment, compounds of the present disclosure have a Bcl-2 WT and / or Bcl-2 G101V IC of less than about 0.025 μM. 50 In another embodiment, compounds of the present disclosure have a Bcl-2 WT and / or Bcl-2 G101V IC of less than about 0.010 μM. 50 In another embodiment, compounds of the present disclosure have a Bcl-2 WT and / or Bcl-2 G101V IC of less than about 0.005 μM. 50 In another embodiment, compounds of the disclosure have a Bcl-2 WT and / or Bcl-2 G101V IC of less than about 0.0025 μM. 50In another embodiment, compounds of the present disclosure have a Bcl-2 WT and / or Bcl-2 G101V IC of less than about 0.001 μM. 50 It has.

[0114] In one embodiment, the disclosure provides a method of treating or preventing a hyperproliferative disorder in a subject (eg, a human), the method comprising administering a therapeutically effective amount of a compound of the disclosure.

[0115] In another embodiment, the present disclosure provides a method for treating or preventing cancer in a subject, the method comprising administering a therapeutically effective amount of a compound of the present disclosure. Without being limited to a particular mechanism, in some examples, the compounds of the present disclosure can treat or prevent cancer by inhibiting Bcl-2 proteins, e.g., Bcl-2 WT and / or Bcl-2 G101V. Examples of cancers that can be treated include, but are not limited to, any one or more of the cancers in Table 2. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0116] 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.

[0117] 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).

[0118] In another embodiment, the cancer is esophageal squamous cell carcinoma (ESCC), bladder cancer, or cervical cancer.

[0119] In another embodiment, the cancer is a leukemia, e.g., a leukemia selected from acute monocytic leukemia, acute myeloid leukemia, chronic myelogenous 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.

[0120] In another embodiment, the cancer is adrenocortical carcinoma, bladder urothelial carcinoma, invasive breast cancer, 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 cancer, prostate cancer, renal clear cell carcinoma, skin melanoma, gastric adenocarcinoma, uterine carcinosarcoma, or endometrial carcinoma.

[0121] In another embodiment, the present disclosure provides a therapeutic method for modulating gene expression, cell proliferation, cell differentiation, and / or apoptosis of cancer (e.g., the cancers described above) in vivo by administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure.

[0122] The compounds of the present disclosure may be administered to a subject in the form of raw chemicals without any other components present. The compounds of the present disclosure may also be administered to a subject as part of a pharmaceutical composition, which comprises the compound in combination with one or more suitable pharmaceutically acceptable vectors. Such vectors may be selected from pharmaceutically acceptable excipients and auxiliaries. The term "pharmaceutically acceptable vector" or "pharmaceutically acceptable vehicle" encompasses any standard pharmaceutical vector, solvent, surfactant, or vehicle. Suitable pharmaceutically acceptable vehicles include aqueous and non-aqueous solvents. Standard pharmaceutical vectors and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th Edition, 1995.

[0123] Pharmaceutical compositions within the scope of the present disclosure include all compositions combining a compound of the present disclosure with one or more pharmaceutically acceptable vectors. In one embodiment, the compound of the present disclosure is present in the composition in an amount effective to achieve its intended therapeutic purpose. While individual needs may vary, determining the optimal range for each compound's effective amount is within the skill of the art. Typically, compounds of the present disclosure can be orally administered to a mammal (e.g., a human) daily at a dose of about 0.0025 mg / kg to about 1500 mg / kg of mammalian body weight, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, to treat a particular disorder. An effective oral dose of a compound of the present disclosure administered to a mammal is about 0.0025 to about 50 mg / kg of mammalian body weight, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. For intramuscular injection, the dose is typically about half the oral dose.

[0124] A unit oral dose may contain about 0.01 mg to about 1 g of a compound of the present disclosure, e.g., about 0.01 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, or 0.01 mg to about 50 mg, e.g., about 0.1 mg to about 10 mg of a compound of the present disclosure. A unit dose may be administered one or more times daily, for example, in one or more tablets or capsules, each tablet or capsule containing about 0.01 mg to about 1 g of the compound or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.

[0125] The compounds of the present disclosure or pharmaceutical compositions comprising the compounds of the present disclosure may be administered to any patient or subject who may benefit from the beneficial effects of the compounds of the present disclosure. These patients or subjects are most importantly mammals, e.g., humans and companion animals, although the present disclosure is not intended to be so limited. In one embodiment, the patient or subject is a human.

[0126] The compounds of the present disclosure or pharmaceutical compositions containing the compounds of the present disclosure can be administered in any form that achieves its desired purpose. For example, administration may be by oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, intranasal, transmucosal, rectal, intravaginal or buccal route, or by inhalation route. The dosage and route of administration will vary depending on the circumstances of the particular subject and will take into account factors such as the recipient's age, sex, health status and weight, the condition or disorder being treated, the type of concurrent treatment (if any), the frequency of treatment, and the nature of the desired effect.

[0127] In one embodiment, the compound of the present disclosure or a pharmaceutical composition comprising the compound of the present disclosure may be administered orally. In another embodiment, the pharmaceutical composition of the present disclosure may be administered orally and may be formulated into a tablet, dragee, capsule, or oral liquid formulation. In one embodiment, the oral formulation comprises extruded multiparticulates comprising the compound of the present disclosure.

[0128] Alternatively, compounds of the present disclosure or pharmaceutical compositions containing compounds of the present disclosure may be administered rectally and formulated into a suppository.

[0129] Alternatively, a compound of the present disclosure or a pharmaceutical composition comprising a compound of the present disclosure may be administered by injection.

[0130] Alternatively, compounds of the present disclosure or pharmaceutical compositions containing compounds of the present disclosure may be administered transdermally.

[0131] Alternatively, compounds of the present disclosure or pharmaceutical compositions comprising compounds of the present disclosure may be administered by inhalation or by intranasal or transmucosal administration.

[0132] Alternatively, the compounds of the present disclosure or pharmaceutical compositions containing the compounds of the present disclosure may be administered by the vaginal route.

[0133] The pharmaceutical compositions of the present disclosure may comprise about 0.01% to 99% by weight, e.g., about 0.25% to 75% by weight, of a compound of the present disclosure, 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% by weight of a compound of the present disclosure.

[0134] The pharmaceutical compositions of the present disclosure are prepared in a form known per se based on the present disclosure, for example, by conventional mixing, granulation, dragee-making, dissolving, extrusion or lyophilization methods. Thus, the pharmaceutical compositions for oral use can be obtained by the following method: mixing the active compound with a solid excipient, adding suitable auxiliaries (if needed or necessary), and then optionally grinding the resulting mixture to process the granular mixture to obtain tablets or dragee cores.

[0135] Suitable excipients include sugars (e.g., lactose, sucrose, mannitol, or sorbitol), cellulose preparations, fillers such as calcium phosphate (e.g., tricalcium phosphate or calcium hydrogen phosphate), and starch pastes (e.g., using corn starch, wheat starch, rice starch, or potato starch), gelatin, gum tragacanth, adhesives such as methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If necessary, one or more disintegrating agents may be added, such as the above-mentioned starches and carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (e.g., sodium alginate).

[0136] Auxiliaries are usually flow regulators and lubricants, such as silica, talc, stearic acid or its salts (e.g., magnesium stearate or calcium stearate), and polyethylene glycol. The sugar-coated cores have a suitable gastric juice-resistant coating. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. To produce a gastric juice-resistant coating, suitable cellulose preparations, such as solutions of cellulose acetate phthalate or hydroxypropylmethylcellulose phthalate, can be used. For example, dyes or pigments can be added to the tablets or sugar-coated coatings to identify or characterize the dosage combination of the active compound.

[0137] Other examples of orally available pharmaceutical preparations include push-fit capsules made of gelatin or soft-sealed capsules made of gelatin and a plasticizer such as glycerin or sorbitol. Push-fit capsules may contain the compound in particulate form, which may be mixed with a filler (e.g., lactose), an adhesive (e.g., starch), and / or a lubricant (e.g., talc or magnesium stearate), and optional stabilizers, or may contain the compound in extruded multiparticulate form. In soft-sealed capsules, the active compounds are preferably dissolved or suspended in a suitable liquid, such as fatty oils or liquid paraffin. Stabilizers may also be added.

[0138] Possible pharmaceutical preparations for rectal administration include, for example, suppositories, which consist of a combination of one or more active compounds with a suppository matrix.Suitable suppository matrices include natural or synthetic triglycerides, paraffin hydrocarbons, etc.Gelatin rectal capsules may also be used, which consist of a combination of an active compound with a matrix material (for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons).

[0139] Suitable formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form, such as a water-soluble salt, basic solution, or acidic solution. Alternatively, a suspension of the active compound may be made into an oily suspension. Suitable lipophilic solvents or vehicles used in suspensions and the like may include fatty oils (e.g., sesame oil), synthetic fatty acid esters (e.g., ethyl oleate), triglycerides, or polyethylene glycols (e.g., polyethylene glycol-400 (PEG-400)). Aqueous suspensions may contain one or more substances that increase the viscosity of the suspension, including, for example, sodium carboxymethylcellulose, sorbitol, and / or dextran. Suspensions may optionally contain stabilizers.

[0140] In another embodiment, the present disclosure provides a kit comprising a compound of the present disclosure (or a pharmaceutical composition comprising a compound of the present disclosure), wherein the compound of the present disclosure (or a pharmaceutical composition comprising a compound of the present disclosure) is packaged in a form convenient for their use to practice a method of the present disclosure. In one embodiment, the kit comprises a compound of the present disclosure (or a pharmaceutical composition comprising a compound of the present disclosure) packaged in a container, e.g., a sealed bottle or container, wherein a label is affixed to the container or included in the kit, and the label describes the use of the compound or composition to practice a method of the present disclosure. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit may further comprise a device suitable for administering the composition according to a desired route of administration.

[0141] In another embodiment, a compound of the present disclosure is administered to a subject in combination with a second therapeutic agent. The second therapeutic agent is different from the compound of the present disclosure. The compound of the present disclosure and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect. Furthermore, the compound of the present disclosure and the second therapeutic agent can be administered as a single composition or as two separate compositions.

[0142] The second therapeutic agent is administered in an amount that provides its desired therapeutic effect. Effective dose ranges for each second therapeutic agent are known in the art, and the second therapeutic agent is administered to an individual in need thereof within such established ranges.

[0143] The compound of the present disclosure and the second therapeutic agent may be administered together in a single unit dose, or may be administered separately in multiple unit doses, where the compound of the present disclosure is administered before the second therapeutic agent, or vice versa. One or more doses of the compound of the present disclosure and / or one or more doses of the second therapeutic agent may be administered. Thus, the compound of the present disclosure may be used in combination with one or more second therapeutic agents, such as, but not limited to, anticancer agents.

[0144] 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 epigenetic regulators. Examples of epigenetic regulators include histone lysine methyltransferase, histone arginine methyltransferase, histone deacetylase, histone deacetylase, histone acetylase, and DNA methyltransferase. Histone deacetylase inhibitors include, but are not limited to, vorinostat.

[0145] In another embodiment, the compounds of the present disclosure can be combined with chemotherapeutic agents or other antiproliferative agents 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, radiation therapy (e.g., gamma radiation, neutron therapy, electron beam therapy, proton therapy, brachytherapy, and whole-body radioisotopes), endocrine therapy, biological response modifiers (e.g., interferons, interleukins, tumor necrosis factors (TNF)), hyperthermia and cryotherapy, agents that attenuate any adverse effects (e.g., antiemetics), and any other approved chemotherapeutic agents.

[0146] Examples of anti-proliferative compounds include, but are not limited to, aromatase inhibitors, antiestrogens, antiandrogens, gonadorelin agonists, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule activators, alkylating agents, retinoids, carotenoids, or tocopherols, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, antimetabolites, platinum compounds, methionine aminopeptidase inhibitors, bisphosphonates, anti-proliferative antibodies, heparanase inhibitors, Ras oncogenic isoform inhibitors, telomerase inhibitors, proteasome inhibitors, compounds for treating hematological malignancies, Flt-3 inhibitors, Hsp90 inhibitors, kinesin spindle protein inhibitors, MEK inhibitors, antitumor antibiotics, nitrosoureas, compounds that target / reduce protein or lipid kinase activity, compounds that target / reduce protein or lipid phosphatase activity, or any other anti-angiogenic compound.

[0147] Non-limiting exemplary aromatase inhibitors include, but are not limited to, steroids such as atamestane, exemestane, and formestane, and non-steroids such as aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole.

[0148] Non-limiting examples of antiestrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Examples of antiandrogens include, but are not limited to, bicalutamide. Examples of gonadorelin agonists include, but are not limited to, abarelix, goserelin, and goserelin acetate.

[0149] Exemplary topoisomerase I inhibitors include, but are not limited to, topotecan, gimatecan, 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.

[0150] Microtubule-active agents include microtubule-stabilizing compounds, microtubule-destabilizing compounds, and microtubulin 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, discodermolide, colchicine, and epothilones and their derivatives.

[0151] Exemplary, non-limiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas such as carmustine and lomustine.

[0152] Exemplary, non-limiting cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acids and derivatives thereof (e.g., celecoxib, rofecoxib, etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids, (e.g., lumiracoxib)).

[0153] Exemplary, non-limiting matrix metalloproteinase inhibitors ("MMP inhibitors") include collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives, batimastat, marimastat, prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B, and AAJ996.

[0154] Exemplary, non-limiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus, everolimus, CCI-779, and ABT578.

[0155] Exemplary, non-limiting antimetabolites include 5-fluorouracil (5-FU), capecitabine, gemcitabine, DNA demethylating compounds (e.g., 5-azacytidine and decitabine), methotrexate and edatrexate, and folate antagonists (e.g., pemetrexet).

[0156] Exemplary, non-limiting platinum compounds include carboplatin, cisplatin, cisplatinum, and oxaliplatin.

[0157] Exemplary, non-limiting methionine aminopeptidase inhibitors include bengamide or a derivative thereof and PPI-2458.

[0158] Exemplary, non-limiting bisphosphonates include etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid.

[0159] Exemplary, non-limiting antiproliferative 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.

[0160] Exemplary, non-limiting heparanase inhibitors include compounds that target, reduce, or inhibit heparin sulfate degradation, such as PI-88 and OGT2115.

[0161] As used herein, the term "Ras oncogenic isoform inhibitor," such as H-Ras, K-Ras, or N-Ras, refers to compounds that target, reduce, or inhibit the oncogenic activity of Ras, e.g., farnesyltransferase inhibitors such as L-744832, DK8G557, tipifarnib, and lonafarnib.

[0162] Exemplary, non-limiting telomerase inhibitors include compounds that target, decrease, or inhibit the activity of telomerase, for example, compounds that inhibit the telomerase receptor, such as telomestatin.

[0163] Exemplary, non-limiting proteasome inhibitors include compounds that target, decrease, or inhibit the activity of the proteasome, including, but not limited to, bortezomib.

[0164] As used herein, the phrase "compounds used in the treatment of hematological malignancies" includes FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R), interferons, I-β-D-arabinofuranosylcytosine (ara-c) and busulfan, and ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase.

[0165] Exemplary, non-limiting Flt-3 inhibitors include PKC412, midostaurin, staurosporine derivatives, SU11248, and MLN518.

[0166] 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 proteasome pathway, compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90, 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.

[0167] As used herein, the phrase "compounds which target / reduce 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 which target, reduce or inhibit the activity of platelet-derived growth factor receptor (PDGFR), for example compounds which target, reduce or inhibit the activity of PDGFR, for example N-phenyl-2-pyrimidine-amine derivatives such as imatinib, SU101, SU6668 and GFB-111; b) compounds which target, reduce or inhibit the activity of fibroblast growth factor receptor (FGFR); c) compounds which target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), for example compounds which target, reduce or inhibit the activity of IGF-IR; e) compounds which target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family or ephrin B4 inhibitors, e) compounds which target, reduce or inhibit the activity of the Axl receptor tyrosine kinase family, f) compounds which target, reduce or inhibit the activity of the Ret receptor tyrosine kinase, g) compounds which target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, for example imatinib, h) compounds which target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase, for example imatinib, i) compounds which target, reduce or inhibit the activity of members of the c-Abl family, their gene fusion products (e.g. Bcr-Abl kinase) and mutants, for example N-phenyl-2-pyrimidine-amine derivatives such as imatinib or nilotinib, PD180970, AG957, NSC680410, PD173955, or dasatinib, j) compounds that target, decrease, or inhibit the activity of protein kinase C (PKC) and Raf family members of serine / threonine kinases, MEK, SRC, JAK, FAK, PDK1, PKB / Akt, and Ras / MAPK family members and / or cyclin-dependent kinase family (CDK) members, e.g., staurosporine derivatives disclosed in U.S. Pat. No. 5,093,330, such as midostaurin; other exemplary compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine, ilmofosine, RO 318220 and RO 320432, GO 6976, Isis 3521, LY333531 / LY379196, isoquinoline compounds, farnesyltransferase inhibitors, PD184352 or QAN697, or AT7519, k) compounds which target, decrease or inhibit the activity of protein tyrosine kinases, for example imatinib mesylate or tyrosine phosphorylation inhibitors, for example 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 adafostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester, NSC 680410, adafostin), l) compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor tyrosine kinase family (EGFR, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their mutants, such as CP 358774, ZD 1839, ZM 105180, 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, and (m)These include compounds that target, decrease or inhibit the activity of the c-Met receptor.

[0168] Exemplary compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase include phosphatase 1, phosphatase 2A or CDC25 inhibitors, such as okadaic acid or a derivative thereof.

[0169] Other anti-angiogenic compounds include compounds that have alternative mechanisms for activity unrelated to protein or lipid kinase inhibition, such as thalidomide and TNP-470.

[0170] Additional non-limiting exemplary chemotherapeutic compounds, one or more of which may be used in combination with a compound of the present disclosure, include daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, PKC412, 6-mercaptopurine (6-MP), fludarabine phosphate, octreotide, SOM230, FTY720, 6-thioguanine, cladribine, 6-mercaptopurine, pentostatin, hydroxyurea, 2-hydroxybenzoates, and the like. 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, anthranilic acid amide, ZD4190, ZD6474, SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macugon, FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, RPI 4610, bevacizumab, porfimer sodium, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, dexamethasone, fluocinolone, plant alkaloids, hormonal compounds and / or antagonists, biological response modifiers (such as lymphokines or interferons), antisense oligonucleotides or oligonucleotide derivatives, shRNA and siRNA.

[0171] Other examples of second therapeutic agents, one or more of which can be combined with a compound of the present disclosure, include drugs for treating Alzheimer's disease, such as donepezil and rivastigmine; drugs for treating Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; drugs for treating multiple sclerosis (MS), such as beta interferons (e.g., AVONEX® and REBIF®), glatiramer acetate, and mitoxantrone; drugs for treating asthma, such as albuterol and montelukast; drugs for treating schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1 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 agents; drugs for treating cardiovascular disease, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers or statins; drugs for treating liver disease, such as corticosteroids, cholestyramine, interferons and antivirals; drugs for treating blood disorders, such as corticosteroids, anti-leukemia agents or growth factors; or drugs for treating immune deficiency disorders, such as gamma globulin.

[0172] The second therapeutically active agents are prepared and administered as described in the art, one or more of which may be used in combination with the compounds of the present disclosure. [Example]

[0173] Synthesis Examples

[0174] Intermediate 1: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0175] Step A: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl)benzoate [ka]

[0176] Under argon gas protection, piperazine (9.0 g, 105 mmol) and dipotassium hydrogen phosphate (12.2 g, 69.9 mmol) were added to a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (10.0 g, 34.9 mmol) in anhydrous DMSO (100 mL), and the reaction mixture was stirred at 100° C. for 4 h. After cooling to room temperature, the resulting mixture was poured into ice water and extracted twice with EA. The combined organic layers were washed with water and brine, dried over NaSO, and concentrated under reduced pressure to give the title compound (12 g, crude) as a white solid, which was used directly in the next step without purification. MS: 353.2 (M+H + ).

[0177] Step B: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 1) [ka]

[0178] To a stirred solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl)benzoate (Step A, 4 g, 11.35 mmol) and 2-bromo-4,4-dimethylcyclohex-1-ene-1-acetal (4.4 g, 20.4 mmol) in anhydrous DCE (100 mL) was added sodium triacetoxyborohydride (4.8 g, 22.7 mmol) at room temperature under argon gas protection. The reaction mixture was then heated to 50 °C and reacted for 6 h. After cooling to room temperature, the resulting mixture was washed with aqueous NaHCO and brine, dried over NaSO, and concentrated under reduced pressure to give a yellow oil, which was purified by silica gel column (MeOH:DCM, 1:35) to give the title compound (4.8 g, 76% yield for two steps) as a white powder. MS: 553.2 (M+H + ).

[0179] Example 1: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(2-methylthiophen-3-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide [ka]

[0180] Step A: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(2-methylthiophen-3-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0181] Under N protection, to a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 1, 100 mg, 0.18 mmol) in DME (1.5 mL) and 2 M Na2CO3 (0.5 mL) was added 4,4,5,5-tetramethyl-2-(2-methylthiophen-3-yl)-1,3,2-dioxaborolane (61 mg, 0.27 mmol) and PdCl2(dppf)·CHCl2 (29.5 mg, 0.036 mmol). The mixture was stirred at 100 °C for 0.5 h under microwave irradiation. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a brown oil, which was loaded onto a silica gel column and eluted with ethyl acetate / hexane (hexane:ethyl acetate, 1:1) to give the title compound (60 mg, 58%) as a yellow oil. MS: 571.3 (M+H + ).

[0182] Step B: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(2-methylthiophen-3-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid [ka]

[0183] To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(2-methylthiophen-3-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step A, 60 mg, 0.11 mmol) in a mixed solvent of MeOH (1 mL), THF (1 mL), and HO (1 mL) was added sodium hydroxide (42 mg, 1.1 mmol). The mixture was stirred at 50 °C for 4 h. After cooling to room temperature and removing the volatiles, the reaction mixture was acidified with 1 M HCl to adjust the pH to 5-6 and extracted twice with ethyl acetate. The resulting organic layers were combined, dried over NaSO, and concentrated under reduced pressure to give the title compound (50 mg, crude), which was used directly in the next step without purification. MS: 557.3 (M+H + ).

[0184] Step C: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(2-methylthiophen-3-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (Example 1) [ka]

[0185] To a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(2-methylthiophen-3-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step B, 50 mg, crude) in anhydrous DCM (3 mL) was added N,N-dimethylpyridin-4-amino (27 mg, 0.23 mmol), EDCI (25 mg, 0.14 mmol), and 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (28 mg, 0.09 mmol) under N protection. The reaction mixture was stirred at 40 °C for 12 h. After cooling to room temperature and removing the volatiles, the mixture was diluted with ethyl acetate and washed with HO and brine. The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give a yellow oil, which was purified by C18 preparative HPLC column to give the title compound (15.9 mg, 21% yield over two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1 H), 8.58 (t, J = 5.6 Hz, 1 H), 8.53 (d, J = 2.0 Hz, 1 H), 8.02 (d, J = 2.5 Hz, 1 H), 7.77 (dd, J = 9.3, 1.5 Hz, 1 H), 7.53 - 7.46 (m, 3 H), 7.18 (d, J = 5.1 Hz, 1 H), 7.07 (d, J = 9.3 Hz, 1 H), 6.68 (dd, J = 9.0, 1.9 Hz, 1 H), 6.62 (d, J = 5.1 Hz, 1 H), 6.37 (dd, J = 3.1, 1.8 Hz, 1 H), 6.20 (d, J = 1.9 Hz, 1 H), 3.90 - 3.79 (m, 2 H), 3.30 - 3.20 (m, 4 H), 3.12 - 2.99 (m, 4 H), 2.73 - 2.59 (m, 2 H), 2.24 - 2.09 (m, 9 H), 1.93 - 1.77 (m, 3 H), 1.67 - 1.54 (m, 2 H), 1.38 (t, J = 6.3 Hz, 2 H), 1.32 - 1.24 (m, 2 H), 0.92 (s, 6 H); MS: 854.3 (M+H) + ).

[0186] Example 2: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-methylthiophen-3-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide [ka]

[0187] Essentially the same scheme was used to prepare Example 1 to give the example (30 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1 H), 8.59 (t, J = 5.7 Hz, 1 H), 8.55 (d, J = 2.1 Hz, 1 H), 8.03 (d, J = 2.5 Hz, 1 H), 7.79 (dd, J = 9.2, 1.9 Hz, 1 H), 7.54 - 7.47 (m, 3 H), 7.14 - 7.04 (m, 2 H), 6.94 (d, J = 3.1 Hz, 1 H), 6.68 (dd, J = 9.0, 1.9 Hz, 1 H), 6.38 (dd, J = 3.2, 1.8 Hz, 1 H), 6.19 (d, J = 1.8 Hz, 1 H), 3.89 - 3.80 (m, 2 H), 3.30 - 3.22 (m, 4 H), 3.12 - 3.01 (m, 4 H), 2.71 - 2.59 (m, 2 H), 2.26 - 2.08 (m, 6 H), 1.96 (s, 3 H), 1.92 - 1.80 (m, 3 H), 1.66 - 1.56 (m, 2 H), 1.38 (t, J = 6.3 Hz, 2 H), 1.32 - 1.22 (m, 2 H), 0.92 (s, 6 H); MS: 854.2 (M+H) + ).

[0188] Example 3: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(5-(trifluoromethyl)thiophen-3-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide [ka]

[0189] Using essentially the same scheme as used to prepare Example 1, the example (15 mg) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1 H), 8.64 (t, J = 5.8 Hz, 1 H), 8.59 (d, J = 2.2 Hz, 1 H), 8.07 (d, J = 2.6 Hz, 1 H), 7.83 (dd, J = 9.2, 2.0 Hz, 1 H), 7.64 (d, J = 1.4 Hz, 1 H), 7.60 - 7.58 (m, 1 H), 7.56 (d, J = 2.4 Hz, 1 H), 7.55 - 7.50 (m, 2 H), 7.14 (d, J = 9.4 Hz, 1 H), 6.72 (dd, J = 9.0, 2.0 Hz, 1 H), 6.42 (dd, J = 3.3, 1.9 Hz, 1 H), 6.23 (d, J = 2.0 Hz, 1 H), 3.88 (dd, J = 11.3, 3.0 Hz, 2 H), 3.33 - 3.23 (m, 3 H), 3.17 - 3.03 (m, 4 H), 2.88 (s, 2H), 2.33 - 2.21 (m, 4 H), 2.21 - 2.14 (m, 2 H), 2.05 (s, 2 H), 1.97 - 1.85 (m, 1 H), 1.64 (d, J = 11.4 Hz, 2 H), 1.39 (t, J = 6.3 Hz, 2 H), 1.35 - 1.21 (m, 3 H), 0.95 (s, 6 H); MS: 908.9 (M+H + ).

[0190] Example 4: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylthiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide [ka]

[0191] Essentially the same scheme was used to prepare Example 1 to give the example (3.7 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.2 Hz, 1 H), 7.98 (d, J = 1.9 Hz, 1 H), 7.77 (dd, J = 9.3, 2.1 Hz, 1 H), 7.52 - 7.46 (m, 3 H), 7.34 (d, J = 5.0 Hz, 1 H), 7.06 (d, J = 9.4 Hz, 1 H), 6.83 (d, J = 5.1 Hz, 1 H), 6.74 (d, J = 9.3 Hz, 1 H), 6.38 (d, J = 3.4 Hz, 1 H), 6.28 - 6.24 (m, 1 H), 3.87 - 3.81 (m, 6 H), 3.62 - 3.51 (m, 2 H), 3.31 - 3.19 (m, 4 H), 2.23 - 2.13 (m, 2 H), 2.03 - 1.94 (m, 6 H), 1.92 (s, 3 H), 1.88 - 1.78 (m, 1 H), 1.63 - 1.54 (m, 2 H), 1.43 (t, J = 6.2 Hz, 2 H), 1.30 - 1.26 (m, 2 H), 0.91 (s, 6 H); MS: 854.3 (M+H + ).

[0192] Example 5: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-methylthiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide [ka]

[0193] Using essentially the same scheme as used to prepare Example 1, the example (4.5 mg) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.52 - 8.45 (m, 1 H), 8.02 - 7.93 (m, 1 H), 7.73 (d, J = 9.5 Hz, 1 H), 7.53 - 7.40 (m, 3 H), 7.01 (d, J = 9.7 Hz, 1 H), 6.94 (s, 1 H), 6.69 (d, J = 8.2 Hz, 1 H), 6.61 (s, 1 H), 6.36 (d, J = 3.2 Hz, 1 H), 6.25 - 6.15 (m, 1 H), 3.86 - 3.79 (m, 2 H), 3.31 - 3.19 (m, 4H), 3.16 - 2.95 (m, 6 H), 2.35 - 2.23 (m, 4 H), 2.17 - 2.13 (m, 2 H), 2.12 (s, 3 H), 2.01 - 1.98 (m, 2 H), 1.91 - 1.79 (m, 1 H), 1.63 - 1.54 (m, 2 H), 1.33 (t, J = 6.0 Hz, 2 H), 1.29 - 1.24 (m, 2 H), 0.88 (s, 6 H); MS: 854.0 (M+H + ).

