Hot-melt extruded solid dispersions containing a bcl2 inhibitor

Abstract

An apoptosis-promoting solid dispersion comprises a Bcl-2 family protein inhibiting compound of Formula A as defined herein dispersed in a solid matrix comprising (a) a pharmaceutically acceptable water-soluble polymeric carrier, and (b) a pharmaceutically acceptable surfactant. A method for preparing such a solid dispersion comprises subjecting a compound of Formula A, a water-soluble polymeric carrier, and a surfactant to high temperature treatment to provide an extrudable semi-solid mixture; extruding the semi-solid mixture; cooling the resulting extrudate to provide a solid matrix comprising the polymeric carrier and the surfactant and having the compound substantially non-crystalline form dispersed therein. The solid dispersion is suitable for oral administration to a subject in need thereof to treat a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, such as a cancer or an immune or autoimmune disease.

Description

[0001] Related application reference

[0002] This application claims priority to the following patent applications, which are incorporated herein by reference: U.S. Provisional Patent Application No. 62 / 980,700, filed February 24, 2020, and U.S. Provisional Patent Application No. 63 / 053,565, filed July 17, 2020. Invention Field

[0003] This invention relates to solid dispersions containing apoptosis inducers, pharmaceutical dosage forms containing such dispersions, processes for preparing such dispersions and dosage forms, and methods of using such dispersions to treat diseases characterized by overexpression of anti-apoptotic Bcl-2 family proteins. Background of the Invention

[0005] Apoptosis, also known as programmed cell death, is a conserved, regulated process and the primary mechanism for removing aging, damaged, and unwanted cells. The ability to block apoptotic signals is a key hallmark of cancer and is therefore crucial for tumorigenesis, tumor maintenance, and chemoresistance [Hanahan, D. & Weinberg, RA. The hallmarks of cancer. Cell 100, 57-70 (2000)]. The dynamic binding between pro-apoptotic proteins (e.g., BCL-2-associated X protein (BAX), BCL-2 antagonist / killer 1 (BAK), BCL-2-associated cell death agonist (BAD), BCL-2-like 11 (BIM)) and pro-survival proteins (e.g., BCL-2, BCL-XL, BCL-2-like 2 (BCL-W), myeloid leukemia sequence 1 protein (MCL-1), and BCL-2-associated protein A1 (BFL-1)) in the BCL-2 family controls the process of programmed cell death. Altering the balance between these opposing factions provides a means for cancer cells to disrupt normal apoptosis and gain a survival advantage [Youle, RJ & Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol. 9, 47-59 (2008)].

[0006] BCL-2 was the first confirmed regulator of apoptosis, initially cloned from the breakpoint of the t(14;18) translocation in human B-cell lymphoma [Tsujimoto, Y., et al. Science 228, 1440-1443 (1985); Cleary, ML, et al. Cell 47, 19-28 (1986); Boise, L. He et al. Cell 74, 597-608 (1993)]. It has since been shown to play a dominant role in the survival of various lymphomas [Vaux, DL, et al. pre-Bcells. Nature 335, 440-442 (1988)]. Overexpression of BCL-2 protein in various cancers and immune system diseases is associated with one or more of the following: chemotherapy resistance, clinical outcomes, disease progression, and overall prognosis. According to PCT / US2004 / 36770 (published in WO 2005 / 049593) and PCT / US2004 / 37911 (published in WO / 2005 / 049594), BCL-2 protein is involved in bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphocytic leukemia, follicular lymphoma, T-cell or B-cell lymphoma, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, etc. BCL-2 protein is also involved in immune and autoimmune diseases, as reported in *Current Allergy and Asthma Reports* 2003, 3, 378-384; *British Journal of Hematology* 2000, 110(3), 584-90; *Blood* 2000, 95(4), 1283-92; and *New England Journal of Medicine* 2004, 351(14), 1409-1418. BCL-2 protein involvement in arthritis has been reported in WO 2009 / 064938. BCL-2 protein involvement in bone marrow transplant rejection has been reported in US2008-0182845 A1. All of the above references are included in this article.

[0007] Over the past decade, several BCL-2 inhibitors, such as ABT-737, ABT-263, and ABT-199, have been identified and entered human clinical trials for the treatment of cancer.

[0008]

[0009] ABT-737 was discovered through nuclear magnetic resonance (NMR) screening, parallel synthesis, and structure-based fragment drug design [Tillman Oltersdorf, et al., Nature, Vol 435, 2005, p 677]. ABT-737 is a small molecule inhibitor of the anti-apoptotic proteins BCL-2, Bcl-XL, and Bcl-w, with an affinity two to three orders of magnitude stronger than previously reported compounds. Mechanistic studies show that ABT-737 does not directly initiate the apoptosis process but rather enhances the effect of death signaling, exhibiting synergistic cytotoxicity with chemotherapy and radiotherapy. ABT-737 demonstrates single-agent-based killing efficacy against lymphoma and small cell lung cancer cell lines, as well as cells derived from primary patients; in animal models, ABT-737 improved survival, led to established tumor regression, and produced a cure in a high proportion of mice. Unfortunately, ABT-737 cannot be administered orally, and its intravenous formulation is also limited by its low water solubility.

[0010] Through extensive efforts by MedChem, an orally administered BCL-2 inhibitor, ABT-263 (Navitoclax), has been developed [Cheol-Min Park, et al J. Med. Chem. 2008, 51, 6902-6915]. ABT-263 is a potent inhibitor of Bcl-xL, BCL-2, and Bcl-w, with Ki values ​​≤0.5 nM, ≤1 nM, and ≤1 nM, respectively. ABT-263 showed an IC50 of ≤0.5 nM for SCLC H146 cell line. 50 The concentration was 110 nM. When ABT-263 was administered at 100 mg / kg / day in the H345 xenograft model, significant antitumor efficacy was observed—TGI 80% and 20% tumor treatment, indicating a reduction in tumor volume of at least 50%. Complete tumor regression was observed in xenograft models of small cell lung cancer and acute lymphoblastic leukemia after oral administration of ABT-263 alone [TseC, et al. Cancer Res. 2008, 68(9), 3421-3428]. However, in clinical trials, inhibition of BCL-XL by ABT-263 (navitoclax) induced a rapid and dose-dependent decrease in circulating platelet count. This mechanism-based thrombocytopenia was attributed to dose-limiting toxicities in patients treated with navitoclax alone, limiting the ability of ABT-263 to push drug concentrations to high efficacy levels.

[0011] Therefore, BCL-2 selective (BCL-XL channeling) inhibitors will ultimately significantly reduce thrombocytopenia while maintaining efficacy against lymphocytic malignancies. The resulting increased therapeutic window should allow for greater BCL-2 inhibition and clinical efficacy against BCL-2 dose-dependent tumor types. Through extensive efforts by MedChem, ABT-199 (GDC-0199) has been successfully developed [Andrew J Souers, et al, Nature Medicine, Volume 19, 22, p202, 2013]. ABT-199 is a selective BCL-2 inhibitor with Ki < 0.01 nM, >4800-fold selectivity for Bcl-xL and Bcl-w, and no activity against Mcl-1. ABT-199 effectively inhibits RS4;11 cells and EC... 50 The concentration was 8 nM. Furthermore, ABT-199 induced rapid apoptosis in RS4;11 cells, leading to cytochrome c release, caspase activation, and sub-G0 / G1 DNA accumulation. Quantitative Western blotting showed that sensitivity to ABT-199 was closely related to BCL-2 expression, including in NHL, DLBCL, MCL, AML, and ALL cell lines. ABT-199 also induced apoptosis in CLL, with an average EC50 of 8 nM. 50 The concentration is 3.0 nM. A single dose of 100 mg / kg of ABT-199 achieved a maximum tumor growth inhibition rate of 95% and a tumor growth delay rate of 152% in RS4;11 xenografts. ABT-199, as a single agent or in combination with bendamustine and other drugs, also inhibits the growth of xenografts (DoHH2, Granta-519). Phase I and II human clinical trial data showed that ABT-199 has good efficacy in CLL with 17p deletion and received FDA approval for production in 2016.

[0012] WO / 2017 / 132474, WO / 2019 / 040550, WO / 2019 / 040573, PCT / US2019 / 047404, and PCT / US2019 / 047403 disclose a novel class of BCL-2 inhibitors. Given the very low water solubility of Bcl-2 binding compounds, formulators face significant challenges in ensuring oral bioavailability of Bcl-2, which largely depends on its solubility in the gastrointestinal aqueous medium. This is true even when binding affinity is very high. This challenge is further amplified when considering the need to provide sufficient drug loading in formulations to deliver an effective therapeutic dose in small-volume products.

[0013] Liquid dosage forms (including encapsulated liquids) are useful for some drugs with low water solubility, provided a suitable, pharmaceutically acceptable solvent system (usually lipid-based) can be found to provide sufficient drug loading without causing solubility or storage stability issues. Other methods proposed for such drugs include solid dispersions, but these also present additional challenges.

[0014] Solid dosage forms are generally more popular than liquid dosage forms, mainly due to patient compliance, masking of drug taste, or other reasons. However, in most cases, the bioavailability of oral solid dosage forms is lower than that of oral solutions.

[0015] Researchers have long sought to improve the bioavailability of solid dosage forms by developing solid dispersions of drugs, more specifically, solid solutions. Solid dispersions or solutions are the preferred physical systems because their components readily form liquid solutions upon contact with liquid media (such as gastric juice). The ease with which drugs dissolve can be attributed, at least in part, to the fact that less energy is required to dissolve a component from a solid dispersion or solid solution than from a crystalline or microcrystalline solid phase. However, it is crucial that drugs released from solid dispersions or solid solutions retain their water solubility in the aqueous humor of the gastrointestinal tract; otherwise, they may precipitate in the gastrointestinal tract, leading to reduced bioavailability.

[0016] WO 01 / 00175 discloses mechanically stable pharmaceutical dosage forms, which are solid solutions of active ingredients in an excipient matrix. This matrix contains a homopolymer or copolymer of N-vinylpyrrolidone and a liquid or semi-solid surfactant.

[0017] WO 00 / 57854 discloses mechanically stable pharmaceutical dosage forms for oral administration, which contain at least one active compound, at least one thermoplastic excipient that forms a matrix, and a surfactant in a weight ratio of more than 10% to up to 40%, wherein the surfactant has an HLB value between 2 and 18, and the dosage form is a liquid at 20°C or has a drop point between 20 and 50°C.

[0018] US2005 / 0208082 discloses a solubilizing composition comprising a mixture of vitamin E TPGS (α-tocopherol polyethylene glycol succinate or vitamin E polyethylene glycol succinate) and linoleic acid. This solubilizing composition can be used to disperse lipophilic compounds in an aqueous phase.

[0019] Hot melt extrusion technology is increasingly used to improve the bioavailability of poorly water-soluble drug compounds. It is a solvent-free, environmentally friendly process and is said to have many advantages over traditional solid dosage forms in terms of robustness and versatility (Crowley et al. (2007) Drug Development and Industrial Pharmacy 33:908-926).

[0020] Hot melt extrusion technology has been shown to improve the pharmacokinetic properties of certain drugs better than alternative formulations. For example, see Kleinet al. (2007) J. Acquir. Immune Defic. Syndr. 44:401-410.

[0021] Apoptosis-inducing agents targeting Bcl-2 family proteins (such as Bcl-2 and Bcl-Xχ) are best administered via a regimen of continuous (e.g., daily) plasma concentration replenishment to maintain effective therapeutic plasma concentrations. This can be achieved through daily injection, such as intravenous (iv) or intraperitoneal (ip). However, in clinical settings, especially for outpatients, daily injection is often impractical. To improve the clinical utility of apoptosis inducers, such as for use as chemotherapy drugs in cancer patients, there is an urgent need for an orally administered solid dosage form. Such a dosage form and its oral administration regimen would represent a significant advancement in the treatment of many types of cancer, including NHL, CLL, and ALL, and would facilitate combination therapy with other chemotherapy drugs. Summary of the Invention

[0022] One aspect of the invention described herein provides a solid dispersion (such as a hot melt extrusion) comprising a compound of formula (A) in a substantially non-crystalline (e.g., amorphous) form or a pharmaceutically acceptable salt thereof.

[0023]

[0024] in

[0025] Q4 is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or spiroheterocyclic;

[0026] Q5 is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or spiroheterocyclic;

[0027] R1, R2, R7, R8, R9 and R 10 Each of the following can be independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halogen, nitro, oxo, cyano, OR a SR a alkyl-Ra NH(CH2) p R a C(O)R a S(O)R a SO2R a C(O)OR a OC(O)R a NR b R c C(O)N(R) b )R c 、N(R b )C(O)R c -P(O)R b R c ,-alkyl-P(O)R b R c -S(O)(=N(R) b ))R c -N=S(O)R b R c =NR b SO2N(R) b )R c or N(R) b SO2R c The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. d replace;

[0028] R a R b R c R bb R cc and R d Independently, it is H, D, alkyl, spiroalkyl, alkenyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally surrounded by one or more R e replace;

[0029] R e Independently, it is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxyl, =O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;

[0030] Z1 is a bond, (CH2)p ,N(H),O,S,C(O),S(O2),OC(O),C(O)O,OSO2,S(O2)O,C(O)S,SC(O),C(O)C(O),C(O)N(H),N(H)C(O) , S(O2)N(H), N(H)S(O2), OC(O)O, OC(O)S, OC(O)N(H), N(H)C(O)O, N(H)C(O)S, N(H)C(O)N(H), (CH2) p N(H)(CH2) q (CH2) p N(H)C(O)(CH2) q (CH2) p C(O)N(H)(CH2) q OC(O)N(H)(CH2) p+1 N(H)(CH2) q Divalent alkenyl groups or divalent alkynyl groups;

[0031] L is -L1-L2-;

[0032] L1 is a bond, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein the alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally bounded by one or more R d replace;

[0033] L2 is a bond or alkyl group, wherein one or more -L i -Optionally inserted between any two adjacent carbon atoms;

[0034] -L i -is-N(R) a )-, -O-, -S-, -C(O)-, -S(O2)-, -OC(O)-, -C(O)O-, -OSO2-, -S(O2)O-, -C(O)S-, -SC(O)-, -C(O)C(O)-, -C(O)N(R a )-、-N(R a )C(O)-、-S(O2)N(R a )-、-N(R a )S(O2)-, -OC(O)O-, -OC(O)S-, -OC(O)N(R a )-、-N(R a )C(O)O-、-N(R a )C(O)S-、-N(R a )C(O)N(R a-, divalent alkenyl group, divalent alkynyl group, divalent cycloalkyl group, divalent heterocyclic alkyl group, divalent aryl group, divalent heteroaryl group;

[0035] Two of the R1 groups, together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group of R1 is optionally surrounded by one or more R groups. d replace;

[0036] Two of the R2 groups, together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group of R2 is optionally surrounded by one or more R groups. d replace;

[0037] Two of the R7 groups, together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group of R7 is optionally surrounded by one or more R groups. d replace;

[0038] R 10 Two of the groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein R 10 The cycloalkyl or heteroalkyl group is optionally surrounded by one or more R d replace;

[0039] The R7 and L groups, together with the atoms to which they are attached, may optionally form cycloalkyl or heterocycloalkyl groups, wherein the cycloalkyl or heterocycloalkyl groups of R7 and L are optionally surrounded by one or more R groups. e replace;

[0040] R b and R c The groups, together with the atoms to which they are attached, may optionally form cycloalkyl or heterocycloalkyl groups, wherein R b and R c The cycloalkyl or heteroalkyl group is optionally surrounded by one or more R e replace;

[0041] R d Two of the groups, together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group of Rd is optionally surrounded by one or more R groups. e replace;

[0042] R e Two of the groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein R eThe cycloalkyl or heterocycloalkyl group is optionally substituted with one or more groups selected from the group consisting of: H, D, alkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxyl, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxy, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;

[0043] k, g, m, n, p, and q are each independently 0, 1, 2, 3, 4, or 5;

[0044] s is 0 or 1; and

[0045] f is 0 or 1; the compound of formula (A) or a pharmaceutically acceptable salt thereof is dispersed in a solid matrix comprising (a) at least one pharmaceutically acceptable water-soluble polymer carrier, (b) at least one pharmaceutically acceptable surfactant, and optionally, and optionally (c) at least one pharmaceutically acceptable antioxidant.

[0046] Another aspect of the invention described herein also provides a solid, orally deliverable dosage form comprising such a solid dispersion, optionally together with one or more additional excipients.

[0047] Another aspect of the invention described herein also provides a method for preparing the above-described solid dispersion. The method comprises: (a) subjecting the following to an elevated temperature: (i) an active pharmaceutical ingredient (API) comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, (ii) a pharmaceutically acceptable water-soluble polymer carrier, (iii) a pharmaceutically acceptable surfactant, and optionally (iv) a pharmaceutically acceptable antioxidant, to provide an extrudable semi-solid mixture.

[0048]

[0049] in

[0050] Q4 is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or spiroheterocyclic;

[0051] Q5 is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or spiroheterocyclic;

[0052] R1, R2, R7, R8, R9 and R 10 Each of the following can be independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halogen, nitro, oxo, cyano, OR a SR a alkyl-Ra NH(CH2) p R a C(O)R a S(O)R a SO2R a C(O)OR a OC(O)R a NR b R c C(O)N(R) b )R c 、N(R b )C(O)R c -P(O)R b R c ,-alkyl-P(O)R b R c -S(O)(=N(R) b ))R c -N=S(O)R b R c =NR b SO2N(R) b )R c or N(R) b SO2R c The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. d replace;

[0053] R a R b R c R bb R cc and R d Independently, it is H, D, alkyl, spiroalkyl, alkenyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally surrounded by one or more R e replace;

[0054] R e Independently, it is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxyl, =O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;

[0055] Z1 is a bond, (CH2)p ,N(H),O,S,C(O),S(O2),OC(O),C(O)O,OSO2,S(O2)O,C(O)S,SC(O),C(O)C(O),C(O)N(H),N(H)C(O) , S(O2)N(H), N(H)S(O2), OC(O)O, OC(O)S, OC(O)N(H), N(H)C(O)O, N(H)C(O)S, N(H)C(O)N(H), (CH2) p N(H)(CH2) q (CH2) p N(H)C(O)(CH2) q (CH2) p C(O)N(H)(CH2) q OC(O)N(H)(CH2) p+1 N(H)(CH2) q Divalent alkenyl groups or divalent alkynyl groups;

[0056] L is -L1-L2-;

[0057] L1 is a bond, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein the alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally bounded by one or more R d replace;

[0058] L2 is a bond or alkyl group, wherein one or more -L i -Optionally inserted between any two adjacent carbon atoms;

[0059] -L i -is-N(R) a )-, -O-, -S-, -C(O)-, -S(O2)-, -OC(O)-, -C(O)O-, -OSO2-, -S(O2)O-, -C(O)S-, -SC(O)-, -C(O)C(O)-, -C(O)N(R a )-、-N(R a )C(O)-、-S(O2)N(R a )-、-N(R a )S(O2)-, -OC(O)O-, -OC(O)S-, -OC(O)N(R a )-、-N(R a )C(O)O-、-N(R a )C(O)S-、-N(R a )C(O)N(R a-, divalent alkenyl group, divalent alkynyl group, divalent cycloalkyl group, divalent heterocyclic alkyl group, divalent aryl group, divalent heteroaryl group;

[0060] Two of the R1 groups, together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group of R1 is optionally surrounded by one or more R groups. d replace;

[0061] Two of the R2 groups, together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group of R2 is optionally surrounded by one or more R groups. d replace;

[0062] Two of the R7 groups, together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group of R7 is optionally surrounded by one or more R groups. d replace;

[0063] R 10 Two of the groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein R 10 The cycloalkyl or heteroalkyl group is optionally surrounded by one or more R d replace;

[0064] The R7 and L groups, together with the atoms to which they are attached, may optionally form cycloalkyl or heterocycloalkyl groups, wherein the cycloalkyl or heterocycloalkyl groups of R7 and L are optionally surrounded by one or more R groups. e replace;

[0065] R b and R c The groups, together with the atoms to which they are attached, may optionally form cycloalkyl or heterocycloalkyl groups, wherein R b and R c The cycloalkyl or heteroalkyl group is optionally surrounded by one or more R e replace;

[0066] R d Two of the groups, together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group of Rd is optionally surrounded by one or more R groups. e replace;

[0067] R e Two of the groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein R eThe cycloalkyl or heterocycloalkyl group is optionally substituted with one or more groups selected from the group consisting of: H, D, alkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxyl, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxy, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;

[0068] k, g, m, n, p, and q are each independently 0, 1, 2, 3, 4, or 5;

[0069] s is 0 or 1; and

[0070] f is 0 or 1;

[0071] (b) Extruding the semi-solid mixture; and

[0072] (c) Cooling the resulting extrudate to provide a solid matrix comprising the polymer carrier and the surfactant (and optionally the antioxidant), and dispersing the compound or its salt therein in a substantially non-crystalline form.

[0073] As used herein, a “melt” is a liquid or semi-solid (e.g., rubbery) state induced by elevated temperature, in which a first component is potentially uniformly distributed within a matrix containing a second component. Typically, the second (matrix) component, such as a polymer carrier, is in this state, while other components, such as compounds of formula (A) or salts thereof, are dissolved in the melt, thus forming a solution.

[0074] As used herein, “elevation temperature” refers to a temperature above the softening point of the polymer carrier, which is affected by other components, such as plasticizers or surfactants (if present). In some cases, the elevation temperature is about 100°C to about 200°C, about 125°C to about 175°C, or about 140-160°C.

[0075] Melt preparation can be carried out in various ways. Mixing of the components can occur before, during, or after melt formation. For example, the components can be mixed first and then subjected to elevated temperatures to form a melt; or mixing and melting can be performed simultaneously. In one embodiment, the polymer carrier is first melted, optionally together with the surfactant component, and then the API is added to the formed melt. Typically, the melt is thoroughly mixed at elevated temperatures to ensure uniform API dispersion.

[0076] A related aspect of the present invention provides a solid dispersion prepared by the above method.

[0077] A further related aspect of the invention provides an orally deliverable pharmaceutical dosage form, including the solid dispersion of the invention.

[0078] Another aspect of the invention provides a method for treating neoplastic, immune, or autoimmune diseases, comprising orally administering a therapeutically effective amount of the solid dispersion of the invention, or one or more solid dosage forms comprising such a dispersion, to a subject suffering from the disease.

[0079] Neoplastic diseases include cancer. A specific illustrative type of cancer that can be treated with this method is non-Hodgkin's lymphoma (NHL). Another specific illustrative type of cancer that can be treated with this method is chronic lymphocytic leukemia (CLL). Yet another specific illustrative type of cancer that can be treated with this method is acute lymphoblastic leukemia (ALL), for example, in pediatric patients.

[0080] Other embodiments of the invention are provided below, including more specific aspects of the embodiments described above. It should be understood that any embodiment of the invention, including those described only in one aspect of the invention or only in the embodiments, may be combined with any other embodiment of the invention, unless the invention expressly denies or considers such a combination inappropriate.

[0081] Detailed description of the invention

[0082] The present invention provides a solid dispersion comprising an active ingredient that is substantially non-crystalline or amorphous and is generally more soluble than in its crystalline form.

[0083] The term "solid dispersion" includes a system having small solid particles (e.g., substantially amorphous or non-crystalline particles) of one phase dispersed in another solid phase. In particular, the solid dispersions of the present invention comprise particles of one or more active ingredients dispersed in an inert support or matrix, which can be prepared by melting (e.g., hot melt extrusion or HME) or solvent (e.g., spray drying) methods, or both. According to the present invention, the hot melt extrusion method described herein is preferred.

[0084] The “amorphous” described in this article refers to particles that do not have a definite structure, that is, they lack a crystalline structure.

[0085] The term "fundamentally amorphous" in this document refers to a crystallinity observed by X-ray diffraction analysis of no more than about 5% (e.g., no more than about 2% or 1%). In one specific embodiment, undetectable crystallinity is observed by one or both of X-ray diffraction analysis and polarization microscopy. When no detectable crystallinity is observed, the solid dispersions described herein may be additionally described as solid solutions.

[0086] Therefore, the present invention provides a solid dispersion containing a compound of formula (A).

[0087]

[0088] in

[0089] Q4 is a cycloalkyl, cycloalkenyl, heterocyclic, heterocyclic, aryl, heteroaryl, or spirocyclic heterocycle;

[0090] Q5 is a cycloalkyl, cycloalkenyl, heterocyclic, heterocyclic, aryl, heteroaryl, or spirocyclic heterocycle;

[0091] Each R1, R2, R7, R8, R9 and R 10 Independently, it is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, spiroheterocyclic, heterocyclic alkenyl, aryl, heteroaryl, halogen, nitro, oxo, cyano, OR a SR a alkyl-R a NH(CH2) p R a C(O)R a S(O)R a SO2R a C(O)OR a OC(O)R a NR b R c C(O)N(R) b )R c 、N(R b )C(O)R c -P(O)R b R c ,-alkyl-P(O)R b R c -S(O)(=N(R) b ))R c -N=S(O)R b R c =NR b SO2N(R) b )R c or N(R) b SO2R c The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups may be derived from one or more R groups. d Selective substitution;

[0092] R a R b R c R bb R ccand R d Independently, it is H, D, alkyl, spiroalkyl, alkenyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, heterocyclic, spirocycloalkyl, heterocyclic alkenyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocyclic alkenyl, aryl, or heteroaryl can be one or more R e Selective substitution;

[0093] R e Independently, it is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxyl, =O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;

[0094] Z1 is a bond, (CH2) p ,N(H),O,S,C(O),S(O2),OC(O),C(O)O,OSO2,S(O2)O,C(O)S,SC(O),C(O)C(O),C(O)N(H),N(H)C(O) , S(O2)N(H), N(H)S(O2), OC(O)O, OC(O)S, OC(O)N(H), N(H)C(O)O, N(H)C(O)S, N(H)C(O)N(H), (CH2) p N(H)(CH2) q (CH2) p N(H)C(O)(CH2) q (CH2) p C(O)N(H)(CH2) q OC(O)N(H)(CH2) p +1N(H)(CH2) q Divalent alkenyl group or divalent alkynyl group;

[0095] L is -L1-L2-;

[0096] L1 is a bond, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein the alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl group may be one or more R groups. d Selective substitution;

[0097] L2 is a bond or alkyl group, wherein one or more -L i - Can be selectively inserted between any two adjacent carbon atoms;

[0098] -L i-is-N(R) a )-, -O-, -S-, -C(O)-, -S(O2)-, -OC(O)-, -C(O)O-, -OSO2-, -S(O2)O-, -C(O)S-, -SC(O)-, -C(O)C(O)-, -C(O)N(R a -N(Ra)C(O)- -S(O2)N(R) a )-、-N(R a )S(O2)-, -OC(O)O-, -OC(O)S-, -OC(O)N(R a )-、-N(R a )C(O)O-、-N(R a )C(O)S-、-N(R a )C(O)N(R a )-, divalent alkenyl group, divalent alkynyl group, divalent cycloalkyl group, divalent heterocyclic group, divalent aryl group, divalent heteroaryl group;

[0099] The two R1 groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group of R1 may be formed by one or more R1 groups. d Selective substitution;

[0100] The two R2 groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heteroalkyl group, wherein the cycloalkyl or heteroalkyl group of the R2 may be formed by one or more R groups. d Selective substitution;

[0101] The two R7 groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heteroalkyl group, wherein the cycloalkyl or heteroalkyl group of the R7 may be formed by one or more R7 groups. d Selective substitution;

[0102] Two Rs 10 The groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the R 10 Cycloalkyl or heterocycloalkyl groups can be produced by one or more R groups. d Selective substitution;

[0103] The R7 and L groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group of R7 and L may be formed by one or more R groups. e Selective substitution;

[0104] R b and R c The groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the Rb and R c Cycloalkyl or heterocycloalkyl groups can be produced by one or more R groups. e Selective substitution;

[0105] Two Rs d The groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the R d Cycloalkyl or heterocycloalkyl groups can be produced by one or more R groups. e Selective substitution;

[0106] Two Rs e The groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the R e The cycloalkyl or heterocycloalkyl group may be optionally substituted by one or more groups selected from H, D, alkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxyl, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, oxy, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;

[0107] Each k, g, m, n, p, and q is independently 0, 1, 2, 3, 4, or 5;

[0108] s is 0 or 1; and

[0109] f is 0 or 1, or a pharmaceutically acceptable salt thereof; dispersed in a solid matrix comprising (a) at least one pharmaceutically acceptable water-soluble polymer carrier, (b) at least one pharmaceutically acceptable surfactant, and optionally (c) at least one pharmaceutically acceptable antioxidant.