[0194] Example 6: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(5-methylthiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide [ka]

[0195] Using essentially the same scheme as used to prepare Example 1, the example (6.6 mg) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.51 - 8.44 (m, 1 H), 8.00 - 7.94 (m, 1 H), 7.71 (d, J = 8.8 Hz, 1 H), 7.52 - 7.41 (m, 3 H), 6.98 (d, J = 8.3 Hz, 1 H), 6.69 (d, J = 8.8 Hz, 1 H), 6.63 - 6.59 (m, 1 H), 6.56 (d, J = 3.1 Hz, 1 H), 6.35 (d, J = 2.8 Hz, 1 H), 6.26 - 6.16 (m, 1 H), 3.94 - 3.88 (m, 2 H), 3.25 - 3.21 (m, 4 H), 3.17 - 3.00 (m, 6 H), 2.42 - 2.27 (m, 7 H), 2.18 - 2.08 (m, 2 H), 1.99 - 1.96 (m, 2 H), 1.90 - 1.78 (m, 1 H), 1.62 - 1.51 (m, 2 H), 1.32 (t, J = 6.0 Hz, 2 H), 1.28 - 1.21 (m, 2 H), 0.86 (s, 6 H); MS: 854.2 (M+H + ).

[0196] Examples 7 and 8: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-isopropylthiophen-3-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (Example Example 7), and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (Example 8). [ka]

[0197] Step A: 2-(4-bromothiophen-3-yl)propan-2-ol [ka]

[0198] To a solution of 4-bromothiophene-3-carboxylate (4 g, 18.1 mmol) in anhydrous THF (100 mL) was added MeMgBr (14 mL, 3 M 2-MeTHF solution, 41.6 mmol) under N protection at 0 °C, and the reaction mixture was stirred at room temperature for 20 h. The mixture was quenched with saturated NH4Cl, diluted with ethyl acetate (100 mL), and washed with HO (100 mL) and brine (100 mL). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:1) to give the title compound (3.3 g, 82%) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 3.7 Hz, 1 H), 7.43 (d, J = 3.7 Hz, 1 H), 5.20 (s, 1H), 1.51 (s, 6 H).

[0199] Step B: 3-Bromo-4-isopropylthiophene [ka]

[0200] To a solution of 2-(4-bromothiophen-3-yl)propan-2-ol (Step A, 1.6 g, 7.24 mmol) in anhydrous DCM (70 mL) under N protection, triethylsilane (2.52 g, 21.71 mmol) and 2,2,2-trifluoroacetic acid (4.13 g, 36.2 mmol) were added, and the mixture was stirred at room temperature for 3 h. After removing the effluent, the resulting mixture was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:10) to give the title compound (1.05 g, 71%) as a colorless oil.1 H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 3.3 Hz, 1 H), 7.35 (d, J = 3.3 Hz, 1 H), 2.98 - 2.86 (m, 1 H), 1.20 (d, J = 6.9 Hz, 6 H).

[0201] Step C: (4-Isopropylthiophen-3-yl)boronic acid and (4-Isopropylthiophen-2-yl)boronic acid [ka]

[0202] Under N protection, n-butyllithium (2.6 mL, 2.5 M hexane solution, 6.59 mmol) was added dropwise to a solution of 3-bromo-4-isopropylthiophene (Step B, 900 mg, 4.39 mmol) in anhydrous THF (30 mL) at −78° C., and the mixture was stirred at −78° C. for 20 minutes. Boric acid triisopropyl ester (1.65 g, 8.78 mmol) was added, and the reaction mixture was stirred at −78° C. for 2 hours, then warmed to room temperature and stirred for 12 hours. The mixture was quenched with 2M HCl, diluted with ethyl acetate, and washed with H2O and brine. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with MeOH and DCM (1:20) to give the mixed title compounds (570 mg, 76%) as a yellow oil. MS: 171.1 (M+H + ).

[0203] Step D: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-isopropylthiophen-3-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate and Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0204] To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 1, 70 mg, 0.13 mmol) in DME (1.5 mL) and 2 M Na2CO3 (0.5 mL) was added a mixture of (4-isopropylthiophen-3-yl)boronic acid and (4-isopropylthiophen-2-yl)boronic acid (Step C, 32.3 mg, 0.19 mmol) and PdCl2(dppf)·CHCl2 (20.7 mg, 0.02 mmol) under N2 protection. The reaction mixture was stirred at 100 °C for 0.5 h under microwave assistance. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with HO and brine. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:1) to give the mixed title compounds (50 mg, 66%) as a yellow oil. MS: 599.3 (M+H + ).

[0205] Step E: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-isopropylthiophen-3-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid, and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid [ka]

[0206] To a mixture of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-isopropylthiophen-3-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate and methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step D, 76 mg, 0.13 mmol) in MeOH (1 mL), THF (1 mL), and HO (1 mL) was added NaOH (51 mg, 1.3 mmol), and the reaction mixture was stirred at 50 °C for 4 h. After cooling to room temperature, the mixture was acidified with 1M HCl to adjust the pH to 4-5 and extracted twice with ethyl acetate. The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the title compound (72 mg, crude) as a yellow oil, which was used directly in the next step without purification. MS: 585.3 (M+H + ).

[0207] Step F: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-isopropylthiophen-3-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (Example 7), and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (Example 8). [ka]

[0208] To a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-isopropylthiophen-3-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step E, 36 mg, 0.06 mmol) in anhydrous DCM (2 mL) was added N,N-dimethylpyridin-4-amino (18.8 mg, 0.15 mmol), EDCI (17.7 mg, 0.09 mmol), and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step E, 36 mg, 0.06 mmol)). (mM) and 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (19.4 mg, 0.06 mmol) were added, and the reaction mixture was stirred at 40° C. for 12 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with HO and brine. The organic layer was dried over NaSO and concentrated under reduced pressure to give a yellow oil, which was purified by C18 preparative HPLC column to give the title compound (Example 7: 17 mg, 31% yield over two steps, Example 8: 4 mg, 7% yield over two steps) as a yellow solid.

[0209] Example 7: 11H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1 H), 11.48 (s, 1 H), 8.61 (t, J = 5.5 Hz, 1 H), 8.55 (d, J = 1.9 Hz, 1 H), 8.03 (d, J = 2.5 Hz, 1 H), 7.79 (dd, J = 9.1, 1.4 Hz, 1 H), 7.56 - 7.46 (m, 3 H), 7.15 (d, J = 3.0 Hz, 1 H), 7.10 (d, J = 9.1 Hz, 1 H), 6.93 (d, J = 3.1 Hz, 1 H), 6.68 (dd, J = 8.9, 1.8 Hz, 1 H), 6.41 - 6.36 (m, 1 H), 6.18 (d, J = 1.5 Hz, 1 H), 3.88 - 3.81 (m, 2 H), 3.32 - 3.22 (m, 4 H), 3.12 - 3.00 (m, 4 H), 2.76 - 2.53 (m, 3 H), 2.35 - 2.20 (m, 4 H), 2.21 - 2.09 (m, 2 H), 2.02 - 1.97 (m, 1 H), 1.92 - 1.84 (m, 2 H), 1.65 - 1.57 (m, 2 H), 1.38 (t, J = 6.4 Hz, 2 H), 1.31 - 1.24 (m, 2 H), 1.12 - 1.06 (m, 6 H), 0.92 (s, 6 H); MS: 882.4 (M+H + ).

[0210] Example 8: 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1 H), 11.50 (s, 1 H), 8.60 (t, J = 5.5 Hz, 1 H), 8.54 (d, J = 2.0 Hz, 1 H), 8.03 (d, J = 2.5 Hz, 1 H), 7.77 (d, J = 10.4 Hz, 1 H), 7.56 - 7.46 (m, 3 H), 7.08 (d, J = 9.2 Hz, 1 H), 6.98 (s, 1 H), 6.79 (s, 1 H), 6.70 (dd, J = 9.0, 1.8 Hz, 1 H), 6.37 (dd, J = 3.1, 1.8 Hz, 1 H), 6.23 (d, J = 1.6 Hz, 1 H), 3.88 - 3.81 (m, 2 H), 3.32 - 3.22 (m, 4 H), 3.13 - 3.05 (m, 4 H), 3.02 - 2.94 (m, 2 H), 2.89 - 2.77 (m, 1 H), 2.32 - 2.23 (m, 4 H), 2.21 - 2.12 (m, 2 H), 2.07 - 2.02 (m, 2 H), 1.95 - 1.81 (m, 1 H), 1.66 - 1.55 (m, 2 H), 1.35 (t, J = 6.2 Hz, 2 H), 1.31 - 1.24 (m, 2 H), 1.15 (d, J = 6.8 Hz, 6 H), 0.90 (s, 6 H); MS: 882.4 (M+H + )。

[0211] Examples 9 and 10: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-isopropylthiophen-3-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide (Example Example 9), and (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide (Example 10). [ka]

[0212] Using essentially the same scheme as used to prepare Examples 7 and 8, the examples (Example 9: 3.6 mg, Example 10: 9.6 mg) were obtained as yellow solids.

[0213] Example 9: 11H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1 H), 8.60 - 8.49 (m, 2 H), 8.06 - 7.97 (m, 1 H), 7.78 (d, J = 9.1 Hz, 1 H), 7.52 - 7.46 (m, 3 H), 7.16 (d, J = 3.0 Hz, 1 H), 7.05 (d, J = 10.3 Hz, 1 H), 6.93 (d, J = 3.0 Hz, 1 H), 6.72 - 6.64 (m, 1 H), 6.40 - 6.34 (m, 1 H), 6.25 - 6.15 (m, 1 H), 3.84 - 3.75 (m, 3 H), 3.69 - 3.57 (m, 2 H), 3.54 - 3.44 (m, 2 H), 3.33 - 3.28 (m, 2 H), 3.12 - 3.00 (m, 4 H), 2.75 - 2.60 (m, 3 H), 2.36 - 2.20 (m, 2 H), 2.17 - 2.09 (m, 2 H), 2.06 - 1.94 (m, 4 H), 1.38 (t, J = 6.2 Hz, 2 H), 1.11 - 1.06 (m, 6 H), 0.92 (s, 6 H); MS: 884.4 (M+H + ).

[0214] Example 10: 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1 H), 11.51 (s, 1 H), 8.62 - 8.50 (m, 2 H), 8.02 (d, J = 2.3 Hz, 1 H), 7.79 (d, J = 9.0 Hz, 1 H), 7.54 - 7.45 (m, 3 H), 7.07 (d, J = 9.2 Hz, 1 H), 6.98 (s, 1 H), 6.79 (s, 1 H), 6.70 (dd, J = 8.9, 1.3 Hz, 1 H), 6.39 - 6.34 (m, 1 H), 6.28 - 6.18 (m, 1 H), 3.86 - 3.74 (m, 3 H), 3.69 - 3.55 (m, 2 H), 3.54 - 3.43 (m, 2 H), 3.33 - 3.27 (m, 2 H), 3.14 - 3.04 (m, 4 H), 3.02 - 2.94 (m, 2 H), 2.88 - 2.79 (m, 1 H), 2.35 - 2.22 (m, 4 H), 2.21 - 2.12 (m, 2 H), 2.08 - 2.02 (m, 2 H), 1.35 (t, J = 6.1 Hz, 2 H), 1.15 (d, J = 6.8 Hz, 6 H), 0.90 (s, 6 H); MS: 884.4 (M+H + ).

[0215] Examples 11 and 12: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(2-isopropylthiophen-3-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (Example Example 11), and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(5-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (Example 12). [ka]

[0216] Step A: (2-Isopropylthiophen-3-yl)boronic acid and (5-Isopropylthiophen-2-yl)boronic acid [ka]

[0217] In a flame-dried 100 mL round-bottom flask, 3-bromo-2-isopropylthiophene (0.6 g, 2.93 mmol) was dissolved in anhydrous THF (10 mL) under argon gas protection to give a solution. At −78 °C, n-butyllithium (1.4 mL, 2.5 M n-hexane solution, 3.51 mmol) was added to the reaction mixture. After stirring at −78 °C for 30 minutes, boric acid triisopropyl ester (0.825 g, 4.39 mmol) was added. The reaction mixture was stirred at −78 °C for 2 hours and then at room temperature overnight. 1 N HCl (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL × 2). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with methanol and dichloromethane (1:50) to give the title compound mixture (0.4 g, 80%) as a pale yellow oil.

[0218] Step B: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(2-isopropylthiophen-3-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate, and Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(5-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0219] In a flame-dried 100 mL round-bottom flask, methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (50 mg, 0.09 mmol), a mixture of (2-isopropylthiophen-3-yl)boronic acid and (5-isopropylthiophen-2-yl)boronic acid (Step A, 46.1 mg, 0.27 mmol), K2CO3 (44.9 mg, 0.325 mmol), and Pd(Ph3P)4 (20.88 mg, 0.018 mmol) were dissolved in a mixture of 1,4-dioxane (6 mL) and water (2 mL) under argon gas protection to give a solution. The reaction mixture was stirred at room temperature for 10 min and then at 100 °C for 5 h. To the reaction mixture was added saturated NaHCO3 (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with methanol and dichloromethane (1:40) to give the mixed title compounds (40 mg, 74%) as a pale yellow oil. MS: 599.8 (M+H + ).

[0220] Step C: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(2-isopropylthiophen-3-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid, and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(5-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid [ka]

[0221] In a flame-dried 100 mL round-bottom flask, a mixture of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(2-isopropylthiophen-3-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate and methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(5-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step B, 70 mg, 0.117 mmol) was dissolved in a mixture of THF (2 mL), water (1 mL), and MeOH (1 mL) under argon gas protection to give a solution. The resulting solution was diluted with sodium hydroxide (80 mg, 2.0 mL). (mmol) was added, and the reaction mixture was stirred at 40°C for 5 hours. After cooling to room temperature, 1N HCl (2 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (10 mL x 2). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with methanol and dichloromethane (1:50) to give the mixed title compounds (68 mg, 99%) as a pale yellow oil. MS: 585.5 (M+H + ).

[0222] Step D: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(2-isopropylthiophen-3-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (Example 1 1), and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(5-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (Example 12) [ka]

[0223] In a flame-dried 100 mL round-bottom flask, a mixture of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(2-isopropylthiophen-3-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)-piperazin-1-yl)benzoic acid and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(5-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step C, 50 mg, 0.086 mmol), 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (40.4 mg, 0.128 mmol), and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(5-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step C, 50 mg, 0.086 mmol)) was added. N,N-dimethylpyridin-4-amino (31.3 mg, 0.257 mmol) was dissolved in anhydrous CHCl (10 mL) under argon gas protection to obtain a solution. 3-(((ethylamino)methylene)amino)-N,N-dimethylpropan-1-amino hydrochloride (32.8 mg, 0.171 mmol) was added at 0° C., and the reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 16 hours. Saturated NaHCO (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over NaSO and concentrated under reduced pressure to obtain a yellow oil, which was purified by C18 preparative HPLC to obtain the title compound (Example 11: 4 mg, 7%, Example 12: 4 mg, 7%) as a yellow solid.

[0224] Example 11: 11H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1 H), 8.63 (brs, 1 H), 8.56 (s, 1 H), 8.05 (d, J = 2.2 Hz, 1 H), 7.80 (d, J = 9.0 Hz, 1 H), 7.57 - 7.48 (m, 3 H), 7.27 (d, J = 5.1 Hz, 1 H), 7.11 (d, J = 9.0 Hz, 1 H), 6.71 (dd, J = 9.0, 1.9 Hz, 1 H), 6.61 (d, J = 5.1 Hz, 1 H), 6.43 - 6.38 (m, 1 H), 6.22 (d, J = 1.7 Hz, 1 H), 3.87 (dd, J = 11.0, 3.2 Hz, 2 H), 3.35 - 3.24 (m, 4 H), 3.17 - 3.05 (m, 4 H), 3.03 - 2.94 (m, 1 H), 2.82 - 2.72 (m, 1 H), 2.67 - 2.59 (m, 1 H), 2.34 - 2.20 (m, 3 H), 2.19 - 2.11 (m, 2 H), 2.10 - 1.99 (m, 1H), 1.99 - 1.86 (m, 2 H), 1.85 - 1.74 (m, 1 H), 1.64 (d, J = 12.3 Hz, 2 H), 1.41 (t, J = 6.3 Hz, 2 H), 1.34 - 1.27 (m, 2 H), 1.18 (d, J = 6.6 Hz, 6 H), 0.95 (s, 6 H); MS: 883.2 (M+H + ).

[0225] Example 12: 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1 H), 8.69 - 8.50 (m, 2 H), 8.04 (s, 1 H), 7.77 (s, 1 H), 7.59 - 7.47 (m, 3 H), 7.24 (s, 1 H), 6.77 - 6.68 (m, 2 H), 6.65 (d, J = 3.5 Hz, 1 H), 6.39 (s, 1 H), 6.26 (s, 1 H), 3.87 (dd, J = 10.9, 3.6 Hz, 2 H), 3.35 - 3.24 (m, 4 H), 3.16 - 3.05 (m, 5 H), 3.02 (s, 2 H), 2.34 - 2.24 (m, 4 H), 2.24 - 2.16 (m, 2 H), 2.05 (s, 2 H), 1.96 - 1.83 (m, 1 H), 1.63 (d, J = 11.5 Hz, 2 H), 1.37 (t, J = 6.0 Hz, 2 H), 1.34 - 1.28 (m, 2 H), 1.24 (s, 6 H), 0.93 (s, 6 H); MS: 883.2 (M+H + ).

[0226] Examples 13 and 14: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(2-isopropylthiophen-3-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide (Example Example 13), and (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(5-isopropylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide (Example 14). [ka]

[0227] Using essentially the same scheme as used to prepare Examples 11 and 12, the examples (Example 13: 1.4 mg, Example 14: 0.5 mg) were obtained as yellow solids.

[0228] Example 13: 1 H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1 H), 8.57 - 8.38 (m, 2 H), 7.97 (s, 1 H), 7.72 (s, 1 H), 7.52 (d, J = 9.0 Hz, 1 H), 7.46 (s, 1 H), 7.31 - 7.14 (m, 2 H), 6.71 - 6.62 (m, 1 H), 6.62 - 6.53 (m, 2 H), 6.34 (s, 1 H), 6.22 (s, 1 H), 3.85 - 3.73 (m, 3 H), 3.70 - 3.57 (m, 2 H), 3.56 - 3.40 (m, 4 H), 3.10 - 2.97 (m, 7 H), 2.30 - 2.18 (m, 4 H), 2.17 - 2.08 (m, 2 H), 1.97 (s, 2 H), 1.42 - 1.34 (m, 2 H), 1.15 (d, J = 4.0 Hz, 6 H), 0.92 (s, 6 H); MS: 885.2 (M+H + ).

[0229] Example 14: 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1 H), 8.53 - 8.37 (m, 2 H), 7.96 (s, 1 H), 7.68 (s, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.44 (s, 1 H), 7.35 (s, 1 H), 7.21 (s, 1 H), 6.71 - 6.65 (m, 2 H), 6.63 (d, J = 3.5 Hz, 1 H), 6.32 (s, 1 H), 6.26 (s, 1 H), 3.84 - 3.73 (m, 3 H), 3.70 - 3.56 (m, 2 H), 3.52 - 3.42 (m, 4 H), 3.10 - 3.04 (m, 5 H), 3.00 (s, 2 H), 2.32 - 2.23 (m, 4 H), 2.22 - 2.12 (m, 2 H), 2.02 (s, 2 H), 1.40 - 1.31 (m, 2 H), 1.23 - 1.19 (m, 6 H), 0.90 (s, 6 H); MS: 884.6 (M+H + ).

[0230] Example 15: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(5-(4-fluorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0231] Step A: 5-(4-fluorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine [ka]

[0232] In a flame-dried 100 mL round-bottom flask, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1 g, 7.18 mmol) and (4-fluorophenyl)boronic acid (2.010 g, 14.37 mmol) were dissolved in anhydrous CHCl (5 mL) under argon gas protection to give a solution. Copper acetate hydrate (1.43 g, 7.18 mmol) and triethylamine (2.18 g, 21.55 mmol) were added at room temperature, and the reaction mixture was stirred at room temperature for 16 h. After removal of the eluent, the residue was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:3) to give the title compound (1.2 g, 72%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.32 (d, J = 5.1 Hz, 1 H), 7.09 - 6.99 (m, 4 H), 6.90 (d, J = 5.1 Hz, 1 H), 4.22 (s, 2 H), 3.53 (t, J = 5.7 Hz, 2 H), 2.89 (t, J = 5.6 Hz, 2 H); MS: 233.6 (M+H + ).

[0233] Step B: (5-(4-fluorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)boronic acid [ka]

[0234] In a flame-dried 100 mL round-bottom flask, 5-(4-fluorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Step A, 250 mg, 1.1 mmol) was dissolved in anhydrous THF (10 mL) under argon gas protection at -78 °C to obtain a solution. LDA (1.1 mL, 2 M THF solution, 2.14 mmol) was added at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Boric acid triisopropyl ester (443 mg, 2.36 mmol) was added dropwise within 30 minutes. The reaction mixture was stirred at -78 °C for 30 minutes, then gradually warmed to room temperature and stirred for 1 hour. MeOH (10 mL) was added to quench the reaction. After removal of the effluent, the residue was used directly in the next step without further purification. MS: 277.3 (M+H + ).

[0235] Step C: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(5-(4-fluorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate methyl [ka]

[0236] In a flame-dried 100 mL round-bottom flask, (5-(4-fluorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)boronic acid (Step B, crude), methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 1, 297 mg, 0.536 mmol), PdCl(dppf) CHCl (175 mg, 0.214 mmol), and NaCO (568 mg, 5.36 mmol) were dissolved in a mixture of 1,4-dioxane (7.5 mL) and water (1.5 mL) under argon gas protection to give a solution. At room temperature, Na2CO3 (568 mg, 5.36 mmol) was added, and the reaction mixture was stirred at 100 °C for 12 h. After cooling to room temperature, saturated NaHCO3 (10 mL) was added to the reaction mixture, and it was extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with methanol and dichloromethane (1:50) to give the title compound (300 mg, 40% yield for two steps) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1 H), 7.99 (d, J = 2.4 Hz, 1 H), 7.75 (d, J = 9.0 Hz, 1 H), 7.49 - 7.44 (m, 1 H), 7.41 (d, J = 2.6 Hz, 1 H), 7.08 - 6.96 (m, 4 H), 6.76 (dd, J = 9.0, 2.3 Hz, 1 H), 6.61 (s, 1 H), 6.40 - 6.34 (m, 2 H), 4.13 (s, 2 H), 3.64 (s, 3 H), 3.50 (t, J = 5.6 Hz, 2 H), 3.21 - 3.10 (m, 4 H), 3.04 (s, 2 H), 2.88 - 2.78 (m, 2 H), 2.37 - 2.26 (m, 4 H), 2.26 - 2.13 (m, 2 H), 2.03 (s, 2 H), 1.36 (t, J = 6.3 Hz, 2 H), 0.91 (s, 6 H); MS: 706.0 (M+H + ).

[0237] Step D: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(5-(4-fluorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid [ka]

[0238] In a flame-dried 100 mL round-bottom flask, methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(5-(4-fluorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step C, 300 mg, 0.43 mmol) was dissolved in a mixture of water (2 mL), THF (4 mL), and MeOH (2 mL) under argon gas protection to give a solution. Sodium hydroxide (170 mg, 4.25 mmol) was added at room temperature, and the reaction mixture was stirred at 45 °C for 16 h. 1N HCl (4 mL) was added to the reaction mixture, and the resulting mixture was concentrated under reduced pressure to give the crude product as a pale solid, which was used directly in the next step without purification. MS: 693.3 (M+H + ).

[0239] Step E: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(5-(4-fluorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide (Example 15) [ka]

[0240] In a flame-dried 100 mL round-bottom flask, 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(5-(4-fluorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step D, 60 mg, crude), N,N-dimethylpyridin-4-amino (53.0 mg, 0.43 mmol), and (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (27.5 mg, 0.087 mmol) were added to anhydrous CHCl (10 mL) under argon gas protection. The resulting solution was dissolved in 1 mL of ethyliminomethyleneamino-N,N-dimethylpropan-1-amino hydrochloride (49.9 mg, 0.26 mmol) at room temperature, and the reaction mixture was stirred at 40° C. for 12 hours. After cooling to room temperature, saturated NaHCO (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL×2). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give a yellow oil, which was purified by C18 preparative HPLC to give the title compound (15 mg, 18% yield for two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1 H), 8.56 - 8.39 (m, 2 H), 7.99 (s, 1 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 7.49 - 7.37 (m, 2 H), 7.09 - 6.92 (m, 5 H), 6.69 (d, J = 7.3 Hz, 1 H), 6.60 (s, 1 H), 6.35 (s, 1 H), 6.25 (s, 1 H), 4.14 (s, 2 H), 3.84 - 3.74 (m, 4 H), 3.64 (t, J = 10.2 Hz, 2 H), 3.54 - 3.42 (m, 4 H), 3.40 - 3.32 (m, 1 H), 3.13 - 3.06 (m, 4 H), 3.03 (s, 2 H), 2.87 - 2.78 (m, 2 H), 2.36 - 2.26 (m, 4 H), 2.22 - 2.13 (m, 2 H), 2.03 (s, 2 H), 1.36 (t, J = 6.2 Hz, 2 H), 0.91 (s, 6 H); MS: 991.8 (M+H + ).

[0241] Example 16: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(5-(4-fluorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0242] Essentially the same scheme was used to prepare Example 15 to give the example (5 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1 H), 8.59 - 8.40 (m, 2 H), 8.02 (s, 1 H), 7.76 (d, J = 8.1 Hz, 1 H), 7.57 - 7.43 (m, 3 H), 7.11 - 6.95 (m, 5 H), 6.69 (d, J = 9.1 Hz, 1 H), 6.60 (s, 1 H), 6.36 (s, 1 H), 6.24 (s, 1 H), 4.21 (s, 1 H), 4.13 (s, 2 H), 3.50 (t, J = 5.5 Hz, 2 H), 3.28 - 3.21 (m, 2 H), 3.14 - 3.08 (m, 4 H), 3.03 (s, 2 H), 2.89 - 2.75 (m, 2 H), 2.34 - 2.24 (m, 4 H), 2.23 - 2.14 (m, 2 H), 2.03 (s, 2 H), 1.73 - 1.59 (m, 3 H), 1.58 - 1.50 (m, 2 H), 1.39 - 1.29 (m, 4 H), 1.19 - 1.06 (m, 5 H), 0.91 (s, 6 H); MS: 1018.2 (M+H + ).

[0243] Example 17: (S)-5-(2-((4-(4-(((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)phenyl)piperazin-1-yl)methyl)-5,5-dimethylcyclohex-1-en-1-yl)-N-phenylthiophene-3-carboxamide [ka]

[0244] Step A: 5-Bromo-N-phenylthiophene-3-carboxamide [ka]

[0245] Under argon gas protection, to a solution of 5-bromothiophene-3-carboxylic acid (1.0 g, 4.83 mmol) in anhydrous DCM (25 mL) were added aniline (0.45 g, 4.83 mmol), EDCI (1.39 g, 7.24 mmol), and DMAP (1.18 g, 9.66 mmol), and the reaction mixture was stirred at 40 °C for 2 h. After cooling to room temperature, the mixture was washed with 1N HCl and brine, dried over NaSO, and concentrated under reduced pressure to give the title compound (800 mg, crude) as a gray solid, which was used directly in the next step without purification. MS: 283.9 (M+H + ).

[0246] Step B: N-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carboxamide [ka]

[0247] Under argon gas protection, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (108 mg, 0.425 mmol), potassium acetate (104 mg, 1.063 mmol), and PdCl(dppf) (25.9 mg, 0.035 mmol) were added to a solution of 5-bromo-N-phenylthiophene-3-carboxamide (Step A, 100 mg, crude) in anhydrous dioxane (8 mL). The reaction mixture was heated to 100 °C and reacted for 6 h. After cooling to room temperature, the resulting mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (crude) as a yellow oil, which was used directly in the next step without purification. MS: 330.1 (M+H + ).

[0248] Step C: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(phenylcarbamoyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0249] N-Phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carboxamide (Step B, 117 mg, crude), NaCO (113 mg, 1.066 mmol), and PdCl(dppf) (26 mg, 0.036 mmol) were added to a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 1, 98 mg, 0.178 mmol) in dioxane (10 mL) and water (2 mL) under argon gas protection. The mixture was stirred at 90 °C for 16 h. After cooling to room temperature and removing the volatiles, the residue was purified by silica gel column (hexane:EA, 1:1) to give the title compound as a yellow oil (80 mg, 33% yield over three steps). MS: 676.9 (M+H + ).

[0250] Step D: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(phenylcarbamoyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid [ka]

[0251] To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(phenylcarbamoyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step C, 80 mg, 0.12 mmol) in a mixed solvent of THF (4 mL) and MeOH (4 mL) was added 3N NaOH (4 mL), and the reaction mixture was stirred at 40° C. for 16 hours. After cooling to room temperature, the pH of the mixture was adjusted to 3-4 with 1N HCl. The resulting mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (60 mg, crude) as a yellow solid, which was used directly in the next step without purification. MS: 663.0 (M+H + ).

[0252] Step E: (S)-5-(2-((4-(4-(((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)phenyl)piperazin-1-yl)methyl)-5,5-dimethylcyclohex-1-en-1-yl)-N-phenylthiophene-3-carboxamide (Example 17) [ka]

[0253] To a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(phenylcarbamoyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step D, 60 mg, crude) in a mixture of anhydrous DMF (2 mL) and DCM (10 mL) was added (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (28.8 mg, 0.091 mmol), DMAP (27.7 mg, 0.227 mmol), and EDCI (26.1 mg, 0.136 mmol) under argon gas protection. The reaction mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the resulting mixture was diluted with DCM, washed with 1N HCl and brine, dried over Na2SO4, and concentrated under reduced pressure to give a yellow oil, which was purified by C18 preparative HPLC column to give the title compound (15 mg, 17% yield for two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1 H), 10.01 (s, 1 H), 8.61 (brs, 1 H), 8.57 (s, 1 H), 8.25 (d, J = 1.0 Hz, 1 H), 8.06 (d, J = 2.4 Hz, 1 H), 7.82 (d, J = 9.3 Hz, 1 H), 7.74 (d, J = 7.8 Hz, 2 H), 7.57 - 7.48 (m, 3 H), 7.41 - 7.31 (m, 3 H), 7.11 (t, J = 7.3 Hz, 2 H), 6.74 (d, J = 7.5 Hz, 1 H), 6.40 (s, 1 H), 6.26 (s, 1 H), 3.88 - 3.76 (m, 3 H), 3.71 - 3.58 (m, 2 H), 3.56 - 3.45 (m, 3 H), 3.37 - 3.28 (m, 2 H), 3.21 - 3.09 (m, 4 H), 3.08 - 2.98 (m, 2 H), 2.37 - 2.27 (m, 4 H), 2.26 - 2.19 (m, 2 H), 2.17 - 2.08 (m, 2 H), 1.41 (t, J = 6.0 Hz, 2 H), 0.97 (s, 6 H); MS: 962.1 (M+H) + ).

[0254] Example 18: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-benzoylaminothiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0255] Step A: 5-Bromothiophene-3-amino [ka]

[0256] Under argon gas protection, TFA (3 mL) was added to a solution of tert-butyl (5-bromothiophen-3-yl)carbamate (200 mg, 0.719 mmol) in DCM (3 mL), and the reaction mixture was stirred at room temperature for 16 hours. After removing the effluent, the resulting yellow oil was used directly in the next step without purification as the title compound (128 mg, TFA salt, crude). MS: 179.7 (M+H + ).

[0257] Step B: N-(5-bromothiophen-3-yl)benzamide [ka]

[0258] Under argon gas protection, EtN (727 mg, 7.19 mmol) and benzoyl chloride (101 mg, 0.719 mmol) were added to a solution of 5-bromothiophene-3-amino (Step A, 128 mg, crude) in anhydrous DCM (5 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with DCM, washed with aqueous NaHCO and brine, dried over NaSO, and concentrated under reduced pressure to give a yellow oil, which was purified by silica gel column (DCM:MeOH, 20:1) to give the title compound (150 mg, 74% yield over two steps) as a yellow oil. MS: 283.9 (M+H + ).

[0259] Step C: N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl)benzamide [ka]

[0260] Under argon gas protection, 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis(1,3,2-dioxaborolane) (203 mg, 0.797 mmol), PdCl(dppf) (38.9 mg, 0.053 mmol), and potassium acetate (157 mg, 1.595 mmol) were added to a solution of N-(5-bromothiophen-3-yl)benzamide (Step B, 150 mg, 0.532 mmol) in anhydrous dioxane (10 mL), and the reaction mixture was stirred at 100° C. for 6 h. After cooling to room temperature, the resulting mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (crude) as a yellow oil, which was used directly in the next step without purification. MS: 330.2 (M+H + ).

[0261] Step D: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-benzoylaminothiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0262] To a solution of N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl)benzamide (Step C, 175 mg, crude) in dioxane (15 mL) and water (3 mL) was added methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 1, 88 mg, 0.159 mmol), PdCl(dppf) (38.9 mg, 0.053 mmol), and NaCO (169 mg, 1.595 mmol) under argon gas protection, and the reaction mixture was stirred at 100 °C for 16 h. After cooling to room temperature and removing the volatiles, the residue was purified by silica gel column (hexane:EA, 1:1) to give the title compound as a yellow oil (13 mg, 4% yield over two steps). MS: 676.6 (M+H + ).

[0263] Step E: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-benzoylaminothiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid

[0264] [ka] To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-benzoylaminothiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step D, 13 mg, 0.019 mmol) in a mixed solvent of MeOH (3 mL) and THF (3 mL) was added 3M NaOH (3 mL), and the reaction mixture was stirred at 40° C. for 16 hours. After cooling to room temperature, the pH of the resulting mixture was adjusted to 3-4 with 1N HCl. The resulting mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the title compound (10 mg, crude) as a yellow solid, which was used directly in the next step without purification. MS: 662.5 (M+H) + ).

[0265] Step F: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-benzoylaminothiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide (Example 18) [ka]

[0266] Under argon gas protection, to a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-benzoylaminothiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step E, 10 mg, crude) in a mixed solvent of anhydrous DMF (2 mL) and anhydrous DCM (10 mL) was added (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (4.79 mg, 0.015 mmol), DMAP (4.61 mg, 0.038 mmol), and EDCI (4.34 mg, 0.023 mmol), and the reaction mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the resulting mixture was diluted with DCM, washed with 1N HCl and brine, dried over Na2SO4, and concentrated under reduced pressure to give a yellow oil, which was purified by C18 preparative HPLC column to give the title compound (6 mg, 41% yield over two steps) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1 H), 10.62 (s, 1 H), 8.60 (brs, 1 H), 8.57 (s, 1 H), 8.06 (d, J = 2.3 Hz, 1 H), 8.00 - 7.90 (m, 2 H), 7.82 (d, J = 9.2 Hz, 1 H), 7.67 - 7.48 (m, 7 H), 7.14 - 7.04 (m, 2 H), 6.74 (d, J = 8.9 Hz, 1 H), 6.40 (s, 1 H), 6.27 (s, 1 H), 3.86 - 3.78 (m, 3 H), 3.71 - 3.60 (m, 2 H), 3.56 - 3.49 (m, 2 H), 3.36 - 3.31 (m, 2 H), 3.19 - 3.11 (m, 4 H), 3.11 - 3.04 (m, 2 H), 2.41 - 2.28 (m, 4 H), 2.27 - 2.19 (m, 2 H), 2.11 - 2.06 (m, 2 H), 1.41 (t, J = 6.1 Hz, 2 H), 0.96 (s, 6 H); MS: 962.3 (M+H + ).

[0267] Example 19: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(pyrimidin-2-ylamino)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0268] Step A: (4-((t-butoxycarbonyl)amino)thiophen-2-yl)boronic acid [ka]

[0269] Under argon gas protection, tert-butyl (5-bromothiophen-3-yl)carbamate (1 g, 3.6 mmol), PdCl(dppf) (0.263 g, 0.36 mmol), and potassium acetate (1.06 g, 10.8 mmol) were added to a solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (1.1 g, 4.31 mmol) in anhydrous dioxane (15 mL). The reaction mixture was stirred at 100 °C for 6 h. After cooling to room temperature, the resulting mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (crude) as a pale yellow oil, which was used directly in the next step without purification. MS: 244.2 (M+H + ).

[0270] Step B: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-((t-butoxycarbonyl)amino)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate methyl [ka]

[0271] Under argon gas protection, to a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 1, 660 mg, 1.192 mmol) in a mixed solvent of dioxane (20 mL) and water (4 mL) was added (4-((t-butoxycarbonyl)amino)thiophen-2-yl)boronic acid (Step A, 580 mg, crude), PdCl(dppf) (87 mg, 0.119 mmol), and NaCO (379 mg, 3.58 mmol), and the reaction mixture was stirred at 100 °C for 16 h. After cooling to room temperature and removing the volatiles, the residue was filtered through a short silica gel column (DCM:MeOH, 15:1) to give the title compound (1.2 g, crude) as a yellow oil, which was used directly in the next step without purification. MS: 672.9 (M+H + ).

[0272] Step C: Methyl 4-(4-((2-(4-((t-butoxycarbonyl)amino)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate [ka]

[0273] Under argon gas protection, to a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-((t-butoxycarbonyl)amino)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step B, 1.2 g, crude) in anhydrous THF (30 mL) was slowly added NaH (90 mg, 2.14 mmol) at 0-10°C, and the mixture was stirred at 0-10°C for 15 min. Then, TsCl (0.34 g, 1.79 mmol) was added, and the reaction mixture was stirred for 2 h. The resulting mixture was poured into ice water and extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give a yellow oil, which was purified by silica gel column (hexane:EA, 1:1) to give the title compound (700 mg, 3-step yield 47%) as a yellow oil. MS: 827.1 (M+H + ).

[0274] Step D: Methyl 4-(4-((2-(4-aminothiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate [ka]

[0275] Under argon gas protection, TFA (5 mL) was added to a solution of methyl 4-(4-((2-(4-((t-butoxycarbonyl)amino)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (Step C, 700 mg, 0.85 mmol) in DCM (5 mL), and the reaction mixture was stirred at 15-20 °C for 16 h. After removing the effluent, the resulting mixture was diluted with DCM, washed with aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated under reduced pressure to give a yellow oil, which was eluted through a silica gel column (DCM:MeOH, 20:1) to give the title compound (400 mg, 65%) as a yellow oil. MS: 726.5 (M+H + ).

[0276] Step E: Methyl 4-(4-((4,4-dimethyl-2-(4-(pyrimidin-2-ylamino)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate [ka]

[0277] To a solution of methyl 4-(4-((2-(4-aminothiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (Step D, 150 mg, 0.21 mmol) in anhydrous dioxane (10 mL) was added 2-bromopyrimidine (49.3 mg, 0.31 mmol), CsCO (202 mg, 0.62 mmol), Pd(dba) (18.92 mg, 0.021 mmol), and Xantphos (11.96 mg, 0.021 mmol) under argon gas protection, and the reaction mixture was stirred at 100 °C for 6 h. After cooling to room temperature and removing the volatiles, the residue was purified by silica gel column (DCM:MeOH, 20:1) to give the title compound (90 mg, 54%) as a yellow oil. MS: 805.1 (M+H + ).

[0278] Step F: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(pyrimidin-2-ylamino)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid [ka]

[0279] To a solution of methyl 4-(4-((4,4-dimethyl-2-(4-(pyrimidin-2-ylamino)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (Step E, 90 mg, 0.112 mmol) in a mixed solvent of THF (5 mL) and MeOH (2 mL) was added 3N NaOH (5 mL), and the reaction mixture was stirred at 50° C. for 6 h. After cooling to room temperature, the resulting mixture was diluted with water, adjusted to pH 4-5 with 1N HCl, and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (70 mg, crude) as a yellow solid, which was used directly in the next step without purification. MS: 636.5 (M+H + ).

[0280] Step G: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(pyrimidin-2-ylamino)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide (Example 19) [ka]

[0281] Under argon gas protection, (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (34.9 mg, 0.11 mmol), DMAP (33.6 mg, 0.28 mmol), and EDCI (31.7 mg, 0.17 mmol) were added to a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(pyrimidin-2-ylamino)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step F, 70 mg, crude) in a mixture of anhydrous DMF (2 mL) and DCM (10 mL), and the mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the resulting mixture was diluted with DCM, washed with 1N HCl and brine, dried over Na2SO4, and concentrated under reduced pressure to give a yellow oil, which was purified by C18 preparative HPLC to give the title compound (20 mg, 19% yield over two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1 H), 9.88 (s, 1 H), 8.60 - 8.51 (m, 2 H), 8.46 (d, J = 4.8 Hz, 2 H), 8.04 (d, J = 2.6 Hz, 1 H), 7.80 (d, J = 9.3 Hz, 1 H), 7.57 - 7.46 (m, 4 H), 7.07 (d, J = 9.1 Hz, 1 H), 6.96 (d, J = 4.7 Hz, 1 H), 6.80 (t, J = 4.8 Hz, 1 H), 6.72 (dd, J = 9.0, 2.0 Hz, 1 H), 6.38 (dd, J = 3.3, 1.9 Hz, 1 H), 6.26 (d, J = 1.9 Hz, 1 H), 3.86 - 3.74 (m, 3 H), 3.70 - 3.57 (m, 2 H), 3.55 - 3.45 (m, 2 H), 3.44 - 3.37 (m, 2 H), 3.16 - 3.08 (m, 4 H), 3.07 - 3.01 (m, 2 H), 2.39 - 2.29 (m, 4 H), 2.25 - 2.17 (m, 2 H), 2.09 - 2.04 (m, 2 H), 1.38 (t, J = 6.3 Hz, 2 H), 0.94 (s, 6 H); MS: 936.2 (M+H + ).

[0282] Example 20: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-((2,4-difluorophenyl)amino)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0283] Essentially the same scheme was used to prepare Example 19 to give the example (2 mg) as a yellow solid.1 H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1 H), 8.55 - 8.41 (m, 2 H), 7.99 (s, 1 H), 7.88 (s, 1 H), 7.74 (d, J = 10.5 Hz, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 7.46 (s, 1 H), 7.29 - 7.12 (m, 2 H), 6.93 - 6.87 (m, 1 H), 6.73 (s, 1 H), 6.71 - 6.62 (m, 3 H), 6.60 (s, 1 H), 6.34 (s, 1 H), 6.24 (s, 1 H), 3.84 - 3.75 (m, 3 H), 3.69 - 3.57 (m, 2 H), 3.53 - 3.32 (m, 4 H), 3.11 - 3.05 (m, 4 H), 3.03 (s, 2 H), 2.36 - 2.24 (m, 4 H), 2.22 - 2.12 (m, 2 H), 2.05 (s, 2 H), 1.40 - 1.31 (m, 2 H), 0.91 (s, 6 H); MS: 970.1 (M+H + ).

[0284] Example 21: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(5-(morpholinomethyl)thiophen-3-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide [ka]

[0285] Step A: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid [ka]

[0286] To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 1, 150 mg, 0.27 mmol) in a mixed solvent of MeOH (1 mL), THF (1 mL), and HO (1 mL) was added sodium hydroxide (108 mg, 2.71 mmol), and the reaction mixture was stirred at 50° C. for 4 hours. After cooling to room temperature, the resulting mixture was acidified with 1 M HCl to adjust the pH to 4-5 and extracted twice with ethyl acetate. The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the title compound (131 mg, crude), which was used directly in the next step without purification. MS: 539.2 (M+H + ).

[0287] Step B: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide [ka]

[0288] Under argon gas protection, to a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step A, 131 mg, crude) in anhydrous DMF (3 mL) were added N,N-dimethylpyridin-4-amino (74.2 mg, 0.61 mmol), EDCI (69.8 mg, 0.36 mmol), and 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (77.0 mg, 0.24 mmol), and the reaction mixture was stirred at 40 °C for 12 h. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with HO and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with methanol and dichloromethane (1:20) to give the title compound as a yellow solid (126 mg, 62% yield over two steps). MS: 836.2 (M+H + ).

[0289] Step C: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(5-(morpholinomethyl)thiophen-3-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (Example 21) [ka]

[0290] Under argon gas protection, to a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (Step B, 42 mg, 0.05 mmol) in DME (1.5 mL) and 2 M Na2CO3 (0.5 mL) was added (5-(morpholinomethyl)thiophen-3-yl)boronic acid (11.4 mg, 0.05 mmol) and PdCl2(dppf)·CHCl2 (8.2 mg, 10 μmol), and the reaction mixture was stirred at 100 °C for 0.5 h under microwave irradiation. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was purified by C18 preparative HPLC to give the title compound (7.9 mg, 17%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1 H), 8.59 (t, J = 5.2 Hz, 1 H), 8.54 (d, J = 2.1 Hz, 1 H), 8.03 (d, J = 2.6 Hz, 1 H), 7.78 (dd, J = 9.3, 1.8 Hz, 1 H), 7.53 - 7.47 (m, 3 H), 7.09 (d, J = 9.4 Hz, 1 H), 7.04 (s, 1H), 6.76 (s, 1 H), 6.68 (dd, J = 9.1, 2.1 Hz, 1 H), 6.38 (dd, J = 3.2, 1.9 Hz, 1 H), 6.21 (d, J = 1.8 Hz, 1 H), 3.91 - 3.79 (m, 2 H), 3.62 (s, 2 H), 3.57 - 3.49 (m, 4 H), 3.30 - 3.23 (m, 4 H), 3.13 - 3.03 (m, 4 H), 2.94 - 2.79 (m, 2 H), 2.41 - 2.33 (m, 4 H), 2.29 - 2.18 (m, 4 H), 2.15 - 2.09 (m, 2 H), 1.99 - 1.96 (m, 2 H), 1.93 - 1.81 (m, 1 H), 1.66 - 1.55 (m, 2 H), 1.35 (t, J = 6.2 Hz, 2 H), 1.31 - 1.25 (m, 2 H), 0.90 (s, 6 H); MS: 939.4 (M+H + ).

[0291] Example 22: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(morpholinomethyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0292] Step A: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0293] To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 1, 0.4 g, 0.72 mmol) in anhydrous 1,4-dioxane (7 mL) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis(1,3,2-dioxaborolane) (0.28 g, 1.08 mmol), potassium acetate (0.21 g, 2.17 mmol), and PdCl(dppf) (0.053 g, 0.072 mmol). The reaction mixture was gassed with N three times and stirred at 100 °C for 12 h. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with DCM and MeOH (30:1) to give the title compound (0.33 g, 76%) as a yellow oil. MS: 601.4 (M+H + ).

[0294] Step B: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(morpholinomethyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0295] To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step A, 130 mg, 0.22 mmol) in 1,4-dioxane (2.4 mL) and water (0.4 mL) was added 4-((5-bromothiophen-3-yl)methyl)morpholine (85 mg, 0.33 mmol), K2CO3 (90 mg, 0.66 mmol), and PdCl2(dppf) (15.8 mg, 0.022 mmol). (mmol) was added, and the reaction mixture was gassed with N2 three times and stirred at 100 °C for 45 min under microwave assistance. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with DCM and MeOH (30:1) to give the title compound (45 mg, 32%) as a yellow oil. MS: 656.3 (M+H + ).

[0296] Step C: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(morpholinomethyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid

[0297] [ka] To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(morpholinomethyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step B, 45 mg, 0.07 mmol) in MeOH (1 mL) and THF (1 mL) was added a solution of sodium hydroxide (21.9 mg, 0.57 mmol) in water (0.5 mL), and the reaction mixture was stirred at 45 °C for 4 h. After cooling to room temperature, the resulting mixture was acidified with 1 N HCl to adjust the pH to 4–5 and extracted twice with ethyl acetate. The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the title compound product (40 mg, 91%, crude) as a yellow solid, which was used directly in the next step without purification. MS: 642.3 (M+H + ).

[0298] Step D: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(morpholinomethyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide (Example 22) [ka]

[0299] Under argon gas protection, to a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(morpholinomethyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step C, 40 mg, crude) in a mixture of anhydrous DCM (1.5 mL) and anhydrous DMF (1.5 mL) was added N,N-dimethylpyridin-4-amino (19.0 mg, 0.16 mmol), EDCI (17.9 mg, 0.09 mmol), and (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (19.8 mg, 0.06 mmol), and the reaction mixture was stirred at 40 °C for 12 h. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid, which was purified by C18 preparative HPLC to give the title compound (6.6 mg, 11% yield over two steps) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1 H), 8.59 - 8.48 (m, 2 H), 8.03 - 8.01 (m, 1 H), 7.78 (d, J = 9.9 Hz, 1 H), 7.54 - 7.46 (m, 3 H), 7.20 (s, 1 H), 7.05 (d, J = 9.0 Hz, 1 H), 6.79 (s, 1 H), 6.69 (d, J = 8.3 Hz, 1 H), 6.41 - 6.33 (m, 1 H), 6.26 - 6.19 (m, 1 H), 3.85 - 3.74 (m, 3 H), 3.69 - 3.61 (m, 2 H), 3.59 - 3.42 (m, 10 H), 3.13 - 3.05 (m, 4 H), 3.01 - 2.94 (m, 2 H), 2.39 - 2.32 (m, 4 H), 2.30 - 2.23 (m, 4 H), 2.22 - 2.15 (m, 2 H), 2.07 - 2.02 (m, 2 H), 1.40 - 1.32 (m, 2 H), 0.91 (s, 6 H); MS: 941.4 (M+H +).

[0300] Example 23: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(morpholinomethyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0301] Essentially the same scheme was used to prepare Example 22 to give the example (7.5 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1 H), 8.56 (t, J = 5.1 Hz, 1 H), 8.52 (d, J = 1.2 Hz, 1 H), 8.02 (d, J = 2.3 Hz, 1 H), 7.74 (d, J = 9.0 Hz, 1 H), 7.52 - 7.47 (m, 3 H), 7.19 (s, 1 H), 7.01 (d, J = 9.2 Hz, 1 H), 6.79 (s, 1 H), 6.69 (dd, J = 8.8, 1.3 Hz, 1 H), 6.39 - 6.34 (m, 1 H), 6.22 (d, J = 1.2 Hz, 1 H), 3.97 (s, 1 H), 3.53 - 3.50 (m, 4 H), 3.43 - 3.42 (m, 2 H), 3.25 (t, J = 6.1 Hz, 2 H), 3.10 - 3.07 (m, 4 H), 2.98 - 2.95 (m, 2 H), 2.36 - 2.32 (m, 4 H), 2.27 - 2.24 (m, 4 H), 2.20 - 2.16 (m, 2 H), 2.06 - 2.04 (m, 2 H), 1.56 - 1.46 (m, 5 H), 1.39 - 1.33 (m, 4 H), 1.27 - 1.24 (m, 2 H), 1.08 (s, 3 H), 0.91 (s, 6 H); MS: 967.4 (M+H + ).

[0302] Example 24: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(morpholinomethyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0303] Essentially the same scheme was used to prepare Example 22 to provide the example (15.7 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1 H), 8.55 - 8.52 (m, 2 H), 8.02 (d, J = 2.4 Hz, 1 H), 7.75 (d, J = 9.3 Hz, 1 H), 7.53 - 7.47 (m, 3 H), 7.19 (s, 1 H), 7.03 (d, J = 9.3 Hz, 1 H), 6.79 (s, 1 H), 6.69 (dd, J = 8.9, 1.4 Hz, 1 H), 6.39 - 6.36 (m, 1 H), 6.22 (d, J = 1.3 Hz, 1 H), 4.26 (s, 1 H), 3.53 - 3.50 (m, 4 H), 3.45 - 3.41 (m, 2 H), 3.29 - 3.25 (m, 2 H), 3.13 - 3.05 (m, 4 H), 2.97 - 2.95 (m, 2 H), 2.39 - 2.30 (m, 4 H), 2.28 - 2.22 (m, 4 H), 2.20 - 2.14 (m, 2 H), 2.05 - 2.03 (m, 2 H), 1.70 - 1.62 (m, 3 H), 1.52 - 1.51 (m, 2 H), 1.36 - 1.29 (m, 4 H), 1.15 - 1.13 (m, 2 H), 1.09 (s, 3 H), 0.91 (s, 6 H); MS: 967.3 (M+H + ).

[0304] Example 25: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(2-(morpholinomethyl)thiophen-3-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide [ka]

[0305] Essentially the same scheme was used to prepare Example 22 to give the example (6 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1 H), 8.61 (s, 1 H), 8.55 (s, 1 H), 8.04 (s, 1 H), 7.78 (d, J = 7.1 Hz, 1 H), 7.57 - 7.46 (m, 3 H), 7.36 (d, J = 5.0 Hz, 1 H), 7.14 - 7.02 (m, 1 H), 6.71 (d, J = 8.2 Hz, 1 H), 6.66 (d, J = 5.1 Hz, 1 H), 6.40 (s, 1 H), 6.23 (s, 1 H), 3.92 - 3.82 (m, 2 H), 3.63 - 3.50 (m, 4 H), 3.36 - 3.23 (m, 8 H), 3.14 - 3.01 (m, 4 H), 2.41 - 2.29 (m, 4 H), 2.28 - 2.04 (m, 5 H), 1.97 - 1.78 (m, 2 H), 1.69 - 1.58 (m, 2 H), 1.46 - 1.37 (m, 2 H), 1.34 - 1.21 (m, 4 H), 0.95 (s, 6 H); MS: 940.8 (M+H + ).

[0306] Example 26: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(5-(morpholinomethyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide [ka]

[0307] Essentially the same scheme was used to prepare Example 22 to give the example (6 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1 H), 8.64 (t, J = 5.8 Hz, 1 H), 8.57 (d, J = 2.0 Hz, 1 H), 8.06 (d, J = 2.4 Hz, 1 H), 7.81 (d, J = 9.0 Hz, 1 H), 7.57 - 7.48 (m, 3 H), 7.12 (d, J = 9.3 Hz, 1 H), 6.82 (d, J = 3.2 Hz, 1 H), 6.73 (d, J = 9.2 Hz, 1 H), 6.68 (d, J = 3.3 Hz, 1 H), 6.41 (s, 1 H), 6.25 (s, 1 H), 3.87 (d, J = 8.3 Hz, 2 H), 3.71 - 3.62 (m, 2 H), 3.60 - 3.50 (m, 4 H), 3.32 - 3.24 (m, 2 H), 3.17 - 3.06 (m, 4 H), 3.07 - 2.98 (m, 2 H), 2.47 - 2.36 (m, 4 H), 2.34 - 2.25 (m, 4 H), 2.24 - 2.15 (m, 2 H), 2.10 - 2.02 (m, 2 H), 1.97 - 1.84 (m, 1 H), 1.64 (d, J = 12.4 Hz, 2 H), 1.37 (t, J = 6.2 Hz, 2 H), 1.32 - 1.19 (m, 4 H), 0.90 (s, 6 H); MS: 940.7 (M+H + ).

[0308] Example 27: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)thiophen-2-yl)cyclohexan-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0309] Step A: (4-Formylthiophen-2-yl)boronic Acid [ka]

[0310] Under argon gas protection, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (3.99 g, 15.70 mmol), potassium acetate (3.08 g, 31.4 mmol), and PdCl(dppf) (766 mg, 1.047 mmol) were added to a solution of 5-bromothiophene-3-acetal (2 g, 10.47 mmol) in anhydrous dioxane (25 mL), and the reaction mixture was stirred at 70 °C for 16 h. After cooling to room temperature, the resulting mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (crude) as a yellow oil, which was used directly in the next step without purification. MS: 156.9 (M+H + ).

[0311] Step B: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-formylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0312] To a solution of (4-formylthiophen-2-yl)boronic acid (Step A, 500 mg, crude) in dioxane (40 mL) and water (8 mL) was added methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 1, 887 mg, 1.6 mmol), PdCl(dppf) (235 mg, 0.32 mmol), and NaCO (1.02 g, 9.62 mmol) under argon gas protection, and the reaction mixture was stirred at 100 °C for 16 h. After cooling to room temperature and removing the volatiles, the residue was purified by silica gel column (hexane:ethyl acetate, 1:1) to give the title compound (600 mg, 32% yield over two steps) as a yellow oil. MS: 585.9 (M+H + ).

[0313] Step C: tert-Butyl 6-((5-(2-((4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5,5-dimethylcyclohex-1-en-1-yl)thiophen-3-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka]

[0314] To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-formylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step B, 40 mg, 0.07 mmol) in 1,2-dichloroethane (2 mL) was added tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (27.1 mg, 0.14 mmol) and NaBH(OAc) (29.0 mg, 0.14 mmol) under argon gas protection, and the reaction mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with dichloromethane and washed with HO and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and purified with methanol and dichloromethane (1:30) to give the title compound (41 mg, 78%) as a yellow oil. MS: 767.4 (M+H + ).