[0110] In some embodiments, the compound is represented by formula (A-1):

[0111]

[0112] In some embodiments, the compound is represented by formula (A-2):

[0113]

[0114] In some embodiments, the compound is represented by formula (A-3):

[0115]

[0116] In some embodiments, the compound is selected from the group consisting of:

[0117] (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzene)sulfonyl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0118] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzene)sulfonyl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0119] (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0120] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0121] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0122] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0123] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((5aS,8aR)-5a,6,8,8a-tetrahydrofuran[3,4-b]pyrrolo[3',2':5,6]pyrido[3,2-e][1,4]azin-5(1H)-yl)benzamide,

[0124] (R)-4-(4-((4'-chloro-2'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0125] 4-(4-((4'-tetrahydro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0126] 4-(4-((4'-tetrahydro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)3-nitrophenyl)sulfonyl)benzamide,

[0127] (S)N-((4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0128] (R)N-((4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0129] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0130] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0131] N-((4-((((R)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5)-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0132] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5)-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0133] N-((4-((((R)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5)-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0134] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0135] (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0136] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5)-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0137] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5)-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0138] (S)N-((4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0139] (S)-N-((4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-3,4),5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0140] 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolidine[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-(((S)-5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)benzamide,

[0141] 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolidine[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-(((R)-5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)benzamide,

[0142] N-(((R)-3-((S)-1,4-dioxane-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolidine[3',2':5,6]pyrrolo[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0143] N-(((S)-3-((S)-1,4-dioxane-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolidine[3',2':5,6]pyrrolo[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0144] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrido[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)benzamide,

[0145] (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrido[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)benzamide,

[0146] N-(((R)-3-((S)-1,4-dioxane-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)-4-(4-

[0147] ((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo)

[0148] [3',2':5,6]pyrrolo[2,3-b][1,4]azine-1(7H)-yl)benzamide,

[0149] N-(((S)-3-((S)-1,4-dioxane-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)-4-(4-

[0150] ((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo)

[0151] [3',2':5,6]pyrrolo[2,3-b][1,4]azine-1(7H)-yl)benzamide,

[0152] In some embodiments, the amount of the parent compound equivalent of the compound or salt in the solid dispersion is from about 5% to about 40% (by weight).

[0153] The “parent compound equivalent” described in this article includes the amount of pharmaceutically acceptable salt of the parent compound, equivalent to the molar amount of the parent compound.

[0154] In some embodiments, at least one polymer carrier includes N-vinyl lactam, cellulose ester, cellulose ether, high molecular weight polyalkylene oxide, polyacrylate, polymethacrylate, polyacrylamide, homopolymers and copolymers of vinyl acetate polymers, polyethylene glycol, graft copolymers of polyvinyl caprolactam and polyvinyl acetate, oligomers, polymers and / or mixtures thereof.

[0155] In some embodiments, at least one polymer carrier includes povidone, convitaminone (such as...) VA64 type covitamin), HPMCs, graft copolymers of polyethylene glycol / polycaprolactam / polyvinyl acetate, and / or mixtures thereof; or, at least one polymer carrier comprises, substantially comprises, or contains VA64 type covitone.

[0156] In some embodiments, at least one surfactant comprises a nonionic surfactant.

[0157] In some embodiments, at least one surfactant is a nonionic surfactant.

[0158] In some embodiments, at least one surfactant includes polyoxyethylene glycerol ester, fatty acid monoester of sorbitol, polysorbate (e.g., ... 80 brand polysorbate 80 or polyoxyethylene (20) sorbitol monooleate), α-tocopherol polyethylene glycol succinate (TPGS) and / or mixtures thereof.

[0159] In some embodiments, at least one antioxidant includes ascorbic acid, ascorbate, bisulfite, unsymmetrical disulfide, sulfite, curcumin, curcumin derivatives, ursolic acid, resveratrol, resveratrol derivatives, alpha-lipoic acid, thioglycerol, a polyphenol, catarrhalmycin, grape seed extract, green tea extract, citric acid, methionine, cysteine, glutathione, tocopherol, propyl gallic acid, sodium thioglycolate, sodium formaldehyde sulfonate, ascorbate palmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin, vitamin E, uric acid, and / or mixtures thereof.

[0160] In some embodiments, at least one antioxidant includes ascorbic acid or ascorbate ester.

[0161] In some embodiments, at least one antioxidant is ascorbic acid or ascorbate ester.

[0162] In some embodiments, the solid dispersion further includes at least one flow aid.

[0163] In some embodiments, at least one flow aid comprises colloidal silica.

[0164] In some embodiments, the parent compound equivalent of the compound or salt is about 5% to 40% (by weight), the amount of at least one polymer carrier is about 40% to 85% (by weight), the amount of at least one surfactant is about 2.5% to 20% (by weight), and the amount of at least one antioxidant is about 0.25% to 5% (by weight).

[0165] In some embodiments, the parent compound equivalent of the compound or salt is about 5% to 25% (e.g., about 12-20%, about 15-20%, or about 18%), the amount of at least one polymer carrier is about 50% to 80% (e.g., about 60-80%, or about 70-80%), the amount of at least one surfactant is about 2.5% to 15% (e.g., about 5-10%, or about 7-9%), and the amount of at least one antioxidant is about 0.5% to about 2.5% (e.g., about 0.5-2%, or about 0.5-1%).

[0166] In some embodiments, the solid dispersion further comprises at least one disintegrant (e.g., 10-30 wt% Croscarmellose Sodium), at least one lubricant (e.g., 0.2-1.0 wt% Sodium Stearyl Fumarate), and / or at least one coating (e.g., 2-5 wt% Sodium Stearyl Fumarate). II 85F92209-CN Yellow).

[0167] In some embodiments, the compound is

[0168] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0169] (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0170] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzene)sulfonyl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0171] (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzene)sulfonyl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0172] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0173] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0174] 4-(4-((4'-tetrahydro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0175] 4-(4-((4'-tetrahydro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((4-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)3-nitrophenyl)sulfonyl)benzamide,

[0176] (S)N-((4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0177] (R)N-((4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0178] (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0179] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0180] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5)-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0181] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrrolo[2,3-b][1,4]azin-1(7H)-yl)benzamide.

[0182] In some embodiments, at least one polymer carrier is a convitaminone or a vinylpyrrolidone-vinyl acetate copolymer (e.g., VA64 (brand / type of covitamin). The term "VA64" as used in this article... "VA64" refers to VA64 type covitamin, whose physical, chemical and / or biological properties are similar to those of the specific brand of covitamin used in the formulations of this invention (i.e., The brands are essentially the same. For simplicity, this term includes (but is not limited to) the specific brand of covitone (i.e., [brand name missing]) used in the formulations of this invention. (Brand). This also applies to products with any other brand name or trademark, such as... 80 Brands and Others Branded products.

[0183] In some embodiments, at least one surfactant is a polysorbate (such as polysorbate 80 surfactant).

[0184] In some embodiments, at least one antioxidant is ascorbic acid or sodium ascorbate.

[0185] In some embodiments, the solid dispersion further includes at least one flow aid.

[0186] In some embodiments, at least one flow aid comprises colloidal silica.

[0187] In some embodiments, the solid dispersion is prepared using hot melt extrusion (HME), or the solid dispersion is a hot melt extrusion (HME) formulation.

[0188] In some embodiments, the solid dispersion comprises any of the formulations of Examples 7-24 and 26-29, and wherein the API is any of the compounds described herein, including any of the following compounds:

[0189] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0190] (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0191] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzene)sulfonyl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0192] (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzene)sulfonyl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0193] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0194] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0195] 4-(4-((4'-tetrahydro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0196] 4-(4-((4'-tetrahydro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((4-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)3-nitrophenyl)sulfonyl)benzamide,

[0197] (S)N-((4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0198] (R)N-((4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0199] (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0200] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0201] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5)-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0202] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrrolo[2,3-b][1,4]azin-1(7H)-yl)benzamide.

[0203] In some embodiments, when a dose of 100 mg of the solid dispersion is administered orally to a 5-10 kg beagle via gavage, the solid dispersion exhibits an AUC of at least about 25,000-150,000 h*ng / ml, at least about 30,000-100,000 h*ng / ml, at least about 40,000-80,000 h*ng / ml, or at least about 50,000-60,000 h*ng / ml. (0-t) Numerical value.

[0204] The present invention also provides a process for preparing a solid dispersion, comprising: (a) placing (i) an active pharmaceutical ingredient (API) at a high temperature, comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, (ii) a pharmaceutically acceptable water-soluble polymer carrier, (iii) a pharmaceutically acceptable surfactant, and optionally, (iv) a pharmaceutically acceptable antioxidant, to provide an extrudable semi-solid mixture:

[0205]

[0206] in

[0207] Q4 is a cycloalkyl, cycloalkenyl, heterocyclic, heterocyclic, aryl, heteroaryl, or spirocyclic heterocycle;

[0208] Q5 is a cycloalkyl, cycloalkenyl, heterocyclic, heterocyclic, aryl, heteroaryl, or spirocyclic heterocycle;

[0209] Each R1, R2, R7, R8, R9 and R 10Independently, it is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, spiroheterocyclic, heterocyclic alkenyl, aryl, heteroaryl, halogen, nitro, oxo, cyano, OR a SR a alkyl-R a NH(CH2) p R a C(O)R a S(O)R a SO2R a C(O)OR a OC(O)R a NR b R c C(O)N(R) b )R c 、N(R b )C(O)R c -P(O)R b R c ,-alkyl-P(O)R b R c -S(O)(=N(R) b ))R c -N=S(O)R b R c =NR b SO2N(R) b )R c or N(R) b SO2R c The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups may be derived from one or more R groups. d Selective substitution;

[0210] R a R b R c R bb R cc and R d Independently, it is H, D, alkyl, spiroalkyl, alkenyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, heterocyclic, spirocycloalkyl, heterocyclic, aryl, or

[0211] Heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocyclic alkenyl, aryl, or heteroaryl group can be one or more R e Selective substitution;

[0212] R eIndependently, it is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxyl, =O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;

[0213] Z1 is a bond, (CH2) p ,N(H),O,S,C(O),S(O2),OC(O),C(O)O,OSO2,S(O2)O,C(O)S,SC(O),C(O)C(O),C(O)N(H),N(H)C(O) , S(O2)N(H), N(H)S(O2), OC(O)O, OC(O)S, OC(O)N(H), N(H)C(O)O, N(H)C(O)S, N(H)C(O)N(H), (CH2) p N(H)(CH2) q (CH2) p N(H)C(O)(CH2) q (CH2) p C(O)N(H)(CH2) q OC(O)N(H)(CH2) p +1N(H)(CH2) q Divalent alkenyl group or divalent alkynyl group;

[0214] L is -L1-L2-;

[0215] L1 is a bond, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein the alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl group may be one or more R groups. d Selective substitution;

[0216] L2 is a bond or alkyl group, wherein one or more -L i - Can be selectively inserted between any two adjacent carbon atoms;

[0217] -L i -is-N(R) a )-, -O-, -S-, -C(O)-, -S(O2)-, -OC(O)-, -C(O)O-, -OSO2-, -S(O2)O-, -C(O)S-, -SC(O)-, -C(O)C(O)-, -C(O)N(R a -N(Ra)C(O)- -S(O2)N(R) a )-、-N(R a)S(O2)-, -OC(O)O-, -OC(O)S-, -OC(O)N(R a )-、-N(R a )C(O)O-、-N(R a )C(O)S-、-N(R a )C(O)N(R a )-, divalent alkenyl group, divalent alkynyl group, divalent cycloalkyl group, divalent heterocyclic group, divalent aryl group, divalent heteroaryl group;

[0218] The two R1 groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group of R1 may be formed by one or more R1 groups. d Selective substitution;

[0219] The two R2 groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heteroalkyl group, wherein the cycloalkyl or heteroalkyl group of the R2 may be formed by one or more R groups. d Selective substitution;

[0220] The two R7 groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heteroalkyl group, wherein the cycloalkyl or heteroalkyl group of the R7 may be formed by one or more R7 groups. d Selective substitution;

[0221] Two Rs 10 The groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the R 10 Cycloalkyl or heterocycloalkyl groups can be produced by one or more R groups. d Selective substitution;

[0222] The R7 and L groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group of R7 and L may be formed by one or more R groups. e Selective substitution;

[0223] R b and R c The groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the R b and R c Cycloalkyl or heterocycloalkyl groups can be produced by one or more R groups. e Selective substitution;

[0224] Two Rs d The groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the R d Cycloalkyl or heterocycloalkyl groups can be produced by one or more R groups. eSelective substitution;

[0225] Two Rs e The groups, together with the atoms they are attached to, may optionally form a cycloalkyl or heterocycloalkyl group, wherein the R e The cycloalkyl or heterocycloalkyl group may be optionally substituted by one or more groups selected from H, D, alkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxyl, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, oxy, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;

[0226] Each k, g, m, n, p, and q is independently 0, 1, 2, 3, 4, or 5;

[0227] s is 0 or 1; and

[0228] f is 0 or 1;

[0229] (b) Extrusion of semi-solid mixtures; and

[0230] (c) Cooling the resulting extrudate to provide a solid matrix including a polymer carrier and a surfactant, and to disperse the compound or its salt therein in a substantially non-crystalline form.

[0231] In some embodiments, the compound is represented by formula (A-1):

[0232]

[0233] In some embodiments, the compound is represented by formula (A-2):

[0234]

[0235] In some embodiments, the compound is represented by formula (A-3):

[0236]

[0237] In some embodiments, the API, polymer carrier, surfactant, and antioxidant are mixed together before being subjected to high temperatures.

[0238] In some embodiments, the API, polymer carrier, surfactant, and antioxidant are mixed together when subjected to high temperatures.

[0239] In some embodiments, the high temperature is approximately 100°C to 200°C.

[0240] In some embodiments, the high temperature is about 125°C to 175°C, or about 140-160°C.

[0241] In some embodiments, the process further includes calendering the extrudate before or during cooling.

[0242] In some embodiments, the polymer carrier comprises convitaminone, for example... VA64 type covitone.

[0243] In some embodiments, the surfactant includes polysorbates, such as TWEEN 80 polysorbate 80.

[0244] In some embodiments, the antioxidant includes ascorbic acid or sodium ascorbate.

[0245] The present invention also provides an orally available pharmaceutical dosage form, including the solid dispersion of the present invention as described herein.

[0246] The present invention also provides a method for treating neoplastic, immune, or autoimmune diseases, comprising orally administering a therapeutically effective amount of the solid dispersion of the present invention to a subject suffering from the disease.

[0247] In some embodiments, the disease is a neoplastic disease, such as cancer, mesothelioma, bladder cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma of the skin or eye, ovarian cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, bone cancer, colon cancer, rectal cancer, anal cancer, stomach cancer, gastrointestinal (stomach, colon, and / or duodenal) cancer, chronic lymphocytic leukemia, acute lymphoblastic leukemia, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, testicular cancer, hepatocellular (liver and / or bile duct) cancer, primary or secondary central nervous system cancer. Tumors, primary or secondary brain tumors, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, follicular lymphoma, T-cell or B-cell lymphoma, melanoma, multiple myeloma, oral cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, kidney and / or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumors, primary central nervous system lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, spleen cancer, fibrosarcoma, neuroblastoma, retinoblastoma, and combinations thereof.

[0248] In some embodiments, the neoplastic disease is chronic lymphocytic leukemia or acute lymphoblastic leukemia.

[0249] In some embodiments, the neoplastic disease is non-Hodgkin's lymphoma or Hodgkin's lymphoma.

[0250] In some embodiments, the disease is an immune or autoimmune disease.

[0251] In some embodiments, the solid dispersion is administered at a parent compound equivalent of about 10 to about 1,000 mg of compound of formula A or its salt per day, with an average treatment interval of about 6 hours to 7 days.

[0252] In some embodiments, the compound is selected from the group consisting of:

[0253] (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzene)sulfonyl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0254] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzene)sulfonyl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0255] (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0256] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0257] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0258] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0259] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((5aS,8aR)-5a,6,8,8a-tetrahydrofuran[3,4-b]pyrrolo[3',2':5,6]pyrido[3,2-e][1,4]azin-5(1H)-yl)benzamide,

[0260] (R)-4-(4-((4'-chloro-2'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0261] 4-(4-((4'-tetrahydro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0262] 4-(4-((4'-tetrahydro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((4-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)3-nitrophenyl)sulfonyl)benzamide,

[0263] (S)N-((4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0264] (R)N-((4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0265] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,

[0266] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0267] N-((4-((((R)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5)-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0268] N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5)-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0269] N-((4-((((R)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5)-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0270] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0271] (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0272] (S)N-((4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0273] (S)-N-((4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-3,4),5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0274] 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolidine[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-(((S)-5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)benzamide,

[0275] 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolidine[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-(((R)-5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)benzamide,

[0276] N-(((R)-3-((S)-1,4-dioxane-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolidine[3',2':5,6]pyrrolo[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0277] N-(((S)-3-((S)-1,4-dioxane-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolidine[3',2':5,6]pyrrolo[2,3-b][1,4]azin-1(6H)-yl)benzamide,

[0278] (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrido[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)benzamide,

[0279] (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrido[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)benzamide,

[0280] N-(((R)-3-((S)-1,4-dioxane-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrrolo[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0281] N-(((S)-3-((S)-1,4-dioxane-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]azin-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrrolo[2,3-b][1,4]azin-1(7H)-yl)benzamide,

[0282] Having described the general aspects of the invention, the following sections will describe various aspects of the invention in more detail.

[0283] Part 1: Chemical Synthesis

[0284] In one embodiment, the active pharmaceutical ingredient (or API) present in the solid dispersion is a compound of formula (A).

[0285] In another embodiment, the API of the solid dispersion of the present invention is a compound specifically identified in WO / 2017 / 132474, WO / 2019 / 040550, WO / 2019 / 040573, PCT / US2019 / 047404, and PCT / US2019 / 047403, as well as pharmaceutically acceptable salts of such compounds, whether or not these compounds are individually contained in Formula A. The compounds in these samples and the illustrative procedures for their synthesis are described again below.

[0286] In another embodiment, the API present in the solid dispersion is selected from compounds and their pharmaceutically acceptable salts, but only to the extent that these samples are individually included in Formula A of the present invention. The full disclosures of WO / 2017 / 132474, WO / 2019 / 040550, WO / 2019 / 040573, PCT / US2019 / 047404, and PCT / US2019 / 047403 are hereby expressly incorporated by reference.

[0287] The synthetic descriptions of representative compounds are given below. As will be apparent to those skilled in the art, other compounds of formula A can be prepared using essentially similar methods. When providing NMR data, 1 HPLC spectra were obtained at an XL400 (400 MHz) and reported in ppm at low magnetic field for Me4Si. Proton number, fold, and coupling constant are expressed in Hertz. For HPLC data, analysis was performed using an Agilent 1100 system. For LC / MS data, analysis was performed using an Applied Biosystems API-100 mass spectrometer and a Shimadzu SCL-10A LC column.

[0288] INT-1: Preparation of 1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine

[0289] Synthesis of 2-bromo-4,4-dimethylcyclohexane-1-carboxaldehyde 2: A solution of anhydrous chloroform (57 mL) and anhydrous N,N-dimethylformamide (9 mL) was cooled to ~3°C (internal temperature) under nitrogen atmosphere, and then phosphorus tribromide (10 mL, 0.1 mol) was added dropwise at a controlled rate, maintaining the reaction at ~3°C. After the addition of phosphorus tribromide, the reaction was slowly heated to approximately 10°C, then the temperature was raised to 70°C and maintained for 30 minutes. The reaction was cooled to room temperature, and 3,3-dimethylcyclohexanone 1 (5 g, 0.04 mol) was slowly added over 20 minutes. After the addition was complete, the reaction was heated to 70°C and stirred for 1.5 hours. The mixture was then cooled to 0°C, and 4M sodium acetate solution (53 mL) was slowly added. The pH of the resulting solution was adjusted to ~7 with 5M NaOH solution, and the mixture was then extracted with heptane (100 mL x 3). The combined organic components were dried with Na2SO4, filtered, and concentrated under reduced pressure to give 2-bromo-4,4-dimethylcyclohexane-1-encarbaldehyde 2 (4 g, 49%) as a yellow oil.

[0290] Synthesis of 2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-carboxaldehyde 3: A degassed solution of 2-bromo-4,4-dimethylcyclohexane-1-ene 2 (5 g, 0.023 mol) and 4-chlorophenylboronic acid (3.6 g, 0.023 mol) in 1,4-dioxane (50 mL) was added to 2 M Na₂CO₃ (20.4 mL) at room temperature. Nitrogen gas was bubbled through the mixture for 2 min, followed by the addition of PdCl₂ (dppf) (0.5 g). The reaction flask was heated to 120 °C and maintained for 3 h. The suspension was then cooled to room temperature and filtered through a Celite filter. The collected solid was washed with additional dichloromethane, and the combined filtrate and washes were concentrated under reduced pressure. Purified by silica gel column chromatography (PE:EA = 20:1), 2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-encarbaldehyde 3 (3 g, 53%) was given as a white solid. MS: 249 [M+H] +

[0291] Synthesis of (2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methanol 4. A solution of 2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enaldehyde 3 (20 g, 80.6 mmol) in MeOH (100 mL) was cooled to 0 °C. NaBH4 (3.1 g, 80.6 mmol) was added to the reaction mixture in portions at a controlled rate, maintaining the reaction temperature between 0 and 5 °C. After the addition, the mixture was stirred at 0 °C for 1 hour. Water was slowly added to the mixture, and the mixture was extracted with EA (200 mL x 3). The organic layer was washed with brine and dry Na2SO4, filtered, and concentrated under reduced pressure to give (2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methanol 4 (15 g, 75%) as a white solid. MS: 233[M+H-H2O] + .

[0292] Synthesis of 1-(2-(bromomethyl)-5,5-dimethylcyclohexane-1-enyl)-4-chlorobenzene 5: A solution of (2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methanol 4 (15 g, 0.060 mol) in Et2O (300 mL) was cooled to 0 °C, and then phosphorus tribromide (7.5 mL) was added dropwise to the mixture. After addition, the mixture was stirred at 0 °C for 1 hour and 90 minutes. H2O was added to the reaction mixture before extraction with EA. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1-(2-(bromomethyl)-5,5-dimethylcyclohexane-1-yl)-4-chlorobenzene 5 (18 g, 96%) as a colorless oil.

[0293] Synthesis of 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane)methyl)piperazine-1-carboxylate—A solution of 1-bromo-2-(bromomethyl)-5,5-dimethyl-1-cyclohexene 5 (21 g, 0.067 mol) and tert-butylpiperazine-1-carboxylate (12.4 g, 0.067 mol) in dichloromethane (200 mL) was added to triethanolamine (12.2 g, 0.12 mol) at room temperature. The reaction mixture was stirred for 2 h, and the reaction mixture was concentrated under reduced pressure to give a crude product. Purification was performed by silica gel column chromatography (PE:EA = 20:1) to give tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazine-1-carboxylate 6 (21 g, 75%).

[0294] Synthesis of 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazine hydrochloride: Hydrochloric acid (50 mL) was added to a solution of tert-butyl 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane)methyl)piperazine-1-carboxylate 6 (30 g, 0.072 mol) in MeOH (20 mL). The reaction was stirred for 24 h, and then concentrated under reduced pressure. A saturated solution of Na₂CO₃ was added to adjust the pH to ~8-9, and the mixture was then extracted with dichloromethane (x²). The combined extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The oil was treated with MeOH / HCl (g) (3M, 500mL) and stirred for 1 hour, then concentrated under reduced pressure to give product 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazine hydrochloride IM-14-1 (23g, 83%). MS: 319 [M+H] +1 H NMR (400MHz, DMSO) δ11.51(s,1H),9.60(s,1H),9.18(s,1H),7.45(d,J=8.2Hz,2H),7.15(d,J=8. 0Hz,2H),3.43(s,8H),2.84(s,2H),2.39(s,2H),2.03(s,2H),1.45(t,J=6.0Hz,2H),0.96(s,6H).

[0295] INT-2: Preparation of 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide

[0296] In a 500 mL round-bottom three-necked flask equipped with a mechanical stirrer, add 23.7 g (100 mmol) of 4-chloro-3-nitrobenzenesulfonamide, 12.9 g (100 mmol) of DIPEA, 11.5 g (100 mmol) of (tetrahydro-2H-pyran-4-yl)methylamine, and 200 mL of acetonitrile. Adjust the reaction mixture to an internal temperature of 80 °C and stir for at least 12 hours. Cool the product solution to 40 °C and stir for at least 1 hour until precipitation is observed. Further cool the product slurry to 20 °C. Slowly add water (80 mL) over at least 1 hour and cool the mixture to 10 °C, stirring for at least 2 hours, then filter and collect. Wash the wet filter cake with a 1:1 acetonitrile:water mixture (40 mL). Rinse the wet filter cake with water (80 mL) at 40 °C for at least 1 hour, then filter and collect. The wet filter cake was rinsed with water (20 mL) and dried under vacuum at 75 °C to give 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (24.5 g, 78%) as an orange solid. 1H NMR (400MHz, DMSO) δ8.60(t,J=5.9Hz,1H),8.48(d,J=2.2Hz,1H),7.84(dd,J=9.2,2.0Hz,1H),7.54–7.18(m,3H),3.86(dd,J=11.3,3.2 Hz,2H),3.35(s,2H),3.27(t,J=10.9Hz,2H),1.92(ddd,J=11.2,7.4,3.9Hz,1H),1.62(d,J=11.4Hz,2H),1.27(qd,J=12.3,4.4Hz,2H).

[0297] INT-3: Preparation of 4-[[(4-fluorooxy-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide

[0298] In a 50 mL round-bottom flask, (4-fluorooxy-4-yl)methylamine hydrochloride (500 mg, 2.95 mmol, 1.00 equivalence), 4-fluoro-3-nitrobenzene-1-sulfonamide (650 mg, 2.95 mmol, 1.00 equivalence), tetrahydrofuran (15 mL), and Cs₂CO₃ (2.8 g, 8.59 mmol, 3.00 equivalence) were added. The resulting solution was stirred in an oil bath at 50 °C for 14 hours. The reaction mixture was cooled to room temperature. The resulting mixture was filtered and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (4:1). 650 mg (66%) of 4-[[(4-fluorooxy-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide was produced as a yellow solid. LCMS(ES,m / z):M+1:334.H-NMR:(300MHz,DMSO,ppm):δ8.58(t,J=6.3Hz,1H),8.49(d,J=2.1Hz,1H),7.90– 7.80(m,1H),7.44(d,J=9.3Hz,1H),7.34(s,2H),3.87–3.70(m,4H),3.61–3.50(m,2H),1.95–1.70(m,4H).

[0299] INT-4: Preparation of (S)-4-((1,4-dioxane-2-yl)methylamino)-3-nitrobenzenesulfonamide

[0300] Synthesis of (R)-1-chloro-3-(2-chloroethoxy)propane-2-ol: (R)-2-(chloromethyl)ethylene oxide (500.0 g, 5.4 mol, 1.00 equivalent) was slowly added at 45 °C to a stirred solution of 2-chloroethanol (870.0 g, 10.8 mol, 2.00 equivalent) and BF3·Et2O (38.0 g, 27 mmol, 0.05 equivalent). The reaction mixture was heated in an oil bath at 45 °C for 3 hours. The reaction mixture was cooled to room temperature, and diethyl ether (100 mL) was added to the solution. The organic layer was washed with water (2 x 300 mL), dried over magnesium sulfate, and concentrated to give (R)-1-chloro-3-(2-chloroethoxy)propane-2-ol (800.0 g, quantitative), a light brown liquid. ¹H NMR: (300 MHz, DMSO-d) 6, ppm)δ: 3.85-3.47 (m, 9H).