[0315] Step D: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)thiophen-2-yl)-4,4-dimethylcyclohexan-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0316] To a solution of tert-butyl 6-((5-(2-((4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5,5-dimethylcyclohex-1-en-1-yl)thiophen-3-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Step C, 41 mg, 0.05 mmol) in DCM (5 mL) was added TFA (0.5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After removal of the effluent, the title compound (35 mg, crude) was obtained as a yellow oil, which was used directly in the next step without purification. MS: 667.3 (M+H + ).

[0317] Step E: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)thiophen-2-yl)cyclohexan-1-yl)methyl)piperazin-1-yl)benzoate methyl [ka]

[0318] Under argon gas protection, to a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)thiophen-2-yl)-4,4-dimethylcyclohexan-1-yl)methyl)piperazin-1-yl)benzoate (Step D, 35 mg, crude) in anhydrous DCM (2 mL) were added triethylamine (53.1 mg, 0.5 mmol) and MsCl (9.0 mg, 0.08 mmol), and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with DCM and washed with HO and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with methanol and dichloromethane (1:40) to give the title compound (29 mg, 74% yield over two steps) as a yellow oil. MS: 745.3 (M+H + ).

[0319] Step F: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)thiophen-2-yl)cyclohexan-1-yl)methyl)piperazin-1-yl)benzoic acid [ka]

[0320] To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)thiophen-2-yl)cyclohexan-1-yl)methyl)piperazin-1-yl)benzoate (Step E, 29 mg, 0.03 mmol) in a mixed solvent of MeOH (2 mL), THF (2 mL), and HO (2 mL) was added sodium hydroxide (12.5 mg, 0.3 mmol), and the reaction mixture was stirred at 40 °C for 8 h. After cooling to room temperature, the resulting mixture was acidified with 1 N HCl to adjust the pH to 4–5 and extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the title compound (crude) as a yellow solid, which was used directly in the next step without purification. MS: 731.3 (M+H + ).

[0321] Step G: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)thiophen-2-yl)cyclohexan-1-yl)methyl)piperazin-1-yl)benzamide (Example 27) [ka]

[0322] Under argon gas protection, a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)thiophen-2-yl)cyclohexan-1-yl)methyl)piperazin-1-yl)benzoic acid (Step F, 29 mg, crude) in a mixture of anhydrous DCM (1.5 mL) and anhydrous DMF (1.5 mL) was treated with N,N-dimethylpyridin-4-amino (12.1 mg, 0.10 mmol), EDCI (11.4 mg, 0.06 mmol), and (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (12.6 mg, 0.04 mmol). (mmol) was added, and the reaction mixture was stirred at 40 °C for 12 h. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was purified by C18 preparative HPLC to give the title compound (2.6 mg, 6% yield over two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1 H), 8.46 - 8.44 (m, 2 H), 7.96 (d, J = 2.3 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.45 (t, J = 2.7 Hz, 1 H), 7.38 - 7.36 (m, 1 H), 7.30 - 7.19 (m, 1 H), 6.93 (d, J = 8.9 Hz, 1 H), 6.75 (s, 1 H), 6.67 (dd, J = 9.1, 1.5 Hz, 2 H), 6.33 - 6.32 (m, 1 H), 6.25 (d, J = 1.5 Hz, 1 H), 3.95 (s, 2 H), 3.83 - 3.75 (m, 3 H), 3.70 - 3.55 (m, 6 H), 3.54 - 3.43 (m, 8 H), 3.10 - 3.06 (m, 4 H), 2.98 - 2.99 (m, 2 H), 2.94 (s, 3 H), 2.28 - 2.26 (m, 4 H), 2.18 (t, J = 7.4 Hz, 2 H), 2.04 - 2.02 (m, 2 H), 1.35 (t, J = 7.7 Hz, 2 H), 0.91 (s, 6 H); MS: 1030.4 (M+H + ).

[0323] Example 28: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-((4-morpholinopiperidin-1-yl)methyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0324] Step A: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-((4-morpholinopiperidin-1-yl)methyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0325] Under argon gas protection, 4-(piperidin-4-yl)morpholine (20.4 mg, 0.12 mmol) and NaBH(OAc) (25.4 mg, 0.12 mmol) were added to a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-formylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step B of Example 27, 35 mg, 0.06 mmol) in 1,2-dichloroethane (2 mL), and the reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with DCM and washed with HO and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with methanol and dichloromethane (1:40) to give the title compound (31 mg, 70% yield over two steps) as a yellow solid. MS: 739.4 (M+H + ).

[0326] Step B: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-((4-morpholinopiperidin-1-yl)methyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid [ka]

[0327] To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-((4-morpholinopiperidin-1-yl)methyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step A, 31 mg, 0.04 mmol) in a mixed solvent of MeOH (2 mL), THF (2 mL), and HO (2 mL) was added sodium hydroxide (13.4 mg, 0.33 mmol), and the reaction mixture was stirred at 45 °C for 8 h. After cooling to room temperature, the resulting mixture was acidified with 1 N HCl to adjust the pH to 4–5 and extracted twice with ethyl acetate. The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the title compound (30 mg, crude) as a yellow oil, which was used directly in the next step without purification. MS: 725.4 (M+H + ).

[0328] Step C: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-((4-morpholinopiperidin-1-yl)methyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide (Example 28) [ka]

[0329] To a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-((4-morpholinopiperidin-1-yl)methyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step B, 30 mg, crude) in a mixture of anhydrous DCM (1.5 mL) and anhydrous DMF (1.5 mL) was added N,N-dimethylpyridin-4-amino (12.6 mg, 0.10 mmol), EDCI (11.9 mg, 0.06 mmol), and (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (13.1 mg, 0.04 mmol) under argon gas protection, and the reaction mixture was stirred at 40 °C for 12 h. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was purified by C18 preparative HPLC to give the title compound (20 mg, 47% yield over two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1 H), 8.45 - 8.42 (m, 2 H), 7.96 (d, J = 2.6 Hz, 1 H), 7.69 (dd, J = 9.1, 1.7 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.45 (t, J = 2.9 Hz, 1 H), 7.36 (d, J = 2.1 Hz, 1 H), 7.30 (s, 1 H), 6.91 (d, J = 9.3 Hz, 1 H), 6.83 (s, 1 H), 6.66 (dd, J = 8.9, 1.9 Hz, 1 H), 6.33 - 6.32 (m, 1 H), 6.24 (d, J = 1.8 Hz, 1 H), 3.84 - 3.73 (m, 4 H), 3.70 - 3.56 (m, 6 H), 3.50 - 3.47 (m, 6 H), 3.09 - 3.02 (m, 4 H), 2.99 - 2.93 (m, 4 H), 2.47 - 2.38 (m, 4 H), 2.32 - 2.14 (m, 8 H), 2.06 - 2.04 (m, 2 H), 1.77 - 1.74 (m, 2 H), 1.49 - 1.42 (m, 2 H), 1.36 (t, J = 6.2 Hz, 2 H), 0.91 (s, 6 H); MS: 1024.4 (M+H + ).

[0330] Example 29: N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(((3S,5R)-3,4,5-trimethylpiperazin-1-yl)methyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0331] Essentially the same scheme was used to prepare Example 28 to give the example (8 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1 H), 8.45 (d, J = 1.7 Hz, 1 H), 8.41 (brs, 1 H), 7.97 (d, J = 2.4 Hz, 1 H), 7.66 (d, J = 8.3 Hz, 1 H), 7.56 (d, J = 8.7 Hz, 1 H), 7.46 (s, 1 H), 7.32 (s, 1 H), 7.22 (s, 1 H), 6.86 (d, J = 9.3 Hz, 1 H), 6.79 (s, 1 H), 6.70 (d, J = 8.7 Hz, 1 H), 6.32 (s, 2 H), 3.87 - 3.76 (m, 3 H), 3.71 - 3.61 (m, 2 H), 3.55 - 3.46 (m, 4 H), 3.33 - 3.24 (m, 4 H), 3.19 - 3.08 (m, 4 H), 3.00 - 2.91 (m, 2 H), 2.88 - 2.75 (m, 3 H), 2.50 - 2.42 (m, 2 H), 2.33 - 2.25 (m, 4 H), 2.24 - 2.17 (m, 2 H), 2.10 - 2.05 (m, 2 H), 2.04 - 1.93 (m, 2 H), 1.44 - 1.35 (m, 2 H), 1.08 (d, J = 5.8 Hz, 6 H), 0.94 (s, 6 H); MS: 983.1 (M+H + ).

[0332] Example 30: N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(((R)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0333] Essentially the same scheme was used to prepare Example 28 to give the example (13 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1 H), 8.54 (s, 2 H), 8.04 (s, 1 H), 7.79 (d, J = 8.2 Hz, 1 H), 7.55 (d, J = 8.9 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 2 H), 7.21 (s, 1 H), 7.05 (d, J = 9.4 Hz, 1 H), 6.81 (s, 1 H), 6.71 (d, J = 8.2 Hz, 1 H), 6.39 (s, 1 H), 6.26 (s, 1 H), 3.89 - 3.76 (m, 3 H), 3.75 - 3.59 (m, 4 H), 3.59 - 3.48 (m, 6 H), 3.17 - 2.92 (m, 8 H), 2.79 - 2.57 (m, 4 H), 2.36 - 2.26 (m, 4 H), 2.24 - 2.02 (m, 8 H), 1.78 - 1.65 (m, 1 H), 1.44 - 1.33 (m, 2 H), 0.94 (s, 6 H); MS: 997.9 (M+H + ).

[0334] Example 31: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-((4-(oxetan-3-yl)piperazin-1-yl)methyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0335] Essentially the same scheme was used to prepare Example 28 to give the example (10 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1 H), 8.54 (s, 2 H), 8.03 (d, J = 2.0 Hz, 1 H), 7.79 (d, J = 8.5 Hz, 1 H), 7.55 (d, J = 8.8 Hz, 1 H), 7.50 (d, J = 10.1 Hz, 2 H), 7.25 (s, 1 H), 7.05 (d, J = 9.3 Hz, 1 H), 6.83 (s, 1 H), 6.71 (d, J = 8.4 Hz, 1 H), 6.39 (s, 1 H), 6.25 (s, 1 H), 4.48 (t, J = 6.4 Hz, 2 H), 4.36 (t, J = 5.9 Hz, 2 H), 3.86 - 3.78 (m, 3 H), 3.72 - 3.43 (m, 16 H), 3.38 - 3.23 (m, 15 H), 3.14 - 3.07 (m, 4 H), 3.03 - 2.94 (m, 2 H), 2.49 - 2.13 (m, 12 H), 2.11 - 2.04 (m, 2 H), 1.42 - 1.33 (m, 2 H), 0.94 (s, 6 H); MS: 997.3 (M+H + ).

[0336] Example 32: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-((4,4-difluoropiperidin-1-yl)methyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0337] Essentially the same scheme was used to prepare Example 28 to give the example (13 mg) as a yellow solid.1 H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1 H), 8.60 - 8.40 (m, 2 H), 8.00 (d, J = 2.2 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 1 H), 7.49 - 7.46 (m, 1 H), 7.44 (s, 1 H), 7.19 (s, 1 H), 7.07 - 6.94 (m, 1 H), 6.77 (s, 1 H), 6.73 - 6.64 (m, 1 H), 6.35 (dd, J = 2.8, 1.6 Hz, 1 H), 6.23 (d, J = 1.7 Hz, 1 H), 3.85 - 3.75 (m, 3 H), 3.69 - 3.56 (m, 2 H), 3.52 - 3.43 (m, 4 H), 3.41 - 3.30 (m, 2 H), 3.13 - 3.02 (m, 4 H), 2.97 (s, 2 H), 2.47 - 2.39 (m, 4 H), 2.30 - 2.22 (m, 4 H), 2.21 - 2.13 (m, 2 H), 2.05 (s, 2 H), 1.97 - 1.81 (m, 4 H), 1.35 (t, J = 6.3 Hz, 2 H), 0.91 (s, 6 H); MS: 975.7 (M+H + ).

[0338] Example 33: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-fluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0339] Step A: 3-(4-fluorophenyl)thiophene [ka]

[0340] Under argon gas protection, (4-fluorophenyl)boronic acid (1.03 g, 7.36 mmol), PdCl(dppf) (0.449 g, 0.613 mmol), and NaCO (1.95 g, 18.4 mmol) were added to a solution of 3-bromothiophene (1 g, 6.13 mmol) in a mixed solvent of dioxane (20 mL) and water (4 mL), and the reaction mixture was stirred at 100 °C for 3 h. After cooling to room temperature and removing the volatiles, the residue was purified by silica gel column (hexane:EA, 20:1) to give the title compound (700 mg, 64%) as a pale yellow solid.

[0341] 1 H NMR (400 MHz, DMSO-d6) δ 7.92 - 7.86 (m, 1 H), 7.83 - 7.76 (m, 2 H), 7.70 - 7.65 (m, 1 H), 7.61 - 7.54 (m, 1 H), 7.31 - 7.22 (m, 2 H).

[0342] Step B: (4-(4-fluorophenyl)thiophen-2-yl)boronic acid [ka]

[0343] Under argon gas protection, LDA (2.8 mL, 2 M THF solution, 5.61 mmol) was added to a solution of 3-(4-fluorophenyl)thiophene (Step A, 500 mg, 2.81 mmol) in anhydrous THF (10 mL) at 0 °C, and the mixture was stirred for 0.5 h. Boric acid triisopropyl ester (1.06 g, 5.61 mmol) was slowly added, and the reaction mixture was gradually warmed to room temperature and stirred for 1 h. The reaction was quenched with aqueous NH4Cl and extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a yellow oil, which was purified by silica gel column (hexane:EA, 3:1) to give the title compound (400 mg, 64%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 2 H), 8.06 (d, J = 4.5 Hz, 2 H), 7.76 - 7.69 (m, 2 H), 7.33 - 7.25 (m, 2 H).

[0344] Step C: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-fluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0345] Under argon gas protection, to a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 1, 100 mg, 0.181 mmol) in a mixed solvent of dioxane (10 mL) and water (2 mL) was added (4-(4-fluorophenyl)thiophen-2-yl)boronic acid (Step B, 80 mg, 0.361 mmol), PdCl(dppf) (132 mg, 0.181 mmol), and NaCO (19.15 mg, 0.181 mmol), and the reaction mixture was stirred at 100 °C for 16 h. After cooling to room temperature and removing the volatiles, the residue was purified by silica gel column (DCM:MeOH, 25:1) to give the title compound (60 mg, 51%) as a yellow oil. MS: 651.5 (M+H + ).

[0346] Step D: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-fluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid [ka]

[0347] To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-fluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step C, 60 mg, 0.092 mmol) in a mixed solvent of MeOH (3 mL) and THF (3 mL) was added 3N NaOH (3 mL), and the reaction mixture was stirred at 40° C. for 16 h. After cooling to room temperature, the pH of the mixture was adjusted to 3-4 with 1N HCl and extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (50 mg, crude) as a yellow solid, which was used directly in the next step without purification. MS: 637.5 (M+H + ).

[0348] Step E: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-fluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide (Example 33) [ka]

[0349] To a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-fluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step D, 50 mg, crude) in a mixture of anhydrous DMF (2 mL) and DCM (10 mL) was added (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (24.92 mg, 0.079 mmol), DMAP (23.98 mg, 0.196 mmol), and EDCI (22.58 mg, 0.118 mmol) under argon gas protection, and the reaction mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the resulting mixture was diluted with DCM, washed with 1N HCl and brine, dried over Na2SO4, and concentrated under reduced pressure to give a yellow oil, which was purified by C18 preparative HPLC to give the title compound (14 mg, 19% yield over two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1 H), 8.63 - 8.58 (m, 1 H), 8.56 (d, J = 1.6 Hz, 1 H), 8.05 (d, J = 2.4 Hz, 1 H), 7.81 (d, J = 8.6 Hz, 1 H), 7.78 - 7.67 (m, 3 H), 7.58 - 7.45 (m, 3 H), 7.32 (s, 1 H), 7.24 (t, J = 8.8 Hz, 2 H), 7.09 (d, J = 9.2 Hz, 1 H), 6.73 (d, J = 7.8 Hz, 1 H), 6.40 (s, 1 H), 6.26 (s, 1 H), 3.90 - 3.75 (m, 3 H), 3.73 - 3.58 (m, 2 H), 3.61 - 3.48 (m, 2 H), 3.38 - 3.28 (m, 2 H), 3.19 - 3.10 (m, 4 H), 3.10 - 2.99 (m, 2 H), 2.39 - 2.26 (m, 4 H), 2.27 - 2.18 (m, 2 H), 2.17 - 2.09 (m, 2 H), 1.40 (t, J = 6.1 Hz, 2 H), 0.98 (s, 6 H); MS: 937.1(M+H) + ).

[0350] Example 34: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-phenylthiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide [ka]

[0351] Essentially the same scheme was used to prepare Example 33 to give the example (7 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1 H), 8.60 (brs, 1 H), 8.54 (s, 1 H), 8.04 (s, 1 H), 7.78 (s, 2H), 7.69 (d, J = 7.7 Hz, 2 H), 7.58 - 7.45 (m, 3 H), 7.43 - 7.24 (m, 4 H), 7.14 - 7.02 (m, 1 H), 6.72 (d, J = 7.7 Hz, 1 H), 6.39 (s, 1 H), 6.26 (s, 1 H), 3.87 (d, J = 8.5 Hz, 2 H), 3.32 - 3.26 (m, 2 H), 3.18 - 3.08 (m, 4 H), 3.07 - 3.00 (m, 2 H), 2.39 - 2.28 (m, 4 H), 2.27 - 2.19 (m, 2 H), 2.14 (s, 2 H), 1.96 - 1.81 (m, 1 H), 1.70 - 1.58 (m, 2 H), 1.45 - 1.36 (m, 2 H), 1.31 - 1.24 (m, 4 H), 0.96 (s, 6 H); MS: 917.2 (M+H + ).

[0352] Example 35: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(2-phenylthiophen-3-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide [ka]

[0353] Essentially the same scheme was used to prepare Example 33 to give the example (7 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1 H), 8.66 (t, J = 5.8 Hz, 1 H), 8.59 (d, J = 2.1 Hz, 1 H), 8.09 (d, J = 2.5 Hz, 1 H), 7.83 (d, J = 9.4 Hz, 1 H), 7.62 - 7.49 (m, 4 H), 7.40 - 7.30 (m, 4 H), 7.28 - 7.18 (m, 2 H), 7.15 (d, J = 9.4 Hz, 1 H), 6.70 (dd, J = 9.1, 2.0 Hz, 1 H), 6.44 (dd, J = 3.2, 1.9 Hz, 1H), 6.20 (s, 1 H), 3.88 (dd, J = 11.2, 3.0 Hz, 2 H), 3.37 - 3.23 (m, 7 H), 3.14 - 3.00 (m, 4 H), 2.32 - 2.06 (m, 4 H), 2.01 - 1.84 (m, 2 H), 1.65 (d, J = 11.8 Hz, 2 H), 1.41 - 1.18 (m, 6 H), 0.95 - 0.66 (m, 6 H); MS: 917.2 (M+H + ).

[0354] Example 36: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-fluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0355] Essentially the same scheme was used to prepare Example 33 to give the example (10 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1 H), 8.63 (brs, 1 H), 8.57 (d, J = 1.8 Hz, 1 H), 8.07 (d, J = 2.5 Hz, 1 H), 7.80 (d, J = 9.1 Hz, 1 H), 7.77 - 7.70 (m, 3 H), 7.57 - 7.49 (m, 3 H), 7.32 (s, 1 H), 7.24 (t, J = 8.8 Hz, 2 H), 7.09 (d, J = 9.3 Hz, 1 H), 6.73 (d, J = 8.9 Hz, 1 H), 6.41 (s, 1 H), 6.25 (s, 1 H), 4.00 (s, 1 H), 3.31 - 3.25 (m, 2 H), 3.19 - 3.01 (m, 6 H), 2.39 - 2.28 (m, 4 H), 2.27 - 2.19 (m, 2 H), 2.18 - 2.11 (m, 2 H), 1.64 - 1.20 (m, 11 H), 1.11 (s, 3 H), 0.96 (s, 6 H); MS: 963.3 (M+H + ).

[0356] Example 37: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-fluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0357] Essentially the same scheme was used to prepare Example 33 to give the example (10 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1 H), 8.55 (s, 2 H), 8.05 (s, 1 H), 7.82 - 7.68 (m, 4 H), 7.56 - 7.44 (m, 3 H), 7.31 (s, 1 H), 7.28 - 7.18 (m, 2 H), 7.05 (d, J = 8.9 Hz, 1 H), 6.72 (d, J = 9.9 Hz, 1 H), 6.39 (s, 1 H), 6.26 (s, 1 H), 4.28 (s, 1 H), 3.31 - 3.25 (m, 2 H), 3.16 - 3.02 (m, 6 H), 2.38 - 2.28 (m, 4 H), 2.26 - 2.19 (m, 2 H), 2.17 - 2.09 (m, 2 H), 1.80 - 1.15 (m, 11 H), 1.12 (s, 3 H), 0.96 (s, 6 H); MS: 963.4 (M+H) + ).

[0358] Example 38: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-chlorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0359] Essentially the same scheme was used to prepare Example 33 to give the example (26 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1 H), 8.57 (s, 2 H), 8.05 (s, 1 H), 7.87 - 7.64 (m, 4 H), 7.59 - 7.41 (m, 5 H), 7.34 (s, 1 H), 7.09 (d, J = 8.6 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 6.40 (s, 1 H), 6.26 (s, 1 H), 3.92 - 3.76 (m, 3 H), 3.73 - 3.58 (m, 2 H), 3.59 - 3.41 (m, 4 H), 3.18 - 3.01 (m, 6 H), 2.39 - 2.19 (m, 6 H), 2.17 - 2.07 (m, 2 H), 1.49 - 1.35 (m, 2 H), 0.96 (s, 6 H); MS: 953.5 (M+H + ).

[0360] Example 39: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-isopropylphenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0361] Essentially the same scheme was used to prepare Example 33 to give the example (35 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1 H), 8.64 - 8.52 (m, 2 H), 8.05 (d, J = 1.9 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.58 - 7.49 (m, 3 H), 7.40 - 7.26 (m, 3 H), 7.19 (d, J = 3.5 Hz, 2 H), 7.10 (d, J = 9.4 Hz, 1 H), 6.83 (s, 1 H), 6.71 (d, J = 7.9 Hz, 1 H), 6.40 (s, 1 H), 6.24 (s, 1 H), 3.89 - 3.75 (m, 3 H), 3.72 - 3.59 (m, 2 H), 3.58 - 3.48 (m, 2 H), 3.46 - 3.40 (m, 2 H), 3.16 - 3.03 (m, 7 H), 2.36 - 2.18 (m, 6 H), 2.16 - 2.08 (m, 2 H), 1.48 - 1.34 (m, 2 H), 1.07 (d, J = 6.8 Hz, 6 H), 0.96 (s, 6 H); MS: 961.2 (M+H + ).

[0362] Example 40: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(4-(trifluoromethyl)phenyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0363] Essentially the same scheme was used to prepare Example 33 to give the example (11 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1 H), 8.62 - 8.46 (m, 2 H), 8.02 (d, J = 2.5 Hz, 1 H), 7.95 (d, J = 1.3 Hz, 1 H), 7.91 (s, 1 H), 7.89 (s, 1 H), 7.80 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.3 Hz, 2 H), 7.54 - 7.45 (m, 3 H), 7.39 (d, J = 1.3 Hz, 1 H), 7.06 (d, J = 9.1 Hz, 1 H), 6.70 (dd, J = 9.0, 2.0 Hz, 1 H), 6.37 (dd, J = 3.2, 1.8 Hz, 1 H), 6.23 (d, J = 1.9 Hz, 1 H), 3.85 - 3.74 (m, 3 H), 3.69 - 3.57 (m, 2 H), 3.53 - 3.44 (m, 2 H), 3.42 - 3.32 (m, 2 H), 3.16 - 3.07 (m, 4 H), 3.04 (s, 2 H), 2.36 - 2.25 (m, 4 H), 2.26 - 2.17 (m, 2 H), 2.12 (s, 2 H), 1.39 (t, J = 6.3 Hz, 2 H), 0.94 (s, 6 H); MS: 987.1 (M+H + ).

[0364] Example 41: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(4-(trifluoromethyl)phenyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0365] Essentially the same scheme was used to prepare Example 33 to give the example (9 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1 H), 8.53 (s, 2 H), 8.02 (d, J = 2.4 Hz, 1 H), 7.95 (d, J = 1.3 Hz, 1 H), 7.90 (d, J = 8.2 Hz, 2 H), 7.77 (d, J = 8.2 Hz, 1 H), 7.73 (d, J = 8.3 Hz, 2 H), 7.55 - 7.44 (m, 3 H), 7.39 (d, J = 1.4 Hz, 1 H), 7.04 (d, J = 8.7 Hz, 1 H), 6.69 (dd, J = 9.0, 2.1Hz, 1H), 6.40 - 6.33 (m, 1 H), 6.23 (d, J = 1.9 Hz, 1 H), 4.22 (s, 1 H), 3.29 - 3.24 (d, J = 6.7 Hz, 2 H), 3.11 (s, 4 H), 3.04 (s, 2 H), 2.30 (s, 4 H), 2.22 (s, 2 H), 2.12 (s, 2 H), 1.74 - 1.59 (m, 3 H), 1.58 - 1.49 (m, 2 H), 1.39 (t, J = 6.4 Hz, 2 H), 1.32 (dd, J = 12.6, 3.5 Hz, 2 H), 1.18 - 1.10 (m, 2 H), 1.10 (s, 3 H), 0.94 (s, 6 H); MS: 1013.3 (M+H + ).

[0366] Example 42: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,4-difluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0367] Step A: 2-chloro-4-(2,4-difluorophenyl)thiophene [ka]

[0368] Under argon gas protection, to a solution of 4-bromo-2-chlorothiophene (800 mg, 4.0 mmol) in DME (12 mL) and 2 M Na2CO3 (4 mL) was added (2,4-difluorophenyl)boronic acid (960 mg, 6 mmol) and PdCl2(dppf)·CHCl2 (331 mg, 0.4 mmol), and the reaction mixture was stirred at 100 °C for 0.5 h. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a pale yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:10) to give the title compound (850 mg, 91%) as a colorless oil. 1 H NMR (400 MHz, CD3OD) δ 7.63 - 7.55 (m, 1 H), 7.48 - 7.44 (m, 1 H), 7.29 - 7.26 (m, 1 H), 7.06 - 6.95 (m, 2 H).

[0369] Step B: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,4-difluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0370] Under argon gas protection, 2-chloro-4-(2,4-difluorophenyl)thiophene (Step A, Example 22, 156 mg, 0.67 mmol), KCO (186 mg, 1.35 mmol), and PdCl(dppf) (32.9 mg, 0.045 mmol) were added to a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step A, Example 22, 270 mg, 0.45 mmol) in a mixed solvent of 1,4-dioxane (24 mL) and HO (4 mL), and the mixture was stirred at 100 °C for 45 min under microwave irradiation. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with DCM and MeOH (40:1) to give the title compound (100 mg, 33%) as a yellow oil. MS: 669.3 (M+H + ).

[0371] Step C: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,4-difluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid [ka]

[0372] To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,4-difluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step B, 100 mg, 0.15 mmol) in a mixed solvent of MeOH (2 mL), THF (2 mL), and HO (2 mL) was added sodium hydroxide (47.8 mg, 1.19 mmol), and the reaction mixture was stirred at 45 °C for 8 h. After cooling to room temperature, the resulting mixture was acidified with 1 N HCl to adjust the pH to 4–5 and extracted twice with ethyl acetate. The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the title compound (65 mg, crude) as a yellow oil, which was used directly in the next step without purification. MS: 655.3 (M+H + ).

[0373] Step D: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,4-difluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide (Example 42) [ka]

[0374] Under argon gas protection, to a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,4-difluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step C, 65 mg, crude) in a mixture of anhydrous DCM (2.5 mL) and anhydrous DMF (0.5 mL) was added N,N-dimethylpyridin-4-amino (30.3 mg, 0.25 mmol), EDCI (28.5 mg, 0.15 mmol), and (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (31.5 mg, 0.10 mmol), and the reaction mixture was stirred at 40 °C for 12 h. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was purified by C18 preparative HPLC column to give the title compound (10.5 mg, 11% yield over two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1 H), 8.44 - 8.24 (m, 2 H), 7.90 (d, J = 2.4 Hz, 1 H), 7.78 - 7.71 (m, 2 H), 7.70 (s, 1 H), 7.60 - 7.56 (m, 2 H), 7.40 - 7.39 (m, 1 H), 7.33 - 7.28 (m, 1 H), 7.22 (s, 1 H), 7.15 - 7.10 (m, 1 H), 6.78 - 6.76 (m, 1 H), 6.65 (dd, J = 8.9, 2.0 Hz, 1 H), 6.30 - 6.25 (m, 2 H), 3.82 - 3.75 (m, 3 H), 3.66 - 3.58 (m, 2 H), 3.51 - 3.43 (m, 4 H), 3.09 - 3.03 (m, 6 H), 2.38 - 2.32 (m, 4 H), 2.22 (t, J = 6.2 Hz, 2 H), 2.12 - 2.10 (m, 2 H), 1.38 (t, J = 6.2 Hz, 2 H), 0.94 (s, 6 H); MS: 954.3 (M+H + ).

[0375] Example 43: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,4-difluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0376] Essentially the same scheme was used to prepare Example 42 to give the example (9 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1 H), 8.54 - 8.53 (m, 2 H), 8.03 (d, J = 2.5 Hz, 1 H), 7.78 - 7.71 (m, 2 H), 7.70 (s, 1 H), 7.56 - 7.44 (m, 3 H), 7.33 - 7.28 (m, 1 H), 7.22 (s, 1 H), 7.12 (td, J = 8.4, 2.3 Hz, 1 H), 7.06 - 7.03 (m, 1 H), 6.70 (dd, J = 8.9, 1.7 Hz, 1 H), 6.37 - 6.36 (m, 1 H), 6.22 (d, J = 1.5 Hz, 1 H), 4.25 (s, 1 H), 3.28 - 3.26 (m, 2 H), 3.15 - 3.06 (m, 4 H), 3.04 - 3.02 (m, 2 H), 2.33 - 2.25 (m, 4 H), 2.24 - 2.17 (m, 2 H), 2.11 - 2.09 (m, 2 H), 1.69 - 1.62 (m, 3 H), 1.56 - 1.52 (m, 2 H), 1.39 - 1.29 (m, 4 H), 1.16 - 1.13 (m, 2 H), 1.09 (s, 3 H), 0.93 (s, 6 H); MS: 980.4 (M+H + ).

[0377] Example 44: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-chloro-2-fluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0378] Essentially the same scheme was used to prepare Example 42 to give the example (6 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1 H), 8.61 - 8.52 (m, 2 H), 8.05 (d, J = 2.3 Hz, 1 H), 7.85 - 7.78 (m, 2 H), 7.78 - 7.73 (m, 1 H), 7.55 - 7.48 (m, 4 H), 7.35 (dd, J = 8.4, 1.9 Hz, 1 H), 7.28 (s, 1 H), 7.08 (d, J = 9.2 Hz, 1 H), 6.73 (d, J = 10.6 Hz, 1 H), 6.39 (s, 1 H), 6.26 (s, 1 H), 3.87 - 3.77 (m, 3 H), 3.72 - 3.60 (m, 2 H), 3.56 - 3.48 (m, 2 H), 3.46 - 3.41 (m, 2 H), 3.17 - 3.01 (m, 6 H), 2.38 - 2.20 (m, 6 H), 2.18 - 2.09 (m, 2 H), 1.45 - 1.38 (m, 2 H), 0.96 (s, 6 H); MS: 971.6 (M+H + ).

[0379] Example 45: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(3,4,5-trifluorophenyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0380] Essentially the same scheme was used to prepare Example 42 to give the example (5.5 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1 H), 8.61 - 8.51 (m, 2 H), 8.06 (d, J = 2.6 Hz, 1 H), 7.94 (d, J = 1.0 Hz, 1 H), 7.81 (dd, J = 9.2, 2.1 Hz, 1 H), 7.71 (dd, J = 9.6, 6.8 Hz, 2 H), 7.57 - 7.48 (m, 3 H), 7.39 (d, J = 1.2 Hz, 1 H), 7.09 (d, J = 9.4 Hz, 1 H), 6.71 (dd, J = 9.0, 2.1 Hz, 1 H), 6.40 (dd, J = 3.3, 1.9 Hz, 1 H), 6.23 (d, J = 2.0 Hz, 1 H), 4.25 (s, 1 H), 3.31 - 3.24 (m, 2 H), 3.18 - 2.97 (m, 6 H), 2.38 - 2.18 (m, 6 H), 2.16 - 2.07 (m, 2 H), 1.75 - 1.51 (m, 5 H), 1.43 - 1.21 (m, 6 H), 1.12 (s, 3 H), 0.95 (s, 6 H); MS: 999.2 (M+H + ).

[0381] Example 46: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(2,3,4-trifluorophenyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0382] Essentially the same scheme was used to prepare Example 42 to give the example (13 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1 H), 8.62 - 8.52 (m, 2 H), 8.07 (d, J = 2.4 Hz, 1 H), 7.85 - 7.78 (m, 2 H), 7.60 - 7.49 (m, 4 H), 7.43 - 7.33 (m, 1 H), 7.27 (s, 1 H), 7.10 (d, J = 9.2 Hz, 1 H), 6.73 (d, J = 7.5 Hz, 1 H), 6.41 (s, 1 H), 6.26 (s, 1 H), 4.26 (s, 1 H), 3.32 - 3.27 (m, 2H), 3.21 - 3.02 MS: 999.3 (M+H + ).

[0383] Example 47: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(2,4,6-trifluorophenyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0384] Essentially the same scheme was used to prepare Example 42 to give the example (25 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1 H), 8.58 (s, 2 H), 8.07 (s, 1 H), 7.83 (d, J = 8.7 Hz, 1 H), 7.68 (s, 1 H), 7.61 - 7.47 (m, 3 H), 7.29 (t, J = 8.8 Hz, 2 H), 7.15 - 7.04 (m, 2 H), 6.73 (d, J = 8.3 Hz, 1 H), 6.41 (s, 1 H), 6.25 (s, 1 H), 4.26 (s, 1 H), 3.31 - 3.23 (m, 2 H), 3.19 - 2.99 (m, 6 H), 2.41 - 2.18 (m, 6 H), 2.16 - 2.08 (m, 2 H), 1.75 - 1.53 (m, 5 H), 1.43 - 1.25 (m, 6 H), 1.13 (s, 3 H), 0.96 (s, 6 H); MS: 999.3 (M+H) + ).

[0385] Example 48: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-(difluoromethyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0386] Essentially the same scheme was used to prepare Example 42 to provide the example (18.8 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1 H), 8.63 - 8.49 (m, 2 H), 8.02 (d, J = 2.5 Hz, 1 H), 7.86 (d, J = 0.7 Hz, 1 H), 7.82 - 7.78 (m, 3 H), 7.58 - 7.56 (m, 2 H), 7.51 - 7.47 (m, 3 H), 7.36 (d, J = 1.1 Hz, 1 H), 7.18 - 6.87 (m, 2 H), 6.70 (dd, J = 8.9, 1.9 Hz, 1 H), 6.37 (dd, J = 3.2, 1.8 Hz, 1 H), 6.23 (d, J = 1.8 Hz, 1 H), 3.82 - 3.75 (m, 3 H), 3.67 - 3.59 (m, 2 H), 3.53 - 3.44 (m, 2 H), 3.42 - 3.34 (m, 2 H), 3.15 - 3.09 (m, 4 H), 3.05 - 3.03 (m, 2 H), 2.33 - 2.27 (m, 4 H), 2.25 - 2.18 (m, 2 H), 2.13 - 2.11 (m, 2 H), 1.38 (t, J = 6.1 Hz, 2 H), 0.94 (s, 6 H); MS: 968.3 (M+H) + ).

[0387] Example 49: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-(difluoromethyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0388] Essentially the same scheme was used to prepare Example 42 to provide the example (9.3 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1 H), 8.59 - 8.49 (m, 2 H), 8.03 (d, J = 2.4 Hz, 1 H), 7.87 - 7.85 (m, 1 H), 7.82 - 7.76 (m, 3 H), 7.58 - 7.56 (m, 2 H), 7.54 - 7.44 (m, 3 H), 7.37 - 7.35 (m, 1 H), 7.16 - 6.88 (m, 2 H), 6.69 (dd, J = 8.9, 1.7 Hz, 1 H), 6.37 (d, J = 1.7 Hz, 1 H), 6.23 (d, J = 1.5 Hz, 1 H), 4.22 (s, 1 H), 3.28 - 3.26 (m, 2 H), 3.15 - 3.07 (m, 4 H), 3.04 - 3.02 (m, 2 H), 2.32 - 2.27 (m, 4 H), 2.22 - 2.18 (m, 2 H), 2.12 - 2.10 (m, 2 H), 1.70 - 1.62 (m, 3 H), 1.56 - 1.53 (m, 2 H), 1.40 - 1.30 (m, 4 H), 1.17 - 1.14 (m, 2 H), 1.10 (s, 3 H), 0.94 (s, 6 H); MS: 994.4 (M+H + ).

[0389] Example 50: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(3,4-difluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0390] Essentially the same scheme was used to prepare Example 42 to provide the example (23.6 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1 H), 8.56 - 8.54 (m, 2 H), 8.02 (d, J = 2.5 Hz, 1 H), 7.86 - 7.71 (m, 3 H), 7.57 - 7.38 (m, 5 H), 7.32 (d, J = 1.0 Hz, 1 H), 7.07 (d, J = 9.0 Hz, 1 H), 6.69 (dd, J = 9.0, 1.8 Hz, 1 H), 6.37 (dd, J = 3.2, 1.8 Hz, 1 H), 6.22 (d, J = 1.8 Hz, 1 H), 3.80 - 3.75 (m, 3H), 3.67 - 3.58 (m, 2 H), 3.55 - 3.45 (m, 4 H), 3.15 - 3.07 (m, 4 H), 3.04 - 3.02 (m, 2 H), 2.33 - 2.29 (m, 4 H), 2.24 - 2.17 (m, 2 H), 2.11 - 2.09 (m, 2H), 1.37 (t, J = 6.3 Hz, 2H), 0.93 (s, 6 H); MS: 954.3 (M+H + ).

[0391] Example 51: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(3,4-difluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0392] Essentially the same scheme was used to prepare Example 42 to give the example (18 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1 H), 8.54 - 8.52 (m, 2 H), 8.03 - 8.02 (m, 1 H), 7.83 - 7.72 (m, 3 H), 7.54 - 7.38 (m, 5 H), 7.32 - 7.31 (m, 1 H), 7.05 (d, J = 9.4 Hz, 1 H), 6.77 - 6.59 (m, 1 H), 6.38 - 6.32 (m, 1 H), 6.22 - 6.20 (m, 1 H), 4.25 (s, 1 H), 3.29 - 3.25 (m, 2 H), 3.12 - 3.08 (m, 4 H), 3.05 - 3.03 (m, 2 H), 2.31 - 2.28 (m, 4 H), 2.22 - 2.19 (m, 2 H), 2.11 - 2.09 (m, 2 H), 1.70 - 1.66 (m, 3 H), 1.53 - 1.49 (m, 2 H), 1.41 - 1.29 (m, 4 H), 1.16 - 1.13 (m, 2 H), 1.10 (s, 3 H), 0.93 (s, 6 H); MS: 980.4 (M+H + ).

[0393] Example 52: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(5-fluoropyridin-2-yl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0394] Using essentially the same scheme as used to prepare Example 42, the example (1.5 mg) was obtained as a yellow solid. MS: 937.3 (M+H + ).

[0395] Example 53: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(2,4,5-trifluorophenyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0396] Essentially the same scheme was used to prepare Example 42 to provide the example (12.6 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1 H), 8.54 - 8.52 (m, 2 H), 8.05 - 8.02 (m, 1 H), 7.88 - 7.81 (m, 1 H), 7.81 - 7.74 (m, 2 H), 7.63 - 7.56 (m, 1 H), 7.51 - 7.47 (m, 3 H), 7.28 - 7.24 (m, 1 H), 7.06 - 7.04 (m, 1 H), 6.71 - 6.68 (m, 1 H), 6.39 - 6.35 (m, 1 H), 6.23 - 6.19 (m, 1 H), 4.26 (s, 1 H), 3.29 - 3.26 (m, 2 H), 3.10 - 3.08 (m, 4 H), 3.03 - 3.01 (m, 2 H), 2.34 - 2.26 (m, 4 H), 2.24 - 2.19 (m, 2 H), 2.11 - 2.09 (m, 2 H), 1.75 - 1.63 (m, 3 H), 1.56 - 1.52 (m, 2 H), 1.39 - 1.30 (m, 4 H), 1.16 - 1.13 (m, 2 H), 1.10 (s, 3 H), 0.93 (s, 6 H); MS: 998.4 (M+H) + ).

[0397] Example 54: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(2,3,6-trifluorophenyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0398] Step A: (5-Chlorothiophen-3-yl)boronic acid [ka]

[0399] To a solution of thiophen-3-ylboronic acid (500 mg, 3.91 mmol) in CHCN (10 mL) was added NCS (522 mg, 3.91 mmol) in one portion, and the reaction mixture was stirred at 60° C. for 12 h. After cooling to room temperature and removing the volatiles, the residue was loaded onto a silica gel column and eluted with methanol and dichloromethane (containing 0.1% AcOH) (1:50) to give the title compound (270 mg, 43%) as a pale yellow oil. 1 H NMR (400 MHz, CD3OD) δ 7.65 (s, 1 H), 7.15 (s, 1 H).

[0400] Step B: 2-chloro-4-(2,3,6-trifluorophenyl)thiophene [ka]

[0401] Under argon gas protection, 2-bromo-1,3,4-trifluorophenyl (421 mg, 1.99 mmol) and PdCl(dppf)·CHCl(13.06 mg, 0.166 mmol) were added to a solution of (5-chlorothiophen-3-yl)boronic acid (Step A, 270 mg, 1.66 mmol) in DME (9 mL) and 2M NaCO (3 mL), and the reaction mixture was stirred at 100 °C for 0.5 h. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:10) to give the title compound (270 mg, 65%) as a yellow oil. MS: 249.1 (M+H + ).

[0402] Step C: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4-(2,3,6-trifluorophenyl)thiophen-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example 54) [ka]

[0403] Starting from the compound obtained from Step B and using essentially the same scheme as used to prepare Example 42, the example (12 mg) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1 H), 8.54 - 8.53 (m, 2 H), 8.03 - 8.02 (m, 1 H), 7.83 - 7.71 (m, 2 H), 7.51 - 7.40 (m, 4 H), 7.24 - 7.19 (m, 1 H), 7.11 - 7.09 (m, 1 H), 7.06 - 7.04 (m, 1 H), 6.99 - 6.72 (m, 1 H), 6.44 - 6.32 (m, 1 H), 6.24 - 6.20 (m, 1 H), 4.25 (s, 1 H), 3.28 - 3.27 (m, 2 H), 3.13 - 3.06 (m, 4 H), 3.04 - 3.02 (m, 2 H), 2.35 - 2.25 (m, 4 H), 2.25 - 2.18 (m, 2 H), 2.13 - 2.11 (m, 2 H), 1.73 - 1.63 (m, 3 H), 1.56 - 1.53 (m, 2 H), 1.41 - 1.28 (m, 4 H), 1.17 - 1.14 (m, 2 H), 1.10 (s, 3 H), 0.93 (s, 6 H); MS: 998.3 (M+H + ).

[0404] Example 55: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(3-cyano-5-fluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0405] Step A: 3-(5-chlorothiophen-3-yl)-5-fluorobenzonitrile [ka]

[0406] To a solution of 4-bromo-2-chlorothiophene (300 mg, 1.52 mmol) in DME (9 mL) and 2 M Na2CO3 (3 mL) was added (3-cyano-5-fluorophenyl)boronic acid (376 mg, 2.28 mmol) and PdCl2(dppf)·CHCl2 (124 mg, 0.15 mmol) under argon gas protection, and the reaction mixture was stirred at 100 °C for 0.5 h. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:10) to give the title compound (330 mg, 91%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.84 (t, J = 1.3 Hz, 1 H), 7.74 - 7.69 (m, 2 H), 7.47 - 7.42 (m, 2 H).

[0407] Step B: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0408] To a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (400 mg, 0.74 mmol) in anhydrous THF (6 mL) were added t-butyl pivalimidate (0.12 g, 0.74 mmol) and BF OEt (0.85 g, 5.93 mmol) under argon gas protection, and the reaction mixture was stirred at room temperature for 12 h. The resulting mixture was quenched with saturated NaHCO, diluted with ethyl acetate, and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:1) to give the title compound (310 mg, 70%) as a white solid. MS: 595.2 (M+H + ).

[0409] Step C: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0410] Under argon gas protection, to a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step B, 0.31 g, 0.52 mmol) in 1,4-dioxane (15 mL) were added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-di(1,3,2-dioxaborolane) (200 mg, 0.78 mmol), potassium acetate (150 mg, 1.56 mmol), and PdCl(dppf) (38 mg, 0.052 mmol), and the reaction mixture was stirred at 100 °C for 12 h. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with HO and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with DCM and MeOH (40:1) to give the title compound (320 mg, 96%) as a yellow oil. MS: 643.2 (M+H + )

[0411] Step D: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(3-cyano-5-fluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0412] To a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step C, 270 mg, 0.42 mmol) in DME (12 mL) and HO (3 mL) was added 3-(5-chlorothiophen-3-yl)-5-fluorobenzonitrile (Step A, 100 mg, 0.42 mmol), NaCO (134 mg, 0.13 mmol), and Pd(dppf)Cl (34.3 mg, 0.042 mmol) under argon gas protection, and the reaction mixture was stirred at 120 °C for 45 min. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with DCM and MeOH (30:1) to give the title compound (100 mg, 33%) as a yellow oil. MS: 718.3 (M+H + ).

[0413] Step E: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(3-cyano-5-fluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid [ka]

[0414] Under argon gas protection, to a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(3-cyano-5-fluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step D, 100 mg, 0.14 mmol) in DCM (5 mL) was added TFA (0.5 mL), and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with dichloromethane and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (60 mg, crude) as a yellow oil, which was used directly in the next step without purification. MS: 662.3 (M+H + ).

[0415] Step F: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(3-cyano-5-fluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example 55) [ka]

[0416] Under argon gas protection, a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(3-cyano-5-fluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step E, 60 mg, crude) in a mixture of DCM (5 mL) and DMF (1 mL) was added 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amino hydrochloride (26.1 mg, 0.14 mmol), N,N-dimethylpyridin-4-amino (22.5 mg, 0.18 mmol), and 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (31.1 mg, 0.1 mmol). mg, 0.091 mmol) was added, and the reaction mixture was stirred at 35 °C for 12 h. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was purified by C18 preparative HPLC column to give the title compound (19.9 mg, 22% yield over two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1 H), 8.53 - 8.50 (m, 2 H), 8.12 - 8.09 (m, 1 H), 8.07 - 8.05 (m, 1 H), 8.03 - 8.01 (m, 1 H), 7.98 - 7.96 (m, 1 H), 7.78 - 7.68 (m, 2 H), 7.52 - 7.47 (m, 4 H), 7.04 - 7.02 (m, 1 H), 6.72 - 6.66 (m, 1 H), 6.39 - 6.34 (m, 1 H), 6.24 - 6.20 (m, 1 H), 4.22 (s, 1 H), 3.28 - 3.25 (m, 2 H), 3.17 - 3.13 (m, 4 H), 3.04 - 3.02 (m, 2 H), 2.33 - 2.26 (m, 4 H), 2.25 - 2.18 (m, 2 H), 2.12 - 2.10 (m, 2 H), 1.71 - 1.67 (m, 3 H), 1.56 - 1.53 (m, 2 H), 1.39 - 1.29 (m, 4 H), 1.16 - 1.13 (m, 2 H), 1.10 (s, 3 H), 0.94 (s, 6 H); MS: 987.4 (M+H) + ).

[0417] Example 56: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-(2-cyanopropan-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0418] Step A: 2-(4-(5-chlorothiophen-3-yl)phenyl)-2-methylpropanenitrile [ka]

[0419] Under argon gas protection, (5-chlorothiophen-3-yl)boronic acid (Step A of Example 54, 540 mg, 3.35 mmol) and PdCl(dppf) CHCl (1.82 g, 2.23 mmol) were added to a solution of 2-(4-bromophenyl)-2-methylpropanenitrile (500 mg, 2.23 mmol) in a mixed solvent of DCE (9 mL) and 2M NaCO (3 mL), and the reaction mixture was stirred at 100 °C for 0.5 h under microwave irradiation. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:10) to give the title compound (130 mg, 22%) as a yellow solid. MS: 262.1 (M+H + ).

[0420] Step B: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-(2-cyanopropan-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example 56) [ka]

[0421] Starting from the compound obtained from Step A and using essentially the same scheme as used to prepare Example 55, the example (18 mg) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1 H), 8.55 - 8.51 (m, 2 H), 8.03 (d, J = 2.6 Hz, 1 H), 7.79 -7.77 (m, 2 H), 7.72 - 7.70 (m, 2 H), 7.52 - 7.48 (m, 5 H), 7.30 (d, J = 1.3 Hz, 1 H), 7.06 (d, J = 9.2 Hz, 1 H), 6.70 (dd, J = 9.0, 2.1 Hz, 1 H), 6.38 - 6.37 (m, 1 H), 6.22 (d, J = 2.0 Hz, 1 H), 4.22 (s, 1 H), 3.28 - 3.27 (m, 2 H), 3.13 - 3.09 (m, 4 H), 3.04 - 3.02 (m, 2 H), 2.33 - 2.31 (m, 4 H), 2.21 - 2.19 (m, 2 H), 2.13 - 2.11 (m, 2 H), 1.69 (s, 6 H), 1.67 - 1.63 (m, 3 H), 1.56 - 1.53 (m, 2 H), 1.41 - 1.28 (m, 4 H), 1.17 - 1.14 (m, 2 H), 1.10 (s, 3 H), 0.94 (s, 6 H); MS: 1011.4 (M+H + ).

[0422] Example 57: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4,6-difluoro-1H-indol-7-yl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0423] Step A: 4,6-Difluoro-7-(thiophen-3-yl)-1H-indole [ka]

[0424] In a flame-dried 100 mL round-bottom flask, 7-bromo-4,6-difluoro-1H-indole (100 mg, 0.431 mmol), thiophen-3-ylboronic acid (83 mg, 0.646 mmol), and Na2CO3 (228 mg, 2.155 mmol) were dissolved in a mixture of 1,4-dioxane (5 mL) and water (1 mL) under argon gas protection to obtain a solution. PdCl2(dppf)·CHCl2 (35.2 mg, 0.043 mmol) was added to the reaction mixture at room temperature, and the reaction mixture was stirred at 100 °C for 12 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, which was then extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with methanol and dichloromethane (1:30) to give the title compound (75 mg, 74%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1 H), 7.81 - 7.77 (m, 1 H), 7.77 - 7.73 (m, 1 H), 7.37 (d, J = 4.9 Hz, 1 H), 7.34 (t, J = 2.8 Hz, 1 H), 6.94 (t, J = 10.7 Hz, 1 H), 6.57 - 6.54 (m, 1 H); MS: 236.1 (M+H + ).

[0425] Step B: 4,6-Difluoro-7-(thiophen-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole [ka]

[0426] In a flame-dried 100 mL round-bottom flask, 4,6-difluoro-7-(thiophen-3-yl)-1H-indole (Step A, 500 mg, 2.125 mmol) and DIEA (824 mg, 6.38 mmol) were dissolved in anhydrous CHCl (5 mL) under argon gas protection to give a solution. At room temperature, (2-(chloromethoxy)ethyl)trimethylsilane (709 mg, 4.25 mmol) was added, and the reaction mixture was stirred at 22 °C for 12 h. Saturated NaHCO (10 mL) was added to the reaction mixture, which was then extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:5) to give the title compound (600 mg, 77%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.44 (dd, J = 4.9, 3.0 Hz, 1 H), 7.37 (dd, J = 3.0, 1.2 Hz, 1 H), 7.16 (dd, J = 4.9, 1.2 Hz, 1 H), 7.09 (d, J = 3.4 Hz, 1 H), 6.71 (t, J = 9.8 Hz, 1 H), 6.62 (d, J = 3.4 Hz, 1 H), 4.88 (s, 2 H), 3.15 - 3.06 (m, 2 H), 0.79 - 0.72 (m, 2 H), 0.02 (s, 9 H).

[0427] Step C: (4-(4,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)thiophen-2-yl)boronic acid [ka]

[0428] In a flame-dried 100 mL round-bottom flask, 4,6-difluoro-7-(thiophen-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (Step B, 300 mg, 0.821 mmol) was dissolved in anhydrous THF (10 mL) under argon gas protection at −78 °C to give a solution. LDA (820 mL, 2 M THF solution, 1.64 mmol) was added to the reaction mixture at −78 °C, and the mixture was stirred at −78 °C for 1 h. Then, boric acid triisopropyl ester (309 mg, 1.64 mmol) was added dropwise, and the reaction mixture was stirred at −78 °C for 0.5 h. The mixture was then gradually warmed to room temperature and stirred for 1 h. MeOH (10 mL) was added to quench the reaction, and the resulting mixture was partitioned between aqueous NH4Cl and EA. The aqueous layer was extracted twice with EA. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with methanol and dichloromethane (1:30) to give the title compound (336 mg, quantitative) as an off-white solid.

[0429] Step D: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0430] In a flame-dried 100 mL round-bottom flask, methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 1, 150 mg, 0.271 mmol), (4-(4,6-difluoro-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-indol-7-yl)thiophen-2-yl)boronic acid (Step C, 333 mg, 0.813 mmol), and Na2CO3 (144 mg, 1.355 mmol) were added to 1,4-dioxane (7.5 mL) and water (1.5 mL) under argon gas protection. PdCl(dppf)·CHCl (44.3 mg, 0.054 mmol) was added at room temperature, and the reaction mixture was stirred at 100° C. for 12 hours. After cooling to room temperature, saturated NaHCO (10 mL) was added to the reaction mixture, which was then extracted with dichloromethane (10 mL×2). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with MeOH and DCM (1:50) to give the title compound (100 mg, 44%) as an off-white solid. MS: 839.1 (M+H + ).

[0431] Step E: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid [ka]

[0432] In a flame-dried 100 mL round-bottom flask, methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step D, 55 mg, 0.066 mmol) was dissolved in a mixture of water (2 mL), THF (4 mL), and MeOH (2 mL) under argon gas protection to obtain a solution. Sodium hydroxide (26.2 mg, 0.656 mmol) was added at room temperature, and the reaction mixture was stirred at 40 °C for 16 h. 1N HCl (1 mL) was added to adjust the pH to 4-5, and the resulting mixture was concentrated under reduced pressure. The residue was used as the title compound (crude) directly in the next step without purification. MS: 825.1 (M+H + ).

[0433] Step F: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4,6-difluoro-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-indol-7-yl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0434] In a flame-dried 100 mL round-bottom flask, (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (32.3 mg, 0.1 mmol), 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)-piperazin-1-yl)benzoic acid (Step E, 42 mg, crude), and N,N-dimethylpyridin-4-amino (18.7 mg, 0.15 mmol) were dissolved in anhydrous CHCl (5 mL) under argon gas protection to give a solution. The solution was heated at room temperature to give EDCI (19.5 mL). mg, 0.1 mmol) was added, and the reaction mixture was stirred at 40° C. for 12 hours. Saturated NaHCO (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with methanol and dichloromethane (1:40) to give the title compound (12 mg, 21% yield over two steps) as a yellow solid. MS: 1124.0 (M+H + ).

[0435] Step G: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4,6-difluoro-1H-indol-7-yl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide (Example 57) [ka]

[0436] In a flame-dried 100 mL round-bottom flask, (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide (Step F, 12 mg, 10.68 μmol) was dissolved in anhydrous CHCl (1.5 mL) under argon gas protection to give a solution. TFA (0.5 mL) was added and the reaction mixture was stirred at 22 °C for 1 h. After removal of the product, the residue was purified by C18 preparative HPLC column to give the title compound (2 mg, 19%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1 H), 11.30 (brs, 1 H), 8.34 (d, J = 2.0 Hz, 1 H), 8.29 (t, J = 5.3 Hz, 1 H), 7.89 (d, J = 2.6 Hz, 1 H), 7.67 (s, 1 H), 7.63 - 7.52 (m, 2 H), 7.39 (s, 1 H), 7.20 (d, J = 2.6 Hz, 2 H), 7.14 (s, 1 H), 6.91 (t, J = 10.7 Hz, 1 H), 6.74 (d, J = 9.1 Hz, 1 H), 6.70 - 6.66 (m, 1 H), 6.64 (d, J = 8.7 Hz, 1 H), 6.54 (d, J = 3.2 Hz, 1 H), 6.29 (d, J = 1.9 Hz, 1 H), 6.26 (d, J = 3.3 Hz, 1 H), 3.82 - 3.72 (m, 3 H), 3.68 - 3.57 (m, 2 H), 3.54 - 3.46 (m, 2 H), 3.08 (s, 2 H), 3.07 - 2.98 (m, 4 H), 2.37 - 2.30 (m, 4 H), 2.28 - 2.20 (m, 2 H), 2.16 (s, 2 H), 2.05 - 1.91 (m, 2H), 1.51 - 1.36 (m, 2 H), 0.95 (s, 6 H); MS: 994.0 (M+H + ).