[0301] Synthesis of (R)-2-((2-chloroethoxy)methyl)ethylene oxide. (R)-1-chloro-3-(2-chloroethoxy)propane-2-ol (800.0 g, crude, 4.7 mol, 1.0 equivalent) was added dropwise to a stirred solution of NaOH (465.0 g, 11.6 mol, 2.5 equivalent) in water (500 mL) in an ice bath. The ice bath was immediately removed after the addition of (R)-1-chloro-3-(2-chloroethoxy)propane-2-ol. After stirring at ambient temperature for 2 hours, diethyl ether (1.5 L) and water (500 mL) were added. The organic layer was washed with water (1 x 50 mL), dried over sodium sulfate, and concentrated to give (R)-2-((2-chloroethoxy)methyl)ethylene oxide (400.0 g) as a light brown liquid. ¹H-NMR: (300 MHz, CDCL₃) , ppm)δ:3.82-3.52(m,5H),3.40-3.35(m,1H),3.11-3.09(m,1H),2.75-2.73.

[0302] Synthesis of (S)-(1,4-dioxane-2-yl)methanol. (R)-2-((2-chloroethoxy)methyl)ethylene oxide (400.0 g, 2.94 mol, 1.0 equivalent) was added at room temperature to a solution of NaOH (294.0 g, 7.35 mol, 2.5 equivalent) in water (2900 mL). The reaction mixture was heated in an oil bath at 90 °C for 2 h. The resulting solution was cooled to room temperature, and the pH was adjusted to 5 with hydrochloric acid (6 M). The mixture was concentrated, and the residue was distilled under vacuum (90-95 °C, 0.1 kPa) to give (S)-(1,4-dioxane-2-yl)methanol (110 g, 31.7%) as a colorless oil. ¹H-NMR: (300 MHz, CDCL₃) ,ppm)δ:3.85-3.42(m,9H),2.15(bs,1H).

[0303] Synthesis of (R)-(1,4-dioxane-2-yl)methyl methanesulfonate. A mixture of (S)-(1,4-dioxane-2-yl)methanol (50.0 g, 0.42 mol, 1.0 equivalent), triethanolamine (63.6 g, 0.63 mol, 1.5 equivalent), and DCM (500 mL) was placed in an ice bath, and MsCl (48.1 g, 0.42 mol, 1.0 equivalent) was added dropwise. The ice bath was then removed, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water (2 x 50 mL), the organic phase was dried over sodium sulfate, and the concentrate was concentrated to give a light brown oil (R)-(1,4-dioxane-2-yl)methyl methanesulfonate (71.0 g, 83%). ¹H-NMR: (300 MHz, CDCL₃) , ppm)δ:4.23-4.20(m,2H),3.82-3.56(m,6H),3.50-3.40(m,1H),3.02(m,3H).

[0304] Synthesis of (S)-(1,4-dioxane-2-yl)methylamine: A solution of (R)-(1,4-dioxane-2-yl)methyl methanesulfonate (70.0 g, 0.36 mol, 1.0 equivalent) in NH3·MeOH (7 M, 500 mL) was stirred at 80 °C for 12 h in a 1000 mL autoclave. The reaction mixture was cooled to room temperature and concentrated to give a light brown oily substance (S)-(1,4-dioxane-2-yl)methylamine (30.0 g, 73%). NMR: (300 MHz, DMSO-d) 6, ppm)δ:8.27(bs,2H),3.82-3.42(m,6H),3.24-3.20(m,1H),2.98-2.62(m,2H).

[0305] Synthesis of (S)-4-((1,4-dioxane-2-yl)methylamine)-3-nitrobenzenesulfonamide: (S)-(1,4-dioxane-2-yl)methylamine (25.0 g, 0.21 mol, 1.0 equivalent), 4-fluoro-3-nitrobenzenesulfonamide (46.0 g, 0.21 mol, 1.0 equivalent), and Cs₂CO₃ (137.3 g, 0.42 mol, 2.0 equivalent) were stirred in THF (700 mL) at 50 °C for 6 hours. LC-MS showed that the materials were completely consumed. The reaction mixture was cooled to room temperature and poured into water (3500 mL). The mixture was filtered, the filter cake was collected and dried in an oven to give a yellow solid (S)-4-((1,4-dioxane-2-yl)methylamino)-3-nitrobenzenesulfonamide (60.0 g, 89.5%). H-NMR: (300MHz, DMSO-d) 6, ppm)δ:8.52-8.47(m,2H),7.86-7.83(m,1H),7.28-7.00(m,3H),3.82-3.29(m,9H).

[0306] INT-5: Preparation of methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)benzoate:

[0307] In a 250 mL round-bottom flask, a solution of Sample 1-1, consisting of 1-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazine (15.09 g, 47.32 mmol, 1.00 equivalence), DIEA (12.9 g, 99.81 mmol, 2.00 equivalence), and 2-bromo-4-fluorobenzoate (11.6 g, 49.78 mmol, 1.00 equivalence) in DMA (150 mL), was added. The resulting solution was stirred at 100 °C for 12 hours. The reaction mixture was cooled to room temperature. Then, 50 mL of water was added to stop the reaction. The resulting solution was extracted with 3 x 100 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 x 100 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1–1:5). This yielded 7 g of crude methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)benzoate as a yellow oil. LC-MS (ES, m / z): M+1 = 533,531.

[0308] INT-6: Preparation of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonyl)benzamide

[0309] The synthesis of methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)benzoate was carried out in a 20,000 mL round-bottom flask containing 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin dihydrochloride (600 g, 1.53 mol, 1 equivalent), methyl 2-bromo-4-fluorobenzoate (357 g, 1.53 mol, 1 equivalent), DBU (319 g, 6.12 mol, 4 equivalent), and DMSO (8000 mL). The resulting solution was stirred at 70 °C for 20 h until LC-MS showed complete consumption of the materials. The resulting mixture was cooled to room temperature and poured into water (32 L). The mixture was filtered, the filter cake was collected, washed with water (3000 mL × 3), and dried in an oven to give 740 g (Y: 91%) of methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)benzoate, as a white solid. ¹H NMR ¹H-NMR ¹H-NW-4-55-400: (300 MHz, DMSO-d) 6, ppm)δ:7.73(d,J=9.0Hz,1H),7.42-7.39(m,2H),7.18-7.12(m,3H),6.97-6.94(m,1H),4.00-3.84(m,2H),3.76(s,2H),3 .57(s,3H),3.51-3.33(m,4H),2.79-2.60(m,2H),2.32-2.30(m,2H),2.03-1.97(m,2H),1.47-1.45(m,2H),0.96(s,6H).

[0310] Synthesis of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)benzoic acid: In a 20,000 mL round-bottom flask, methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)benzoate (730 g, 1.37 mol, 1 equivalent), LiOH (131.5 g, 5.48 mol, 4 equivalents) and MeOH / THF / water (4500 mL / 3000 mL / 1000 mL) were added. The resulting solution was stirred at 70 °C for 16 h until LCMS showed complete consumption of the material. The resulting mixture was cooled to room temperature and concentrated. The residue was diluted with water (5000 mL), and the pH of the mixture was adjusted to 3-5 with hydrochloric acid (6 M). The mixture was then filtered, and the filter cake was collected and dried in an oven to give 650 g (Y: 93%) of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)benzoic acid, a white solid. ¹H NMR spectroscopy: 55-400 (300 MHz, DMSO-d) 6, ppm)δ:10.60(bs,1H),7.73(d,J=8.4Hz,1H),7.42-7.39(m,2H),7.14-7.11(m,3H),6.95-6.92(m,1H),4.00-3.84(m,2H), 3.76(s,2H),3.51-3.33(m,4H),2.79-2.60(m,2H),2.32-2.30(m,2H),2.03-1.97(m,2H),1.47-1.45(m,2H),0.97(s,6H).

[0311] Synthesis of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonyl)benzamide: In a 20,000 mL round-bottom flask, 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonyl)benzamide was added. (-Alkenyl)methyl)piperazin-1-yl)benzoic acid (583 g, 1.13 mol, 1 equivalent), DCM (10 L), 3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (338 g, 1.07 mol, 0.95 equivalent), EDCI (326 g, 1.7 mol, 1.5 equivalent), DMAP (551 g, 4.52 mol, 4 equivalent). The resulting solution was stirred overnight at 25°C until LCMS showed complete consumption of the material. The resulting mixture was then added to dilute hydrochloric acid (1.0 M) (1000 mL x 3), saturated sodium bicarbonate (1000 mL x 3), and brine (1000 mL x 1), and the organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated to give 857 g of product (Y: 93%), 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonyl)benzamide, as a brownish-yellow solid. LC-MS: (ES, m / z): M+1=814 / 816 / 818, R, T=2.01 min. HCl-NMR: (300 MHz, DMSO-d) 6, ppm)δ:8.63-8.61(m,2H),7.94-7.92(m,1H),7.37-7.35(m,3H),7.27-7.24 (m,1H),7.05-7.02(m,3H),6.86-6.83(m,1H),3.87-3.82(m,2H),3.37-3.2 3(m,8H),2.92(s,2H),2.50-2.38(m,4H),2.22-2.20(m,2H),2.00-1.97(m, 2H),1.64-1.60(m,2H),1.48-1.46(m,2H),1.26-1.20(m,2H),0.97(s,6H).

[0312] Preparation of Compound 2-1: 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonyl)benzamide

[0313] In a 250 mL round-bottom flask, 1-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl-1-yl]methyl]piperazine (15.09 g, 47.32 mmol, 1.00 equivalent), DIEA (12.9 g, 99.81 mmol, 2.00 equivalent), and methyl 2-bromo-4-fluorobenzoate (11.6 g, 49.78 mmol, 1.00 equivalent) were added to the DMA (150 mL). The resulting solution was stirred at 100 °C for 12 hours. The reaction mixture was cooled to room temperature. Then, 50 mL of water was added to stop the reaction. The resulting solution was extracted with 3 x 100 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 x 100 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1–1:5). 7 g of crude methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)benzoate was obtained as a yellow oil. LC-MS (ES, m / z): M+1 = 533, 531.

[0314] In a 40 mL round-bottom flask, 10 mL of dioxane-1,3(7),5,8-tetraene (175 mg, 0.57 mmol, 1.00 equivalence) of 4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1,3(7),5,8-tetraene (175 mg, 0.57 mmol, 1.00 equivalence), Cs2CO3 (560 mg, 1.72 mmol, 3.00 equivalence), XantPhos Pd G2 (CAS:1375325-77-1) (53 mg, 0.06 mmol, 0.10 equivalence), and methyl-2-bromo-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methylpiperazin-1-yl)benzoate (334.7 mg, 0.63 mmol, 1.10 equivalence). The resulting solution was stirred at 110°C for 2 hours. The reaction mixture was cooled to room temperature. The solid was filtered off. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1-1:3). 200 mg (46%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1,3(7),5,8-tetraen-10-yl)benzoate was obtained as a yellow oil. LC-MS (ES, m / z): M+1 = 756, R, T = 1.252 min. Residence time was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient.

[0315] In a 50 mL round-bottom flask, 20 mL of tetrahydrofuran (20 mL) was added to 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl)benzoate (200 mg, 0.26 mmol, 1.00 equivalent), TBAF (3 mg, 0.01 mmol), and ethane-1,2-diamine (3 mL). The resulting solution was stirred at 60°C for 24 hours. The reaction mixture was cooled to room temperature. Then 30 mL of water was added to stop the reaction. The resulting solution was extracted with 2 x 30 mL ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2 x 30 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1–1:2). 90 mg (54%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl]benzoate was given as a yellow solid. LC-MS (ES, m / z): M+1 = 626, R, T = 1.052 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient.

[0316] In an 8 mL round-bottom flask, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl]benzoate (90 mg, 0.14 mmol, 1.00 equivalence) and sodium hydroxide (23 mg, 0.57 mmol, 4.00 equivalence) were added. The resulting solution was stirred overnight at 60°C. The reaction mixture was cooled to room temperature. Then 5 mL of water was added to stop the reaction. The pH of the solution was adjusted to 6 with hydrogen chloride (1 mol / L). The resulting solution was extracted with 2 x 10 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 x 10 mL of brine. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1-1:1). The resulting 70 mg (80%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl]benzoic acid was a yellow solid.

[0317] LC-MS (ES, m / z): M+1 = 612, R, T = 1.005 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 μm; eluent A: water (0.05% TFA); eluent B: acetonitrile; linear gradient.

[0318] In an 8 mL round-bottom flask, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl]benzoic acid (35 mg, 0.06 mmol, 1.00 equivalence), 4-dimethylaminopyridine (27.8 mg, 0.23 mmol, 4.00 equivalence), 3-nitro-4-[(oxalate-4-ylmethyl)amino]benzene-1-sulfonamide (21.7 mg, 0.07 mmol, 1.20 equivalence), and EDCI (22 mg, 0.11 mmol, 2.00 equivalence) were added to dichloromethane (5 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC under the following conditions (Waters-2767): column, X-bridge RP18, 5 μm, 19 × 100 mm; mobile phase, 0.03% ammonia (0.03% NH4HCO3 and NH4OH) and CH3CN (32% CH3CN, reaching 52% within 6 min); detector, UV 254 nm. 28.3 mg (54%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-([3-nitro-4-[(oxalo-4-ylmethyl)amino]benzene]sulfonyl)-2-[13-oxalo-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetarisane-1,3(7),5,8-tetraen-10-yl]benzamide was obtained as a yellow solid. LC-MS: (ES, m / z): (ES, m / z): M+1 = 909, R, T = 1.52 min. Residence time was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient.H-NMR: (CDCl3, 300MHz) δ: 8.70 (s, 1H), 8.46 (m, 2H), 8.10-8.06 (m, 1H), 7.89-7.60 (m, 1H),7.10(s,1H),6.94-6.71(m,5H),6.49(s,1H),6.16(s,1H),4.70-4.65(m,2H),4.00 -4.10 (m, 2H), 3.67–3.19 (m, 7H), 3.20–3.00 (m, 4H), 2.78 (s, 1H), 2.58–2.52 (m, 2H), 2.27–2.17 (m, 3H), 2.05–1.98 (m, 4H), 1.74–1.70 (m, 3H), 1.55–1.40 (m, 3H), 0.98 (s, 6H). NMR spectroscopy measurements were performed using a Bruker Avance III HD 300 MHz and BBOF probe.

[0319] Preparation of Compound 2-2: 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((4-4-(((fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)benzenesulfonyl)benzamide

[0320] In an 8 mL round-bottom flask, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl]benzoic acid (35 mg, 0.06 mmol, 1.00 equivalence), 4-dimethylaminopyridine (27.8 mg, 0.23 mmol, 4.00 equivalence), EDCI (22 mg, 0.11 mmol, 2.00 equivalence), and 4-[(4-fluorooxy-4-yl)methyl]amino-3-nitrobenzene-1-sulfonamide (22.7 mg, 0.07 mmol, 1.20 equivalence) were added to dichloromethane (5 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC under the following conditions (Waters-2767): column, X-bridge RP18, 5 μm, 19 × 100 mm; mobile phase, 0.03% ammonia (0.03% NH4HCO3 and NH4OH) and CH3CN (32% CH3CN, reaching 52% within 6 min); detector, UV 254 nm. 26.2 mg (50%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-[(4-[[(4-fluorooxy-4-yl)methyl]amino-3-nitrobenzene)benzenesulfonyl]-2-[13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl]benzamide was obtained as a yellow solid. LC-MS: (ES, m / z): (ES, m / z): M+1 = 927, R, T = 1.27 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.H-NMR: (CDCl3, 300MHz) δ: 12.38 (bs, 1H), 8.69 (d, J = 2.1Hz, 1H), 8.58 (t, J = 6.3Hz, 1H), 8.44 (s, 1H), 8.07 (d, J = 9.0 Hz,1H),7.90-7.87(m,1H),7.24-7.22(m,2H),7.08(s,1H),6.94(m,2H),6.85(s,1H),6.80-6.77(m,2H),6.49(s,1H ), 6.14 (s, 1H), 4.74–4.67 (m, 2H), 3.91–3.80 (m, 2H), 3.80–3.44 (m, 6H), 3.17 (m, 4H), 2.77 (s, 1H), 2.22–2.10 (m, 6H), 2.00 (s, 2H), 1.98–1.75 (m, 3H), 1.80–1.60 (m, 2H), 1.55–1.40 (m, 2H), 0.94 (s, 6H). NMR spectroscopy measurements were performed using a Bruker Avance III HD 300 MHz laser and a BBOF probe.

[0321] Preparation of Compounds 2-3: 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl-2,2,3,3-d4)-N-((4-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)benzenesulfonyl)benzamide

[0322] Synthesis of 4-[[2-(trimethylsilyl)ethoxy]methyl](12,12-2H2)-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-11-one: In an 8 mL vial, 90 mg, 0.28 mmol, 1 equivalent of 4-[[2-(trimethylsilyl)ethoxy]methyl](12,12-2H2)-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-11-one, D2O (1 mL), MeOD (1 mL), and Na2CO3 (89.6 mg, 0.85 mmol, 3.00 equivalent) were added. The resulting solution was stirred in an oil bath at 60 °C for 48 h. The resulting solution was extracted with 3 x 3 mL of dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. 60 mg (66%) of 4-[[2-(trimethylsilyl)ethoxy]methyl](12,12-2H2)-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-11-one was given as a yellow solid. (ES, m / z): M+1 = 322. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 μm; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient, from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40 °C; Flow rate: 1.5 mL / min. H-NMR-PH-PHNW-4-34-2: (d-DMSO, 300 ppm): 7.44–7.41 (m, 2H), 6.43–6.42 (d, J = 6 Hz, 1H), 5.46–5.41 (m, 2H), 3.51–3.46 (m, 2H), 1.24 (s, 1H), 0.86–0.79 (m, 4H), -0.04–-0.05 (m, 9H).

[0323] Synthesis of 4-[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraene: In an 8 mL vial, 60 mg (0.19 mmol, 1 equivalent) of 4-[[2-(trimethylsilyl)ethoxy]methyl](12,12-2H2)-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-11-one and 3 mL of THF were placed. LiAlD4 (31.3 mg, 0.75 mmol, 3.99 equivalent) was then added in portions at 0 °C. The resulting solution was stirred overnight at room temperature. Then 1 mL of D2O was added to stop the reaction. The resulting solution was extracted with 3 x 5 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. 25 mg (43.28%) of 4-[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraene was given as a yellow solid. LC-MS-PH-PHNW-4-34-2: (ES, m / z): M+1 = 931. H-NMR-PH-PHNW-4-34-2: (CDCl3,300ppm):7.35(s,1H),7.17-7.15(d,J=6Hz,1H),6.35-6.34(d,J=3Hz,1H ),5.56-5.53(m,2H),3.58-3.52(m,2H),2.08(s,1H),1.28(s,1H),0.93-0.88(m,3H),-0.04--0.05(m,9H).

[0324] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]11.11,12.12-2H4-13-oxalate-2,4,10-triazacyclic[7.4.0.0^[3,7]]tetane-1(9),7-tetraen-10-yl)benzoate: In an 8 mL vial, 4-[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxalate-2,4,10-triazacyclic[7.4.0.0^[3,7]]tetane-1(9),7-tetraen-10-yl)benzoate was placed. 4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraene (25 mg, 0.08 mmol, 1 equivalent), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)benzoate (55.9 mg, 0.11 mmol, 1.3 equivalent), dioxane (5 mL), Cs2CO3 (52.6 mg, 0.16 mmol, 2 equivalent), chloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthon][2-amino-1,1-biphenyl-2-yl]palladium(II) (5 mg). The resulting solution was stirred in an oil bath at 100 °C for 2 hours. After the reaction was complete, the crude solution was concentrated and the residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1-1:1). 20 mg (32.56%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl](11.11,12.12-2H4)-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5-tetraen-10-yl)benzoate was obtained as a yellow oil. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 μm; eluent A: water (0.05% TFA); eluent B:

[0325] Acetonitrile; linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; oven temperature 40°C; flow rate: 1.5 mL / min.

[0326] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11,11,12,12-2H4)-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl)benzoate. In an 8 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9), (20 mg, 0.03 mmol, 1 equivalence), THF (2 mL), TBAF (100 mg, 0.38 mmol, 14.54 equivalence), and ethane-1,2-diamine (1 mL, 0.02 mmol, 0.63 equivalence) were added. The resulting solution was stirred overnight at 70 °C. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1-1:1). 12 mg (72.40%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11.11,12.12-2H4)-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraen-10-yl]benzoate was obtained as a yellow solid. LC-MS-PH-PHNW-4-34-4: (ES, m / z): M+1 = 630. Residence time measurements were performed using a reversed-phase column (C18). LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0327] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl)benzoate: In an 8 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)2-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-yl]methyl]tetane-1(9),2,5,7-tetraen-10-yl)benzoate was added. [12 mg, 0.02 mmol, 1 equivalent] benzoate (12 mg, 0.02 mmol, 1 equivalent), MeOH (1 mL), H₂O (1 mL), THF (1 mL), NaOH (3.0 mg, 0.08 mmol, 3.94 equivalent). The resulting solution was stirred in an oil bath at 50 °C for 14 h. The pH of the solution was adjusted to 5 with hydrochloric acid (1 mol / L). The reaction mixture was concentrated under vacuum. The residue was treated on a silica gel column with PE / EA (1:0–2:3). Nine milligrams (76.71%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11.11,12.12-2H4)-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9,)2,5,7-tetraen-10-yl]benzoic acid were obtained as a grayish-white solid. LC-MS-PH-PHNW-4-34-5: (ES, m / z): M+1 = 616. Residence time was measured using a reversed-phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0328] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-[(4-[[(4-fluorooxy-4-yl)methyl]amino-3-nitrobenzene)benzenesulfonyl)-2-[(11,11,12,12-2H4)-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzamide: In an 8 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl] Piperazine-1-yl)-2-[(11,11,12,12-2H4)-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl]benzoic acid (9 mg, 0.01 mmol, 1 equivalence), 4-[[(4-fluorooxy-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (6.3 mg, 0.02 mmol, 1.3 equivalence), DCM (2 mL), DMAP (7.1 mg, 0.06 mmol, 3.98 equivalence), EDCI (5.6 mg, 0.03 mmol, 2 equivalence). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with dichloroethane / methanol (10:1). Six milligrams (44.10%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(4-fluorooxy-4-yl)methyl]amino-3-nitrobenzene)benzenesulfonyl-2-[(11,11,12,12-2H4)-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide were obtained as a yellow solid. LC-MS-PH-PHNW-4-34-0: (ES, m / z): M+1 = 931. Residence time was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.H-NMR-PH-PHNW-4-34-0: (d-DMSO,300ppm):8.57(s,1H),8.37(s,1H),7.58-7.5 5(m,1H),7.37-7.35(m,3H),7.08-7.05(m,3H),6.87-6.76(m,3H),3.76-3.73(m ,6H),3.57-3.53(m,6H),3.33(m,3H),2.76-2.73(m,2H),2.26-2.20(m,6H),1.9 8(m,2H),1.81-1.76(m,5H),1.41-1.39(m,5H),1.39(m,4H),0.91-0.88(m,6H).

[0329] Preparation of Compounds 2-4: 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrrolo[2,3-b][1,4]azin-1(6H)-yl)benzamide

[0330] Synthesis of tert-butyl-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yloxy)propane-2-ylcarbamate. Tert-butyl-1-hydroxypropane-2-ylcarbamate (2.28 g, 13.05 mmol, 1.50 equivalence), DMF (30 mL), and NaH (0.87 g, 21.75 mmol, 2.50 equivalence) were placed in a 250 mL round-bottom flask at 0 °C for 10 min. 5-Bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (3.0 g, 8.70 mmol, 1.00 equivalence) was added. The resulting solution was stirred overnight at room temperature. The resulting solution was extracted with 200 mL of H₂O. The resulting solution was extracted with 3 x 300 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 x 200 mL of H₂O and 1 x 200 mL of sodium chloride (aq). The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with PE / EA (5:1). 2.2 g (50%) of tert-butyl-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yloxy)propane-2-ylcarbamate was given as a yellow oil. LC-MS-PH-PHNW-4-35-1 (ES, m / z): LC-MS (M+1): 502; RT = 1.50 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 2.0 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0331] Synthesis of tert-butyl-2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azine-1(6H)-carboxylate. In a 100 mL round-bottom flask, tert-butyl-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yloxy)propane-2-ylcarbamate (2.2 g, 4.39 mmol, 1.00 equivalence), dioxane (25 mL), Cs₂CO₃ (4.30 g, 13.17 mmol, 3.00 equivalence), and X-phosPd 3G (1.04 g, 1.317 mmol, 0.30 equivalence) were added. The resulting solution was stirred overnight at 100 °C under N₂. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with PE / EA (3:1). This yielded 1.26 g (68%) of tert-butyl ester 2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azine-1(6H)-carboxylate as a yellow oil, LC-MS-PH-PHNW-4-35-2 (ES, m / z): LC-MS(M+1):420; RT = 1.84 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-ODS, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 2.6 min; Oven temperature 40°C; Flow rate: 1.0 mL / min.

[0332] Synthesis of 2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,6-tetrahydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azine: In a 250 mL round-bottom flask, 1.26 g (3.00 mmol, 1.00 equivalent) of tert-butyl ester 2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azine-1(6H)-carboxylate, 15 mL of DCM, and 10.0 g (30 mmol, 10.0 equivalent) of ZnBr2 were added. The resulting solution was stirred at room temperature for 3 hours and diluted with 50 mL of NaHCO3. The solution was extracted with 3 x 50 mL of DCM, and the organic layers were combined. The resulting mixture was washed with 1 x 50 mL H₂O and 1 x 50 mL sodium chloride (aq). The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with PE / EA (1:1). 800 mg (83%) of 2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,6-tetrahydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azine was obtained as a yellow oil. LC-MS-PH-PHNW-4-35-3 (ES, m / z): LC-MS (M+1): 320; RT = 1.54 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-ODS, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 2.6 min; Oven temperature 40°C; Flow rate: 1.0 mL / min.

[0333] Synthesis of methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzoate: at 100m In a round-bottom L flask, place tert-butyl ester 1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yloxy)propane-2-ylcarbamate (300 mg, 0.94 mmol, 1.00 equivalence), dioxane (15 mL), Cs2CO3 (920 mg, 2.82 mmol, 3.00 equivalence), Xantphos Pd 2G (83 mg, 0.094 mmol, 0.10 equivalence), and 2-bromo-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate (1.0 g, 1.88 mmol, 2.00 equivalence). The resulting solution was stirred overnight at 100°C under N2. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with PE / EA (5:1). 360 mg (50%) of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-6-((2-(trimethyl)ethoxy)methyl)-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzoate was obtained as a yellow oil. LC-MS-PH-PHNW-4-35-4 (ES, m / z): LC-MS (M+1): 770; RT = 1.56 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-ODS, 2.6 μm; eluent A: water (0.05% TFA); eluent B: acetonitrile; linear gradient, from 5% acetonitrile to 100% acetonitrile, 2.6 min; oven temperature 40 °C; flow rate: 1.0 mL / min.

[0334] The synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzoate was carried out in a 100 mL round-bottom flask. 1,1'-Biphenyl]-2-yl]methyl)piperazin-1-yl)-2-(2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzoate (300 mg, 0.39 mmol, 1.00 equivalence), THF (10 mL), TBAF (3.0 g), ethane-1,2-diamine (5 mL). The resulting solution was stirred overnight at 60 °C. The resulting mixture was concentrated under vacuum. The pH of the mixture was adjusted to <7 with 2N hydrochloric acid. The resulting solution was extracted with 3 x 200 mL DCM, and the organic layers were combined. The resulting mixture was washed with 1 x 10 mL H₂O and 1 x 200 mL sodium chloride (aq). The resulting mixture was concentrated under vacuum. 120 mg (48%) of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrole[3',2':5,6]pyridin[2,3-b][1,4]azin-1(6H)-yl)benzoate was obtained as a yellow oil. LC-MS-PH-PHNW-4-35-5 (ES, m / z): LC-MS (M+1): 640; RT = 2.82 min. Residence time was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u HPH-C18, 2.6 microns; Eluent A: Water (0.05% NH4NH3); Eluent B: Methanol; Linear gradient from 10% acetonitrile to 98% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 0.8 mL / min.

[0335] Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrole[3',2':5,6]pyridin[2,3-b][1,4]azin-1(6H)-yl)benzoic acid. In a 50 mL round-bottom flask, methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzoate (70 mg, 0.11 mmol, 1.00 equivalence), MeOH / H₂O (5 / 5 mL), and NaOH (44 mg, 1.10 mmol, 10 equivalence) were added. The resulting solution was stirred at 60 °C for 3 hours. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with dichloroethane / methanol (10:1). 50 mg (73%) of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzoic acid was obtained as a white solid. LC-MS-PH-PHNW-4-35-6 (ES, m / z): LC-MS (M+1): 626; RT = 2.45 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u HPH-C18, 2.6 microns; Eluent A: Water (0.05% NH4NH3); Eluent B: Methanol; Linear gradient from 10% acetonitrile to 98% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 0.8 mL / min.

[0336] Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide: 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)benzamide was placed in a 50 mL one-necked round-bottom flask. [-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzoic acid (40 mg, 0.064 mol, 1.00 equivalent), DCM (4 mL), EDCI (49 mg, 0.256 mol, 4.00 equivalent), DMAP (16 mg, 0.128 mol, 2.00 equivalent), 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide (28 mg, 0.0832 mol, 1.30 equivalent). The resulting solution was stirred overnight at 40 °C. The resulting mixture was concentrated under vacuum. 2.9 mg (70%) of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzene)sulfonyl)-2-(2-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide was obtained as a yellow ointment. LC-MS-PH-PHNW-4-35-0A (ES, m / z): LC-MS (M+1 = 941; RT = 5.02 min). Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Ascentis Express C18, 2.6 μm; eluent A: water (0.05% TFA); eluent B: methanol; linear gradient from 5% acetonitrile to 95% acetonitrile, 7.0 min; oven temperature 40°C; flow rate: 1.0 mL / min.

[0337] Compounds 2-5: (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzene)sulfonyl)-2-(3-methyl-2,3-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzoyl Preparation of amines and (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)benzamide

[0338] Synthesis of 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl](-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-11-one: In a 100 mL round-bottom flask, 5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-ol (1.5 g, 5.37 mmol, 1 equivalent), DMF (50 mL), and K2CO3 (2.2 g, 16.11 mmol, 3 equivalents) were added dropwise. Then, with stirring at 0 °C, 2-chloropropionyl chloride (1.4 g, 10.74 mmol, 2 equivalents) was added dropwise. The resulting solution was stirred overnight at room temperature. Then, 50 mL of water was added to stop the reaction. The solution was extracted with 50 mL of ethyl acetate. The resulting mixture was washed with 2 x 50 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1-1:3). 500 mg (27.93%) of 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraen-11-one was given as a yellow solid. LC-MS-PH-PHNW-4-37-1: (ES, m / z): M+1 = 334, R, T = 1.123 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 μm; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient, from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40 °C; Flow rate: 1.5 mL / min. H-NMR-PH-PHNW-4-37-1: (CDCl3, 300 ppm): 8.34 (s, 1H), 7.63 (d, J = 3 Hz, 1H), 7. 42–7.28 (m, 1H), 6.46 (d, J = 3 Hz, 1H), 5.68 (s, 2H), 4.92–4.85 (m, 1H), 3.63–3.53 (m, 2H), 1.85–1.81 (d, J = 12 Hz, 3H), 0.94–0.89 (m, 2H), -0.154 (s, 9H). NMR spectroscopy measurements were performed using a Bruker Avance III HD 300 MHz laser and a BBOF probe.

[0339] 12-Methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene and (12R or S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene (hypothetical) and (12S or R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy] Synthesis of 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene (hypothetical): In a 100 mL three-necked round-bottom flask, 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraen-11-one (500 mg, 1.50 mmol, 1 equivalent) and THF (20 mL) were placed. LiAlH4 (113.8 mg, 0.75 mmol, 2 equivalents) was then added in portions at 0 °C. The resulting solution was stirred overnight at room temperature. 20 mL of water was then added to stop the reaction. The solid was filtered off. The resulting solution was extracted with 2 x 20 mL ethyl acetate. The resulting mixture was washed with 2 x 20 mL of brine. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1–1:3). 450 mg (93%) of 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene was given as a yellow solid.

[0340] Crude 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene (450 mg) was purified by Chiral-Prep-HPLC under the following conditions: (SHIMADZU LC-20AT): column, CHIRALPAK IC; mobile phase A: n-hexane, phase B: ethanol; detector, 220 nm. 200 mg (44%) (12R or S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene was obtained as a yellow solid (hypothetically).

[0341] 200 mg (44%) (12S or R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene was obtained as a yellow solid (hypothetically).

[0342] LC-MS-PH-PHNW-4-37-2: (ES, m / z): M+1 = 320, R, T = 1.107 minutes.

[0343] Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 μm; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient, from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40 °C; Flow rate: 1.5 mL / min.

[0344] H-NMR-PH-PHNW-4-37-2: (CDCl3,300ppm):7.63(s,1H),7.17(s,1H),6.36-6.35(d,J=3Hz,1H),5.57-5.52(m,2H ),4.59-4.55(m,1H),3.62-3.46(m,3H),3.18-3.14(m,1H),1.62-1.44(m,3H),0.93-0.88(m,2H),-0.17(s,9H).

[0345] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S or R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclic[7.4.0.0^[3,7,]]tetane-1(9),2,4,10-triazacyclic[7.4.0.0^[3,7,]]tetane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetically): In an 8 mL vial, (12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13- Oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene (200 mg, 0.63 mmol, 1 equivalent), methyl-2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)benzoate (399.6 mg, 0.75 mmol, 1.2 equivalent), Cs2CO3 (611.9 mg, 1.88 mmol, 3 equivalent), dioxane (5 mL), chloro[9,9-dimethyl-4,5-bis(diphenylphosphine)xanthon][2-amino-1,1-biphenyl-2-yl]palladium(II) (120 mg). The resulting solution was stirred in an oil bath at 110 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1-1:10). 250 mg (51.83%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R or S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraen-10-yl]benzoate was obtained as a yellow solid.

[0346] Methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R or S)-12-methyl-13-oxalate-2,4,10-triazacyclic[7.4.0.0^[3,7,]]tetane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetically) is placed in a 100 mL round-bottom flask. [-yl]methyl]piperazine-1-yl)-2-[(12R or S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2 (250 mg, 0.32 mmol, 1 equivalent), TBAF (3 g, 11.47 mmol, 35.36 equivalent), THF (30 mL), ethane-1,2-diamine (2 g, 33.28 mmol, 102.56 equivalent). The resulting solution was stirred in an oil bath at 70 °C for 12 h. Then 50 mL of water was added to stop the reaction. The resulting solution was extracted with 2 x 50 mL of ethyl acetate. The resulting mixture was washed with 3 x 50 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1-1:3). 90 mg (43%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R or S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraen-10-yl]benzoate was obtained as a yellow solid. H-NMR-PH-PHNW-4-37-50: (CDCl3, 300ppm): 8.24 (s, 1H), 7.89-7.86 (d, J=9 Hz,1H),7.32-7.24(m,6H),7.14-7.01(m,1H),6.97-6.94(m,2H),6.73-6.6 5(m,2H),6.18(s,1H),3.67-3.53(m,3H),3.32-3.18(m,3H),2.98-2.80(m, 1H),2.30-2.04(m,6H),1.99(s,2H),1.56-1.50(m,5H),0.91-0.88(m,6H).

[0347] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R or S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tetane-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical). In an 8 mL vial, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R or S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraen-10-yl]benzoate (90 mg, 0.02 mmol, 1 equivalent), MeOH (1 mL), H₂O (1 mL), THF (1 mL), and NaOH (22.5 mg, 0.56 mmol, 4 equivalents) were added. The resulting solution was stirred overnight in an oil bath at 60 °C. The pH of the solution was adjusted to 5 with hydrochloric acid (1 mol / L). The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with dichloroethane / methanol (1:0–10:1). 80 mg (90%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-2H4)-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9,)2,5,7-tetraen-10-yl]benzoic acid was obtained as a yellow solid. LC-MS-PH-PHNW-4-37-60: (ES, m / z): M+1 = 626, R, T = 1.035 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0348] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-[(4-[[(4-fluorooxy-4-yl)methyl]amino-3-nitrobenzene)benzenesulfonyl)-2-[(12R or S)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzamide (hypothesis): In an 8 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R or S)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzamide is added... S)-12-methyl-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzoic acid (90 mg, 0.14 mmol, 1 equivalence), 4-[[(4-fluorooxy-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (57.5 mg, 0.17 mmol, 1.2 equivalence), DCM (5 mL), DMAP (70.2 mg, 0.57 mmol, 4 equivalence), EDCI (55.1 mg, 0.29 mmol, 2.00 equivalence). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. Crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, water (0.1% FA) and ACN (48.0% ACN increased to 53.0% in 7 min, maintained at 95.0% in 1 min, decreased to 48.0% in 1 min, and maintained at 48.0% in 1 min), over 5 min; detector, UV 254 nm. 28 mg (20%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(4-fluorooxy-4-yl)methyl]amino-3-nitrobenzene)benzenesulfonyl-2-[(12R or S)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide was obtained as a yellow solid (hypothesis). 19.8 mg of product was submitted (hypothesis). LC-MS-PH-PHNW-4-37-0: (ES, m / z): M+1 = 941, R, T = 3.04 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.H-NMR-PH-PHNW-4-37-0: (d-DMSO,300ppm):8.59(s,1H),8.54(s,1H),7.55 -7.53(m,1H),7.36-7.29(d,J=6Hz,3H),7.12-7.06(m,3H),6.80-6.72(m,3 H),5.95(m,1H),4.53-4.51(m,1H),3.78-3.43(m,7H),3.21-3.00(m,5H),2 .22-2.17(m,5H),1.96-1.75(m,6H),1.58-1.56(m,5H),0.93-0.88(m,6H)..

[0349] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S or R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclic[7.4.0.0^[3,7,]]tridecane-1(9),2,4,10-triazacyclic[7.4.0.0^[3,7,]]tridecane-1(9),2,2,5,7-tetraen-10-yl]benzoate (hypothetically): In an 8 mL vial, (12S or R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-1 3-Oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene (200 mg, 0.63 mmol, 1 equivalent), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)benzoate (399.6 mg, 0.75 mmol, 1.2 equivalent), Cs2CO3 (611.9 mg, 1.88 mmol, 3 equivalent), dioxane (5 mL), chloro[9,9-dimethyl-4,5-bis(diphenylphosphine)xanthon][2-amino-1,1-biphenyl-2-yl]palladium(II) (120 mg). The resulting solution was stirred in an oil bath at 110 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1–1:10). 250 mg (51%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S or R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,2,5,7-tetraen-10-yl]benzoate was obtained as a yellow solid (hypothetically).

[0350] Methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S or R)-12-methyl-13-oxalate-2,4,10-triazacyclic[7.4.0.0^[3,7,]]tetane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetically) is placed in a 100 mL round-bottom flask. [-yl]methyl]piperazine-1-yl)-2-[(12S or R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tetane-1(9),2 (250 mg, 0.32 mmol, 1 equivalent), TBAF (3 g, 11.47 mmol, 35.36 equivalent), THF (30 mL), ethane-1,2-diamine (2 g, 33.28 mmol, 102.56 equivalent). The resulting solution was stirred in an oil bath at 70 °C for 12 h. Then 50 mL of water was added to stop the reaction. The resulting solution was extracted with 2 x 50 mL of ethyl acetate. The resulting mixture was washed with 3 x 50 mL of brine. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1–1:3). 90 mg (43%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S or R)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraen-10-yl]benzoate was obtained as a yellow solid (hypothetically).

[0351] LC-MS-PH-PHNW-4-38-50: (ES, m / z): M+1 = 640, R, T = 1.424 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 μm; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 1.5 mL / min. H-NMR-PH-PHNW-4-38-50: (CDCl3, 300ppm): 8.24 (s, 1H), 7.89-7.86 (d, J=9 Hz,1H),7.32-7.24(m,6H),7.14-7.01(m,1H),6.97-6.94(m,2H),6.73-6.6 5(m,2H),6.18(s,1H),3.67-3.53(m,3H),3.32-3.18(m,3H),2.98-2.80(m, 1H),2.30-2.04(m,6H),1.99(s,2H),1.56-1.50(m,5H),0.91-0.88(m,6H).

[0352] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S or R)-12-methyl-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl)benzoic acid (hypothesis): In an 8 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S or R)-12-methyl-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl)benzoic acid was added. [12S or R]-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl)benzoate (90 mg, 0.14 mmol, 1 equivalent), MeOH (1 mL), H2O (1 mL), THF (1 mL), NaOH (22.5 mg, 0.56 mmol, 4.00 equivalent). The resulting solution was stirred overnight in an oil bath at 60 °C. The pH of the solution was adjusted to 5 with hydrochloric acid (1 mol / L). The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with chloroform / methanol (1:0–10:1). 80 mg (90%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S or R)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9,)2,5,7-tetraen-10-yl]benzoic acid was obtained as a solid (hypothetically). LC-MS-PH-PHNW-4-38-60: (ES, m / z): M+1 = 626, R, T = 1.039 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0353] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-[(4-[[(4-fluorooxy-4-yl)methyl]amino-3-nitrobenzene)benzenesulfonyl)-2-[(12S or R)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzamide (hypothesis): In an 8 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl] Piperazine-1-yl)-2-[(12S or R)-12-methyl-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzoic acid (90 mg, 0.14 mmol, 1 equivalent), 4-[[(4-fluorooxy-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (57.5 mg, 0.17 mmol, 1.2 equivalent), DCM (5 mL), DMAP (70.2 mg, 0.57 mmol, 4 equivalent), EDCI (55.1 mg, 0.29 mmol, 2 equivalent). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. Crude product - purified by Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, water (0.1% FA) and ACN (48.0% ACN increased to 53.0% in 7 min, maintained at 95.0% in 1 min, decreased to 48.0% in 1 min, and maintained at 48.0% in 1 min) for 5 min; detector, UV 254 nm. 26 mg (19%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(4-fluorooxy-4-yl)methyl]amino]-3-nitrobenzene)benzenesulfonyl-2-[(12S or R)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide was obtained as a yellow solid. 19.6 mg of product was submitted (hypothetically). LC-MS-PH-PHNW-4-38-0: (ES, m / z): M+1 = 941, R, T = 3.036 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.H-NMR-PH-PHNW-4-38-0: (d-DMSO,300ppm):8.56(s,1H),8.36(s,1H),7.62-7.54(m, 1H),7.37-7.30(m,3H),7.14-7.04(m,3H),6.98-6.92(m,3H),5.94(m,1H),4.53(m,1 H),3.79-3.71(m,4H),3.65-3.54(m,3H),3.44(m,4H),2.78-2.73(m,2H),2.23-2.18 (m,6H),1.97-1.91(m,2H),1.87-1.81(m,4H),1.50-1.20(m,5H),0.91-0.88(m,6H).

[0354] Preparation of Compounds 2-6: 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-dimethyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((4-4-(((fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)benzenesulfonyl)benzamide

[0355] Synthesis of 12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1,3(7),5,8-tetraen-11-one: In a 100 mL round-bottom flask, 5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrole[2,3-b]pyridin-6-ol (1 g, 3.58 mmol, 1 equivalent), CH3CN (20 mL), methyl 2-bromo-2-methylpropionate (647.9 mg, 3.58 mmol, 1.0 equivalent), and Cs2CO3 (1.7 g, 5.37 mmol, 1.5 equivalent) were added. The resulting solution was stirred in an oil bath at 80 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1:3). 270 mg (21%) of 12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1,3(7)5,8-tetraen-11-one was obtained as a pale yellow solid. LC-MS-PH-PHNW-4-40-2: (ES, m / z): M+1 = 348, R, T = 1.164 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0356] Synthesis of 12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1.3(7)5,8-tetraene: In an 8 mL vial, 250 mg (0.72 mmol, 1 equivalent) of 12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1.3(7)5,8-tetraen-11-one and 3 mL of THF were placed. LiAlH4 (54.6 mg, 1.44 mmol, 2 equivalents) was then added in portions at 0 °C. The resulting solution was stirred overnight at room temperature. Then 5 mL of water was added to stop the reaction. The solid was filtered off. The resulting solution was extracted with 2 x 10 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1–1:5). 140 mg (58%) of 12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1,3(7)5,8-tetraene was obtained as a yellow solid.

[0357] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclic[7.4.0.0^[3,7]]tetane-1,3(7)5,8-tetraen-10-yl)benzoate: In an 8 mL vial, 12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclic[7.4.0.0^[3,7]]tetane-1,3(7)5,8-tetraen-10-yl)benzoate was placed... [3,7]]tetane-1,3(7)5,8-tetraene (140 mg, 0.42 mmol, 1 equivalent), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)benzoate (267.9 mg, 0.50 mmol, 1.2 equivalent), Cs₂CO₃ (410.3 mg, 1.26 mmol, 3 equivalent), dioxane (2 mL), chloro[9,9-dimethyl-4,2-bis(diphenylphosphine)xanthon][2-amino-1,1-biphenyl-2-yl]palladium(II) (80 mg). The resulting solution was stirred in an oil bath at 110 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1-1:3). 130 mg (39%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,12,12-4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl)benzoate was obtained as a yellow oil. LC-MS-PH-PHNW-4-40-4: (ES, m / z): M+1 = 784, R, T = 1.331 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0358] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(12,12-dimethyl-13-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl)benzoate: In a 40 mL vial, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(12,12-dimethyl-13-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl)benzoate was added. Methylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7), (130 mg, 0.17 mmol, 1 equivalent), TBAF (3 g), THF (100 mL), ethane-1,2-diamine (2 g). The resulting solution was heated in an oil bath at 60 °C. Stir overnight. Then add 10 mL of water to stop the reaction. Extract the resulting solution with 2 x 10 mL of ethyl acetate. Wash the resulting mixture with 3 x 10 mL of brine. Dry the mixture on anhydrous sodium sulfate, then filter and concentrate under vacuum. Treat the residue on a silica gel column with ethyl acetate / petroleum ether (0:1-1:3). Give 110 mg (crude) methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl] Piperazine-1-yl)-2-[12,12-dimethyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl]benzoate, as a yellow solid. LC-MS-PH-PHNW-4-40-5: (ES, m / z): M+1 = 654, R, T = 1.107 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0Kinetex 2.6u XB-C18, 2.6 μm; eluent A: water (0.05% TFA); eluent B: acetonitrile; linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; oven temperature 40°C; flow rate: 1.5 mL / min.

[0359] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[12,12-dimethyl-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl)benzoic acid: In an 8 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethyl]... [12,12-Dimethyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl]benzoate (80 mg, 0.12 mmol, 1 equivalent), MeOH (1 mL), H2O (1 mL), NaOH (19.6 mg, 0.49 mmol, 4 equivalent). The resulting solution was stirred overnight in an oil bath at 60 °C. The pH of the solution was adjusted to 5 with hydrochloric acid (1 mol / L). The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with dichloroethane / methanol (1:0–10:1). The obtained 60 mg (76.64%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[12,12-dimethyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl]benzoic acid was a yellow solid. LC-MS-PH-PHNW-4-40-6: (ES, m / z): M+1 = 640, R, T = 1.359 min. Residence time was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0360] 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(12,12-dimethyl-13-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]-N-(4-[[(4-fluorooxy-4-yl)methyl]amino]- Synthesis of 3-nitrobenzene(benzenesulfonyl)benzamide: In an 8 mL vial, 4-[[(4-fluorooxy-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (37.5 mg, 0.11 mmol, 1.2 equivalences), DCM (5 mL), 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-( 12,12-Dimethyl-13-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1,3(7),5,8-tetraen-10-yl]benzoic acid (60 mg, 0.09 mmol, 1 equivalent), EDCI (35.9 mg, 0.19 mmol, 2 equivalent), DMAP (45.8 mg, 0.37 mmol, 4 equivalent). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, water (0.1% FA) and ACN (48.0% ACN increased to 53.0% in 7 min, maintained at 95.0% in 1 min, and decreased to 48.0% in 1 min) over 5 min; detector, UV. 254 nm. 25 mg (27%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(12,12-dimethyl-13-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]-N-(4-[[(4-fluorooxy-4-yl)methyl]amino]-3-nitrobenzene)benzenesulfonyl)benzamide was obtained as a yellow solid. 20.6 mg of product was submitted. LC-MS-PH-PHNW-4-40-0: (ES, m / z): M+1 = 955, R, T = 2.655 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.H-NMR-PH-PHNW-4-40-0: (d-DMSO,300ppm):8.56(s,1H),8.36(s,1H),7.56-7.49(m,2H),7.36-7.33(m,2H),7.06-7.00(m,3H), 6.93-6.90(m,1H),6.88-6.74(M,2H),5.99(m,1H),3.78-3.74(m,4H),3.67-3.50(m,2H),3.23(m,4H),2.76-2.72(m,2H),2.22- 2.16(m,6H), 1.96-1.75(m,6H), 1.41-1.39(m,8H), 0.91-0.88(m,6H). Preparation of compounds 2-7: 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)benzenesulfonyl)benzamide.

[0361] Synthesis of 3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)benzenesulfonamide: In a 50 mL round-bottom flask, (tetrahydro-2H-pyran-3-yl)methylamine (200 mg, 1.74 mmol, 1.00 equivalence), THF (5 mL), 4-fluoro-3-nitrobenzene-1-sulfonamide (383 mg, 1.74 mmol, 1.00 equivalence), and Cs₂CO₃ (1.134 g, 3.48 mmol, 2.00 equivalence) were added. The resulting solution was stirred in an oil bath at 50 °C for 3 h. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1 / 1). 270 mg (49.3%) of 3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)benzenesulfonamide was produced as a yellow solid. LC-MS-PH-PHNW-4-41-1: (ES, m / z): M+1 = 316, R, T = 1.25 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-ODS, 2.6 μm; Eluent A: Water (0.05% FA); Eluent B: Acetonitrile (0.05% TFA); Linear gradient, from 5% acetonitrile to 100% acetonitrile, 2.6 min; Oven temperature 40°C; Flow rate: 1.0 mL / min.

[0362] Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-(((3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)benzenesulfonyl)benzamide: In a 100 mL round-bottom flask, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(12,12-dimethyl-13-13-oxalate-2,4,10-triazacyclo[7.4.0.0] [3,7][tetrane-1,3(7),5,8-tetraen-10-yl]benzoic acid (50 mg, 0.082 mmol, 1.00 equivalence) in dichloromethane (5 mL), EDCI (63 mg, 0.328 mmol, 4.00 equivalence), 4-dimethylaminopyridine (20 mg, 0.164 mmol, 2.00 equivalence), 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (26 mg, 0.082 mmol, 1.00 equivalence). The resulting solution was stirred overnight at 40 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC under the following conditions (Waters-2767): column, X-bridge. RP18, 5 μm, 19 x 100 mm; mobile phase, 0.03% ammonia (0.03% NH4HCO3 and NH4OH) and CH3CN (32% CH3CN, reaching 52% within 6 minutes); detector, UV. 254 nm. 12.8 mg (17%) of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonyl)benzamide was obtained as a yellow solid. LC-MS-PH-PHNW-4-41-0: (ES, m / z): M+1 = 909, R, T = 1.60 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.0 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.1H NMR(300MHz,Chloroform-d)δ12.40(s,1H),8.72(s,1H),8.63(s,1H),8.44(t,J=5.5Hz,1H),8.10(d,J=9.0Hz,1H),7.93–7.82( m,1H),7.25(s,4H),7.13(t,J=2.9Hz,1H),7.00–6.68(m,6H),6.52(s,1H),6.17(d,J=3.3Hz,1H),4.71(dd,J=23.6,10.7Hz,2H) 3.99–3.79 (m, 3H), 3.70 (s, 1H), 3.57 (dd, J = 18.5, 10.9 Hz, 3H), 3.46–3.17 (m, 7H), 2.80 (s, 2H), 2.29 (s, 3H), 2.21 (s, 2H), 2.03 (d, J = 12.3 Hz, 5H), 1.75–1.60 (m, 4H), 1.44 (d, J = 8.7 Hz, 3H), 1.28 (s, 1H), 0.97 (s, 6H), 0.87 (s, 1H). NMR spectroscopy measurements were performed using a Bruker Avance III HD 300 MHz spectrometer and a BBOF probe.

[0363] Preparation of Compounds 2-8: (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonyl)benzamide

[0364] Synthesis of 6-(tert-butoxy)-N-(diphenylmethylene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-5-amine: In a 250 mL round-bottom flask, a solution of 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine in dioxane (300 mL) (20.7 g, 60 mmol, 1.00 equivalence), t-BuOK (20.5 g, 180 mmol, 3.00 equivalence), xantphos (6.9 g, 12 mmol, 0.20 equivalence), Pd2(dba)3.CHCl3 (5.7 g, 0.10 equivalence), and diphenylmethylamine (14.04 g, 78 mmol, 1.20 equivalence). The resulting solution was stirred overnight at 100°C. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1-1:20). 15 g (crude) of 6-(tert-butoxy)-N-(diphenylmethylene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-5-amine was obtained as a white oil. LC-MS-PH-PHNW-4-7-9: (ES, m / z): M+1 = 500.

[0365] Synthesis of 5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-6-ol hydrogen chloride: In a 100 mL round-bottom flask, 6-(tert-butoxy)-N-(diphenylmethylene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-5-amine (15 g, 30.02 mmol, 1.00 equivalent) in dioxane (120 mL) and dioxane hydrochloride (4 M, 30 mL) were added. The resulting solution was stirred at room temperature for 5 hours. The resulting solution was diluted with 500 mL of diethyl ether. The solid was collected by filtration. Five grams of crude 5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-6-ol hydrogen chloride were obtained as a red solid. Q-NMR showed that it could be converted into three hydrogen chloride salts. LC-MS-PH-PHNW-4-10-1: (ES, m / z): M+1 = 280, R, T = 0.811 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 μm; eluent A: water (0.05% TFA); eluent B: acetonitrile; linear gradient.

[0366] Synthesis of 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl](-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-11-one: In a 100 mL round-bottom flask, 5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-ol (1.5 g, 5.37 mmol, 1 equivalent), DMF (50 mL), and K2CO3 (2.2 g, 16.11 mmol, 3 equivalents) were added dropwise. Then, with stirring at 0 °C, 2-chloropropionyl chloride (1.4 g, 10.74 mmol, 2 equivalents) was added dropwise. The resulting solution was stirred overnight at room temperature. Then, 50 mL of water was added to stop the reaction. The solution was extracted with 50 mL of ethyl acetate. The resulting mixture was washed with 2 x 50 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1-1:3). 500 mg (27.93%) of 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraen-11-one was given as a yellow solid. LC-MS-PH-PHNW-4-37-1: (ES, m / z): M+1 = 334, R, T = 1.123 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 μm; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient, from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40 °C; Flow rate: 1.5 mL / min. H-NMR-PH-PHNW-4-37-1: (CDCl3, 300 ppm): 8.34 (s, 1H), 7.63 (d, J = 3 Hz, 1H), 7.42–7.28 (m, 1H), 6.46 (d, J = 3 Hz, 1H), 5.68 (s, 2H), 4.92–4.85 (m, 1H), 3.63–3.53 (m, 2H), 1.85–1.81 (d, J = 12 Hz, 3H), 0.94–0.89 (m, 2H), -0.154 (s, 9H).

[0367] 12-Methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene and (12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene and (12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy] Synthesis of 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene: In a 100 mL three-necked round-bottom flask, 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraen-11-one (500 mg, 1.50 mmol, 1 equivalent) and THF (20 mL) were added. LiAlH4 (113.8 mg, 0.75 mmol, 2 equivalents) was then added in portions at 0 °C. The resulting solution was stirred overnight at room temperature. 20 mL of water was then added to stop the reaction. The solid was filtered off. The resulting solution was extracted with 2 x 20 mL ethyl acetate. The resulting mixture was washed with 2 x 20 mL of brine. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1–1:3). 450 mg (93%) of 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene was given as a yellow solid.

[0368] Crude 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene (450 mg) was purified by Chiral-Prep-HPLC under the following conditions. (SHIMADZU LC-20AT): column, CHIRALPAK IC; mobile phase A: n-hexane, phase B: ethanol; detector, 220 nm. 200 mg (44%) of (12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraene was obtained as a yellow solid.