[0437] Example 58: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-(dimethylamino)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0438] Step A: N,N-Dimethyl-2-(thiophen-3-yl)aniline [ka]

[0439] In a flame-dried 100 mL round-bottom flask, 2-bromo-N,N-dimethylaniline (0.5 g, 2.5 mmol), thiophen-3-ylboronic acid (0.48 g, 3.75 mmol), and PdCl(dppf) CHCl (204 mg, 0.25 mmol) were dissolved in a mixture of 1,4-dioxane (15 mL) and water (3 mL) under argon gas protection to give a solution. NaCO (795 mg, 7.50 mmol) was added portionwise at room temperature, and the reaction mixture was stirred at 100 °C for 12 h. After cooling to room temperature, saturated NaHCO (20 mL) was added to the reaction mixture, which was then extracted with dichloromethane (20 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a pale yellow oil, which was loaded onto a silica gel column and eluted with methanol and dichloromethane (1:50) to give the title compound (0.4 g, 79%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 3.8 Hz, 2 H), 7.37 - 7.31 (m, 2 H), 7.29 - 7.23 (m, 2 H), 7.05 (d, J = 8.0 Hz, 1 H), 7.00 (t, J = 7.4 Hz, 1 H), 2.59 (s, 6 H).

[0440] Step B: (4-(2-(dimethylamino)phenyl)thiophen-2-yl)boronic acid [ka]

[0441] In a flame-dried 100 mL round-bottom flask, N,N-dimethyl-2-(thiophen-3-yl)aniline (Step A, 0.32 g, 1.574 mmol) was dissolved in anhydrous THF (10 mL) under argon gas protection at −78 °C to give a solution. LDA (1.2 mL, 2 M THF solution, 2.36 mmol) was added at −78 °C, and the mixture was stirred at −78 °C for 1 h. Boric acid triisopropyl ester (0.474 g, 2.52 mmol, 1.6 mL) was then added, and the reaction mixture was stirred at −78 °C for 0.5 h. The mixture was then gradually warmed to room temperature and stirred for 1 h. MeOH (10 mL) was added to quench the reaction, and the resulting mixture was partitioned between EA and aqueous NH4Cl. The aqueous layer was extracted twice with EA, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a pale yellow oil, which was used directly in the next step without further purification. MS: 248.1 (M+H + ).

[0442] Step C: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-(dimethylamino)-phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0443] In a flame-dried 100 mL round-bottom flask, methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (100 mg, 0.181 mmol), (4-(2-(dimethylamino)phenyl)thiophen-2-yl)boronic acid (Step B, 179 mg, crude), and PdCl(dppf) CHCl (14.75 mg, 0.018 mmol) were dissolved in a mixture of 1,4-dioxane (7.5 mL) and water (1.5 mL) under argon gas protection to give a solution. NaCO (96 mg, 0.9 mmol) was added, and the reaction mixture was stirred at 100 °C for 12 h. After cooling to room temperature, saturated NaHCO3 (10 mL) was added to the reaction mixture and extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with methanol and dichloromethane (1:50) to give the title compound (110 mg, 90% yield over two steps) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1 H), 7.99 (d, J = 2.6 Hz, 1 H), 7.75 (d, J = 9.0 Hz, 1 H), 7.52 - 7.45 (m, 2 H), 7.41 (d, J = 2.5 Hz, 1 H), 7.31 - 7.15 (m, 3 H), 7.03 - 6.91 (m, 2 H), 6.77 (dd, J = 9.0, 2.2 Hz, 1 H), 6.41 - 6.34 (m, 2 H), 3.64 (s, 3 H), 3.23 - 3.12 (m, 4 H), 3.07 (s, 2 H), 2.46 (s, 6 H), 2.32 (s, 4 H), 2.25 - 2.18 (m, 2 H), 2.09 (s, 2 H), 1.38 (t, J = 6.0 Hz, 2 H), 0.93 (s, 6 H); MS: 677.0 (M+H + ).

[0444] Step D: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-(dimethylamino)-phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid [ka]

[0445] In a flame-dried 100 mL round-bottom flask, methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-(dimethylamino)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step C, 110 mg, 0.163 mmol) was dissolved in a mixture of water (2 mL), THF (4 mL), and MeOH (2 mL) under argon gas protection to give a solution. Sodium hydroxide (52.1 mg, 1.302 mmol) was added, and the reaction mixture was stirred at 40 °C for 16 h. After cooling to room temperature and diluting with water, the pH was adjusted to 4-5 with 1 N HCl. The resulting mixture was extracted twice with EA. The combined organic layers were dried over NaSO and concentrated under reduced pressure to give a yellow oil, which was used directly without purification. MS: 662.8 (M+H + ).

[0446] Step E: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-(dimethylamino)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide (Example 58) [ka]

[0447] In a flame-dried 100 mL round-bottom flask, 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-(dimethylamino)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step D, 100 mg, crude), N,N-dimethylpyridin-4-amino (55.4 mg, 0.45 mmol), and (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (96 mg, 0.3 mmol) were dissolved in anhydrous CHCl (10 mL) under argon gas protection to give a solution. EDCI (57.9 mg, 0.3 mmol) was added, and the reaction mixture was stirred at 40 °C for 12 h. After cooling to room temperature, saturated NaHCO3 (10 mL) was added to the reaction mixture and extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was purified by C18 preparative HPLC column to give the title compound (36 mg, 25% yield over two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1 H), 11.52 (brs, 1 H), 8.66 - 8.41 (m, 2 H), 8.01 (s, 1 H), 7.79 (d, J = 9.2 Hz, 1 H), 7.54 - 7.45 (m, 4 H), 7.26 (dd, J = 7.5, 1.5 Hz, 1 H), 7.24 - 7.19 (m, 1 H), 7.17 (d, J = 1.0 Hz, 1 H), 7.12 - 7.01 (m, 1 H), 7.00 - 6.89 (m, 2 H), 6.69 (dd, J = 9.0, 1.7 Hz, 1H), 6.40 - 6.32 (m, 1 H), 6.22 (d, J = 1.6 Hz, 1 H), 3.84 - 3.75 (m, 2 H), 3.70 - 3.56 (m, 2 H), 3.54 - 3.44 (m, 2 H), 3.42 - 3.27 (m, 3 H), 3.11 (brs, 4 H), 3.06 (s, 2 H), 2.45 (s, 6 H), 2.37 - 2.25 (m, 4 H), 2.25 - 2.15 (m, 2 H), 2.08 (s, 2 H), 1.38 (t, J = 6.2 Hz, 2 H), 0.92 (s, 6 H); MS: 961.8 (M+H + ).

[0448] Example 59: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((2-(4-(4-(2-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0449] In Example 58, a yellow solid form of Example 58 (50 mg) was obtained by using the same substance. 1 H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1 H), 11.48 (brs, 1 H), 8.63 - 8.47 (m, 2 H), 8.03 (d, J = 2.5 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.68 (d, J = 1.1 Hz, 1 H), ,7.57 (d, J = 8.3 Hz, 2 H), 7.53 - 7.47 (m, 3 H), 7.45 (d, J = 8.4 Hz, 2 H), 7.27 (d, J = 1.0 Hz, 1 H), 7.06 (d, J = 9.2 Hz, 1 H), 6.70 (dd, J = 8.9, 1.6 Hz, 1 H), 6.37 (dd, J = 3.1, 1.8 Hz, 1 H), 6.23 (d, J = 1.5 Hz, 1 H), 5.01 (s, 1 H), 4.25 (s, 1 H), 3.27 (t, J = 6.2 Hz, 2 H), 3.16 - 3.08 (m, 4 H), 3.04 (s, 2 H), 2.37 - 2.26 (m, 4 H), 2.25 - 2.15 (m, 2H), 2.11 (s, 2 H), 1.75 - 1.59 (m, 3 H), 1.54 (d, J = 12.8 Hz, 2 H), 1.42 (s, 6 H), 1.40 - 1.28 (m, 4 H), 1.17 - 1.05 (m, 5 H), 0.93 (s, 6 H); MS: 1003.7 (M+H + ).

[0450] Example 60: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-(1,1,1,3,3,3-tetrafluoro-2-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0451] Essentially the same scheme was used to prepare Example 58 to give the example (70 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1 H), 8.69 (s, 1 H), 8.56 - 8.42 (m, 2 H), 8.01 (d, J = 2.5 Hz, 1 H), 7.85 (d, J = 1.3 Hz, 1 H), 7.81 (d, J = 8.6 Hz, 2 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.67 (d, J = 8.3 Hz, 2 H), 7.51 (d, J = 8.9 Hz, 1 H), 7.49 - 7.43 (m, 2 H), 7.33 (d, J = 1.2 Hz, 1 H), 7.01 (d, J = 8.2 Hz, 1 H), 6.69 (dd, J = 8.9, 2.0 Hz, 1 H), 6.36 (dd, J = 3.2, 1.8 Hz, 1 H), 6.23 (d, J = 1.8 Hz, 1 H), 4.21 (s, 1 H), 3.28 - 3.23 (m, 2 H), 3.14 - 3.07 (m, 4 H), 3.04 (s, 2 H), 2.33 - 2.26 (m, 4 H), 2.25 - 2.18 (m, 2 H), 2.12 (s, 2 H), 1.74 - 1.59 (m, 3 H), 1.58 - 1.50 (m, 2 H), 1.43 - 1.29 (m, 4H), 1.19 - 1.05 (m, 5 H), 0.94 (s, 6 H); MS: 1111.5 (M+H + ).

[0452] Example 61: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-((4-fluorophenyl)ethynyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0453] Essentially the same scheme was used to prepare Example 58 to give the example (2 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1 H), 8.59 - 8.44 (m, 2 H), 8.02 (s, 1 H), 7.76 (s, 2 H), 7.60 - 7.45 (m, 4 H), 7.25 (t, J = 8.9 Hz, 2 H), 7.18 (s, 1 H), 6.95 (s, 1 H), 6.69 (d, J = 8.5 Hz, 1 H), 6.64 (s, 1 H), 6.36 (s, 1 H), 6.23 (s, 1 H), 4.22 (s, 1 H), 3.14 - 3.04 (m, 4 H), 3.03 - 2.94 (m, 2 H), 2.31 - 2.24 (m, 4 H), 2.23 - 2.15 (m, 2 H), 2.06 (s, 2 H), 2.04 - 1.94 (m, 2 H), 1.73 - 1.59 (m, 2 H), 1.57 - 1.50 (m, 2 H), 1.49 - 1.41 (m, 1 H), 1.40 - 1.29 (m, 4 H), 1.19 - 1.03 (m, 5 H), 0.92 (s, 6 H); MS: 987.4 (M+H + ).

[0454] Example 62: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-fluoro-4-(2-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0455] Step A: Methyl 3-fluoro-4-(thiophen-3-yl)benzoate [ka]

[0456] In a flame-dried 100 mL round-bottom flask, methyl 4-bromo-3-fluorobenzoate (5 g, 21.46 mmol), thiophen-3-ylboronic acid (3.43 g, 26.8 mmol), and PdCl(dppf) CHCl (1.752 g, 2.146 mmol) were dissolved in a mixture of 1,4-dioxane (120 mL) and water (30 mL) under argon gas protection to obtain a solution. NaCO (5.69 g, 53.6 mmol) was added portionwise at room temperature, and the reaction mixture was stirred at 100 °C for 16 h. Saturated NaHCO (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a pale yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:50) to give the title compound (4 g, 79%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (dt, J = 2.8, 1.3 Hz, 1 H), 7.90 (t, J = 7.9 Hz, 1 H), 7.82 (dd, J = 8.1, 1.7 Hz, 1 H), 7.77 (dd, J = 11.8, 1.6 Hz, 1 H), 7.72 (dd, J = 5.1, 2.9 Hz, 1 H), 7.57 (dt, J = 5.1, 1.5 Hz, 1 H), 3.87 (d, J = 3.1 Hz, 3 H).

[0457] Step B: 2-(3-fluoro-4-(thiophen-3-yl)phenyl)propan-2-ol [ka]

[0458] In a flame-dried 100 mL round-bottom flask, methyl 3-fluoro-4-(thiophen-3-yl)benzoate (Step A, 1.1 g, 4.66 mmol) was dissolved in anhydrous THF (30 mL) under argon gas protection at 0 °C to give a solution. MeMgBr (4.7 mL, 3 M 2-MeTHF solution, 14 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h, then gradually warmed to room temperature and stirred for 3 h. The reaction was quenched by the slow addition of MeOH (10 mL), and the resulting mixture was partitioned between EA and aqueous NH4Cl. The aqueous layer was extracted twice with EA, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:20) to give the title compound (0.8 g, 73%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.85 - 7.81 (m, 1 H), 7.70 - 7.65 (m, 2 H), 7.51 (d, J = 5.0 Hz, 1 H), 7.39 - 7.32 (m, 2 H), 5.18 (s, 1 H), 1.47 (s, 6 H); MS: 219.4 (M-H2O+H + ).

[0459] Step C: (4-(2-fluoro-4-(2-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)boronic acid [ka]

[0460] In a flame-dried 100 mL round-bottom flask, 2-(3-fluoro-4-(thiophen-3-yl)phenyl)propan-2-ol (Step B, 0.75 g, 3.17 mmol) was dissolved in anhydrous THF (30 mL) under argon gas protection at 0 °C to give a solution. LDA (4.8 mL, 2 M THF solution, 9.52 mmol) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 h. Within 0.5 h, boric acid triisopropyl ester (1.791 g, 9.52 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 0.5 h, then warmed to room temperature and stirred for 12 h. MeOH (10 mL) was added to quench the reaction, and the resulting mixture was concentrated under reduced pressure to give a pale yellow oily crude product, which was used directly in the next step without further purification. MS: 262.9 (M-H2O+H + ).

[0461] Step D: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-fluoro-4-(2-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example 62) [ka]

[0462] Starting from the compound obtained from Step C and using essentially the same scheme as used to prepare Example 58, the example (100 mg) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1 H), 8.59 - 8.50 (m, 2 H), 8.04 (d, J = 2.4 Hz, 1 H), 7.78 (d, J = 9.7 Hz, 1 H), 7.67 (s, 1 H), 7.59 (t, J = 8.4 Hz, 1 H), 7.55 - 7.45 (m, 3 H), 7.33 - 7.26 (m, 2 H), 7.23 (s, 1 H), 7.06 (d, J = 9.4 Hz, 1 H), 6.70 (d, J = 9.1 Hz, 1 H), 6.37 (s, 1 H), 6.23 (s, 1 H), 5.13 (s, 1 H), 4.22 (s, 1 H), 3.29 - 3.24 (m, 2 H), 3.16 - 3.07 (m, 4 H), 3.03 (s, 2 H), 2.34 - 2.25 (m, 4 H), 2.25 - 2.17 (m, 2 H), 2.11 MS: 1021.8 (M+H + ).

[0463] Example 63: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(2-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0464] Essentially the same scheme was used to prepare Example 62 to give the example (120 mg) as a yellow solid.1 H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1 H), 11.47 (brs, 1 H), 8.59 - 8.49 (m, 2 H), 8.03 (d, J = 2.4 Hz, 1 H), 7.78 (d, J = 8.2 Hz, 1 H), 7.64 (s, 1 H), 7.56 - 7.45 (m, 3 H), 7.21 (d, J = 10.1 Hz, 2 H), 7.10 - 7.02 (m, 2 H), 6.70 (dd, J = 9.0, 1.9 Hz, 1 H), 6.37 (s, 1 H), 6.23 (d, J = 1.9Hz, 1H), 5.26(s, 1 H), 4.21 (s, 1 H), 3.31 - 3.25 (m, 2 H), 3.14 - 3.07 (m, 4 H), 3.03 (s, 2 H), 2.35 - 2.25 (m, 4 H), 2.25 - 2.17 (m, 2 H), 2.11 (s, 2 H), 1.73 - 1.59 (m, 3 H), 1.58 - 1.49 (m, 2 H), 1.42 (s, 6 H), 1.40 - 1.28 (m, 4 H), 1.17 - 1.04 (m, 5 H), 0.93 (s, 6 H); MS: 1039.8 (M+H) + ).

[0465] Example 64: (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(2-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0466] Essentially the same scheme was used to prepare Example 62 to give the example (90 mg) as a yellow solid.1 H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1 H), 8.60 - 8.46 (m, 2 H), 8.02 (d, J = 2.4 Hz, 1 H), 7.78 (d, J = 8.7 Hz, 1 H), 7.64 (s, 1 H), 7.53 - 7.45 (m, 3 H), 7.21 (d, J = 6.7 Hz, 2 H), 7.10 - 7.01 (m, 2 H), 6.70 (dd, J = 8.9, 1.9 Hz, 1 H), 6.36 (dd, J = 3.1, 1.8 Hz, 1 H), 6.24 (d, J = 1.9 Hz, 1 H), 5.27 (s, 1 H), 3.84 - 3.73 (m, 3 H), 3.69 - 3.56 (m, 2 H), 3.53 - 3.43 (m, 2 H), 3.42 - 3.34 (m, 2 H), 3.14 - 3.07 (m, 4 H), 3.05 - 2.99 (m, 2 H), 2.32 - 2.26 (m, 4 H), 2.25 - 2.16 (m, 2 H), 2.11 (s, 2 H), 1.42 (s, 6 H), 1.38 (t, J = 6.5 Hz, 2 H), 0.93 (s, 6 H); MS: 1013.9 (M+H) + ).

[0467] Example 65: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((2-(4-(4-(2-hydroxyprolin-2-yl)-2,6-dimethylphenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0468] Essentially the same scheme was used to prepare Example 62 to provide the example (31.2 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1 H), 11.49 (brs, 1 H), 8.64 - 8.49 (m, 2 H), 8.03 (d, J = 2.4 Hz, 1 H), 7.78 (d, J = 8.9 Hz, 1 H), 7.54 - 7.44 (m, 3 H), 7.17 - 7.12 (m, 3 H), 7.06 (d, J = 9.3 Hz, 1 H), 6.69 (d, J = 7.5 Hz, 1 H), 6.62 (s, 1 H), 6.39 - 6.32 (m, 1 H), 6.25 - 6.18 (m, 1 H), 4.92 (s, 1 H), 4.26 (s, 1 H), 3.28 (t, J = 6.0 Hz, 2 H), 3.13 - 3.00 (m, 6 H), 2.30 - 2.15 (m, 6 H), 2.13 - 2.10 (m, 2 H), 2.02 (s, 6 H), 1.72 - 1.58 (m, 3 H), 1.57 - 1.50 (m, 2 H), 1.40 (s, 6 H), 1.37 - 1.22 (m, 4 H), 1.17 - 1.05 (m, 5 H), 0.93 (s, 6 H); MS: 1030.5 (M+H) + ).

[0469] Example 66: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-dichloro-4-(2-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0470] Essentially the same scheme was used to prepare Example 62 to provide the example (17.7 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1 H), 8.36 - 8.32 (m, 1 H), 8.28 (t, J = 5.3 Hz, 1 H), 7.90 (d, J = 2.2 Hz, 1 H), 7.63 - 7.51 (m, 4 H), 7.43 (s, 1 H), 7.38 (d, J = 3.1 Hz, 1 H), 7.20 (d, J = 2.2 Hz, 1 H), 6.80 (s, 1 H), 6.72 (d, J = 9.2 Hz, 1 H), 6.63 (d, J = 8.4 Hz, 1 H), 6.33 - 6.22 (m, 2 H), 5.32 (s, 1 H), 4.25 (s, 1 H), 3.22 - 3.18 (m, 2 H), 3.08 - 3.04 (m, 2 H), 3.04 - 2.97 (m, 4 H), 2.35 - 2.26 (m, 4 H), 2.24 - 2.18 (m, 2 H), 2.14 - 2.09 (m, 2 H), 1.72 - 1.57 (m, 3 H), 1.57 - 1.49 (m, 2 H), 1.43 (s, 6 H), 1.40 - 1.29 (m, 4 H), 1.17 - 1.04 (m, 5 H), 0.94 (s, 6 H); MS: 1070.4 (M+H + ).

[0471] Example 67: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(3-hydroxypentan-3-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0472] Essentially the same scheme was used to prepare Example 62 to give the example (51 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1 H), 11.49 (brs, 1 H), 8.57 - 8.51 (m, 2 H), 8.04 - 8.03 (m, 1 H), 7.79 (d, J = 9.2 Hz, 1 H), 7.59 - 7.44 (m, 4 H), 7.08 - 7.01 (m, 4 H), 6.68 (d, J = 9.2 Hz, 1 H), 6.39 - 6.37 (m, 1 H), 6.22 - 6.19 (m, 1 H), 4.74 (s, 1 H), 4.23 (s, 1 H), 3.28 - 3.27 (m, 2 H), 3.09 - 3.07 (m, 4 H), 2.59 - 2.57 (m, 2 H), 2.11 - 2.09 (m, 4 H), 2.01 - 1.99 (m, 2 H), 1.89 - 1.87 (m, 2 H), 1.79 - 1.60 (m, 7 H), 1.56 - 1.53 (m, 2 H), 1.37 - 1.24 (m, 6 H), 1.10 (s, 3 H), 0.91 (s, 6 H), 0.61 (t, J = 7.2 Hz, 6 H); MS: 1066.4 (M+H + ).

[0473] Example 68: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(2-hydroxyprolin-2-yl-1,1,1,3,3,3-d6)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0474] Essentially the same scheme was used to prepare Example 62 to give the example (54 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1 H), 11.49 (brs, 1 H), 8.58 - 8.46 (m, 2 H), 8.03 (d, J = 2.5 Hz, 1 H), 7.77 (d, J = 9.1 Hz, 1 H), 7.63 (s, 1 H), 7.55 - 7.42 (m, 3 H), 7.26 - 7.16 (m, 2 H), 7.10 - 6.99 (m, 2 H), 6.70 (dd, J = 9.0, 2.0 Hz, 1 H), 6.37 (dd, J = 3.2, 1.8 Hz, 1 H), 6.23 (d, J = 2.0 Hz, 1 H), 5.24 (s, 1 H), 4.21 (s, 1 H), 3.29 - 3.22 (m, 2 H), 3.15 - 3.07 (m, 4 H), 3.03 (s, 2 H), 2.35 - 2.25 (m, 4 H), 2.25 - 2.18 (m, 2 H), 2.11 (s, 2 H), 1.74 - 1.59 (m, 3 H), 1.59 - 1.49 (m, 2 H), 1.42 - 1.28 (m, 4 H), 1.18 - 1.10 (m, 2 H), 1.10 (s, 3 H), 0.93 (s, 6 H); MS: 1045.8 (M+H + ).

[0475] Example 69: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-(1-cyclopropyl-1-hydroxyethyl)-2,6-difluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0476] Step A: 1-(3,5-difluoro-4-(thiophen-3-yl)phenyl)ethan-1-one [ka]

[0477] Under argon gas protection, thiophen-3-ylboronic acid (5.99 g, 46.8 mmol), PdCl(dppf) (1.557 g, 2.127 mmol), and KCO (17.64 g, 128 mmol) were added to a solution of 1-(4-bromo-3,5-difluorophenyl)ethan-1-one (10 g, 42.5 mmol) in anhydrous DMF (100 mL), and the reaction mixture was stirred at 100 °C for 4 h. After cooling to room temperature and filtering through diatomaceous earth, the filtrate was poured into water and extracted twice with EA. The combined organic layers were washed with water and brine, dried over NaSO, and concentrated under reduced pressure to give a yellow oil, which was purified by silica gel column (hexane:EA, 10:1) to give the title compound (7 g, 69%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.79 - 7.75 (m, 1 H), 7.60 - 7.53 (m, 2 H), 7.50 - 7.46 (m, 1 H), 7.46 - 7.43 (m, 1 H), 2.61 (s, 3 H).

[0478] Step B: 1-Cyclopropyl-1-(3,5-difluoro-4-(thiophen-3-yl)phenyl)ethan-1ol [ka]

[0479] Under argon gas protection, cyclopropylmagnesium bromide (3.5 mL, 1 M THF solution, 3.52 mmol) was added to a solution of 1-(3,5-difluoro-4-(thiophen-3-yl)phenyl)ethan-1-one (Step A, 700 mg, 2.94 mmol) in anhydrous THF (15 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. NH4Cl was added to quench the reaction, and the resulting mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:10) to give the title compound (320 mg, 39%) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.80 - 7.76 (m, 1 H), 7.70 - 7.65 (m, 1 H), 7.37 - 7.32 (m, 1 H), 7.29 - 7.22 (m, 2 H), 4.96 (s, 1 H), 1.43 (s, 3 H), 1.25 - 1.19 (m, 1 H), 0.59 - 0.11 (m, 4 H).

[0480] Step C: (4-(2,6-difluoro-4-(3-hydroxypent-3-yl)phenyl)thiophen-2-yl)boronic acid [ka]

[0481] Under argon gas protection, LDA (1.7 mL, 2 M THF solution, 3.3 mmol) was added dropwise to a solution of 1-cyclopropyl-1-(3,5-difluoro-4-(thiophen-3-yl)phenyl)ethan-1ol (Step B, 320 mg, 1.1 mmol) in anhydrous THF (12 mL) at 0 °C, and the mixture was stirred at room temperature for 1 h. Boric acid triisopropyl ester (644 mg, 3.3 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 12 h. 2N HCl was added to quench the reaction, and the resulting mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and purified with ethyl acetate and hexane (1:1) to give the title compound (101 mg, 27%) as a yellow oil. MS: 325.1 (M+H + ).

[0482] Step D: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-(1-cyclopropyl-1-hydroxyethyl)-2,6-difluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example 69) [ka]

[0483] Starting from the compound obtained from Step C and using essentially the same scheme as used to prepare Example 62, the example (20 mg) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1 H), 8.55 - 8.52 (m, 2 H), 8.04 (d, J = 2.6 Hz, 1 H), 7.79 (dd, J = 9.2, 2.0 Hz, 1 H), 7.64 (s, 1 H), 7.55 - 7.50 (m, 2 H), 7.50 - 7.46 (m, 2 H), 7.23 (d, J = 10.0 Hz, 3 H), 7.11 - 7.02 (m, 2 H), 6.70 (dd, J = 9.2, 2.0 Hz, 1 H), 6.37 (dd, J = 3.2, 1.9 Hz, 1 H), 6.23 (d, J = 1.7 Hz, 1 H), 4.94 (s, 1 H), 4.22 (s, 1 H), 3.28 - 3.27 (m, 2 H), 3.13 - 3.07 (m, 4 H), 3.05 - 3.03 (m, 2 H), 2.33 - 2.27 (m, 4 H), 2.23 - 2.17 (m, 2 H), 2.11 - 2.09 (m, 2 H), 1.70 - 1.61 (m, 3 H), 1.56 - 1.52 (m, 2 H), 1.41 (s, 3 H), 1.41 - 1.14 (m, 5 H), 1.10 (s, 3 H), 0.93 (s, 6 H), 0.55 - 0.16 (m, 4 H); MS: 1064.4 (M+H + ).

[0484] Example 70: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((2-(4-(3-(2-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide [ka]

[0485] Essentially the same scheme was used to prepare Example 58 to give the example (60 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1 H), 8.62 - 8.53 (m, 2 H), 8.07 (d, J = 2.6 Hz, 1 H), 7.82 (dd, J = 9.3, 2.0 Hz, 1 H), 7.74 (s, 1 H), 7.72 (d, J = 1.3 Hz, 1 H), 7.58 - 7.45 (m, 4 H), 7.39 (d, J = 7.9 Hz, 1 H), 7.35 - 7.29 (m, 2 H), 7.10 (d, J = 9.4 Hz, 1 H), 6.73 (dd, J = 9.0, 2.1 Hz, 1 H), 6.41 (dd, J = 3.3, 1.8 Hz, 1 H), 6.25 (d, J = 1.9 Hz, 1 H), 5.01 (s, 1 H), 4.24 (s, 1 H), 3.32 - 3.01 (m, 8 H), 2.42 - 2.20 (m, 6 H), 2.17 - 2.09 (m, 2 H), 1.76 - 1.53 (m, 5 H), 1.46 (s, 6 H), 1.44 - 1.32 (m, 4 H), 1.22 - 1.09 (m, 5 H), 0.97 (s, 6 H); MS: 1003.2 (M+H + ).