[0369] 200 mg (44%) of (12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraene was obtained as a yellow solid. LC-MS-PH-PHNW-4-37-2: (ES, m / z): M+1 = 320, R, T = 1.107 min.

[0370] Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 μm; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient, from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40 °C; Flow rate: 1.5 mL / min. H-NMR-PH-PHNW-4-37-2: (CDCl3,300ppm):7.63(s,1H),7.17(s,1H),6.36-6.35(d,J=3Hz,1H),5.57-5.52(m,2H ),4.59-4.55(m,1H),3.62-3.46(m,3H),3.18-3.14(m,1H),1.62-1.44(m,3H),0.93-0.88(m,2H),-0.17(s,9H).

[0371] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclic[7.4.0.0^[3,7,]]tridecane-1(9),2,4,10-triazacyclic[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraen-10-yl]benzoate: In an 8 mL vial, (12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate- 2,4,10-Triazacyclo[7.4.0.0^[3,7,]]tetane-1(9),2,5,7-tetraene (200 mg, 0.63 mmol, 1 equivalent), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)benzoate (399.6 mg, 0.75 mmol, 1.2 equivalent), Cs₂CO₃ (611.9 mg, 1.88 mmol, 3 equivalent), dioxane (5 mL), chloro[9,9-dimethyl-4,5-bis(diphenylphosphine)xanthon][2-amino-1,1-biphenyl-2-yl]palladium(II) (120 mg). The resulting solution was stirred in an oil bath at 110 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1-1:10). 250 mg (51.83%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraen-10-yl]benzoate was obtained as a yellow solid.

[0372] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl)benzoate. In a 100 mL round-bottom flask, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2 (250 mg, 0.32 mmol, 1 equivalent), TBAF (3 g, 11.47 mmol, 35.36 equivalent), THF (30 mL), and ethane-1,2-diamine (2 g, 33.28 mmol, 102.56 equivalent) were added. The resulting solution was stirred in an oil bath at 70 °C for 12 hours. Then, 50 mL of water was added to stop the reaction. The resulting solution was extracted with 2 x 50 mL ethyl acetate. The resulting mixture was washed with 3 x 50 mL of brine. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1–1:3). 90 mg (43%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraen-10-yl]benzoate was obtained as a yellow solid. H-NMR-PH-PHNW-4-37-50: (CDCl3, 300ppm): 8.24 (s, 1H), 7.89-7.86 (d, J=9 Hz,1H),7.32-7.24(m,6H),7.14-7.01(m,1H),6.97-6.94(m,2H),6.73-6.6 5(m,2H),6.18(s,1H),3.67-3.53(m,3H),3.32-3.18(m,3H),2.98-2.80(m, 1H),2.30-2.04(m,6H),1.99(s,2H),1.56-1.50(m,5H),0.91-0.88(m,6H).

[0373] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl)benzoic acid. In an 8 mL vial, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tetane-1(9),2,5,7-tetraen-10-yl]benzoate (90 mg, 0.02 mmol, 1 equivalent), MeOH (1 mL), H₂O (1 mL), THF (1 mL), and NaOH (22.5 mg, 0.56 mmol, 4 equivalents) were added. The resulting solution was stirred overnight in an oil bath at 60 °C. The pH of the solution was adjusted to 5 with hydrochloric acid (1 mol / L). The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with dichloroethane / methanol (1:0–10:1). 80 mg (90%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9,)2,5,7-tetraen-10-yl]benzoic acid was obtained as a yellow solid. LC-MS (ES, m / z): M+1 = 626, R, T = 1.035 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0374] Synthesis of (S)4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonyl)benzamide. In an 8 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12Ror S)-12-methyl-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzoic acid (90 mg, 0.14 mmol, 1 equivalence), 4-[[(4-fluorooxy-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (57.5 mg, 0.17 mmol, 1.2 equivalence), DCM (5 mL), DMAP (70.2 mg, 0.57 mmol, 4 equivalence), EDCI (55.1 mg, 0.29 mmol, 2.00 equivalence). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, water (0.1% FA) and ACN (48.0 g / mL). %ACN increased to 53.0% within 7 minutes, remained at 95.0% within 1 minute, decreased to 48.0% within 1 minute, and remained at 48.0% within 1 minute, within 5 minutes; detector, UV 254 nm. 22 mg (20%) (S)4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2 ,3-Dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]azine-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonyl)benzamide. LC-MS: (ES, m / z): M+1=923, R, T=2.653 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0Kinetex 2.6u XB-C18, 2.6 μm; eluent A: water (0.05% TFA); eluent B: acetonitrile; linear gradient from 5% acetonitrile to 100% acetonitrile, 3.5 min; oven temperature 40°C; flow rate: 1.5 mL / min.H-NMR: (d-CDCl3,300ppm):8.62(s,1H),8.44-8.42(m,2H),8.09-8.06(m, 1H),7.85-7.70(m,1H),7.28-7.22(m,2H),6.94-6.80(m,3H),6.72-6.62(m ,2H),6.10(s,1H),4.05-4.00(m,2H),3.50-3.17(m,10H),2.95-2.35(m,2H ),2.27-2.19(m,4H),1.98-1.70(m,5H),1.60-1.26(m,11H),0.95(s,6H).

[0375] Preparation of Compounds 2-9: (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonyl)benzamide

[0376] Synthesis of N-[(2R)-2-hydroxypropyl]-4-methylbenzene-1-sulfonamide: In a 250 mL round-bottom flask, (2R)-1-aminoprop-2-ol (5 g, 1 equivalent), DCM (70 mL), and TsCl (12.67 g, 1 equivalent) were added. Then, TEA (7.41 g, 1.1 equivalent) was added at 0 °C, and the resulting solution was stirred at 0 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1 / 1) as the eluent. The final product was a white solid, 8 g of N-(2R)-2-hydroxypropyl]-4-methylbenzene-1-sulfonamide. 1 H NMR ((300MHz, DMSO-d6, ppm): δ7.74-7.63(m,2H),7.52-7.34(m,3H),4.66(d,J=4.7Hz, 1H), 3.58 (qd, J = 6.3, 4.8Hz, 1H), 2.73-2.50 (m, 2H), 2.39 (s, 3H), 0.99 (d, J = 6.2Hz, 3H).

[0377] Synthesis of methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)benzoate: A solution of 1-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazine (15.09 g, 47.32 mmol, 1.00 equivalence) in DMA (150 mL), DIEA (12.9 g, 99.81 mmol, 2.00 equivalence), and methyl 2-bromo-4-fluorobenzoate (11.6 g, 49.78 mmol, 1.00 equivalence) were added to a 250 mL round-bottom flask. The resulting mixture was stirred at 100 °C for 12 hours. The reaction mixture was cooled to room temperature, and then quenched with 50 mL of water. The above solution was extracted three times with ethyl acetate (100 mL), and the organic layers were combined. The resulting organic phase was washed three times with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using ethyl acetate / petroleum ether (0:1-1:5) as the eluent. The final product was a yellow oil, 7 g of methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)benzoate. LC-MS (ES, m / z): M+1 = 533, 531.

[0378] Synthesis of N-[(2R)-2-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]propyl]-4-methylbenzene-1-sulfonamide: In a 100 mL round-bottom flask, N-[(2R)-2-hydroxypropyl]-4-methylbenzene-1-sulfonamide (1 g, 1.5 equivalents) and DMF (3 mL) were added, followed by the addition of NaH (0.35 g, 3 equivalents) at 0 °C over 10 minutes. Then, at the same temperature, 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine (1 g, 1 equivalent) was added to the above solution, and the resulting solution was stirred at room temperature for 4 hours. After the reaction was complete, 20 mL of water was added to the reaction solution to quench the reaction. The above solution was extracted three times with ethyl acetate (50 mL), the organic layers were combined and concentrated. The crude product was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1 / 3) as the eluent. The final product was a yellow solid, N-[(2R)-2-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]oxy]propyl]-4-methylbenzene-1-sulfonamide 400 mg. 1H-NMR (300MHz, DMSO-d6, ppm): δ8.18 (s, 1H), 7.72-7.62 (m, 2H), 7.41 (d, J = 3.5Hz, 1H) ,7.28(d,J=8.0Hz,2H),6.42(d,J=3.6Hz,1H),5.50(q,J=10.8Hz,2H),5.16(q,J=6.1H z,1H),3.53-3.38(m,2H),3.13(dd,J=13.4,6.0Hz,1H),2.98(dd,J=13.4,5.8Hz,1H), 2.29(s,3H),1.28(d,J=6.2Hz,3H),0.80(ddt,J=16.1,14.1,7.1Hz,2H),0.13(s,9H).

[0379] Synthesis of (12R)-12-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetrazol-1(9),2,5,7-tetraene: N-[(2R)-2-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]oxy]propyl]-4-methylbenzene-1-sulfonamide (3.9 g, 1 equivalent), dioxane (50 mL), t-BuXPhos 3g (560 mg, 0.1 equivalence) and Cs2O3 (6.9 g, 3 equivalence) were added to a 100 mL round-bottom flask, and nitrogen gas was blown in to maintain an inert atmosphere. The resulting solution was stirred at 90 °C for 4 hours. After the reaction was completed, the reaction solution was concentrated. The crude product was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1 / 3) as the eluent. The final product was a colorless oily product, (12R)-12-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7]]decadecyl-1(9),2,5,7-tetraene 3.3 g. 1 H-NMR (300MHz, DMSO-d6, ppm): δ8.28 (s, 1H), 7.56-7.39 (m, 3H), 7.39-7.30 (m, 2H), 6.52 (d, J = 3.6Hz, 1H), 5.43 (s, 2H), 4.28 ( dd,J=14.6,2.6Hz,1H),3.61-3.41(m,3H),3.26-3.11(m,1H),2.35(s,3H),1.32-1.11(m,3H),0.89-0.74(m,2H),0.11(s,9H).

[0380] Synthesis of (12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecyl-1(9),2,5,7-tetraene: Na (1.31 g, 9.4 equivalents) and naphthalene (0.76 g, 6 equivalents) were added to a 100 mL three-necked round-bottom flask. DME (15 mL) was then added over 30 minutes at room temperature. At -78°C, a THF solution (15 mL) of (12R)-12-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecyl-1(9),2,5,7-tetraene (2.8 g, 1 equivalent)) was added to the above mixture, and the resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, NH4Cl (30 mL) was added to the reaction solution to quench the reaction. The above solution was extracted three times with ethyl acetate (100 mL), the organic layers were combined and concentrated. The crude product was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1 / 3) as the eluent. The final product was a colorless oil, 1.4 g of (12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7]]decadecyl-1(9),2,5,7-tetraene. LC-MS (ES, m / z): [M+H] + =320.

[0381] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tetrazol-1(9),2,5,7-tetraen-10-yl]benzoate: Methyl (12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tetrazol-1(9),2,5,7-tetraen-10-yl]benzoate Cyclo[7.4.0.0^[3,7,]]decadecyl-1(9),2,5,7-tetraene (1.178 g, 1 equivalent), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)benzoate (2.35 g, 1.2 equivalent), dioxane (15 mg, 15 equivalent), Cs₂CO₃ (3.62 g, 3 equivalent), and XantPhos (328 mg, 0.1 equivalent) were added to a 250 mL round-bottom flask, and nitrogen was purged to maintain an inert atmosphere. The resulting solution was stirred at 110 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated. The crude product was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1 / 3) as the eluent. The final product was a yellow solid, 3.2 g of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tetrazol-1(9),2,5,7-tetraen-10-yl]benzoate. LC-MS (ES, m / z): [M+H] + =770.

[0382] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetrazine-1(9),2,5,7-tetraen-10-yl)benzoate: In a 250 mL round-bottom flask, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetrazine-1(9),2,5,7-tetraen-10-yl)benzoate was added... Methyl benzoate (3.2 g, 1 equivalent), THF (50 mL), TBAF (20 g), and 1,2-ethylenediamine (33 g) were prepared by stirring the solution at 70 °C for 5 hours. After the reaction was completed, 50 mL of water was added to the reaction solution to quench the reaction. The above solution was extracted three times with ethyl acetate (100 mL), the organic layers were combined and concentrated. The crude product was purified by silica gel column chromatography with dichloroethane / methanol (10 / 1) as the eluent. Finally, a yellow solid product was obtained.

[0383] 2.2 g of methyl 1,4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tetrazol-1(9),2,5,7-tetraen-10-yl]benzoate. LC-MS-(ES, m / z): [M+H] + =640.

[0384] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetrazine-1(9),5,7-tetraen-10-yl)benzoic acid: Add 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetrazine-1(9),5,7-tetraen-10-yl)benzoic acid to a 250 mL round-bottom flask. -dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetrazol-1(9),2,5,7-tetraen-10-yl]methyl benzoate (2.2 g, 1 equivalent), MEOH / H2O / THF (10 mL / 10 mL / 10 mL), the resulting solution was stirred at 60 °C for 5 hours. After the reaction was completed, the reaction solution was concentrated. The crude product was purified by silica gel column chromatography using dichloroethane / methanol (10 / 1) as the eluent. The final product was a yellow solid, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetrazine-1(9,)

[0385] 1.6 g of 2,5,7-tetraen-10-ylbenzoic acid. LC-MS (ES, m / z): [M+1] + =626.

[0386] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tetrazol-1(9),2,5,7-tetraen-10-yl]-N-(3-nitro-4-[[(oxane-4-yl)methyl]amino]benzenesulfonyl)benzamide: Add 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-yl]methyl]piperazin-1-yl)to an 8 mL reaction flask. [-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetrazine-1(9),2,5,7-tetraen-10-yl]benzoic acid (1.6 g, 1 equivalent), DCM (20 mL), 3-nitro-4-[[(oxane-4-yl)methyl]amino]benzene-1-sulfonamide (890 mg, 1.2 equivalent), DMAP (1.25 g, 4 equivalent), EDCI (980 mg, 2 equivalent). The resulting solution was stirred at room temperature for 14 hours. After the reaction was complete, the reaction solution was concentrated. The crude product was purified by silica gel column chromatography using EA / DCM (1 / 10) as the elution buffer. The final product was a yellow solid, 0.82 g of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tetrazol-1(9),2,5,7-tetraen-10-yl]-N-(3-nitro-4-[[(oxane-4-yl)methyl]amino]benzenesulfonyl)benzamide. LC-MS (ES, m / z): [M+H] + =923. 1H NMR (300MHz, CDCl3, ppm): δ12.48 (s, 1H), 8.62 (d, J = 2.4Hz, 2H), 8.54-8.38 (m, 1H), 8.16-7.95 (m, 1H), 7.81-7.71 (m, 1H), 7. 32-7.12(m,6H),7.07(t,J=2.9Hz,1H),6.97-6.77(m,3H),6.76-6.60(m,2H),6.52(s,1H),6.09(d,J=3.0Hz,1H),4.88(d,J= 7.7Hz,1H),4.02(dd,J=11.8,4.2Hz,2H),3.55-3.34(m,4H),3.32-3.14(m,5H),3.08(s,1H),2.77(d,J=9.6Hz,2H),2.28(s, 3H), 2.19 (s, 2H), 1.99 (d, J = 7.6Hz, 4H), 1.72 (d, J = 12.7Hz, 2H), 1.45 (ddd, J = 24.5, 12.3, 5.8Hz, 6H), 0.94 (d, J = 2.1Hz, 6H).

[0387] Preparation of compound 2-10: 4-(4-[[2-(4-chlorophenyl)-1,4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)-2-[13-thio-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide:

[0388] In a 250 mL round-bottom flask, cysteamine hydrochloride (5.00 g, 44.014 mmol, 1.00 equivalent), DCM (100.00 mL), TEA (13.36 g, 0.132 mmol, 3 equivalent), and acetic anhydride (4.94 g, 0.048 mmol, 1.1 equivalent) were added. The resulting solution was stirred overnight at room temperature. Then, 100 mL of water was added to stop the reaction. The resulting solution was extracted with 3 x 50 mL ethyl acetate and dried over anhydrous sodium sulfate. The resulting solution was concentrated under vacuum. The residue was eluted on a silica gel column with ethyl acetate / petroleum ether (7:1). 7.2 g of (crude) 2-acetamidoethanethiol was given as a pale yellow oil. 1 H 1 HNMR(300MHz,DMSO-d6)δ7.99(s,1H),3.20-3.214(m,2H),2.54–2.47(m,2H),1.90(s,1H),1.81(s,3H).

[0389] In a 100 mL round-bottom flask, 2-acetamidoethanethiol (1.19 g, 9.985 mmol, 1.00 equivalent), DMF (30.00 mL), 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridine (3.45 g, 0.010 mmol, 1 equivalent), and Cs₂CO₃ (9.76 g, 0.030 mmol, 3 equivalents) were added. The resulting solution was stirred in an oil bath at 80 °C for 5 hours. The reaction mixture was cooled to room temperature using a water / ice bath. Then, 50 mL of water was added to stop the reaction. The resulting solution was extracted with 3 x 50 mL ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was eluted on a silica gel column with ethyl acetate / petroleum ether (1 / 1). The collected fractions were combined and concentrated. Two grams (45.07%) of N-[2-[(5-bromo-1-[[2-(trimethoxy)ethoxy]methyl]pyrrolo[2,3-b]pyridin-6-yl]thioyl]ethyl]acetamide were obtained as a yellow oil. LCMS-PH-PHNW-4-121-2 (ES, m / z): M+1: 444 / 446.

[0390] N-[2-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-6-yl]thio]ethyl]acetamide (2.00 g, 0.004 mmol, 1.00 equivalence), DMF (30 mL), Cs₂CO₃ (4.40 g, 0.013 mmol, 3 equivalence), and BrettPhos Pd G3 Precatalyst (0.61 mg, 0.001 mmol, 0.15 equivalence) were placed in a 50 mL round-bottom flask, and nitrogen was purged to maintain an inert atmosphere. The resulting solution was stirred overnight in an oil bath at 100 °C. The reaction was cooled to room temperature, and then 30 mL of water was added to stop the reaction. The resulting solution was extracted with 3 x 50 mL ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was washed on a silica gel column with ethyl acetate / petroleum ether (5:2). De-oxidation. The collected components were combined and concentrated. 670 mg (40.96%) of 1-(4-[[2-(trimethylsilyl)ethoxy]methyl]-13-thio-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraen-10-yl)acetone was obtained as a yellow oil. LCMS-PH-PHNW-4-121-3 (ES, m / z): M+1:364.

[0391] In an 8 mL vial, 1-(4-[[2-(trimethylsilyl)ethoxy]methyl]-13-thio-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraen-10-yl)acetone (600.00 mg, 1.650 mmol, 1.00 equivalence), MeOH (10.00 mL), and NaOH (4 M) (10.00 mL) were added. The resulting solution was stirred overnight in an oil bath at 80 °C. The resulting mixture was concentrated. The solution was extracted with 3 x 30 L ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was eluted on a silica gel column with ethyl acetate / petroleum ether (3:1). The collected fractions were combined and concentrated. 410 mg (77.27%) of 4-[[2-(trimethylsilyl)ethoxy]methyl]-13-thio-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene was obtained as a yellow oil. LC-MS-PH-PHNW-4-121-4:(ES,m / z):M+1:322.

[0392] 4-[[2-(trimethylsilyl)ethoxy]methyl]-13-thio-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene (200.00 mg, 0.622 mmol, 1.00 equivalent), 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene] [[amino]-3-nitrobenzenesulfonyl]benzamide (1016.69 mg, 1.244 mmol, 2 equivalents), DMF (20.00 mL), Cs₂CO₃ (608.04 mg, 1.866 mmol, 3 equivalents), CuI (47.39 mg, 0.249 mmol, 0.4 equivalents), and 1,10-phenanthroline (22.42 mg, 0.124 mmol, 0.2 equivalents) were placed in a 100 mL round-bottom flask, and nitrogen was purged to maintain an inert atmosphere. The resulting solution was stirred in an oil bath at 95 °C for 4 hours. Then 30 mL of water was added to stop the reaction. The solid was filtered off. The resulting solution was extracted with 3 x 20 mL ethyl acetate and concentrated. The residue was eluted on a silica gel column with ethyl acetate / petroleum ether (2:1). The collected fractions were combined and concentrated. 300 mg (45.59%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-13-thio-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide was obtained as a yellow oil. LC-MS-PH-PHNW-4-121-5: (ES, m / z): M+1: 1057.

[0393] In a 100 mL round-bottom flask, place 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-13-thio-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide) 300.00 mg (0.284 mmol, 1.00 equivalence), THF (20.00 mL, 0.277 mmol, 0.98 equivalence), TBAF (741.53 mg, 2.836 mmol, 10.00 equivalence), ethane-1,2-diamine (170.44 mg, 2.836 mmol, 10 equivalence). The resulting solution was stirred overnight in an oil bath at 70°C. The resulting mixture was concentrated. The crude product was purified by Chiral-Prep-HPLC under the following conditions: column, XBridge Prep C18 OBD. 19*150 mm 5 μm; mobile phase, A: 0.1% hydrochloric acid water; B: ACN; gradient: 24-95% B over 7.9 min; flow rate: 20 mL / min; detector, 220 nm. 50 mg (18.29%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2- [Methylene]amino]-3-nitrobenzenesulfonyl)2-]-13-thio-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide hydrochloride, is a yellow solid. LC-MS-PH-PHNW-4-121-0: (ES, m / z): M+1-HCl: 963. HCl-NMR-PH-PHNW-4-121-0: 1 H 1H NMR (300MHz, DMSO-d6) δ8.35(d,J=2.4Hz,1H),7.53(d,J=8.7Hz,1H),7.39(d,J=8.4Hz,2H),7.32(dd,J =9.3,2.4Hz,1H),7.15–7.06(m,3H),6.86(d,J=8.7Hz,1H),6.74(s,1H),6.62(d,J=9.3Hz,1H),6.45(s, 1H),5.94(d,J=3.3Hz,1H),3.88–3.74(m,6H),3.61(d,J=9.9Hz,4H),3.49(dd,J=12.0,9.6Hz,2H),3.4 3–3.26(m,7H),3.15(s,2H),2.74(s,2H),2.21(s,2H),2.03(s,2H),1.45(d,J=6.9Hz,2H),0.94(s,6H).

[0394] Preparation of Compound 2-11: 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)-N-(3-nitro-4-[[(oxalo-4-yl)methyl]amino]benzenesulfonyl)benzamide

[0395] 2-Bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(3-nitro-4-[[(4-oxaloyl)methyl]amino]benzenesulfonyl)benzamide (1568.13 mg, 1.924 mmol, 1.30 equivalent), 3,4-dihydro-2H-1,4-benzoxazine (200 mg, 1.48 mmol, 1.924 mmol, 1.30 equivalent), 0 mmol (1.00 equivalence), DMF (20.00 mL), CS₂CO₃ (1.45 g, 4.450 mmol, 3.01 equivalence), CuI (112.00 mg, 0.588 mmol, 0.40 equivalence), and 1,10-phenanthroline (53.30 mg, 0.296 mmol, 0.20 equivalence) were placed in a 50 mL round-bottom flask, and nitrogen was purged to maintain an inert atmosphere. The resulting solution was stirred in an oil bath at 90 °C for 5 hours. The solid was filtered off. The solution was extracted with 3 x 40 mL ethyl acetate and then concentrated. The residue was eluted on a silica gel column with ethyl acetate / petroleum ether (5:1). The collected fractions were combined and concentrated. 100 mg (7.77%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)-N-(3-nitro-4-[[(4-oxaloyl)methyl]amino]benzenesulfonyl)benzamide was obtained as a yellow solid. LC-MS-PH-PHNW-4-101-0: (ES, m / z): M+1: 869. HCl-NMR-PH-PHNW-4-101-0: 1H NMR (300MHz, DMSO-d6) δ11.87(s,1H),8.64(t,J=6.0Hz,1H),8.36(d,J=2.4Hz,1H),7.69–7.56(m,1H),7.48(d,J=8.7Hz,1H),7.41–7.32(m, 2H),7.13–7.01(m,3H),6.81(dd,J=9.0,2.4Hz,1H),6.73(d,J=2.4Hz,1H),6.58(dd,J=7.8,1.8Hz,1H),6.37(dtd,J=20.1,7.5,1.8Hz,2H),6 .09(dd,J=7.8,1.8Hz,1H),4.22(s,2H),3.88(dd,J=11.4,4.2Hz,2H),3.54(s,2H),3.35(d,J=7.2Hz,2H),3.30(s,2H),3.21(s,4H),2.81(s, 2H), 2.23 (d, J = 24.3Hz, 6H), 1.99 (d, J = 2.1Hz, 3H), 1.66 (d, J = 12.6Hz, 2H), 1.42 (t, J = 6.3Hz, 2H), 1.30 (tt, J = 12.5, 6.3Hz, 2H), 0.95 (s, 6H).

[0396] Preparation of compound 2-12: 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl-N-(3-nitro-4-[[(4-oxaloyl)methyl]amino]benzenesulfonyl)benzenesulfonyl]-2-[2H,3H-pyrido[2,3-b][1,4]azin-4-yl]benzamide)

[0397] 2-Bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(3-nitro-4-[(oxalo-4-methylene]amino]benzenesulfonyl)benzamide (233.51 mg, 0.286 mmol, 1.30 equivalence), DMF (4.00 mL), 2H,3H,4H-pyrido[4,3-b][1,4]azine (30.00 mg, 0.220 mmol, 1.00 equivalence), 1,10-phenanthroline (7.94 mg, 0.0 mL) 44 mmol (0.2 equivalents), CuI (16.79 mg, 0.088 mmol, 0.4 equivalents), and Cs₂CO₃ (215.37 mg, 0.661 mmol, 3 equivalents) were placed in an 8 mL vial, and nitrogen was purged to maintain an inert atmosphere. The resulting solution was stirred in an oil bath at 95 °C for 3 hours. The solid was filtered off. The resulting solution was quenched with 10 mL of water and concentrated and extracted with 3 x 10 mL of ethyl acetate. The crude product was purified by Prep-HPLC under the following conditions (2#SHIMADZU(HPLC-01)): column, SunFire. Prep C18 OBD column, 19*150 mm 5 μm 10 nm; mobile phase, water (0.1% HCl) and ACN (20% Phase B, reaching 40% within 8 min); detector, UV = 254 nm. 8 mg (17%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-[3-nitro-4-[(oxalo-4-methylene)amino]benzenesulfonyl]-2-[2H,3H-pyrido[4,3-b][1,4]azin-4-yl]benzamide was obtained as a yellow solid hydrochloride. LC-MS-PH-PHNW-4-104-0: (ES, m / z): M+1-HCl: 870. HCl-NMR-PH-PHNW-4-104-0: 1H NMR (300MHz, DMSO-d6) δ12.30(s,1H), δ10.37(s,1H),8.64(d,J=6.3Hz,1H),8.43(d,J=2.4Hz,1H),7.88(d,J=6.3Hz,1H ),7.80–7.65(m,1H),7.54(d,J=9.3Hz,1H),7.42(d,J=8.1Hz,2H),7.30(s,1H),7.19–7.09(m,4H),6.96(s,2H),4.58(s ,1H),4.31(s,1H),3.89(dd,J=11.7,4.2Hz,4H),3.66–3.56(m,4H),3.29(d,J=12.0Hz,6H),2.76(d,J=16.8Hz,2H),2.4 2–2.24(m,4H),2.06(s,2H),1.95(s,1H),1.66(d,J=13.2Hz,2H),1.49(d,J=6.6Hz,2H),1.40–1.21(m,2H),0.97(s,6H).