[0486] Example 71: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(3-fluoro-4-(2-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0487] Essentially the same scheme was used to prepare Example 62 to give the example (12 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1 H), 8.59 - 8.51 (m, 2 H), 8.06 (d, J = 2.6 Hz, 1 H), 7.85 - 7.77 (m, 2 H), 7.63 (t, J = 8.5 Hz, 1 H), 7.57 - 7.42 (m, 5 H), 7.35 (d, J = 1.2 Hz, 1 H), 7.07 (d, J = 9.3 Hz, 1 H), 6.72 (dd, J = 9.0, 2.0 Hz, 1 H), 6.40 (dd, J = 3.3, 1.9 Hz, 1 H), 6.25 (d, J = 1.9 Hz, 1 H), 5.27 (s, 1 H), 4.25 (s, 1 H), 3.32 - 3.24 (m, 2 H), 3.19 - 3.01 (m, 6 H), 2.39 - 2.20 (m, 6 H), 2.17 - 2.08 (m, 2 H), 1.75 - 1.55 (m, 5 H), 1.51 (s, 6 H), 1.45 - 1.23 (m, 6 H), 1.13 (s, 3 H), 0.96 (s, 6 H); MS: 1021.5 (M+H + ).

[0488] Example 72: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-fluoro-4-(1-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0489] Step A: 2-(4-bromo-3-fluorophenyl)propanoate [ka]

[0490] Under argon gas protection, LDA (6.1 mL, 2 M THF solution, 12.14 mmol) was added to a solution of 2-(4-bromo-3-fluorophenyl)acetate (1 g, 4.05 mmol) in anhydrous THF (10 mL) at 0° C., and the mixture was stirred at 0° C. for 0.5 h. MeI (3.45 g, 24.29 mmol) was added, and the reaction mixture was stirred for 1 h. Aqueous NH4Cl solution was added to quench the reaction, and the resulting mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give a yellow oil, which was purified by silica gel column (hexane:EA, 30:1) to give the title compound (500 mg, 47%) as a yellow oil. MS: 284.5 (M+Na + ).

[0491] Step B: 2-(3-fluoro-4-(thiophen-3-yl)phenyl)propanoate [ka]

[0492] Under argon gas protection, thiophen-3-ylboronic acid (245 mg, 1.915 mmol), NaCO (609 mg, 5.75 mmol), and PdCl(dppf) (140 mg, 0.192 mmol) were added to a solution of 2-(4-bromo-3-fluorophenyl)propanoate (Step A, 500 mg, 1.92 mmol) in a mixed solvent of dioxane (10 mL) and water (2 mL), and the reaction mixture was stirred at 100 °C for 6 h. After cooling to room temperature and removing the volatiles, the residue was purified by silica gel column (hexane:EA, 20:1) to give the title compound (450 mg, 89%) as a yellow oil. MS: 265.2 (M+H + ).

[0493] Step C: 2-(3-fluoro-4-(thiophen-3-yl)phenyl)propan-1-ol [ka]

[0494] Under argon gas protection, LAH (64.6 mg, 1.7 mmol) was added to a solution of 2-(3-fluoro-4-(thiophen-3-yl)phenyl)propanoate (Step B, 450 mg, 1.703 mmol) in anhydrous THF (15 mL) at 0 °C, and the reaction mixture was stirred for 1 h. NaSO·10H O was added to quench the reaction, and the resulting mixture was diluted with EA and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give a yellow oil, which was purified by silica gel column (hexane:EA, 5:1) to give the title compound (300 mg, 75%) as a yellow oil. MS: 237.2 (M+H + ).

[0495] Step D: (4-(2-fluoro-4-(1-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)boronic acid [ka]

[0496] Under argon gas protection, at 0°C, to a solution of 2-(3-fluoro-4-(thiophen-3-yl)phenyl)propan-1-ol (Step C, 300 mg, 1.270 mmol) in anhydrous THF (10 mL) was added LDA (3.2 mL, 2 M THF solution, 6.35 mmol), and the mixture was stirred for 0.5 h. Boric acid triisopropyl ester (716 mg, 3.81 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. Aqueous NH4Cl was added to quench the reaction, and the resulting mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (crude) as a yellow oil, which was used directly in the next step without purification. MS: 281.2 (M+H + ).

[0497] Step E: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-fluoro-4-(1-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example 72) [ka]

[0498] Starting from the compound obtained from Step D and using essentially the same scheme as used to prepare Example 62, the example (10 mg) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1 H), 8.60 - 8.51 (m, 2 H), 8.06 (d, J = 2.5 Hz, 1 H), 7.80 (dd, J = 9.2, 1.8 Hz, 1 H), 7.68 (s, 1 H), 7.62 - 7.47 (m, 4 H), 7.24 (s, 1 H), 7.18 - 7.03 (m, 3 H), 6.72 (dd, J = 9.0, 1.8 Hz, 1 H), 6.40 (dd, J = 3.2, 1.8 Hz, 1 H), 6.26 (d, J = 1.7 Hz, 1 H), 4.70 (t, J = 5.2 Hz, 1 H), 4.27 (s, 1 H), 3.58 - 3.46 (m, 2 H), 3.31 - 3.25 (m, 2 H), 3.17 - 3.02 (m, 6 H), 2.91 - 2.80 (m, 1 H), 2.39 - 2.19 (m, 6 H), 2.18 - 2.10 (m, 2 H), 1.77 - 1.52 (m, 5 H), 1.45 - 1.29 (m, 4 H), 1.28 - 1.14 (m, 5 H), 1.13 (s, 3 H), 0.96 (s, 6 H). MS: 1021.2 (M+H) + ).

[0499] Example 73: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0500] Step A: 2-(3-fluoro-4-(thiophen-3-yl)phenyl)acetate [ka]

[0501] To a solution of thiophen-3-ylboronic acid (311 mg, 2.43 mmol) in a mixed solvent of dioxane (10 mL) and water (2 mL) was added 2-(4-bromo-3-fluorophenyl)acetate (500 mg, 2.03 mmol), NaCO (643 mg, 6.07 mmol), and PdCl(dppf) (148 mg, 0.202 mmol) under argon gas protection, and the reaction mixture was stirred at 100 °C for 6 h. After cooling to room temperature and removing the volatiles, the residue was purified by silica gel column (hexane:EA, 30:1) to give the title compound (490 mg, 97%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.65 - 7.61 (m, 1 H), 7.56 (t, J = 8.0 Hz, 1 H), 7.47 - 7.40 (m, 2 H), 7.15 (s, 1 H), 7.12 (s, 1 H), 3.76 (s, 3 H), 3.68 (s, 2 H).

[0502] Step B: 1-(3-fluoro-4-(thiophen-3-yl)phenyl)-2-methylpropan-2-ol [ka]

[0503] Under argon gas protection, MeMgBr (2.66 mL, 3 M 2-MeTHF solution, 7.99 mmol) was added to a solution of 2-(3-fluoro-4-(thiophen-3-yl)phenyl)acetate (Step A, 400 mg, 1.598 mmol) in anhydrous THF (10 mL) at 0 °C, and the reaction mixture was stirred for 2 h. Aqueous NH4Cl solution was added to quench the reaction, and the resulting mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give a yellow oil, which was purified by silica gel column (hexane:EA, 5:1) to give the title compound (240 mg, 60%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.65 - 7.62 (m, 1 H), 7.54 (t, J = 8.1 Hz, 1 H), 7.48 - 7.45 (m, 1 H), 7.43 (dd, J = 5.0, 2.9 Hz, 1 H), 7.09 (s, 1 H), 7.07 - 7.04 (m, 1 H), 2.82 (s, 2 H), 1.30 (s, 6 H).

[0504] Step C: (4-(2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl)thiophen-2-yl)boronic acid [ka]

[0505] Under argon gas protection, at 0°C, to a solution of 1-(3-fluoro-4-(thiophen-3-yl)phenyl)-2-methylpropan-2-ol (Step B, 100 mg, 0.399 mmol) in anhydrous THF (10 mL) was added LDA (1 mL, 2 M THF solution, 2 mmol), and the mixture was stirred for 0.5 h. Boric acid triisopropyl ester (225 mg, 1.2 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. Aqueous NH4Cl was added to quench the reaction, and the resulting mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (crude) as a yellow oil, which was used directly in the next step without purification. MS: 295.2 (M+H + ).

[0506] Step D: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example 73) [ka]

[0507] Starting from the compound obtained from Step C and using essentially the same scheme as used to prepare Example 62, the example (20 mg) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1 H), 8.58 - 8.46 (m, 2 H), 8.04 (d, J = 2.4 Hz, 1 H), 7.77 (d, J = 8.7 Hz, 1 H), 7.70 (s, 1 H), 7.61 - 7.52 (m, 2 H), 7.48 (d, J = 2.5 Hz, 2 H), 7.26 (s, 1 H), 7.12 (d, J = 12.8 Hz, 1 H), 7.08 (d, J = 8.0 Hz, 1 H), 7.02 (d, J = 9.4 Hz, 1 H), 6.72 (d, J = 7.2 Hz, 1 H), 6.38 (s, 1 H), 6.27 (s, 1 H), 4.41 (s, 1 H), 4.27 (s, 1 H), 3.30 - 3.25 (m, 2 H), 3.16 - 3.01 (m, 6 H), 2.69 (s, 2 H), 2.39 - 2.19 (m, 6 H), 2.18 - 2.08 (m, 2 H), 1.77 - 1.52 (m, 6 H), 1.45 - 1.31 (m, 5 H), 1.13 (s, 3 H), 1.10 (s, 6 H), 0.96 (s, 6 H); MS: 1035.2 (M+H) + ).

[0508] Example 74: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(1-hydroxy-2-methylpropan-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0509] Step A: 2-(3,5-difluorophenyl)-2-methylpropanenitrile [ka]

[0510] Under argon gas protection, LDA (9.8 mL, 2 M THF solution, 19.59 mmol) was added to a solution of 2-(3,5-difluorophenyl)acetonitrile (1 g, 6.53 mmol) in anhydrous THF (20 mL) at −50° C., and the mixture was stirred for 0.5 h. MeI (3.71 g, 26.1 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 2 h. Aqueous NH4Cl was added to quench the reaction, and the resulting mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give a yellow oil, which was purified by silica gel column (hexane:EA, 20:1) to give the title compound (1 g, 85%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.09 - 7.02 (m, 2 H), 6.86 - 6.77 (m, 1 H), 1.76 (s, 6 H).

[0511] Step B: 2-(3,5-difluoro-4-iodophenyl)-2-methylpropanenitrile [ka]

[0512] Under argon gas protection, n-butyllithium (0.54 mL, 2.5 M n-hexane solution, 1.33 mmol) was added dropwise to a solution of 2-(3,5-difluorophenyl)-2-methylpropanenitrile (Step A, 200 mg, 1.11 mmol) in anhydrous THF (5 mL) at −60 °C, and the mixture was stirred for 0.5 h. A solution of iodine (420 mg, 1.66 mmol) in anhydrous THF was added dropwise at −60 °C, and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. Aqueous NH4Cl was added to quench the reaction, and the resulting mixture was extracted twice with EA. The combined organic layers were washed with aqueous Na2S2O3 and brine, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (230 mg, 68%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.10 - 7.04 (m, 2 H), 1.76 (s, 6 H).

[0513] Step C: 2-(3,5-difluoro-4-(thiophen-3-yl)phenyl)-2-methylpropanenitrile [ka]

[0514] To a solution of 2-(3,5-difluoro-4-iodophenyl)-2-methylpropanenitrile (Step B, 230 mg, 0.75 mmol) in a mixture of dioxane (10 mL) and water (2 mL) was added thiophen-3-ylboronic acid (96 mg, 0.749 mmol), NaCO (238 mg, 2.25 mmol), and PdCl(dppf) (54.8 mg, 0.075 mmol) under argon gas protection. The reaction mixture was stirred at 100 °C for 6 h. After cooling to room temperature and removing the volatiles, the residue was purified by silica gel column (hexane:EA, 20:1) to give the title compound (190 mg, 96%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.69 (s, 1 H), 7.45 (s, 2 H), 7.19 - 7.11 (m, 2 H), 1.78 (s, 6 H).

[0515] Step D: 2-(3,5-difluoro-4-(thiophen-3-yl)phenyl)-2-methylpropanoic acid [ka]

[0516] To a solution of 2-(3,5-difluoro-4-(thiophen-3-yl)phenyl)-2-methylpropanenitrile (Step C, 500 mg, 1.90 mmol) in a mixed solvent of EtOH (3 mL) and water (3 mL) was added NaOH (1.14 g, 28.5 mmol), and the reaction mixture was refluxed for 24 h. After cooling to room temperature, the mixture was treated with 2N HCl to adjust the pH to 2-3 and extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (500 mg, crude) as a yellow solid, which was used directly in the next step without purification. MS: 283.2 (M+H + ).

[0517] Step E: 2-(3,5-difluoro-4-(thiophen-3-yl)phenyl)-2-methylpropan-1-ol [ka]

[0518] Under argon gas protection, BH THF (3.54 mL, 1 M THF solution, 3.54 mmol) was added to a solution of 2-(3,5-difluoro-4-(thiophen-3-yl)phenyl)-2-methylpropanoic acid (Step D, 500 mg, 1.77 mmol) in anhydrous THF (20 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. Aqueous NH Cl was added to quench the reaction, and the resulting mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na SO , and concentrated under reduced pressure to give a yellow oil, which was purified by silica gel column (hexane:EA, 5:1) to give the title compound (220 mg, 46%) as a colorless oil. MS: 269.3 (M+H + ).

[0519] Step F: (4-(2,6-difluoro-4-(1-hydroxy-2-methylpropan-2-yl)phenyl)thiophen-2-yl)boronic acid [ka]

[0520] Under argon gas protection, at 0°C, to a solution of 2-(3,5-difluoro-4-(thiophen-3-yl)phenyl)-2-methylpropan-1-ol (Step E, 100 mg, 0.37 mmol) in THF (10 mL) was added LDA (0.93 mL, 2 M THF solution, 1.863 mmol), and the mixture was stirred for 0.5 h. Boric acid triisopropyl ester (210 mg, 1.12 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. Aqueous NH4Cl was added to quench the reaction, and the resulting mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (crude) as a yellow oil, which was used directly in the next step without purification. MS: 313.2 (M+H + ).

[0521] Step G: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(1-hydroxy-2-methylpropan-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example 74) [ka]

[0522] Starting from the compound obtained from Step F and using essentially the same scheme as used to prepare Example 62, the example (8 mg) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1 H), 8.57 (s, 2 H), 8.06 (d, J = 2.4 Hz, 1 H), 7.81 (d, J = 8.9 Hz, 1 H), 7.66 (s, 1 H), 7.56 - 7.49 (m, 3 H), 7.18 (s, 1 H), 7.15 (s, 1 H), 7.11 - 7.06 (m, 2 H), 6.73 (d, J = 8.6 Hz, 1 H), 6.40 (s, 1 H), 6.26 (s, 1 H), 4.79 (t, J = 5.4 Hz, 1 H), 4.26 (s, 1 H), 3.45 (d, J = 5.3 Hz, 2 H), 3.32 - 3.27 (m, 2 H), 3.18 - 3.00 (m, 6 H), 2.39 - 2.21 (m, 6 H), 2.17 - 2.10 (m, 2 H), 1.76 - 1.52 (m, 6 H), 1.45 - 1.30 (m, 5 H), 1.24 (s, 6 H), 1.13 (s, 3 H), 0.96 (s, 6 H); MS: 1053.2 (M+H + ).

[0523] Example 75: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-fluoro-5-(2-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0524] Essentially the same scheme was used to prepare Example 62 to give the example (35 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 11.44 (brs, 1H), 8.59 - 8.47 (m, 2 H), 8.04 (d, J = 2.6 Hz, 1 H), 7.79 (d, J = 7.5 Hz, 1 H), 7.71 - 7.65 (m, 2 H), 7.52 (d, J = 1.6 Hz, 1 H), 7.51 - 7.46 (m, 2 H), 7.42 - 7.34 (m, 1 H), 7.25 (s, 1 H), 7.18 - 7.11 (m, 1 H), 7.07 (d, J = 9.3 Hz, 1 H), 6.70 (dd, J = 9.0, 2.0 Hz, 1 H), 6.38 (dd, J = 3.3, 1.8 Hz, 1 H), 6.22 (d, J = 1.9 Hz, 1 H), 5.04 (s, 1 H), 4.21 (s, 1 H), 3.28 - 3.23 (m, 2 H), 3.16 - 3.07 (m, 4 H), 3.03 (s, 2 H), 2.39 - 2.26 (m, 4 H), 2.26 - 2.18 (m, 2 H), 2.12 (s, 2 H), 1.74 - 1.59 (m, 3 H), 1.59 - 1.50 (m, 2 H), 1.42 (s, 6 H), 1.41 - 1.37 (m, 2 H), 1.37 - 1.29 (m, 2 H), 1.19 - 1.06 (m, 5 H), 0.94 (s, 6 H); MS: 1021.7 (M+H + ).

[0525] Example 76: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-fluoro-4-(2-methoxypropyl-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0526] Step A: 3-(2-fluoro-4-(2-methoxypropyl-2-yl)phenyl)thiophene [ka]

[0527] In a flame-dried 100 mL round-bottom flask, 2-(3-fluoro-4-(thiophen-3-yl)phenyl)propan-2-ol (Step B of Example 62, 250 mg, 1.06 mmol) was dissolved in a mixture of anhydrous CHCl (4 mL) and MeOH (4 mL) under argon gas protection at 25 °C to obtain a solution. 4-Methylbenzenesulfonic acid (36 mg, 0.212 mmol) was added, and the reaction mixture was stirred at 25 °C for 3 h. Saturated NaHCO (10 mL) was added to the reaction mixture, which was then extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:50) to give the title compound (200 mg, 76%) as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (dt, J = 2.6, 1.2 Hz, 1 H), 7.69 (t, J = 7.4 Hz, 1 H), 7.67 - 7.65 (m, 1 H), 7.50 (dt, J = 5.1, 1.4 Hz, 1 H), 7.27 (t, J = 2.0 Hz, 1 H), 7.24 (dd, J = 7.1, 1.7 Hz, 1 H), 3.02 (s, 3 H), 1.47 (s, 6 H); MS: 219.6 (M-MeOH+H + ).

[0528] Step B: (4-(2-fluoro-4-(2-methoxypropyl-2-yl)phenyl)thiophen-2-yl)boronic acid [ka]

[0529] In a flame-dried 100 mL round-bottom flask, 3-(2-fluoro-4-(2-methoxypropyl-2-yl)phenyl)thiophene (Step A, 200 mg, 0.8 mmol) was dissolved in anhydrous THF (10 mL) under argon gas protection at 0 °C to give a solution. LDA (1.6 mL, 2 M THF solution, 3.19 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 1 h. Boric acid triisopropyl ester (450 mg, 2.4 mmol) was added dropwise, and the reaction mixture was stirred at 0 °C for 0.5 h, then gradually warmed to room temperature and stirred for 12 h. MeOH (10 mL) was added to quench the reaction, and the resulting mixture was partitioned between aqueous NHCl and EA. The aqueous layer was extracted twice with EA, and the combined organic layers were dried over NaSO and concentrated under reduced pressure to give the title compound (crude) as a yellow oil, which was used directly in the next step without purification.

[0530] Step C: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-fluoro-4-(2-methoxypropyl-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example 76) [ka]

[0531] Starting from the compound obtained from Step B and using essentially the same scheme as used to prepare Example 62, the example (3 mg) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1 H), 8.55 - 8.39 (m, 2 H), 7.99 (s, 1 H), 7.75 - 7.69 (m, 2 H), 7.65 (t, J = 8.3 Hz, 1 H), 7.53 (d, J = 8.7 Hz, 1 H), 7.49 - 7.34 (m, 2 H), 7.26 - 7.23 (m, 2 H), 7.21 (dd, J = 6.3, 1.6 Hz, 1 H), 7.18 (s, 1 H), 6.68 (dd, J = 8.7, 1.7 Hz, 1 H), 6.34 (s, 1 H), 6.25 (s, 1 H), 4.21 (s, 1 H), 3.27 - 3.22 (m, 2 H), 3.12 - 3.06 (m, 4 H), 3.03 (s, 2 H), 3.01 (s, 3 H), 2.35 - 2.27 (m, 4 H), 2.25 - 2.19 (m, 2 H), 2.12 (s, 2 H), 1.74 - 1.60 (m, 3 H), 1.59 - 1.51 (m, 2 H), 1.45 (s, 6 H), 1.41 - 1.36 (m, 2 H), 1.35 - 1.29 (m, 2 H), 1.19 - 1.12 (m, 2 H), 1.10 (s, 3 H), 0.94 (s, 6 H); MS: 1033.9 (M+H + ).

[0532] Example 77: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0533] Step A: 1-(4-bromo-3,5-difluorophenyl)cyclobutan-1ol [ka]

[0534] In a flame-dried 100 mL round-bottom flask, 2-bromo-1,3-difluoro-5-iodobenzene (1.5 g, 4.70 mmol) was dissolved in anhydrous THF (30 mL) under argon gas protection at 0 °C to give a solution. i-PrMgCl-LiCl (683 mg, 4.70 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 1 h. Cyclobutanone (330 mg, 4.70 mmol) was then added in one portion at 0 °C, and the reaction mixture was gradually warmed to room temperature and stirred for 16 h. MeOH (10 mL) was added to quench the reaction, and the resulting mixture was partitioned between aqueous NH4Cl and EA. The aqueous layer was extracted twice with EA, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:5) to give the title compound (450 mg, 36%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.38 (d, J = 8.0 Hz, 1 H), 5.74 (s, 1 H), 2.66 - 2.55 (m, 2 H), 2.36 - 2.19 (m, 3 H), 1.87 - 1.73 (m, 1 H); 247.1 (M-H2O+H + ).

[0535] Step B: 1-(3,5-difluoro-4-(thiophen-3-yl)phenyl)cyclobutan-1ol [ka]

[0536] In a flame-dried 100 mL round-bottom flask, 1-(4-bromo-3,5-difluorophenyl)cyclobutan-1ol (Step A, 450 mg, 1.71 mmol), thiophen-3-ylboronic acid (274 mg, 2.14 mmol), and PdCl(dppf) CHCl (140 mg, 0.171 mmol) were dissolved in a mixture of 1,4-dioxane (10 mL) and water (2.5 mL) under argon gas protection to give a solution. NaCO (544 mg, 5.13 mmol) was added, and the reaction mixture was stirred at 100 °C for 16 h. After cooling to room temperature, saturated NaHCO (80 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (80 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:50) to give the title compound (410 mg, 90%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, J = 2.9, 1.4 Hz, 1 H), 7.68 - 7.61 (m, 2 H), 7.41 (d, J = 10.3 Hz, 2 H), 5.64 (s, 1 H), 2.68 - 2.54 (m, 2 H), 2.36 - 2.16 (m, 3 H), 1.86 - 1.75 (m, 1 H); MS: 249.5 (M-H2O+H + ).

[0537] Step C: (4-(2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl)thiophen-2-yl)boronic acid [ka]

[0538] In a flame-dried 100 mL round-bottom flask, 1-(3,5-difluoro-4-(thiophen-3-yl)phenyl)cyclobutan-1ol (Step B, 400 mg, 1.5 mmol) was dissolved in anhydrous THF (30 mL) under argon gas protection at 0 °C to give a solution. LDA (2.4 mL, 2 M THF solution, 4.72 mmol) was added at 0 °C, and the mixture was stirred for 1 h. Boric acid triisopropyl ester (4.85 g, 4.51 mmol) was added dropwise, and the reaction mixture was stirred at 0 °C for 0.5 h, then gradually warmed to room temperature and stirred for 12 h. MeOH (10 mL) was added to quench the reaction, and the resulting mixture was partitioned between aqueous NHCl and EA. The aqueous layer was extracted twice with EA, and the combined organic layers were dried over NaSO and concentrated under reduced pressure to give the title compound (crude) as a yellow oil, which was used directly in the next step without purification. MS: 292.9 (M-HO+H + ).

[0539] Step D: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example 77) [ka]

[0540] Starting from the compound obtained from Step C and using essentially the same scheme as used to prepare Example 62, the example (2.4 mg) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1 H), 8.55 - 8.43 (m, 2 H), 8.03 (d, J = 2.1 Hz, 1 H), 7.94 (d, J = 1.3 Hz, 1 H), 7.76 (d, J = 7.9 Hz, 1 H), 7.56 (d, J = 8.8 Hz, 1 H), 7.50 - 7.43 (m, 2 H), 7.41 (d, J = 1.2 Hz, 1 H), 7.40 (s, 1 H), 7.38 (s, 1 H), 7.00 (d, J = 5.6 Hz, 1 H), 6.71 (d, J = 8.9 Hz, 1 H), 6.38 (s, 1 H), 6.27 (s, 1 H), 5.64 (s, 1 H), 4.24 (s, 1 H), 3.29 - 3.25 (m, 2 H), 3.15 - 3.08 (m, 4 H), 3.05 (s, 2 H), 2.67 - 2.57 (m, 2 H), 2.35 - 2.30 (m, 4 H), 2.28 - 2.20 (m, 3 H), 2.14 (s, 2 H), 2.08 - 1.98 (m, 1 H), 1.86 - 1.77 (m, 1 H), 1.77 - 1.62 (m, 3 H), 1.62 - 1.53 (m, 2 H), 1.45 - 1.38 (m, 2 H), 1.38 - 1.32 (m, 2 H), 1.21 - 1.10 (m, 6 H), 0.97 (s, 6 H); MS: 1051.5 (M+H + ).

[0541] Example 78: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-fluoro-4-(1,1,1-trifluoro-2-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0542] Step A: 1-(3-fluoro-4-(thiophen-3-yl)phenyl)ethan-1-one [ka]

[0543] In a dry 250 mL round-bottom flask, 1-(4-bromo-3-fluorophenyl)ethan-1-one (3 g, 13.82 mmol), thiophen-3-ylboronic acid (2.30 g, 17.97 mmol), and Na2CO3 (4.40 g, 41.5 mmol) were dissolved in 1,4-dioxane (100 mL) and water (20 mL) under argon gas protection to obtain a solution. PdCl2(dppf)·CHCl2 (1.13 g, 1.382 mmol) was added, and the reaction mixture was heated to 100 °C for 12 h. After cooling to room temperature, saturated NaHCO3 (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:10) to give the title compound (2.5 g, 82%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.06 - 8.00 (m, 1 H), 7.90 (t, J = 8.0 Hz, 1 H), 7.85 - 7.78 (m, 2 H), 7.72 (dd, J = 5.0, 3.0 Hz, 1 H), 7.59 (d, J = 5.1 Hz, 1 H), 2.60 (s, 3 H); MS: 221.4 (M+H + ).

[0544] Step B: 1,1,1-trifluoro-2-(3-fluoro-4-(thiophen-3-yl)phenyl)propan-2-ol [ka]

[0545] In a dry 250 mL round-bottom flask, 1-(3-fluoro-4-(thiophen-3-yl)phenyl)ethan-1-one (Step A, 500 mg, 2.27 mmol) and trimethyl(trifluoromethyl)silane (646 mg, 4.54 mmol) were dissolved in anhydrous THF (20 mL) under argon gas protection to give a solution. TBAF (1.19 g, 4.54 mmol) was added, and the reaction mixture was stirred at room temperature for 12 h. After removal of the effluent, the residue was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:10) to give the title compound (560 mg, 85%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.91 - 7.86 (m, 1 H), 7.75 (t, J = 8.4 Hz, 1 H), 7.68 (dd, J = 5.0, 3.0 Hz, 1 H), 7.52 (dt, J = 5.0, 1.4 Hz, 1 H), 7.50 - 7.42 (m, 2 H), 6.77 (s, 1 H), 1.71 (s, 3 H); MS: 291.2 (M+H + ).

[0546] Step C: (4-(2-fluoro-4-(1,1,1-trifluoro-2-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)boronic acid [ka]

[0547] In a flame-dried 100 mL round-bottom flask, 1,1,1-trifluoro-2-(3-fluoro-4-(thiophen-3-yl)phenyl)propan-2-ol (Step B, 290 mg, 1 mmol) was dissolved in anhydrous THF (10 mL) under argon gas protection at 0 °C to obtain a solution. LDA (1.5 mL, 2 M THF solution, 3 mmol) was added at 0 °C, and the mixture was stirred for 1 h. Boric acid triisopropyl ester (564 mg, 3 mmol) was added dropwise, and the reaction mixture was stirred at 0 °C for 0.5 h, then gradually warmed to room temperature and stirred for 16 h. MeOH (10 mL) was added to quench the reaction, and the resulting mixture was partitioned between aqueous NH4Cl and EA. The aqueous layer was extracted twice with EA, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the title compound (crude) as a yellow oil, which was used directly in the next step without purification. MS: 335.1 (M+H + ).