[0398] Compound 2-13: Preparation of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-(((S)-5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl )benzamide and 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-(((R)-5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide

[0399] Synthesis of 3-bromo-4-chloro-5-nitrobenzenesulfonamide: 20.00 g of 4-chloro-3-nitrobenzenesulfonamide (84.520 mmol, 1.00 equivalent) and 20.00 mL of H₂SO₄ were added to a 50 mL round-bottom flask. NBS (22.56 g, 126.753 mmol, 1.50 equivalent) was then added in portions at 50 °C. The resulting solution was stirred at 60 °C for 2 hours. The solution was diluted with 200 mL of cold H₂O. The solution was extracted with 3 x 30 mL of ethyl acetate. The resulting mixture was washed with 1 x 20 mL of H₂O. The resulting mixture was washed with 1 x 20 mL of NaCl (aqueous solution). The residue was loaded onto a silica gel column containing ethyl acetate and eluted with ethyl acetate / petroleum ether (1:3). The final product was 5 g (18.75%) of 3-bromo-4-chloro-5-nitrobenzenesulfonamide, a white solid. LC-MS-1: (ES, m / z): 312.9 [MH]

[0400] Synthesis of 2-amino-2-(oxan-4-yl)ethanol: Amino(oxan-4-yl)acetic acid (4.00 g, 25.128 mmol, 1.00 equivalent), THF (50.00 mL), and LiAlH4 (1.91 g, 50.324 mmol, 2.00 equivalent) were added to a 100 mL round-bottom flask. The resulting solution was stirred in an oil bath at 60 °C for 3 hours. Then, 10 mL of water was added to stop the reaction. The resulting mixture was concentrated. The final product was 6 g (crude) of 2-amino-2-(oxan-4-yl)ethanol, a white solid. LC-MS-21: (ES, m / z): 146.2 [M+H] +

[0401] Synthesis of 3-bromo-4-[[2-hydroxy-1-(oxan-4-yl)ethyl]amino]-5-nitrobenzenesulfonamide: 3-bromo-4-chloro-5-nitrobenzenesulfonamide (5.00 g, 15.847 mmol, 1.00 equivalent), 2-amino-2-(oxan-4-yl)ethanol (5.00 g), CH3CN (30.00 mL, 0.731 mmol), and DIEA (6.10 g, 47.198 mmol, 2.98 equivalent) were added to a 100-mL round-bottom flask. The resulting solution was stirred in an oil bath at 80 °C for 48 hours. The resulting mixture was concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane / methanol (10:1). The final product was 1.2 g (17.85%) of 3-bromo-4-[[2-hydroxy-1-(oxan-4-yl)ethyl]amino]-5-nitrobenzenesulfonamide, a yellow solid. LC-MS-2: (ES, m / z): 424.1 [M+H] + .

[0402] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]tetrazol-1(9),2,5,7-tetraen-10-yl]benzoate. Add (12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]tetrazine-1(9),2,5,7-tetraene (500.00 mg, 1.565 mmol, 1.00 equivalent), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)benzoate (832.48 mg, 1.565 mmol, 1.00 equivalent), and xantphos Pd to a 50-mL round-bottom flask. 2g (138.82mg, 0.157mmol, 0.10 equivalent), Cs₂CO₃ (1529.77mg, 4.695mmol, 3.00 equivalent), dioxane (10.00mL). The resulting solution was stirred at 80°C for 14 hours. The resulting mixture was concentrated. The residue was eluted on a silica gel column with ethyl acetate / petroleum ether (1:3). The final product was 611 mg (50.67%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]tetrazol-1(9),2,5,7-tetraen-10-yl]benzoate, a yellow solid. LC-MS-11: (ES, m / z): 770.4 [M+H] + .

[0403] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]tetrazine-1(9),2,5,7-tetraen-10-yl]benzoate. To an 8 mL vial, add methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]tetrazol-1(9),2,5,7-tetraen-10-yl]benzoate (300.00 mg, 0.389 mmol), ethylene-1,2-diamine (0.20 mL), and a THF solution containing TBAF (1 mL, 2 M). The resulting solution was stirred in an oil bath at 70 °C for 24 hours. The resulting mixture was concentrated. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1:1). The final product was 100 mg (40.12%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]tetrazol-1(9),2,5,7-tetraen-10-yl]benzoate, which was a white solid. LC-MS-11: (ES, m / z): 640.3 [M+H] + .

[0404] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(92,5,7-tetraen-10-yl)benzoic acid. In an 8 mL vial, 100.00 mg (0.156 mmol, 1.00 equivalence) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl)benzoate, 37.49 mg (0.937 mmol, 6.00 equivalence), 0.50 mL of MeOH, 0.50 mL of dioxane, and 0.20 mL of H₂O were added. The resulting solution was stirred in an oil bath at 70 °C for 14 hours. The resulting mixture was concentrated. The resulting solution was extracted with 1 mL of H₂O. The pH of the solution was adjusted to 6 using CH3COOH. The resulting mixture was concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane / methanol (10:1). 60 mg of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R-12-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9,)2,5,7-tetraen-10-yl]benzoic acid was obtained as a brown solid. LC-MS-13: (ES, m / z): 626.3 [M+H] + .

[0405] Synthesis of 5-nitro-3-(oxalo-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide. 3-Bromo-4-[[2-hydroxy-1-(oxalo-4-yl)ethyl]amino]-5-nitrobenzenesulfonamide (1.40 g, 3.300 mmol, 1.00 equivalence), dioxane (20.00 mL), Pd₂(dba)₃ (604.34 mg, 0.660 mmol, 0.20 equivalence), XantPhos (763.73 mg, 1.320 mmol, 0.40 equivalence), and Cs₂CO₃ (3.23 g, 9.913 mmol, 3.00 equivalence) were placed in a 50 mL round-bottom flask, and an inert atmosphere was maintained by blowing nitrogen. The resulting solution was stirred in an oil bath at 100 °C for 2 hours. The resulting mixture was then concentrated. The residue was eluted on a silica gel column with ethyl acetate / petroleum ether (1:1). 230 mg (20.30%) of 5-nitro-3-(oxalo-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide was given as a yellow solid. LC-MS-3: (ES, m / z): 342.1 [MH] -

[0406] Synthesis of (3S)-5-nitro-3-(oxalo-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide and (3R)-5-nitro-3-(oxalo-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide. In a 50 mL round-bottom flask, 150.00 mg of 5-nitro-3-(oxalo-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide and 10 mL of DMF were added. The crude product was purified by Chiral-Prep-HPLC under the following conditions (WATERS 2767): column, CHIRALPAKIA, 250*20 mm, 5 μm; mobile phase: A: n-hexane:DMC = 3:1, 0.1% DEA), B: EtOH; gradient: 10% B over 20 min; detector, 220 nm. 30 mg of (3S)-5-nitro-3-(oxalo-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide was obtained as a yellow solid. 32 mg of (3R)-5-nitro-3-(oxalo-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide was obtained as a yellow solid.

[0407] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-3,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tetane-1(9),2,5,7-tetraen-10-yl]-N-(3S)-5-nitro-3-(oxalate-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-ylsulfonyl]benzamide hydrochloride: In an 8 mL vial, (3S)-5-nitro-3-(oxalate-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-ylsulfonyl]benzamide (2 0 mg (0.058 mmol, 1.00 equivalence), 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(12R)-12-methyl-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzoic acid (36.48 mg, 0.058 mmol, 1.00 equivalence), DCM (0.5 mL), EDC.HCl (22.33 mg, 0.116 mmol, 2.00 equivalence), DMAP (17.79 mg, 0.146 mmol, 2.50 equivalence). The resulting solution was stirred at room temperature for 14 hours. The resulting mixture was concentrated. The residue was purified by Prep-TLC using dichloromethane / methanol (10:1). The crude product (30 mg) was purified by Prep-HPLC under the following conditions: column, XBridge Prep C18 OBD 19*150 mm 5 μm; mobile phase, A: 0.1% hydrochloric acid and water; B: ACN; gradient: 38-58% B over 7 min; flow rate: 20 mL / min; detector, 220 nm. 10 mg (17.38%) of 4-(4-[[2-(4-chlorophenyl)-3,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tetane-1(9),2,5,7-tetraen-10-yl]-N-(3S)-5-nitro-3-(oxalate-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-ylsulfonyl]benzamide hydrochloride was obtained as a yellow solid. LC-MS-OA: (ES, m / z): 951.4 [M-HCl+H] +\ . 1H NMR-0A(300MHz,DMSO,ppm):δ12.15(s,1H),10.86(s,1H),9.68(s,1H),8.78(s,1H),8.05-7.81(m,1H),7.58-7.31(m,1H),7.21-6.72(m,6H),6.70-6.40(m,1H),6.02-5.81(m,1H),4.61-4.11(m,3H),3.92-3.78(m,4H),3.65-3.61(m,2H),3.38-3.13(m,8H),2.90-2.72(m,2H),2.30-2.21(m,2H),2.13-1.94(m,2H),1.92-1.51(m,3H),1.51-1.23(m,8H),0.96(s,6H).

[0408] Synthesis of 4-(4-[[2-(4-chlorophenyl)-3,4-methylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tetane-1(9),2,5,7-tetraen-10-yl]-N-(3R)-5-nitro-3-(oxalate-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-ylsulfonyl]benzamide hydrochloride. In an 8 mL vial, place (3R)-5-nitro-3-(oxalo-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide (20.00 mg, 0.058 mmol, 1.00 equivalence), 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(12R)-12-methyl-1 3-Oxalic acid-2,4,10-triazacyclic[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzoic acid (36.48 mg, 0.058 mmol, 1.00 equivalence), DCM, EDCl (22.33 mg, 0.116 mmol, 2.00 equivalence), DMAP (17.79 mg, 0.146 mmol, 2.50 equivalence). The resulting solution was stirred at room temperature for 14 hours. The resulting mixture was concentrated. The residue was purified by Prep-TLC with DCM / methanol (10:1). The crude product (30 mg) was purified by Prep-HPLC under the following conditions: column, XBridgePrep C18 OBD 19*150 mm 5 μm; mobile phase, A: 0.1% hydrochloric acid water; B: ACN; gradient: 38-58% B over 7 minutes; flow rate: 20 mL / min; detector, 220 nm. 10.3 mg (18.16%) of 4-(4-[[2-(4-chlorophenyl)-3,4-methylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tetane-1(9),2,5,7-tetraen-10-yl]-N-(3R)-5-nitro-3-(oxalate-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-ylsulfonyl]benzamide hydrochloride was obtained as a yellow solid. LC-MS-OB: (ES, m / z): 951.4 [M-HCl+H] + . 1H NMR-0B (300MHz, DMSO, ppm): δ12.16(s,1H),10.89(s,1H),10.02(s,1H),8.78(s, 1H),8.05-7.41(m,5H),7.21-6.52(m,6H),6.02-5.91(m,1H),4.61-4.21(m,2H),4 .15-3.78(m,5H),3.71-3.65(m,2H),3.38-3.13(m,8H),2.88-2.72(m,2H),2.35-2 .30(m,2H),2.13-1.94(m,2H),1.92-1.59(m,3H),1.51-1.23(m,8H),0.96(s,6H).

[0409] Compound 2-14: 4-(4-[[2-(4-chlorophenyl)-3,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-[(3S)-3-[(2S)-1,4-dioxane-2-yl]5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-ylsulfonyl]-2-[(12R)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tetane-1(9),2,5,7-tetraen-10-yl]benzamide salt Synthesis of acid salts and 4-(4-[[2-(4-chlorophenyl)-3,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-[(3R)-3-[(2S)-1,4-dioxane-2-yl]5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-ylsulfonyl]-2-[(12R)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tetane-1(9),2,5,7-tetraen-10-yl]benzamide hydrochloride

[0410] Synthesis of (2R)-1,4-dioxane-2-yl)carbaldehyde: In a 100 mL round-bottom flask, (2S)-1,4-dioxane-2-methanol (2.36 g, 19.978 mmol, 1.00 equivalent), CH3CN (50.00 mL, 1.218 mmol, 0.0 equivalent), and IBX (9.51 g, 33.962 mmol, 1.70 equivalent) were added. The resulting solution was stirred in an oil bath at 70 °C for 4 hours. The solid was filtered off. The resulting mixture was concentrated. 2.0 g (86.22%) of (2R)-1,4-dioxane-2-carbaldehyde was given as a colorless oil. H-NMR-1: 1 H NMR (300MHz, CDCl3, ppm) δ9.66 (s, 1H), 4.12-3.77 (m, 7H).

[0411] Synthesis of 2-amino-2-[(2S)-1,4-dioxane-2-yl]acetonitrile: In a 100 mL pressure vessel reactor, (2R)-1,4-dioxane-2-carboxaldehyde (2.00 g, 17.224 mmol, 1.00 equivalent) was added. NH3 / MeOH (7 M) (40.00 mL) was then added. TMSCN (2.97 g, 29.970 mmol, 1.74 equivalent) was subsequently added. The resulting solution was stirred overnight in an oil bath at 70 °C. The resulting mixture was concentrated. The residue was eluted on a silica gel column with ethyl acetate / petroleum ether (3:1). The collected fractions were combined and concentrated. 2.0 g (81.68%) of 2-amino-2-[(2S)-1,4-dioxane-2-yl]acetonitrile was obtained as a brown oil. LCMS-2(ES,m / z):M+1:143.

[0412] Synthesis of ((2S)-1,4-dioxane-2-yl)acetic acid: In a 20 mL round-bottom flask, 2-amino-2-[(2S)-1,4-dioxane-2-yl]acetonitrile (2.00 g, 14.069 mm, 1.00 equivalent) and NaOH (4 M) (5.00 mL) were added. The resulting solution was stirred overnight in an oil bath at 70 °C. The pH of the solution was adjusted to 6 with HOAc. The solid was collected by filtration. The solid was dried under reduced pressure in an oven. 1.2 g (52.93%) of amino((2S)-1,4-dioxane-2-yl)acetic acid was given as a white solid. M+1:162.

[0413] Synthesis of 2-amino-2-[(2S)-1,4-dioxane-2-yl]ethanol: In a 100 mL round-bottom flask, amino((2S)-1,4-dioxane-2-yl)acetic acid (1.20 g, 7.446 mmol, 1.00 equivalence), THF (40.00 mL, 0.555 mmol, 0.07 equivalence), and LiAlH4 (0.85 g, 22.396 mmol, 3.01 equivalence) were added. The resulting solution was stirred in an oil bath at 60 °C for 4 hours. Then, 2.4 g of Na2SO4·10H2O was added to stop the reaction. The solid was filtered off. The resulting mixture was concentrated to give 1.8 g (crude) 2-amino-2-[(2S)-1,4-dioxane-2-yl]ethanol as a colorless oil. LCMS-4(ES,m / z):M+1:148.

[0414] Synthesis of 3-bromo-4-([1-[(2S)-1,4-dioxane-2-yl]-2-hydroxyethyl]amino)-5-nitrobenzenesulfonamide: In a 50 mL round-bottom flask, 3-bromo-4-chloro-5-nitrobenzenesulfonamide (1.19 g, 3.772 mmol, 1.00 equivalence), 2-amino-2-[(2S)-1,4-dioxane-2-yl]ethanol (0.72 g, 0.005 mmol, 1.3 equivalence), CH3CN (30.00 mL), and DIEA (1.46 g, 0.011 mmol, 3 equivalence) were added. The resulting solution was stirred in an oil bath at 80 °C for 48 h. The resulting mixture was concentrated. The residue was eluted on a silica gel column with ethyl acetate / petroleum ether (9:1). The collected fractions were combined and concentrated. 120 mg (7.46%) of 3-bromo-4-([1-[(2S)-1,4-dioxane-2-yl]-2-hydroxyethyl]amino)-5-nitrobenzenesulfonamide was obtained as a yellow solid. LCMS-5 (ES, m / z): M-1: 424

[0415] Synthesis of (3S)-3-[(2S)-1,4-dioxane-2-yl]-5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide and (3R)-3-[(2S)-1,4-dioxane-2-yl]-5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide (hypothetically): 3-bromo-4-([1-[(2S)-1,4-dioxane-2-yl]-2-hydroxyethyl]amino)-5-nitrobenzenesulfonamide (120.00 mg, 0.282 mmol, 1.00 equivalence), dioxane (8.00 mL), Cs₂CO₃ (229.32 mg, 0.704 mmol, 2.50 equivalence), t-BuXPhos Pd G3 (22.33 mg, 0.028 mmol, 0.1 equivalence) was placed in an 8 mL round-bottom flask and an inert atmosphere was maintained by blowing nitrogen. The resulting solution was stirred in an oil bath at 100 °C for 8 hours. Then, 8 mL of water was added to stop the reaction. The resulting solution was extracted with 3 x 8 mL ethyl acetate and concentrated. The crude product was purified by Prep-HPLC under the following conditions: column, X-bridge RP18; mobile phase, 0.05% ammonia and CH3CN (45% CH3CN reached 60% within 5 minutes); detector, UV 254 nm. 7 mg (7.20%) of (3S or 3R)-3-[(2S)-1,4-dioxane-2-yl]-5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide was obtained as a yellow solid. 10 mg (10.29%) of (3R or 3S)-3-[(2S)-1,4-dioxane-2-yl]-5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide was obtained as a yellow solid. LC-MS-6: (ES, m / z): M-1: 344.

[0416] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(3S)-3-[(2S)-1,4-dioxane-2-yl]-5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide]-2-[(12R)-12-methyl-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide hydrochloride (hypothesis): In an 8 mL round-bottom flask, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl) 2-[(12R)-12-methyl-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzoic acid (12.69 mg, 0.020 mmol, 1.00 equivalence), (3S)-3-[(2S)-1,4-dioxane-2-yl]-5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide (7.00 mg, 0.020 mmol, 1.00 equivalence), DCM (5.00 mL), EDCI (7.77 mg, 0.041 mmol, 2.00 equivalence), DMAP (7.43 mg, 0.061 mmol, 3.00 equivalence). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC under the following conditions (2#SHIMADZU(HPLC-01)): column, Sun Fire Prep C18 OBD column, 19*150 mm 5 μm 10 nm; mobile phase, water (0.05% TFA) and ACN (38% B phase, reaching 58% within 7 min); detector, UV 254 nm. The collected solution was concentrated under vacuum to remove CH3CN, and the resulting solution was lyophilized (with the addition of con.HCl (1 drop)). Five milligrams (24.29%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(3S)-3-[(2S)-1,4-dioxane-2-yl]-5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide]-2-[(12R)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide hydrochloride were obtained as a yellow solid. LC-MS-OA: (ES, m / z): M+1-HCl: 953.

[0417] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(3R)-3-[(2S)-1,4-dioxane-2-yl]-5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide]-2-[(12R)-12-methyl-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide hydrochloride (hypothesis): In an 8 mL round-bottom flask, (3R)-3-[(2S)-1,4-dioxane-2-yl]-5-nitro-3,4-dihydro-2H-1 4-Benzoxazine-7-sulfonamide (10.00 mg, 0.029 mmol, 1.00 equivalence), 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(12R)-12-methyl-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzoic acid (18.13 mg, 0.029 mmol, 1.00 equivalence), DCM (5.00 mL), EDCl (11.10 mg, 0.058 mmol, 2 equivalence), DMAP (14.15 mg, 0.116 mmol, 4 equivalence). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC under the following conditions (2#SHIMADZU(HPLC-01)): column, Sun Fire Prep C18 OBD column, 19*150 mm 5 μm 10 nm; mobile phase, water (0.05% TFA) and ACN (38% B phase, reaching 58% within 7 minutes); detector, UV = 254 nm. The collected solution was concentrated under vacuum to remove CH3CN, and the resulting solution was lyophilized (with the addition of 1 drop of con.HCl). 10 mg of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(3R)-3-[(2S)-1,4-dioxane-2-yl]-5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide]-2-[(12R)-12-methyl-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide hydrochloride was obtained as a yellow solid. LC-MS-OB: (ES, m / z): M+1-HCl: 953; HCl-NMR-OB: 1 H NMR (300MHz, Methanol-d) 4,ppm)δ8.01(s,1H),7.65(d,J=8.4Hz,1H),7.41(d,J=8.4Hz,1H),7.25(s,1H),7.13(d,J=8.4Hz,2 H),6.94(s,2H),6.82(s,1H),6.66(s,1H),5.94(s,1H),4.70(s,1H),4.31(s,1H),4.04(s,1H),3. 98–3.58(m, 12H), 3.48(s, 3H), 3.22(s, 2H), 2.90(s, 2H), 2.33(s, 2H), 2.16(s, 2H), 1.62(t, J = 6.3Hz, 2H), 1.51(d, J = 6.3Hz, 3H), 1.32(s, 1H), 1.05(s, 6H). Compound 2-15: 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane) [alkyl-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)-2-[(11S,15S)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzamide (hypothetical) and 4-(4-[[2-(4-chlorobenzene) Synthesis of (4,4-dimethylcyclohexane-1-en-1-yl)methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)-2-[(11R,15R)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzamide (hypothetical):

[0418] Synthesis of N-[(trans)-2-hydroxycyclopentyl]-4-methylbenzenesulfonamide: (trans)-2-aminocyclopentan-1-ol (2.10 g, 20.761 mmol, 1.00 equivalent), DCM (30.00 mL), and TEA (3.18 g, 31.426 mmol, 1.51 equivalent) were placed in a 250 mL round-bottom flask, and nitrogen was purged to maintain an inert atmosphere. Then, P-toluenesulfonyl chloride (4.35 g, 22.818 mmol, 1.10 equivalent) was added in portions at 0°C, and the resulting solution was stirred at 25°C for 3 hours. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1.5:1). 5 g (94.32%) of N-[(trans)-2-hydroxycyclopentyl]-4-methylbenzenesulfonamide was obtained as a pale yellow oil. 1H NMR(300MHz,Chloroform-d,ppm)δ7.84–7.77(m,2H),7.38–7.30(m,2H),5.27(s,1H),4.06(dt,J=7.2,6.3Hz, 1H),3.25(q,J=7.7Hz,1H),2.91(s,1H),2.45(s,3H),2.06–1.81(m,2H),1.72–1.46(m,3H),1.45–1.23(m,1H).

[0419] Synthesis of N-[(trans)-2-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-6-yl)oxy]cyclopentyl]-4-methylbenzenesulfonamide: N-[(trans)-2-hydroxycyclopentyl]-4-methylbenzenesulfonamide (5.00 g, 19.583 mmol, 1.30 equivalence) and THF (50.00 mL) were placed in a 250 mL round-bottom flask, and nitrogen was purged to maintain an inert atmosphere. Then, NaH (1.81 g, 45.254 mmol, 3.01 equivalence, 60%) was added in portions at 0°C, and the resulting solution was stirred at 0°C for 0.5 h. 5-Bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridine (5.19 g, 15.031 mmol, 1.00 equivalent) was added to the mixture at 0°C. The resulting solution was stirred in an oil bath at 70°C for 2 hours. The reaction mixture was cooled to room temperature. Then, an aqueous solution of NH4Cl was added to stop the reaction. The resulting solution was extracted with 3 x 200 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 x 1000 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1:3). 4.8 g (55.00%) of N-[(trans)-2-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-6-yl)oxy]cyclopentyl]-4-methylbenzenesulfonamide was obtained as a yellow oil. 1H NMR(300MHz,Chloroform-d,ppm)δ8.00(s,1H),7.56–7.47(m,2H),7.19(d,J= 3.6Hz,1H),7.11–7.02(m,2H),6.42(d,J=3.6Hz,1H),5.70(d,J=10.9Hz,1H), 5.49(d,J=10.9Hz,1H),5.33–5.20(m,1H),3.69–3.43(m,3H),2.31(s,3H),1. 93–1.63(m,4H),1.01–0.93(m,2H),0.89(dd,J=7.0,1.5Hz,2H),0.01(s,9H).

[0420] Synthesis of (trans)-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxalate-2,4,10-triazacyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraene: N-[(trans)-2-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-6-yl)oxy]cyclopentane] 2.90 g of 4.995 mmol, 1.00 equivalent of methylbenzenesulfonamide, 30.00 mL of DMF, 902.00 mg of phenol, 5.005 mmol, 1.00 equivalent of phenol, 952.00 mg of CuI, 4.999 mmol, 1.00 equivalent of CuI, and 2.07 g of K₂CO₃, 14.978 mmol, 3.00 equivalent of methylbenzenesulfonamide were placed in a 100 mL round-bottom flask, and nitrogen was purged to maintain an inert atmosphere. The resulting solution was stirred overnight in an oil bath at 120 °C. The reaction mixture was cooled to room temperature. The resulting solution was diluted with 500 mL of water. The resulting solution was extracted with 3 x 200 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 x 1000 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1:3). 2.1 g (84.14%) of (trans)-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxalic acid-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraene was obtained as a colorless oil. 1H NMR(300MHz,Chloroform-d,ppm)δ8.68(s,1H),7.43–7.34(m,2H),7.24(d,J=3.6Hz,1H),7.15(d,J=8.0Hz,2H),6.53(d,J=3.6Hz,1H),5.54(d,J=1.4Hz,2H),4.00(td,J=10.0,7.6Hz,1H),3.52(t,J=8.2Hz,2H),3.43–3.28(m,1H),2.68–2.49(m,1H),2.35(s,3H),2.21–1.88(m,4H),1.77(td,J=10.8,7.6Hz,1H),0.97–0.86(m,2H),-0.05(s,9H)。

[0421] (11S,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraene (hypothetical) and (11R,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraene (false) Synthesis of (e.g.): In a 100 mL round-bottom flask, magnesium (1.92 g, 78.996 mmol, 19.74 equivalences), MeOH (20.00 mL), (trans)-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9), 2,5,7-tetraene (2.00 g, 4.002 mmol, 1.00 equivalences). The resulting solution was stirred in an oil bath at 60 °C for 2 hours. The reaction mixture was cooled to room temperature. The resulting solution was diluted with 300 / 300 mL NaHCO3 and CH2Cl2. The solids were filtered off, and the organic matter was separated. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1:3). The crude product was purified by Chiral-Prep-HPLC under the following conditions: mobile phase: A: n-hexane, B: ETOH; flow rate: 20 mL / min; column: DAICL CHIRALPAK OD, 250*20 mm, 5 μm; gradient: 20% B, 15 min; 220 nm. 360 mg (26.03%) of (11S,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraene (hypothetical) was obtained as a yellow oil. 400 mg (28.92%) of (11R, 15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraene (hypothesized) was obtained as a yellow oil. Peak 1: LC-MS (ES, m / z): M+1 = 346, 11H NMR (300 MHz, Chloroform-d, ppm) δ 7.28 (s, 1H), 7.15 (d, J = 3.5 Hz, 1H), 6.33 (d, J = 3.5 Hz, 1H), 5.56 (s, 2H), 4.30–4.07 (m, 1H), 3.55 (dd, J = 8.8, 7.5 Hz, 2H), 3.29 (dt, J = 11.4, 7.5 Hz, 1H), 2.37–2.19 (m, 1H), 2.18–2.04 (m, 1H), 2.04–1.79 (m, 3H), 1.68–1.40 (m, 1H), 0.90 (dd, J = 8.7, 7.5 Hz, 2H), -0.06 (s, 9H). Peak 2: LC-MS (ES, m / z): M+1 = 346, 1 1H NMR (300 MHz, Chloroform-d, ppm) δ 7.28 (s, 1H), 7.15 (d, J = 3.5 Hz, 1H), 6.33 (d, J = 3.5 Hz, 1H), 5.56 (s, 2H), 4.30–4.07 (m, 1H), 3.55 (dd, J = 8.8, 7.5 Hz, 2H), 3.29 (dt, J = 11.4, 7.5 Hz, 1H), 2.37–2.19 (m, 1H), 2.18–2.04 (m, 1H), 2.04–1.79 (m, 3H), 1.68–1.40 (m, 1H), 0.90 (dd, J = 8.7, 7.5 Hz, 2H), -0.06 (s, 9H).

[0422] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetical): [(11S,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen (Assuming) (340.00 mg, 0.984 mmol, 1.00 equivalence), toluene (15.00 mL), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)benzoate (1.04, 1.955 mmol, 1.99 equivalence), Pd2(dba)3.CHCl3 (204.00 mg, 0.197 mmol, 0.20 equivalence), Xantphos (228.00 mg, 0.394 mmol, 0.40 equivalence), Cs2CO3 (961.00 mg, 2.949 mmol, 3.00 equivalence) were placed in a 40 mL vial, and nitrogen was purged to maintain an inert atmosphere. The resulting solution was stirred in an oil bath at 100 °C for 4 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1:2). 630 mg (80.38%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate was obtained as a yellow solid (hypothetically). LC-MS (ES, m / z): M+1 = 796.

[0423] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15S)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate: In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)- 4,4-Dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl}benzoate (hypothetical) (630.00 mg, 0.791 mmol, 1.00 equivalence), TBAF in THF (10.00 mL, 1.0 M), ethylenediamine (1.30 g, 21.631 mmol, 27.35 equivalence). The resulting solution was stirred in an oil bath at 70 °C for 8 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (2:1). 300 mg (56.93%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15S)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetically) was obtained as a yellow solid. LC-MS (ES, m / z): M+1 = 666.

[0424] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S or S)-2-[(11S,15S)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothesis): In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S or S)-2-[(11S,15S)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid was added. -1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15S)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetical) (300.00 mg, 0.450 mmol, 1.00 equivalence), dioxane (5.00 mL), MeOH (5.00 mL), NaOH (1.00 mL, 4.000 mmol, 8.88 equivalence). The resulting solution was stirred in an oil bath at 70 °C for 4 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The pH of the solution was adjusted to 6-7 with HCl (2 mol / L). The resulting solution was extracted with 3 x 50 mL ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 x 300 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by Prep-TLC with ethyl acetate. 130 mg (44.26%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15S)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetically) was given as a white solid. LC-MS: (ES, m / z): M+1 = 652.

[0425] Synthesis of 4-(4-[[2-(4-chlorophenyl)-1,4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)-2-[(11S,15S or 11R,15R)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzamide (hypothetical): In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl) 2-[(11S,15S)-16-oxalic acid-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetically) (50.00 mg, 0.077 mmol, 1.00 equivalence), DCM (5.00 mL), 4-[[(2S)-1,4-dioxane-2-ylmethyl]amino]-3-nitrobenzenesulfonamide (24.00 mg, 0.076 mmol, 0.99 equivalence), EDCI (30.00 mg, 0.156 mmol, 2.04 equivalence), DMAP (38.00 mg, 0.311 mmol, 4.06 equivalence). The resulting solution was stirred overnight in an oil bath at 30°C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC under the following conditions (Prep-HPLC-006): column, XBridge Shield RP18 OBD column, 5 μm, 19 x 150 mm; mobile phase, water (0.05% NH3·H2O) and ACN (40% B phase, reaching 70% within 7 minutes); detector, UV 254 / 220 nm. 25 mg (34.27%) of 4-(4-[[2-(4-chlorophenyl)-1,4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzene)nitrobenzenesulfonyl)-2-[(11S,15S or 11R,15R)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzamide (hypothetically) was obtained as a yellow solid. LC-MS (ES, m / z): M+1 = 951, 1H NMR(300MHz,DMSO-d6,ppm)δ12.90(s,1H),11.21(s,1H),8.54(s,1H),8.35(d,J=2.3Hz,1H),7.75(d,J=8.6Hz,1H),7.46–7.30(m,3H),7.18–6.99(m,3H),6.93(d,J=9.2Hz,1H),6.80(s,2H),6.49(s,1H),6.07–5.99(m,1H),4.33(d,J=7.2Hz,1H),3.79(dd,J=9.9,5.9Hz,4H),3.73–3.33(m,7H),3.27(d,J=13.6Hz,4H),3.12(d,J=6.5Hz,1H),2.75(s,2H),2.20(s,6H),1.97(s,2H),1.83(s,2H),1.68(s,1H),1.40(s,3H),0.94(d,J=2.2Hz,6H).

[0426] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetical): [(11R,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7- Tetraene (hypothetically) (400.00 mg, 1.158 mmol, 1.00 equivalence), toluene (15 mL), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)benzoate (1.23 g, 2.312 mmol, 2.00 equivalence), Pd₂(dba)₃.CHCl₃ (239.00 mg, 0.231 mmol, 0.20 equivalence), Xantphos (268.00 mg, 0.463 mmol, 0.40 equivalence), Cs₂CO₃ (1.13 g, 2.949 mmol, 3.00 equivalence) were placed in a 40 mL vial, and nitrogen was purged to maintain an inert atmosphere. The resulting solution was stirred in an oil bath at 100 °C for 4 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1:2). 680 mg (73.74%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate was obtained as a yellow solid (hypothetically). LC-MS (ES, m / z): M+1 = 796.

[0427] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15R)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate: In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)- 4,4-Dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl}benzoate (hypothetical) (670.00 mg, 0.841 mmol, 1.00 equivalence), TBAF in THF (10.00 mL, 1.0 M), ethylenediamine (1.30 g, 21.631 mmol, 25.72 equivalence). The resulting solution was stirred in an oil bath at 70 °C for 8 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (2:1). 320 mg (57.10%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15R)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetically) was obtained as a yellow solid. LC-MS (ES, m / z): M+1 = 666.

[0428] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S or S)-2-[(11R, 15R)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothesis): In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-yl]methyl]piperazin-1-yl)-2-[(11S or S)-2-[(11R, 15R)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid was added. 1-En-1-yl]methyl]piperazin-1-yl)-2-[(11R,15R)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetical) (140.00 mg, 0.210 mmol, 1.00 equivalence), dioxane (3.00 mL), MeOH (3.00 mL), NaOH (0.60 mL, 2.400 mmol, 11.42 equivalence). The resulting solution was stirred in an oil bath at 70 °C for 4 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The pH of the solution was adjusted to 6-7 with HCl (2 mol / L). The resulting solution was extracted with 3 x 50 mL ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 x 300 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by Prep-TLC with ethyl acetate. 80 mg (58.37%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15R)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetically) was given as a white solid. LC-MS (ES, m / z): M+1 = 652.

[0429] Synthesis of 4-(4-[[2-(4-chlorophenyl)-1,4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)-2-[(11R,15R or 11S,15S)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzamide: In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)- 2-[(11R,15R)-16-oxalic acid-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid (20.00 mg, 0.031 mmol, 1.00 equivalence), DCM (5.00 mL), 4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonamide (hypothetically) (9.70 mg, 0.031 mmol, 1.00 equivalence), EDCI (12.00 mg, 0.063 mmol, 2.04 equivalence), DMAP (15.00 mg, 0.123 mmol, 4.00 equivalence). The resulting solution was stirred overnight in an oil bath at 30°C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC under the following conditions (Prep-HPLC-006): column, X BridgeShield RP18 OBD column, 5 μm, 19 x 150 mm; mobile phase, water (0.05% NH3·H2O) and ACN (40% B phase, reaching 70% within 7 minutes); detector, UV 254 / 220 nm. 4.7 mg (16.11%) of 4-(4-[[2-(4-chlorophenyl)-1,4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzene)nitrobenzenesulfonyl)-2-[(11R,15R or 11S,15S)-16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzamide (hypothetically) was obtained as a yellow solid. LC-MS (ES, m / z): M+1 = 951, 1H NMR (300MHz, DMSO-d6, ppm) δ12.90(s,1H),11.21(s,1H),8.54(s,1H),8.35(d,J=2.3Hz,1H),7.75(d,J=8.6Hz ,1H),7.46–7.30(m,3H),7.18–6.99(m,3H),6.93(d,J=9.2Hz,1H),6.80(s,2H),6.49(s,1H),6.07–5.99(m,1H ),4.33(d,J=7.2Hz,1H),3.79(dd,J=9.9,5.9Hz,4H),3.73–3.33(m,7H),3.27(d,J=13.6Hz,4H),3.12(d,J=6. 5Hz,1H),2.75(s,2H),2.20(s,6H),1.97(s,2H),1.83(s,2H),1.68(s,1H),1.40(s,3H),0.94(d,J=2.2Hz,6H).

[0430] Compound 2-16: 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15S)-13,16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)benzamide (pseudo) Preparation of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15R)-13,16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)benzamide (hypothetical):

[0431] Synthesis of N-[(trans)-4-hydroxyfuran-3-yl]-4-methylbenzenesulfonamide: 3,6-dioxabicyclo[3.1.0]hexane (5.00 g, 58.079 mmol, 1.00 equivalence), dioxane (100.00 mL), p-toluenesulfonamide (11.93 g, 69.681 mmol, 1.20 equivalence), TEBAC (1.33 g, 5.833 mmol, 0.10 equivalence), and K₂CO₃ (0.80 g, 5.788 mmol, 0.10 equivalence) were placed in a 250 mL round-bottom flask, and an inert atmosphere was maintained by blowing nitrogen. The resulting solution was stirred in an oil bath at 90 °C for 3 days. The reaction mixture was cooled to room temperature. The solid was filtered. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (2:1). 10.69 g (25.75%) of N-[(trans)-4-hydroxyfuran-3-yl]-4-methylbenzenesulfonamide was obtained as a white solid. LC-MS (ES, m / z): M+1 = 258.

[0432] Synthesis of N-[(trans)-4-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-6-yl)oxy]oxopentane-3-yl]-4-methylbenzenesulfonamide: 10.50 g (14.691 mmol, 1.30 equivalent, 36%) of N-[(trans)-4-hydroxyfuran-3-yl]-4-methylbenzenesulfonamide and 100 mL of THF were placed in a 250 mL round-bottom flask, and an inert atmosphere was maintained by blowing nitrogen. Then, 2.71 g (67.756 mmol, 6.01 equivalent, 60%) of NaH was added in portions at 0°C, and the resulting solution was stirred at 0°C for 30 minutes. 5-Bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridine (3.89 g, 11.266 mmol, 1.00 equivalent) was added to the mixture at 0°C. The resulting solution was stirred in an oil bath at 70°C for 4 hours. The reaction mixture was cooled to room temperature. Then, 500 mL of aqueous NH4Cl solution was added to stop the reaction. The resulting solution was extracted with 3 x 300 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 x 1500 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1:2). 3 g (45.71%) of N-[(trans)-4-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-6-yl)oxy]oxopentane-3-yl]-4-methylbenzenesulfonamide was obtained as a pale yellow oil. 1H NMR(300MHz,Chloroform-d,ppm)δ8.04(s,1H),7.78–7.61(m,2H),7.25–7.10(m,3H),6.4 3(d,J=3.6Hz,1H),5.67(d,J=10.8Hz,1H),5.60(d,J=5.7Hz,1H),5.49(d,J=10.8Hz,1H), 5.40(dt,J=6.1,3.1Hz,1H),4.27(dd,J=10.5,5.9Hz,1H),4.21–4.03(m,1H),4.03–3.86( m,2H),3.70–3.52(m,3H),2.32(s,3H),0.93(ddt,J=10.6,5.5,2.6Hz,2H),-0.02(s,9H).

[0433] Synthesis of (trans)-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraene: N-[(trans)-4-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-6-yl)oxy] Cyclopentyl]-4-methylbenzenesulfonamide (3.00 g, 5.149 mmol, 1.00 equivalence), DMF (50.00 mL), phenol (743.00 mg, 4.123 mmol, 0.80 equivalence), CuI (785.00 mg, 4.122 mmol, 0.80 equivalence), and K₂CO₃ (2.14 g, 15.484 mmol, 3.01 equivalence) were placed in a 250 mL round-bottom flask, and nitrogen was purged to maintain an inert atmosphere. The resulting solution was stirred in an oil bath at 120 °C for 2 days. The reaction mixture was cooled to room temperature. The resulting solution was diluted with 500 mL of water. The resulting solution was extracted with 3 x 200 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 x 1000 mL of brine. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1:2). 2.5 g (82.26%) of (trans)-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraene was obtained as a yellow oil. LC-MS: (ES, m / z) M+1 = 502.

[0434] (11S,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraene (hypothetical) and (11R,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraene (false) Synthesis of (e.g.): In a 100 mL round-bottom flask, magnesium (2.04 g, 83.933 mmol, 19.81 equivalences), MeOH (30.00 mL), and (trans)-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13.16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraene (2.50 g, 4.236 mmol, 1.00 equivalences, 85%) were added. The resulting solution was stirred in an oil bath at 60 °C for 2 hours. The reaction mixture was cooled to room temperature. The resulting solution was diluted with 300 / 300 mL NaHCO3 and CH2Cl2. The solid was filtered off, and the organic matter was separated. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1:3). The crude product was purified by Chiral-Prep-HPLC under the following conditions: mobile phase: A: n-hexane (0.1% DEA) B: ETOH; flow rate: 20 mL / min; column: DAICL CHIRALPAK IA, 250 × 20 mm, 5 μm; gradient: 12% B, 20 min; 220 nm. 350 mg (23.78%) of (11R,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13.16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9), 2,5,7-tetraene (hypothetical) was obtained as a yellow oil, and 400 mg (27.18%) of (11S,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13.16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9), 2,5,7-tetraene (hypothetical) was obtained as a yellow oil. Peak 1: LC-MS: (ES, m / z) M+1 = 348. 11H NMR (300 MHz, Chloroform-d, ppm) δ 7.39 (s, 1H), 7.21 (d, J = 3.6 Hz, 1H), 6.37 (d, J = 3.6 Hz, 1H), 5.57 (s, 2H), 4.60 (dt, J = 10.1, 7.6 Hz, 1H), 4.39–4.22 (m, 2H), 3.94 (dd, J = 9.9, 7.9 Hz, 1H), 3.86–3.69 (m, 2H), 3.64–3.45 (m, 2H), 0.91 (dd, J = 8.8, 7.5 Hz, 2H), -0.04 (s, 9H). Peak 2: LC-MS: (ES, m / z) M+1 = 348. 1 1H NMR (300 MHz, Chloroform-d, ppm) δ 7.39 (s, 1H), 7.21 (d, J = 3.6 Hz, 1H), 6.37 (d, J = 3.6 Hz, 1H), 5.57 (s, 2H), 4.60 (dt, J = 10.1, 7.6 Hz, 1H), 4.39–4.22 (m, 2H), 3.94 (dd, J = 9.9, 7.9 Hz, 1H), 3.86–3.69 (m, 2H), 3.64–3.45 (m, 2H), 0.91 (dd, J = 8.8, 7.5 Hz, 2H), -0.04 (s, 9H).

[0435] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetical): The benzoate is prepared by saturating [(11R,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl ... 7-Tetraene (hypothetically) (400.00 mg, 1.151 mmol, 1.00 equivalence), toluene (15.00 mL), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)benzoate (1.22 g, 2.294 mmol, 2.00 equivalence), Pd2(dba)3.CHCl3 (208.00 mg, 0.201 mmol, 0.20 equivalence), Xantphos (234.00 mg, 0.404 mmol, 0.40 equivalence), and Cs2CO3 (985 mg, 3.023 mmol, 3.00 equivalence) were placed in 40 mL vials, and nitrogen was purged to maintain an inert atmosphere. The resulting solution was stirred in an oil bath at 100 °C for 3 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1:2). 720 mg (89.52%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetically) was obtained as a yellow solid. LC-MS: (ES, m / z) M+1 = 798.

[0436] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15S)-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate: In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl) )-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl}benzoate (hypothetically) (720.00 mg, 0.902 mmol, 1.00 equivalence), 1.0 M TBAF / THF (15.00 mL), ethylenediamine (1.30 g, 21.631 mmol, 23.99 equivalence). The resulting solution was stirred in an oil bath at 70 °C for 8 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (2:1). 350 mg (58.09%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15S)-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetically) was obtained as a pale yellow solid. LC-MS: (ES, m / z) M+1 = 668.

[0437] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15S)-2-[(11S,15R)-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothesis): In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15S)-2-[(11S,15R)-13,16-dioxane-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid was added. -1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15S)-13,16-dioxane-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetical) (150.00 mg, 0.224 mmol, 1.00 equivalence), dioxane (3.00 mL), MeOH (3.00 mL), NaOH (0.60 mL, 2.400 mmol, 10.69 equivalence). The resulting solution was stirred in an oil bath at 70 °C for 4 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The pH of the solution was adjusted to 5-6 with HCl (2 mol / L). The resulting solution was extracted with 3 x 50 mL ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 x 300 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by Prep-TLC with dichloromethane / methanol (10:1). 80 mg (54.48%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15S)-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetically) was given as a white solid. LC-MS: (ES, m / z) M+1 = 654.

[0438] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R or S)-2-[(11R, 15S)-13,16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)benzamide (hypothetical): In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl) 2-[(11R,15S)-13.16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetically) (50.00 mg, 0.076 mmol, 1.00 equivalence), DCM (5.00 mL), 4-[[(2S)-1,4-dioxane-2-ylmethyl]amino]-3-nitrobenzenesulfonamide (24.00 mg, 0.076 mmol, 0.99 equivalence), EDCI (29.00 mg, 0.151 mmol, 1.98 equivalence), DMAP (37.00 mg, 0.303 mmol, 3.96 equivalence). The resulting solution was stirred overnight in an oil bath at 30°C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC under the following conditions (Prep-HPLC-006): column, X Bridge Shield RP18 OBD column, 5 μm, 19 x 150 mm; mobile phase, water (0.05% NH3·H2O) and ACN (40% B phase, reaching 70% within 7 minutes); detector, UV 254 / 220 nm. 25 mg (34.31%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R,15S)-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)benzamide (hypothetically) was obtained as a yellow solid. LC-MS: (ES, m / z) M+1 = 953. 1H NMR(300MHz,DMSO-d6,ppm)δ12.27(s,1H),11.05(d,J=66.1Hz,1H),8.42(d,J=30.6Hz,1H),8.32(d,J=2.3Hz,1H),7.57(s,1H),7.36(dd,J=8.4,4.1Hz,3H),7.08(ddd,J=14.1,5.9,2.6Hz,3H),6.78(t,J=29.3Hz,3H),6.57(s,1H),6.06–5.94(m,1H),4.45(dd,J=98.7,9.1Hz,3H),3.96–3.34(m,12H),3.19(d,J=16.7Hz,4H),2.81–2.71(m,2H),2.24(d,J=19.4Hz,6H),1.98(s,2H),1.41(s,2H),0.94(s,6H).

[0439] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetical): The benzoate is prepared by saturating [(11S,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl ... 7-Tetraene (hypothetically) (400.00 mg, 1.151 mmol, 1.00 equivalence), toluene (15.00 mL), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)benzoate (1.22 g, 2.294 mmol, 1.99 equivalence), Pd2(dba)3.CHCl3 (237.00 mg, 0.229 mmol, 0.20 equivalence), Xantphos (266.00 mg, 0.460 mmol, 0.40 equivalence), and Cs2CO3 (1.12 g, 3.437 mmol, 2.99 equivalence) were placed in 40 mL vials, and nitrogen was purged to maintain an inert atmosphere. The resulting solution was stirred in an oil bath at 100 °C for 3 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1:2). 820 mg (89.21%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetically) was obtained as a yellow solid. LC-MS: (ES, m / z) M+1 = 798.

[0440] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15R)-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate: In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl) )-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl}benzoate (hypothetically) (820.00 mg, 1.027 mmol, 1.00 equivalent), TBAF in THF (15.00 mL), ethylenediamine (1.30 g, 21.631 mmol, 21.06 equivalent). The resulting solution was stirred in an oil bath at 70 °C for 8 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (2:1). 380 mg (55.37%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15R)-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetically) was obtained as a pale yellow solid. LC-MS: (ES, m / z) M+1 = 668.

[0441] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15R)-2-[(11S,15R)-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothesis): In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15R)-2-[(11S,15R)-13,16-dioxane-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid was added. -1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15R)-13,16-dioxane-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoate (hypothetical) (150.00 mg, 0.224 mmol, 1.00 equivalence), dioxane (3.00 mL), MeOH (3.00 mL), NaOH (0.60 mL, 2.400 mmol, 10.69 equivalence). The resulting solution was stirred in an oil bath at 70 °C for 4 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The pH of the solution was adjusted to 5-6 with HCl (2 mol / L). The resulting solution was extracted with 3 x 50 mL ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 x 300 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by Prep-TLC with dichloromethane / methanol (10:1). 80 mg (54.48%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15R)-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetically) was given as a white solid. LC-MS: (ES, m / z) M+1 = 654.

[0442] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11R or S)-2-[(11S,15R)-13,16-oxalate-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)benzamide (hypothetical): In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl) 2-[(11S,15R)-13.16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetically) (50.00 mg, 0.076 mmol, 1.00 equivalence), DCM (5.00 mL), 4-[[(2S)-1,4-dioxane-2-ylmethyl]amino]-3-nitrobenzenesulfonamide (24.00 mg, 0.076 mmol, 0.99 equivalence), EDCI (29.00 mg, 0.151 mmol, 1.98 equivalence), DMAP (37.00 mg, 0.303 mmol, 3.96 equivalence). The resulting solution was stirred overnight in an oil bath at 30°C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC under the following conditions (Prep-HPLC-006): column, X Bridge Shield RP18 OBD column, 5 μm, 19 x 150 mm; mobile phase, water (0.05% NH3·H2O) and ACN (40% B phase, reaching 70% within 7 minutes); detector, UV 254 / 220 nm. 25 mg (34.31%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15R)-13,16-dioxo-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadecane-1(9),2,5,7-tetraen-10-yl]-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)benzamide (hypothetically) was obtained as a yellow solid. LC-MS: (ES, m / z) M+1 = 953. 1H NMR (300MHz, DMSO-d6, ppm) δ12.27(s,1H),11.05(d,J=66.1Hz,1H),8.42(d,J=30.6Hz,1H),8.32(d, J=2.3Hz,1H),7.57(s,1H),7.36(dd,J=8.4,4.1Hz,3H),7.08(ddd,J=14.1,5.9,2.6Hz,3H),6.78(t,J =29.3Hz,3H),6.57(s,1H),6.06–5.94(m,1H),4.45(dd,J=98.7,9.1Hz,3H),3.96–3.34(m,12H),3.19 (d,J=16.7Hz,4H),2.81–2.71(m,2H),2.24(d,J=19.4Hz,6H),1.98(s,2H),1.41(s,2H),0.94(s,6H).

[0443] Preparation of compound 2-17: 4-(4-[[2-(4-chlorophenyl)-1,4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)-2-[(12R)-12-methyl-13-oxo-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzamide)

[0444] Synthesis of (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane: In a 3L four-necked round-bottom flask, ethyl vinyl ether (2000.00 g, 27777.778 mmol, 3.00 equivalent) and 4,4,5,5-tetramethyl-1,3,2-dioxoborane (508.00 g, 9259.259 mmol, 1.00 equivalent) were placed. The solution was cooled to 5°C in an ice / salt bath. Subsequently, Pd(OAc)₂ (10.39 g, 46.296 mmol, 0.005 equivalent) was added in portions between 0 and 5°C, and the resulting solution was stirred at room temperature for 18 hours. The resulting mixture was then concentrated. 1500 g (crude) was obtained, purified by rectification, and 25 mmHg was collected at 65–70 °C to give 890 g (Y = 50%, LCMS OK, Q-NMR = 87%) 2-[(Z,E mixture)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3-dioxolane, as a pale yellow oil. LC-MS: (ES, m / z): M+1 = 199, RT = 1.979 min, 2.440 min. ¹H-NMR: (300 MHz, DMSO-d6, ppm): δ 6.71–6.95 (m, 1H), 4.29–4.34 (m, 1H), 3.80–3.93 (m, 2H), 1.15–1.21 (m, 16H).

[0445] Synthesis of N-[(2R)-2-hydroxypropyl]acetamide: (2R)-1-aminoprop-2-ol (10 g, 133.136 mmol, 1 equivalent), DCM (100 mL), and TEA (16 g, 159.764 mmol, 1.2 equivalent) were placed in a 250 mL three-necked round-bottom flask, and nitrogen was purged to maintain an inert atmosphere. Then, a solution of ethyl acetate (13.6 g, 133.136 mmol, 1.0 equivalent) in DCM (10 mL) was added dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature for 14 hours. The resulting mixture was concentrated. The residue was treated on a silica gel column with dichloroethane / methanol (100:5). 13.5 g (69.25%) of N-[(2R)-2-hydroxypropyl]acetamide was obtained as a yellow oil. LC-MS:(ES,m / z):M+1=118.

[0446] Preparation of 4-([[(2S)-1,4-dioxane-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide: 1.43 g of 4-fluoro-3-nitrobenzene-1-sulfonamide (0.007 mmol, 1 equivalent), 1-[(2S)-1,4-dioxane-2-yl]formamide hydrochloride (1 g, 6.510 mmol, 1 equivalent), THF (30 mL), and Cs₂CO₃ (8.48 g, 0.026 mmol, 4 equivalents) were added to a 100 mL round-bottom flask. The resulting solution was stirred overnight in an oil bath at 50 °C. The solid was collected by filtration. The solid was dried under reduced pressure in an oven. 1.82 g (88.10%) of 4-([[(2S)-1,4-dioxane-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide was given as a yellow solid. LC-MS:(ES,m / z):M+1=318,R,T=0.741 minutes.

[0447] Synthesis of methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl]methyl]piperazin-1-yl)benzoate: In a 20,000 mL round-bottom flask, 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazine dihydrochloride (600 g, 1.53 mol, 1 equivalent), methyl 2-bromo-4-fluorobenzoate (357 g, 1.53 mol, 1 equivalent), DBU (319 g, 6.12 mol, 4 equivalent), and DMSO (8,000 mL) were placed. The resulting solution was stirred at 70 °C for 20 h until LC-MS showed complete consumption of the material. The resulting mixture was cooled to room temperature and poured into water (32 L). The mixture was filtered, and the filter cake was collected and washed with water (3,000 mL x 100 mL). 3) After drying in an oven, 740 g (Y = 91%) of methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-yl)methyl)piperazin-1-yl)benzoate was obtained as a white solid. H-NMR: (300 MHz, DMSO-d) 6, ppm)δ:7.73(d,J=9.0Hz,1H),7.42-7.39(m,2H),7.18-7.12(m,3H),6.97-6.94(m,1H),4.00-3.84(m,2H),3.76(s,2H),3 .57(s,3H),3.51-3.33(m,4H),2.79-2.60(m,2H),2.32-2.30(m,2H),2.03-1.97(m,2H),1.47-1.45(m,2H),0.96(s,6H).

[0448] Synthesis of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)benzoic acid: In a 20,000 mL round-bottom flask, methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)benzoate (730 g, 1.37 mol, 1 equivalent), LiOH (131.5 g, 5.48 mol, 4 equivalents) and MeOH / THF / water (4500 mL / 3000 mL / 1000 mL) were added. The resulting solution was stirred at 70 °C for 16 h until LCMS showed complete consumption of the material. The resulting mixture was cooled to room temperature and concentrated. The residue was diluted with water (5000 mL), and the pH of the mixture was adjusted to 35 with hydrochloric acid (6 M). The mixture was then filtered, and the filter cake was collected and dried in an oven to give 650 g of the product 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane)methyl)piperazin-1-enyl)benzoic acid, a white solid. ¹H NMR spectroscopy: 55-400 (300 MHz, DMSO-d) 6, ppm)δ:10.60(bs,1H),7.73(d,J=8.4Hz,1H),7.42-7.39(m,2H),7.14-7.11(m,3H),6.95-6.92(m,1H),4.00-3.84(m,2H), 3.76(s,2H),3.51-3.33(m,4H),2.79-2.60(m,2H),2.32-2.30(m,2H),2.03-1.97(m,2H),1.47-1.45(m,2H),0.97(s,6H).

[0449] Synthesis of 5-bromo-6-fluoropyridine-2-amine: In a 100 L four-necked round-bottom flask, 4500.00 g of 6-fluoropyridine-2-amine (40178.571 mmol, 1.00 equivalent) and 25000.00 mL of ACN were added. NBS (7100.00 g, 41764.706 mmol, 1.03 equivalent) was then added in portions at 5–15 °C (2 h), and the resulting solution was stirred at room temperature for 3 h. The resulting solution was diluted with 50 L of water. The solution was extracted with 2 x 32 L of ethyl acetate. The resulting mixture was washed with 10 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The resulting mixture was washed with 3 x 13 L of PE. The mixture was dried in an oven to give 6900 g (Y = 90%) of 5-bromo-6-fluoropyridine-2-amine as a light brown solid. LC-MS (ES, m / z): M+1 = 191, 193, RT = 0.851 min. H-NMR (300 MHz, DMSO-d6, ppm): δ 7.63–7.71 (m, 1H), 6.57 (s, 2H), 6.27–631 (m, 1H).

[0450] Synthesis of 5-bromo-6-fluoro-3-iodopyridin-2-amine: In a 100 L four-necked round-bottom flask, 6500.00 g of 5-bromo-6-fluoropyridin-2-amine (34219.531 mmol, 1.00 equivalent) and 39000.00 mL of AcOH were added. The solution was cooled to 15 °C in a water / ice bath. Then, NIS (8470.00 g, 37641.484 mmol, 1.10 equivalent) was added in portions at 10–20 °C (3 h), and the resulting solution was stirred at room temperature for 3 h. The resulting solution was added to 100 L of water. The mixture was filtered, the filter cake was collected, washed with water (25 L × 3), and dried in an oven to give 9840 g (Y = 85%) of 5-bromo-6-fluoro-3-iodopyridin-2-amine as a brown solid. LC-MS (ES, m / z): M+1 = 317, 319, RT = 1.072 min. H-NMR (300 MHz, DMSO-d6, ppm): δ 8.17–8.20 (m, 1H), 6.69 (s, 2H).