[0548] Step D: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2-fluoro-4-(1,1,1-trifluoro-2-hydroxyprolin-2-yl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example 78) [ka]

[0549] Starting from the compound obtained from Step C and using essentially the same scheme as used to prepare Example 62, the example (50 mg) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1 H), 8.60 - 8.50 (m, 2 H), 8.08 - 8.03 (m, 1 H), 7.82 - 7.77 (m, 2 H), 7.74 (t, J = 8.4 Hz, 1 H), 7.57 - 7.42 (m, 5 H), 7.29 (s, 1 H), 7.06 (d, J = 9.3 Hz, 1 H), 6.79 (s, 1 H), 6.73 (d, J = 9.1 Hz, 1 H), 6.39 (s, 1 H), 6.26 (s, 1 H), 4.26 (s, 1 H), 3.33 - 3.28 (m, 2 H), 3.17 - 3.10 (m, 4 H), 3.06 (s, 2 H), 2.39 - 2.30 (m, 4 H), 2.29 - 2.20 (m, 2 H), 2.14 (s, 2 H), 1.79 - 1.64 (m, 6 H), 1.61 - 1.51 (m, 2 H), 1.46 - 1.31 (m, 4 H), 1.21 - 1.07 (m, 5 H), 0.97 (s, 6 H); MS: 1075.8 (M+H + ).

[0550] Example 79: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(1-hydroxy-1-methyl-2,3-dihydro-1H-inden-5-yl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0551] Essentially the same scheme was used to prepare Example 69 to give the example (48 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1 H), 8.56 - 8.43 (m, 2 H), 8.00 (d, J = 2.3 Hz, 1 H), 7.74 (d, J = 8.9 Hz, 1 H), 7.65 (s, 1 H), 7.52 (d, J = 8.9 Hz, 1 H), 7.50 - 7.41 (m, 4 H), 7.32 - 7.25 (m, 2 H), 6.99 (d, J = 7.5 Hz, 1 H), 6.69 (d, J = 9.0 Hz, 1 H), 6.35 (s, 1 H), 6.24 (s, 1 H), 4.95 (s, 1 H), 4.22 (s, 1 H), 3.29 - 3.23 (m, 2 H), 3.14 - 3.07 (m, 4 H), 3.03 (s, 2 H), 2.96 - 2.85 (m, 1 H), 2.80 - 2.68 (m, 1 H), 2.35 - 2.26 (m, 4 H), 2.25 - 2.17 (m, 2 H), 2.12 (s, 2 H), 2.05 (t, J = 7.3 Hz, 2 H), 1.74 - 1.60 (m, 3 H), 1.58 - 1.49 (m, 2 H), 1.41 - 1.36 (m, 5 H), 1.36 - 1.28 (m, 2 H), 1.18 - 1.10 (m, 2 H), 1.10 (s, 3 H), 0.94 (s, 6 H); MS: 1015.6 (M+H + ).

[0552] Example 80: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-(2-acetamidopropan-2-yl)-2,6-difluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0553] Step A: N-(2-(3,5-difluoro-4-(thiophen-3-yl)phenyl)propan-2-yl)acetamide [ka]

[0554] In a flame-dried 100 mL round-bottom flask at 25 °C, 2-(3,5-difluoro-4-(thiophen-3-yl)phenyl)propan-2-ol (prepared by the same scheme as in Step B of Example 62, 100 mg, 0.393 mmol) was dissolved in anhydrous acetonitrile (5 mL) under argon gas protection to give a solution. Sulfuric acid (386 mg, 3.93 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 h. Aqueous NaHCO3 solution (10 mL) was slowly added to the reaction mixture, which was then extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was loaded onto a silica gel column and eluted with ethyl acetate and hexane (1:2) to give the title compound (100 mg, 86%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1 H), 7.80 - 7.73 (m, 1 H), 7.72 - 7.64 (m, 1 H), 7.37 - 7.27 (m, 1 H), 7.07 (d, J = 10.2 Hz, 2 H), 1.85 (s, 3 H), 1.53 (s, 6 H); MS: 296.3 (M+H + ).

[0555] Step B: (4-(4-(2-acetamidopropan-2-yl)-2,6-difluorophenyl)thiophen-2-yl)boronic acid [ka]

[0556] In a flame-dried 100 mL round-bottom flask, N-(2-(3,5-difluoro-4-(thiophen-3-yl)phenyl)propan-2-yl)acetamide (Step A, 200 mg, 0.68 mmol) was dissolved in anhydrous THF (10 mL) under argon gas protection at 0 °C to give a solution. LDA (1 mL, 2 M THF solution, 2 mmol) was added at 0 °C, and the mixture was stirred for 1 h. Boric acid triisopropyl ester (382 mg, 2.03 mmol) was added dropwise, and the reaction mixture was stirred at 0 °C for 0.5 h, then gradually warmed to room temperature and stirred for 16 h. MeOH (10 mL) was added to quench the reaction, and the resulting mixture was partitioned between aqueous NHCl and EA. The aqueous layer was extracted twice with EA, and the combined organic layers were dried over NaSO and concentrated under reduced pressure to give the title compound (crude) as a yellow oil, which was used directly in the next step without purification. MS: 340.1 (M+H + ).

[0557] Step C: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(4-(2-acetamidopropan-2-yl)-2,6-difluorophenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example 80) [ka]

[0558] Starting from the compound obtained from Step B and using essentially the same scheme as used to prepare Example 62, the example (30 mg) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1 H), 8.59 - 8.47 (m, 2 H), 8.13 (s, 1 H), 8.03 (d, J = 2.2 Hz, 1 H), 7.78 (d, J = 9.5 Hz, 1 H), 7.63 (s, 1 H), 7.55 - 7.44 (m, 3 H), 7.10 - 6.99 (m, 4 H), 6.70 (d, J = 9.8 Hz, 1 H), 6.37 (s, 1 H), 6.23 (s, 1 H), 4.21 (s, 1 H), 3.30 - 3.23 (m, 2 H), 3.14 - 3.07 (m, 4 H), 3.05 - 2.98 (m, 2 H), 2.36 - 2.25 (m, 4 H), 2.24 - 2.17 (m, 2 H), 2.11 (s, 2 H), 1.84 (s, 3 H), 1.74 - 1.59 (m, 3 H), 1.58 - 1.47 (m, 8 H), 1.42 - 1.28 (m, 4 H), 1.19 - 1.04 (m, 5 H), 0.93 (s, 6 H); MS: 1078.2 (M+H + ).

[0559] Example 81: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(2-hydroxyprolin-2-yl)phenyl)-5-methylthiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ka]

[0560] Essentially the same scheme was used to prepare Example 63 to give the example (30 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1 H), 8.60 - 8.41 (m, 2 H), 8.01 (d, J = 2.5 Hz, 1 H), 7.74 (d, J = 9.7 Hz, 1 H), 7.52 (d, J = 8.8 Hz, 1 H), 7.49 - 7.38 (m, 2 H), 7.22 (d, J = 9.3 Hz, 2 H), 7.00 (d, J = 9.2 Hz, 1 H), 6.72 (s, 1 H), 6.69 (dd, J = 9.0, 2.0 Hz, 1 H), 6.35 (dd, J = 3.2, 1.8 Hz, 1 H), 6.24 (d, J = 1.9 Hz, 1 H), 5.28 (s, 1 H), 4.23 (s, 1 H), 3.26 (t, J = 6.4 Hz, 2 H), 3.12 - 3.03 (m, 6 H), 2.34 - 2.25 (m, 4 H), 2.22 (s, 3 H), 2.21 - 2.15 (m, 2 H), 2.11 - 2.04 (m, 2 H), 1.74 - 1.62 (m, 3 H), 1.58 - 1.49 (m, 2 H), 1.43 (s, 6 H), 1.40 - 1.28 (m, 4 H), 1.18 - 1.10 (m, 2 H), 1.10 (s, 3 H), 0.91 (s, 6H); MS: 1053.5 (M+H + ).

[0561] Example 82: 2-(4-(5-(2-((4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-5,5-dimethylcyclohex-1-en-1-yl)thiophen-3-yl)-3,5-difluorophenyl)-2-methylpropanoic acid [ka]

[0562] Step A: 2-(3,5-difluoro-4-(thiophen-3-yl)phenyl)-2-methylpropanoate [ka]

[0563] To a solution of 2-(3,5-difluoro-4-(thiophen-3-yl)phenyl)-2-methylpropanoic acid (Step D of Example 74, 500 mg, 1.77 mmol) in a mixed solvent of MeOH (15 mL) and DMF (1 mL) was added SOCl (1.05 g, 8.86 mmol) dropwise at 15-20°C, and the reaction mixture was stirred at room temperature for 6 hours. After removing the effluent, the resulting mixture was treated with EA, washed with aqueous sNaHCO and brine, dried over NaSO, and concentrated under reduced pressure to give a yellow oil, which was purified by silica gel column (hexane:EA, 10:1) to give the title compound (300 mg, 57%) as a yellow oil. MS: 297.2 (M+H + ).

[0564] Step B: (4-(2,6-difluoro-4-(1-methoxy-2-methyl-1-oxopropan-2-yl)phenyl)thiophen-2-yl)boronic acid [ka]

[0565] Under argon gas protection, at 0°C, to a solution of 2-(3,5-difluoro-4-(thiophen-3-yl)phenyl)-2-methylpropanoate (Step A, 120 mg, 0.41 mmol) and boric acid triisopropyl ester (152 mg, 0.81 mmol) in anhydrous THF (10 mL) was added LDA (410 μL, 0.81 mmol), and the reaction mixture was stirred at room temperature for 1 h. Aqueous NH4Cl solution was added to quench the reaction, and the resulting mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (crude) as a yellow oil, which was used directly in the next step without purification. MS: 341.1 (M+H + ).

[0566] Step C: 2-(4-(5-(2-((4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-5,5-dimethylcyclohex-1-en-1-yl)thiophen-3-yl)-3,5-difluorophenyl)-2-methylpropanoate [ka]

[0567] Under argon gas protection, a solution of (4-(2,6-difluoro-4-(1-methoxy-2-methyl-1-oxopropan-2-yl)phenyl)thiophen-2-yl)boronic acid (Step B, 79 mg, crude) in a mixed solvent of dioxane (15 mL) and water (3 mL) was charged with 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (prepared by the same scheme as in Step B of Example 21, 100 mg, 0.116 mmol), PdCl(dppf) (8.46 mg, 0.012 mmol), and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4- ... (36.8 mg, 0.347 mmol) and Na2CO3 (36.8 mg, 0.347 mmol) were added, and the reaction mixture was stirred at 100 °C for 16 h. After cooling to room temperature and removing the volatiles, the residue was purified by silica gel column (hexane:EA, 1:4) to give the title compound (50 mg, 40% yield over two steps) as a yellow oil. MS: 1081.3 (M+H + ).

[0568] Step D: 2-(4-(5-(2-((4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-5,5-dimethylcyclohex-1-en-1-yl)thiophen-3-yl)-3,5-difluorophenyl)-2-methylpropanoic acid (Example 82) [ka]

[0569] Under argon gas protection, to a solution of 2-(4-(5-(2-((4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(((4-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-5,5-dimethylcyclohex-1-en-1-yl)thiophen-3-yl)-3,5-difluorophenyl)-2-methylpropanoate (Step C, 50 mg, 0.046 mmol) in MeOH (4 mL) and THF (4 mL) was added 3N NaOH (4 mL), and the reaction mixture was stirred at 25° C. for 16 hours. The resulting mixture was diluted with water, adjusted to pH 4-5 with 1N HCl, and extracted twice with DCM. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give a yellow oil, which was purified by C18 preparative HPLC column to give the title compound (8 mg, 16%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1 H), 8.62 - 8.50 (m, 2 H), 8.06 (d, J = 2.3 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.69 (s, 1 H), 7.57 - 7.46 (m, 3 H), 7.21 - 7.01 (m, 4 H), 6.73 (d, J = 7.9 Hz, 1 H), 6.40 (s, 1 H), 6.26 (s, 1 H), 4.28 (s, 1 H), 3.30 - 3.26 (m, 2 H), 3.18 - 3.01 (m, 6H), 2.40 - 2.19 MS: 1067.2 (M+H + ).

[0570] Examples 83 and 84: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-((R)-1-hydroxyethyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example Example 83), and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-((S)-1-hydroxyethyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example 84). [ka]

[0571] Step A: 1-(3,5-difluoro-4-(thiophen-3-yl)phenyl)ethan-1ol [ka]

[0572] To a solution of 1-(3,5-difluoro-4-(thiophen-3-yl)phenyl)ethan-1-one (Step A of Example 69, 22 g, 92 mmol) in THF (200 mL) was added NaBH (3.49 g, 92 mmol) portionwise at 0° C., and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with 0.5 N HCl, and the resulting mixture was separated with brine and EA. The aqueous layer was extracted twice with EA. The combined organic layers were washed with brine, dried over Na SO , and concentrated under reduced pressure to give the title compound (20.5 g, crude) as a yellow oil, which was used directly in the next step without purification. MS: 223.1 (M-H O + H + ).

[0573] Step B: (4-(2,6-difluoro-4-(1-hydroxyethyl)phenyl)thiophen-2-yl)boronic acid [ka]

[0574] Under argon gas protection, at 0°C, to a solution of 1-(3,5-difluoro-4-(thiophen-3-yl)phenyl)ethan-1ol (Step A, 2 g, crude) and boric acid triisopropyl ester (4.7 g, 24.97 mmol) in anhydrous THF (50 mL) was slowly added LDA (12.5 mL, 2 M THF solution, 24.97 mmol), and the reaction mixture was stirred at 0-10°C for 2 h. Aqueous NH4Cl was added to quench the reaction, and the resulting mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (crude) as a yellow oil, which was used directly in the next step without purification. MS: 267.1 (M-H2O+H + ).

[0575] Step C: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(1-hydroxyethyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate [ka]

[0576] Under argon gas protection, to a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 1, 2.5 g, 4.52 mmol) in a mixed solvent of dioxane (50 mL) and water (10 mL) were added (4-(2,6-difluoro-4-(1-hydroxyethyl)phenyl)thiophen-2-yl)boronic acid (Step B, 2 g, crude), KCO (2.92 g, 21.1 mmol), and PdCl(dppf) (515 mg, 0.704 mmol), and the reaction mixture was stirred at 100 °C for 4 h. After cooling to room temperature, the resulting mixture was poured into water and extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil, which was purified by silica gel column (EA:hexane, 3:1) to give the title compound as a yellow solid (2.6 g, 52% yield over three steps). MS: 713.9 (M+H + ).

[0577] Step D: (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(1-hydroxyethyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate methyl (P1), and (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(1-hydroxyethyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate methyl (P2) [ka]

[0578] Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(1-hydroxyethyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Step C, 26.75 g) was subjected to chiral SFC separation using a Lux Cellulose-4 column to afford the title compound as a yellow solid (P1: 8.72 g, 99.8% ee, P2: 9.91 g, 98.1% ee).

[0579] Step E: (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(1-hydroxyethyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid [ka]

[0580] To a solution of (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(1-hydroxyethyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)methyl benzoate (P1 from Step D, 4.5 g, 6.31 mmol) in a mixed solvent of MeOH (30 mL) and THF (30 mL) was slowly added 3N NaOH (30 mL) at room temperature, and the reaction mixture was stirred at 40 °C for 6 h. After cooling to room temperature, the pH of the resulting mixture was adjusted to 3-4 with 1N HCl and extracted twice with DCM. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the title compound (4.4 g, crude) as a yellow solid, which was used directly in the next step without purification. MS: 699.5 (M+H + ).

[0581] Step F: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-((R)-1-hydroxyethyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example 83) [ka]

[0582] Under argon gas protection, to a solution of (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-(1-hydroxyethyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (Step E, 4g, crude) in anhydrous DCM (60 mL) was added DMAP (1.75 g, 14.31 mmol), 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (1.97 g, 5.72 mmol), and EDC (1.65 g, 8.59 mmol) in small portions, and the reaction mixture was stirred at 20-25 °C for 16 h. The resulting mixture was diluted with DCM (50 mL), washed with 1N HCl (30 mL) and brine (20 mL), dried over NaSO, and concentrated under reduced pressure to give a yellow oil, which was purified by C18 preparative HPLC column to give the title compound (2.5 g, 43% yield over two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1 H), 8.63 - 8.55 (m, 2 H), 8.07 (d, J = 2.6 Hz, 1 H), 7.83 - 7.78 (m, 1 H), 7.67 (s, 1 H), 7.57 - 7.49 (m, 3 H), 7.18 - 7.07 (m, 4 H), 6.73 (dd, J = 9.0, 1.6 Hz, 1 H), 6.40 (dd, J = 3.2, 1.8 Hz, 1 H), 6.26 (d, J = 1.6 Hz, 1 H), 5.46 (d, J = 4.5 Hz, 1 H), 4.81 - 4.71 (m, 1 H), 4.29 (s, 1 H), 3.31 (t, J = 6.1 Hz, 2 H), 3.18 - 3.09 (m, 4 H), 3.09 - 2.99 (m, 2 H), 2.38 - 2.27 (m, 4 H), 2.27 - 2.19 (m, 2 H), 2.16 - 2.11 (m, 2 H), 1.76 - 1.53 (m, 5 H), 1.44 - 1.31 (m, 7 H), 1.20 - 1.08 (m, 5 H), 0.95 (s, 6 H). MS: 1025.1 (M+H) + ).

[0583] Step G: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(4-(2,6-difluoro-4-((S)-1-hydroxyethyl)phenyl)thiophen-2-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (Example 84) [ka]

[0584] Starting from P2 in Step D and using essentially the same scheme as used to prepare Example 83, the example was obtained as a yellow solid (185 mg, salt form with AcOH, 25% yield over two steps). 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1 H), 11.71 (s, 1 H), 8.64 - 8.51 (m, 2 H), 8.07 (s, 1 H), 7.81 (d, J = 9.0 Hz, 1 H), 7.67 (s, 1 H), 7.59 - 7.46 (m, 3 H), 7.20 - 7.02 (m, 4 H), 6.73 (d, J = 8.4 Hz, 1 H), 6.40 (s, 1 H), 6.26 (s, 1 H), 5.46 (d, J = 4.0 Hz, 1 H), 4.84 - 4.66 (m, 1 H), 4.28 (s, 1 H), 3.32 - 3.26 (m, 2 H), 3.19 - 3.01 (m, 6 H), 2.39 - 2.18 (m, 6 H), 2.16 - 2.07 (m, 2 H), 1.94 (s, 3 H), 1.79 - 1.51 (m, 5 H), 1.44 - 1.30 (m, 7 H), 1.22 - 1.05 (m, 5 H), 0.95 (s, 6 H); MS: 1025.1 (M+H + ).

[0585] Biological Examples

[0586] Bcl-2 WT and Bcl-2 G101V inhibition: Assay conditions: Assay Plate: Greiner Bio-One 655209, black flat-bottom 96-well plate Assay buffer: 100 mM potassium phosphate, pH 7.5, 100 μg / mL bovine gamma globulin, 0.02% sodium azide + 0.01% Triton X (added before assay) Assay volume: 100 μL Final [DMSO] = 2.5% (2.5 μL compound in DMSO + 97.5 μL protein / tracer mixture or tracer only in assay buffer) Incubation time: 1 hour Final concentration: [Bcl2]=20nM, [Flu-BIM]=5nM Experimental Procedure: Assay solution preparation: (a) The following conjugate solutions (protein + Flu-BIM) were prepared: 20.5 nM Bcl2 protein and 5.1 nM Flu-BIM in assay buffer. (b) A positive control, i.e., assay buffer without Flu-BIM (5.1 nM), was prepared. Note: These solutions were then mixed with the compound solution, and the concentrations of protein and tracer were adjusted at this point to a final concentration of 20 nM and 5 nM, respectively.

[0587] DMSO stock solutions of test compounds were prepared at a concentration of 10 mM, and these solutions were used to prepare DMSO working solutions of the highest concentration of each compound to be tested in the binding assay (typically, for initial screening, 100 μM (final concentration) is the highest concentration, and the test concentration range needs to be adjusted after IC50 values ​​are established).

[0588] Compounds were diluted 3-fold for a total of 11 dose points.

[0589] 2.5 μL of compound was added to the assay plate.

[0590] All control and blank wells received 2.5 μL of DMSO.

[0591] Blank wells received 97.5 μL of assay buffer only (these wells are blank controls and are used between assay plates).

[0592] Positive control wells received 97.5 μL of a solution containing tracer only, which equates to 100% inhibition.

[0593] To the negative control wells, 97.5 μL of conjugate solution was added, which equates to 0% inhibition.

[0594] To the other wells of the assay plate, 97.5 μL of the conjugate solution was added.

[0595] The assay plate was covered with aluminum foil, placed on a shaker and incubated for approximately 1 hour, and the polarization values ​​were assayed in a microplate reader: excitation wavelength was 485 nm and emission wavelength was 530 nm.

[0596] The IC was calculated by nonlinear regression fitting with Graphpad Prism 8.2.1 (mP value vs. compound concentration) to the log(inhibitor) and slope of the response variable (four parameters). 50 The value was confirmed.

[0597] RS4,Bcl-2-G101V, RS4,Bcl-2-D103E, RS4,Bcl-2-V156D, and RS4,Bcl-2-G101V-D103E cells were obtained from Cobioer Biosciences. Cells were cultured in RPMI-1640 medium containing 10% FBS, 1% P / S, and puromycin (1 μg / mL) at 37°C in a 5% CO atmosphere.

[0598] CTG assay: The effect of representative compounds of the present disclosure on cell viability was determined using the CellTiter-Glo® (CTG) Luminescent Cell Viability Assay (Promega, USA) according to the manufacturer's specifications. 95 μL of cell suspension (10,000 cells / well) was aspirated from the culture medium and seeded into a 96-well plate and cultured for 4 hours. Each test compound was serially diluted with blank medium, and 5 μL of the compound dilution was added to the corresponding well of the cell plate. After adding the test compound, the cells were incubated at 37°C in a 5% CO2 atmosphere for 3 days. After 3 days, 30 μL of CTG solution was added to each well of the cell plate, and the contents were mixed on an orbital shaker for 2 minutes. The cell plate was incubated at room temperature for 15 minutes to stabilize the signal, and RLU was recorded using a Biotek microplate reader. Readings were normalized to vector cells, and IC was calculated using GraphPad Prism 8 software. 50 was calculated.

[0599] MV-4-11 cells were obtained from the University of Michigan. Cells were cultured in RPMI-1640 medium containing 10% FBS and 1% P / S at 37°C in a 5% CO atmosphere.

[0600] CCK-8 assay: The effects of representative compounds of the present disclosure on cell viability were determined using a Cell Count Kit-8 (CCK-8) assay (Shanghai Life iLab Biotech) according to the manufacturer's specifications. Each test compound was serially diluted in culture medium, and 100 μL of compound dilution was added to the corresponding well of a cell plate. 100 μL of MV-4-11 cell suspension (20,000 cells / well) was aspirated from the culture medium and seeded into a 96-well plate. The cells were incubated at 37°C in a 5% CO2 atmosphere for 3 days. After 3 days, 20 μL of CCK-8 solution was added to each well of the cell plate and incubated for 1-4 hours. Readings were taken at 450 nm using a Biotek microplate reader. Readings were normalized to vector cells, and IC values ​​were calculated using GraphPad Prism 8 software.50 was calculated. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 3]

[0601] After the present invention has been fully described, those skilled in the art will appreciate that the present invention can be practiced within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof.

[0602] Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. The specification and examples are considered to be exemplary only, with the true scope and spirit of the invention being defined by the appended claims.

[0603] All patents and publications cited herein are hereby incorporated by reference in their entirety.

Claims

1. Formula I: 【Chemistry 1】 wherein ring X is a 5- or 6-membered ring containing one or more additional degrees of unsaturation; Each R １ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ independently selected from the group consisting of haloalkyl and halogen; p is 0, 1 or 2; Ring Y is a 5- to 9-membered monocyclic or fused ring system containing at least one S and optionally containing one or more additional heteroatoms selected from O, N, or S, and containing one or more degrees of unsaturation; R ２ (CH ２ ) ｔ -R ４ , C.O.N.H.-R. ４ , NHC(O)-R ４ , N.H.R. ４ and (C≡C)-R ４ are independently selected from the group consisting of: Each R ４ is independently １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, aryl, C ３－１０ heterocyclyl, heteroaryl, Each R ４ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, halogen, C ３－６ Cycloalkyl, C ３－６ Heterocyclyl, OSO ２ CH ３ , N.H. ２ , N.H.C. １－６ Alkyl, N(C １－６ Alkyl), C １－６ Alkoxy, OH, C １－６ Alkyl-OH, C ２－６ Alkyl (OH) (C ３－６ Cycloalkyl), C １－６ Haloalkyl-OH, C ３－６ Cycloalkyl-OH, C １－６ Alkyl-COOH, C １－６ Alkyl-O-C １－６ Alkyl, C, N １－６ Alkyl-CN,C １－６ Alkyl-NHC(O)-C １－６ Alkyl and C １－６ may be substituted with one or more of the groups alkyl-C(O)NH-C1-6 alkyl; q is 1 or 2; each t is 0, 1, 2, 3, 4, 5, or 6; Ring Z is a saturated 6-membered ring optionally containing one or more O; Each R ３ is C １－６ Alkyl, C １－６ selected from the group consisting of one or more of alkoxy and OH; or a pharma- ceutically acceptable salt or solvate thereof, wherein r is 0, 1 or 2.

2. Ring X is a 6-membered cyclohexenyl ring and the compound has formula Ix: 【Chemistry 2】 Compound.

3. p is 2, and each R １ The compound according to claim 1 or 2, wherein:

4. Each R １ is C １－６ The compound of claim 3, wherein the aryl group is an alkyl group.

5. Each R １ The compound of claim 4 , wherein is methyl.

6. Each methyl is para to the indicated point of attachment of the piperazine-methylene to the compound of formula Ixi: 【Chemistry 3】 compound.

7. The compound according to any one of claims 1 to 5, wherein ring Y is thiophene.

8. The S atom is located at the α-position of ring X, and the compound has formula Iy: 【Chemistry 4】 The compounds listed above.

9. The compound according to any one of claims 1 to 8, wherein q is 1.

10. Each R ２ are independently represented by (CH ２ ) ｔ -R ４ 11. The compound of claim 10,

11. t is 0 and R ４ The compound of claim 10 , wherein directly replaces the thiophene shown.

12. q is 1 and R ４ is substituted β-position to the indicated S in the indicated thiophene ring, and said compound has the formula Iyi: 【Chemistry 5】 The compound according to claim 1,

13. R ４ is aryl.

14. R ４ is phenyl.

15. R ４ is C １－６ Alkyl, C １－６ Haloalkyl, halogen, OH, C １－６ Alkyl-OH and C １－６ 15. The compound of claim 13 or 14, substituted with one or more of the following groups: haloalkyl-OH.

16. R ４ is halogen, C １－６ Alkyl-OH and C １－６ 16. The compound of claim 15, substituted with one or more haloalkyl-OH groups.

17. The compound of any one of claims 1 to 16, wherein ring Z is selected from substituted cyclohexyl and 1,4-dioxane.

18. The same atom of the cyclohexyl is substituted with a methyl and an OH group, respectively, and the substitutions are para to the point of attachment to the amine as shown: 【Chemistry 6】

19. The compound has the stereochemistry shown: 【Chemistry 7】

20. The compound has the stereochemistry shown: 【Chemistry 8】

21. A compound selected from the group consisting of: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】

22. The compound according to any one of claims 1 to 22, wherein the pharma- ceutically acceptable salt form is a trifluoroacetate or formate salt.

23. The compound according to any one of claims 1 to 22, wherein at least one hydrogen atom is replaced with a deuterium atom.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable vector.

25. 25. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition is for treating a hyperproliferative disease.

26. 26. The pharmaceutical composition of claim 25, wherein the hyperproliferative disease is cancer.

27. 27. The pharmaceutical composition of claim 26, wherein the cancer is selected from one or more of the cancers in Table 2.

28. The pharmaceutical composition of claim 26, 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.

29. 23. Use of a compound according to any one of claims 1 to 22, or a pharma- ceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment of a hyperproliferative disease.

30. 30. The use according to claim 29, wherein the hyperproliferative disease is cancer.

31. 31. The use of claim 30, wherein the cancer is selected from one or more of the cancers in Table 2.

32. 31. The use according to claim 30, 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. 23. A kit comprising a compound according to any one of claims 1 to 22, or a pharma- ceutically acceptable salt or solvate thereof, and instructions for administering said compound, or a pharma- ceutically acceptable salt or solvate thereof, to a patient suffering from a hyperproliferative disease.

34. 34. The kit of claim 33, wherein the hyperproliferative disease is cancer.

35. 35. The kit of claim 34, wherein the cancer is selected from one or more of the cancers in Table 2.

36. 35. The kit of claim 34, 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.

37. The kit of any one of claims 33 to 36, wherein the kit further comprises one or more additional therapeutic agents.

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