[0451] Synthesis of 5-bromo-3-(2-ethoxyvinyl)-6-fluoropyridine-2-amine: 5-bromo-6-fluoro-3-iodopyridine-2-amine (855.00 g, 2705.696 mmol, 1.00 equivalent), i-PrOH (10000.00 mL), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3-dioxolane (1000.00 g, 5... 0.505 mmol (1.87 equivalents), K3PO4 (1720.00 g, 8113.207 mmol, 3.00 equivalents), Ruphos (12.00 g, 27.060 mmol, 0.02 equivalents), and Pd(OAc)2 (12.00 g, 88 mmol, 0.02 equivalents) were added to a 20 L four-necked round-bottom flask purged and maintained under nitrogen inert gas. The resulting solution was stirred in a liquid nitrogen bath at room temperature for 12 h. The solid was filtered. The filter cake was washed with 3 x 2 L DCM. The organic layer was collected and concentrated. The residue was eluted on a silica gel column with ethyl acetate / petroleum ether (1:5). After concentration, 680 g (80%) of 5-bromo-3-[(Z,E mixture)-2-ethoxyvinyl]-6-fluoropyridine-2-amine was obtained as a dark brown oil. LC-MS:(ES,m / z):M+1=261,263,RT=1.090 minutes.

[0452] Synthesis of 5-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine: 680.00 g (2605.364 mmol, 1.00 equivalent), EtOH (5000.00 mL), and HCl (1000.00 mL) were placed in a 10 L four-necked round-bottom flask, and nitrogen was purged to maintain an inert atmosphere. The resulting solution was stirred at room temperature for 5 hours. The resulting mixture was concentrated. The pH of the solution was adjusted to 6 with NaOH (4 mol / L). The solid was collected by filtration and washed with 3 x 500 mL of water. 410 g (Y = 75%) of 5-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine was given as a light brown solid. (ES, m / z): M+1 = 215, 217, RT = 0.993 min. H-NMR: (300MHz, DMSO-d6, ppm): δ9.53 (brs, 1H), 8.19–8.22 (d, J = 9.0Hz, 1H), 7.32–7.34 (m, 1H), 6.50–6.52 (m, 1H).

[0453] Synthesis of 5-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine: 200.00 g (930.232 mmol, 1.00 equivalent) and 2500.00 mL of DMF were placed in a 5 L four-necked round-bottom flask. The solution was cooled to 0 °C in a water / ice bath. NaH (75.00 g, 1860.464 mmol, 2.00 equivalent) was then added in portions at 0 °C. SEM-Cl (233.00 g, 1395.210 mmol, 1.50 equivalent) was added dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature for 1 hour. The reaction was then stopped by adding 1000 mL of water / ice. The resulting solution was diluted with 5 L of water. The resulting solution was extracted with 2 x 10 L of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 x 5 L of water. The resulting mixture was then washed with 3 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was eluted on a silica gel column with ethyl acetate / petroleum ether (1:20). 298 g (87%) of 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridine was given as a pale yellow oil. LC-MS: (ES, m / z): M+1=345,347, RT=1.435min.H-NMR (300MHz, DMSO-d6, ppm): δ8.46–8.49 (d, J=9.0Hz, 1H), 7.68–7.69(m,1H),6.57–6.58(m,1H),5.52–5.55(m,2H),3.47–3.60(m,2H),0.79–0.90(m,2H),0.01(s,9H).

[0454] Synthesis of (R)-N-(2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-oxy)propyl)acetamide: In a 50 mL round-bottom flask, N-[(2R)-2-hydroxypropyl]acetamide (680 mg, 5.8 mmol, 2.00 equivalent) and dioxane (10 mL) were placed. Subsequently, NaH (348 mg, 8.7 mmol, 3 equivalent) was added in portions at 15 °C. The resulting solution was stirred at room temperature for 10 min. A solution of 5-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1 g, 2.9 mmol, 1 equivalent) in dioxane (5 mL) was added. The resulting solution was stirred in an oil bath at 80 °C for 4 h. The reaction was cooled to room temperature, and then 5 mL of water was added to stop the reaction. The resulting solution was extracted with 3 x 10 mL of ethyl acetate. The resulting mixture was washed with 3 mL of H₂O. The resulting mixture was washed with 1 x 10 mL of NaCl(aq). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was treated on a silica gel column with PE / EA (100:20). 880 g (73%) of ⁻(R)-N-[2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)-methyl]pyrrolo[2,3-b]pyridin-6-yl]thioyl]ethyl]acetamide was obtained as a yellow oil.

[0455] Synthesis of 1-[(12R-4-(trimethylsilyl)ethoxy]methyl)-12-methyl-13-oxalic acid-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]-1: (R)-N-[2-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-6-yl]thio]ethyl]acetamide (500 mg, 1.13 mmol, 1 equivalent), dioxane (8 mL), Cs2Cs2CO3 (1.1 g, 3.4 mmol, 3 equivalent), BrettPhos Pd G3 Precatalyst (102 mg, 0.11 mmol, 0.10 equivalence) was placed in a 25 mL round-bottom flask and nitrogen was purged to maintain an inert atmosphere. The resulting solution was stirred in an oil bath at 80 °C for 14 hours. The resulting mixture was concentrated. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (50:50). 500 mg (73.3%) of 1-methyl[(12R)-4-(trimethylsilyl)ethoxy]methyl]yl-4-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraen-10-]-1-one was obtained as a yellow solid.

[0456] Synthesis of (12R)-4-(trimethylsilyl)ethoxy]methyl)-12-2H4)-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraene: In an 8 mL vial, 4-[[-4-(trimethylsilyl)ethoxy]methyl](-12-2H2)-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-1-one (60 mg, 0.19 mmol, 0.5 equivalence), NaOH / H2O (1 M, 0.5 mL). The resulting solution was stirred in an oil bath at 80 °C for 14 h. The resulting mixture was concentrated. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1:1). 15 mg (34%) of (12R)-4-(trimethylsilyl)ethoxy]methyl)-12--13-thio-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene was obtained as a yellow oil.

[0457] 4-(4-[[2-(4-chlorophenyl)-1,4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)-12--2-[-13-thio-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9) Preparation of 2,5,7-tetraen-10-yl]benzamide: 12-[[2-(trimethylsilyl)ethoxy]methyl]-13-thio-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1(9),2,5,7-tetraene (200.00 mg, 0.622 mmol, 1.00 equivalent), 2-bromo-4-(4-[[2-( (4-Chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)benzamide (1016.69 mg, 1.244 mmol, 1 equivalent), DMF (2.00 mL), CuI (23.84 mg, 0.125 mmol, 0.40 equivalent), N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide (20.53 mg, 0.063 mmol, 0.20 equivalent), K2CO3 (129.78 mg, 0.939 mmol, 3.00 equivalent). The solution was placed in an 8 mL round-bottom flask and inert under nitrogen. The resulting solution was stirred in an oil bath at 100 °C for 4 hours. The resulting solution was extracted with 10 mL of H₂O. The solution was then extracted with 3 x 5 mL of ethyl acetate. The resulting mixture was washed with 3 mL of H₂O. The mixture was dried over anhydrous sodium sulfate. The residue was loaded onto a silica gel column and eluted with dichloromethane / methanol (10:1). 220 mg (66.57%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(12R / -12-4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-13-thio-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide was obtained as a yellow oil. LC-MS: (ES, m / z): 1055.5 [M+H].

[0458] Synthesis of 4-(4-[[2-(4-chlorophenyl)-1,4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)-2-[(12R / -12--13-thio-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzamide: 4-(4-[[2-(4-chlorophenyl)cycloheptan-1-en-1-yl] [2S]-1,4-dioxane-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-(-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl)benzamide (210.00 mg, 0.115 mmol, 1.00 equivalent), ethylenediamine (138.46 mg, 2.304 mmol, 1 0.00 equivalent), THF (10 mL), and TBAF (602.37 mg, 2.304 mmol, 5.00 equivalent) were added to a 25 mL round-bottom flask. The resulting solution was stirred in an oil bath at 70 °C for 14 hours. The resulting mixture was concentrated. The resulting solution was diluted with 20 mL of DCM. The resulting mixture was washed with 3 x 5 mL of H2O. The mixture was dried over anhydrous sodium sulfate. The residue was purified by Prep-TLC using dichloromethane / methanol (100:5). 70 mg (38.02%) of 4-(4-[[2-(4) (-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-13-thio-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzamide, is a yellow oil. LC-MS: (ES, m / z): 925.4 [M+H]. 1H NMR (300MHz, CDCl3, ppm): δ12.38(s,1H),8.68–8.46(m,3H),8.16–7.97(m,1H) ,7.90-7.81(m,1H),7.28–7.05(m,3H),7.02–6.78(m,3H),6.77–6.63(m,2H),6. 54(s,1H),6.11–6.03(m,1H),4.98–4.83(m,1H),4.10–2.99(m,17H),2.91-2.7 9(m,2H),2.40-2.17(m,6H),2.10-2.02(m,2H),1.70-1.61(m,3H),0.97(s,6H).

[0459] Preparation of compound 2-18: 4-(4-[[2-(4-chlorophenyl)-1,4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)-2-[11-oxo-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide:

[0460] Synthesis of 5-bromo-6-fluoropyridine-2-amine: In a 5000 mL three-necked round-bottom flask, 220 g of 6-fluoropyridine-2-amine (2 mol, 1.00 equivalent), 2.0 L of CH3CN, and 420 g of NBS (2.2 mol, 1.20 equivalent) were added. The resulting solution was stirred overnight at room temperature. Then, 2 L of water was added to stop the reaction. The resulting solution was extracted with 3 x 1 L of ethyl acetate, and the organic layers were combined. The resulting organic phase was washed with 3 x 1 L of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1–1:5). 200 g (60%) of 5-bromo-6-fluoropyridine-2-amine was given as a white solid. LCMS: (ES, m / z): M+1: 191, 193.

[0461] Synthesis of 5-bromo-6-fluoro-3-iodopyridin-2-amine. In a 2000 mL four-necked round-bottom flask, 200 g of 5-bromo-6-fluoropyridin-2-amine (1.05 mol, 1.00 equivalent) and 200 g of iodothioamine (NIS, 1.15 mol, 1.10 equivalent) were placed in AcOH (1500 mL). The resulting solution was stirred overnight at room temperature. Then, 3000 mL of water was added to stop the reaction. The solid was collected by filtration and washed with Et₂O. 170 g (50%) of 5-bromo-6-fluoro-3-iodopyridin-2-amine was given as a white solid. The organic phase was concentrated under vacuum to give 150 g of crude product oil. 1 H-NMR: (CDCl3, 300MHz) δ: 7.98 (d, J = 14.4Hz, 1H), 4.94-5.00 (bs, 2H).

[0462] Synthesis of 5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridine-2-amine: In a 3000 mL three-necked round-bottom flask, a solution of 5-bromo-6-fluoro-3-iodopyridine-2-amine (170 g, 536.45 mmol, 1.00 equivalence) in tetrahydrofuran (1500 mL), CuI (10.2 g, 53.56 mmol, 0.10 equivalence), TEA (500 mL), palladium dichloroisocyanurate; bis(triphenylphosphine) (11.2 g, 15.96 mmol, 0.03 equivalence), and ethyl(ethynyl)dimethylsilane (63 g, 561.27 mmol, 1.20 equivalence). The resulting solution was stirred at room temperature for 16 hours. Then, 2000 mL of water was added to stop the reaction. The resulting solution was extracted with 3 x 1000 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 x 1000 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1–1:1). 120 g (78%) of 5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridine-2-amine was given as a pale yellow oil. LC-MS (ES, m / z): M+1: 289, 287.

[0463] Synthesis of N-[5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridin-2-yl]acetamide. In a 2000 mL four-necked round-bottom flask, a solution of 5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridin-2-amine (84 g, 292.48 mmol, 1.00 equivalence) in dichloromethane (1000 mL) and pyridine (57.8 g, 730.72 mmol, 2.50 equivalence) were placed. Acetyl chloride (50.2 g, 639.51 mmol, 2.20 equivalence) was then added dropwise with stirring at 0 °C. The resulting solution was stirred overnight at room temperature. Then, 1000 mL of water was added to stop the reaction. The resulting mixture was washed with 2 x 1000 mL of water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1–1:10). 80 g (83%) of N-[5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridin-2-yl]acetamide was given as a white solid. LC-MS (ES, m / z): M+1 = 331.

[0464] Synthesis of 5-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine: In a 2000 mL round-bottom flask, a solution of N-[5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridin-2-yl]acetamide (80 g, 242.98 mmol, 1.00 equivalence) in tetrahydrofuran (300 mL) and TBAF (1 M in tetrahydrofuran) (729 mL, 3.00 equivalence) was placed. The resulting solution was stirred at 70 °C for 12 h. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. Then 500 mL of water was added to stop the reaction. The resulting solution was extracted with 3 x 300 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 x 300 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / ethyl ether (0:1–4:1). 15 g (29%) of 5-bromo-6-fluoro-1H-pyrrole[2,3-b]pyridine was obtained as a white solid. LC-MS (ES, m / z): M+1 = 213.

[0465] Synthesis of 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl)-1H-pyrrolo[2,3-b]pyridine: A solution of 5-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine (15 g, 69.76 mmol, 1.00 equivalence) in N,N-dimethylformamide (150 mL) was placed in a 250 mL three-necked round-bottom flask, and nitrogen was purged to maintain an inert atmosphere. Sodium hydride (4.2 g, 175.00 mmol, 1.50 equivalence) was then added in portions at 0°C. After stirring for 0.5 hours, SEM-Cl (14 g, 84.34 mmol, 1.20 equivalence) was added dropwise with stirring at 0°C. The resulting solution was stirred, and the reaction was allowed to proceed at room temperature for another 3 hours. Then, 300 mL of water was added to stop the reaction. The resulting solution was extracted with 3 x 200 mL ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 x 200 mL of brine. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1–1:10). 15 g (62%) of 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrole[2,3-b]pyridine was given as a yellow oil.

[0466] Synthesis of 6-(tert-butoxy)-N-(diphenylmethylene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-5-amine: In a 250 mL round-bottom flask, a solution of 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine in dioxane (300 mL) (20.7 g, 60 mmol, 1.00 equivalence), t-BuOK (20.5 g, 180 mmol, 3.00 equivalence), xantphos (6.9 g, 12 mmol, 0.20 equivalence), Pd2(dba)3.CHCl3 (5.7 g, 0.10 equivalence), and diphenylmethylamine (14.04 g, 78 mmol, 1.20 equivalence). The resulting solution was stirred overnight at 100°C. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1-1:20). 15 g (crude) of 6-(tert-butoxy)-N-(diphenylmethylene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-5-amine was obtained as a white oil. LC-MS (ES, m / z): M+1 = 500.

[0467] Synthesis of 5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-6-ol hydrogen chloride. In a 100 mL round-bottom flask, 6-(tert-butoxy)-N-(diphenylmethylene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-5-amine (15 g, 30.02 mmol, 1.00 equivalent) in dioxane (120 mL) and dioxane hydrochloride (4 M, 30 mL) were added. The resulting solution was stirred at room temperature for 5 hours. The resulting solution was diluted with 500 mL of diethyl ether. The solid was collected by filtration. Five grams of crude 5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-6-ol hydrogen chloride were obtained as a red solid. Q-NMR showed that it could be converted into three hydrogen chloride salts. LC-MS (ES, m / z): M+1 = 280.

[0468] Synthesis of 4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1,3(7),5,8-tetraen-11-one: In a 250 mL round-bottom flask, 5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-ol hydrochloride (5 g, 17.89 mmol, 1.00 equivalence) was placed in N,N-dimethylformamide (100 mL), potassium carbonate (7.4 g, 53.54 mmol, 3.00 equivalence), and 2-chloroacetyl chloride (4 g, 35.42 mmol, 2.00 equivalence) was added dropwise at 0 °C. The resulting solution was stirred overnight at 70 °C. The reaction mixture was cooled to room temperature. Then 200 mL of water was added to stop the reaction. The resulting solution was extracted with 3 x 100 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 x 100 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1-1:1). 2.5 g (44%) of 4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7,]]tridecane-1,3(7),5,8-tetraen-11-one was given as a white solid. LC-MS (ES, m / z): M+1 = 320.

[0469] Synthesis of methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl]methyl]piperazin-1-yl)benzoate: In a 2000 mL round-bottom flask, 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin dihydrochloride (60 g, 0.153 mol, 1 equivalent), methyl 2-bromo-4-fluorobenzoate (35.7 g, 0.153 mol, 1 equivalent), and DBU (31.9 g, 0.612 mol) were added. The solution was prepared by stirring at 70°C for 20 hours until LC-MS showed complete consumption of the material. The resulting mixture was cooled to room temperature and poured into water (3 L). The mixture was filtered, the filter cake was collected, washed with water (300 mL × 3), and dried in an oven to give 74 g (Y: 91%) of methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)benzoate as a white solid.

[0470] Synthesis of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)benzoic acid: In a 2000 mL round-bottom flask, methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)benzoate (73 g, 0.137 mol, 1 equivalent), LiOH (13.15 g, 0.548 mol, 4 equivalents) and MeOH / THF / water (450 mL / 300 mL / 100 mL) were added. The resulting solution was stirred at 70 °C for 16 hours until LCMS showed complete consumption of the material. The resulting mixture was cooled to room temperature and concentrated. The residue was diluted with water (500 ml), and the pH of the mixture was adjusted to 3-5 with hydrochloric acid (6 M). The mixture was then filtered, the filter cake was collected, and dried in an oven to obtain 65 g (Y: 93%) of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)benzoic acid, which was a white solid.

[0471] Synthesis of 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)benzamide. In a 20,000 mL round-bottom flask, 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-enyl)methyl)piperazin-1-yl)benzoic acid (55 g, 0.107 mol, 1 equivalent), DCM (1 L), (S)-4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (32 g, 0.102 mol, 0.95 equivalent), EDCI (30.8 g, 0.161 mol, 1.5 equivalent), and DMAP (52.2 g, 0.428 mol, 4 equivalent) were added. The resulting solution was stirred overnight at 25°C until LC-MS showed complete consumption of the material. The resulting mixture was then added with dilute hydrochloric acid (1.0 M) (100 mL x 3), saturated sodium bicarbonate (100 mL x 3), and brine (100 mL x 1). The organic phase was then dried over Na₂SO₄ and filtered. The filtrate was concentrated to give 81 g (Y: 93%) of 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)benzamide as a brownish-yellow solid. LC-MS (ES, m / z): M+1 = 816 / 819, RT = 2.01 min.

[0472] Synthesis of 4-(4-[[2-(4-chlorophenyl)-1,4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)-2-(11-oxo-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxo-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide. In a 40 mL round-bottom flask, 2-bromo-4-(4-chlorophenyl)-1,4,4-dimethylcyclohexane-1-en-1-yl]piperazin-1-yl) -[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)benzamide (214.89 mg, 0.263 mmol, 1.2 equivalents), 4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-11-one (70.00 mg, 0.219 mmol, 1.2 equivalents). 0.00 equivalent), 4,7-dimethoxy-1,10-phenanthroline (26.33 mg, 0.110 mmol, 0.5 equivalent), Cs₂CO₃ (214.20 mg, 0.657 mmol, 3 equivalent), dioxane (10.00 mL), CuI (20.87 mg, 0.110 mmol, 0.5 equivalent). The resulting solution was stirred at 110 °C for 3 hours until LCMS showed complete consumption of the material. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0:1-1:1). 200 mg (86.45%) of 4-(4-[ [2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(11-4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)-2-(11-oxo-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzamide, is a yellow crude solid. LC-MS: (ES, m / z): M+1=1055.

[0473] Synthesis of 4-(4-[[2-(4-chlorophenyl)-1,4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)-2-[11-oxo-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide. In a 40 mL round-bottom flask, place 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)2-(11-oxo-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzamide (20 0.00 mg (0.189 mmol, 1.00 equivalence), THF (10 mL), ethylenediamine (227.71 mg, 3.789 mmol, 20.00 equivalence), TBAF (990.65 mg, 3.789 mmol, 20 equivalence). The resulting solution was stirred at 70°C for 12 hours, and then 10 mL of water was added to stop the reaction. The solution was extracted with 2 x 10 mL of ethyl acetate and concentrated. The crude product was purified by Prep-HPLC under the following conditions (Waters-2767): column, X-bridge RP18, 5 μm, 19 x 100 mm; mobile phase, 0.03% acidic water (0.03% HCl) and CH3CN (32% CH3CN reached 52% within 6 min); detector, UV. 254 nm. 25 mg (14.26%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxane-2-methylene]amino]-3-nitrobenzenesulfonyl)-2-[11-oxo-13-oxa-2,4,10-triazacyclo[7.4.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide was obtained as a yellow solid. LC-MS (ES, m / z): M+1 = 925. 1H NMR (300MHz, DMSO-d6) δ11.32(d,J=7.2Hz,1H),8.52(s,1H),8.37(dd,J=4.6,2.3Hz,1H),7.72(d,J =8.5Hz,1H),7.65(s,1H),7.41(d,J=8.1Hz,2H),7.19(d,J=5.8Hz,1H),7.11(d,J=8.3Hz,2H),6.92( d,J=9.7Hz,2H),6.60(d,J=1.8Hz,1H),6.15–6.07(m,1H),4.67(d,J=15.0Hz,1H),4.36(s,1H),3.9 8–3.75(m,5H),3.75–3.47(m,7H),3.32(s,4H),2.80(s,2H),2.05(s,2H),1.48(s,2H),0.96(s,6H).

[0474] Preparation of Compound 3-1: 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrole)[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonyl)benzamide

[0475] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxalate-2,4,10-triazacyclo[7.5.0.0^[3,7,]]tetane-1(9),2,5,7-tetraen-10-yl]benzoate: 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl] Methyl[[methyl]piperazin-1-yl]benzoate (999.0 mg, 1.88 mmol, 4.00 equivalent), toluene (20 mL), 4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxalic acid-2,4,10-triazacyclo[7.5.0.0^[3,7]]tridecane-1(9), 2,5,7-tetraene (150 mg, 0.47 mmol, 1 equivalent), Cs2CO3 (764.9 mg, 2.35 mmol, 5 equivalent), XantPhos Pd 2 g (333.2 mg, 0.38 mmol, 0.8 equivalence) was placed in a 250 mL three-necked round-bottom flask and nitrogen was purged to maintain an inert atmosphere. The resulting solution was stirred overnight at 110 °C. The resulting solution was diluted with 300 mL of water. The resulting solution was extracted with 2 x 100 mL of ethyl acetate. The resulting mixture was washed with 1 x 300 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (1:2). 200 mg (55.29%) of methyl 4-(4-[ [2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxalate-2,4,10-triazacyclo[7.5.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl)benzoate, as a yellow solid. LC-MS (ES, m / z): M+H = 769, R, T = 3.076 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Shim-pack XR-ODS, 2.2 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 5.0 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0476] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxalate-2,4,10-triazacyclo[7.4.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl)benzoate: In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en- 1-yl]methyl]piperazine-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxalic acid-2,4,10-triazacyclo[7.5.0.0^[3,7]]tetane-1(9), 2,5,7-tetraene-1 (200 mg, 0.26 mmol, 1 equivalent), THF (20 mL), TBAF.3H2O (2.5 g), ethane-1,2-diamine (1.5 g, 24.96 mmol, 96 0.15 equivalents). The resulting solution was stirred overnight in an oil bath at 70°C. The resulting solution was diluted with 200 mL of water. The resulting solution was extracted with 3 x 30 mL of ethyl acetate. The resulting mixture was washed with 2 x 200 mL of brine. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (2:1). 130 mg (78.22%) of methyl 4-(4-[[2-(4-chlorophenyl)-4-) ,4-Dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxalate-2,4,10-triazacyclo[7.5.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzoate, was a pale yellow solid. LC-MS:(ES,m / z):M+=639,R,T=1.388 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Shim-pack XR-ODS, 2.2 μm; eluent A: water (0.05% TFA); eluent B: acetonitrile; linear gradient from 5% acetonitrile to 100% acetonitrile, 2.6 min; oven temperature 40°C; flow rate: 1.5 mL / min.

[0477] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxalate-2,4,10-triazacyclo[7.5.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzoic acid: In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-yl]methyl]piperazin-1-yl)-2-[14-oxalate-2,4,10-triazacyclo[7.5.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzoic acid was added. [-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxalate-2,4,10-triazacyclo[7.5.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzoate (130 mg, 0.20 mmol, 1 equivalent), MeOH (6 mL), THF (6 mL), H2O (2 mL), NaOH (81.2 mg, 2.03 mmol, 10.00 equivalent). The resulting solution was stirred overnight in an oil bath at 60 °C. The resulting mixture was concentrated under vacuum. The pH of the solution was adjusted to 5-6 with HCl (2 mol / L). The resulting solution was extracted with 2 x 50 mL dichloromethane / MeOH (v:v = 10:1). The resulting mixture was washed with 2 x 200 mL brine. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The obtained 80 mg (62.92%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxalate-2,4,10-triazacyclo[7.5.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzoic acid was a pale yellow solid. LC-MS (ES, m / z): M+ = 625, R, T = 1.336 min. Residence time was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Shim-pack XR-ODS, 2.2 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 2.6 min; Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0478] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-[(3-nitro-[[(oxalo-4-yl)methyl]amino]benzenesulfonyl)-2-[14-oxalo-2,4,10-triazacyclo[7.5.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide: In a 40 mL round-bottom flask, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin -1-yl)-2-[14-oxalate-2,4,10-triazacyclo[7.5.0.0^[3,7]]tetane-1(9),2,5,7-tetraen-10-yl]benzoic acid (50 mg, 0.08 mmol, 1 equivalent), DCM (3 mL), 3-nitro-4-[[(oxalate-4-yl)methyl]amino]benzene-1-sulfonamide (25.2 mg, 0.08 mmol, 1.00 equivalent), EDCI (30.6 mg, 0.16 mmol, 2 equivalent), DMAP (39.0 mg, 0.32 mmol, 4 equivalent). The resulting solution was stirred overnight at 25°C, and the resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with dichloroethane / methanol (10:1). Crude product was purified by Prep-HPLC under the following conditions (IntelFlash-1): column, C18 reversed-phase column; mobile phase, water (10 mmol / L NH4HCO3 + 0.05% NH3·H2O) and CH3CN (20.0% CH3CN, reaching 90.0% within 30 minutes); detector, UV 220 nm. 19.1 mg (25.90%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-([3-nitro-4-[(oxalo-4-yl)methyl)amino]benzenesulfonyl)-2-[14-oxalo-2,4,10-triazacyclo[7.5.0.0^[3,7]]tridecane-1(9),2,5,7-tetraen-10-yl]benzamide was obtained as a yellow solid. LC-MS (ES, m / z): M+1 = 923, R, T = 3.463 min. Residence time was measured using a reversed-phase column (C18). Shimadzu LCMS 2020; 50*3.0 Agilent Poroshell HPH-C18, 2.7 microns; Eluent A: Water (0.05% ammonia); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 95% acetonitrile, 7.0 min; Oven temperature 40°C; Flow rate: 1.5 mL / min. 1 H NMR (300MHz, DMSO-d) 6,ppm)δ11.91(s,1H),11.26(s,1H),8.56(s,1H),8.47(d,J=2.1Hz,1H),7.61(d,J=9.0Hz,1H),7.48(d,J=9.2 Hz,1H),7.37(d,J=8.3Hz,2H),7.20(s,1H),7.07(d,J=8.3Hz,2H),6.99–6.83(m,2H),6.76(d,J=29.2Hz,2H ), 6.14(s, 1H), 4.21(s, 2H), 3.85(d, J = 9.3 Hz, 2H), 3.52(s, 2H), 3.30–3.14(m, 8H), 2.79(s, 1H), 2.23(d, J = 20.0 Hz, 5H), 1.99(s, 4H), 1.85(s, 1H), 1.61(d, J = 11.3 Hz, 2H), 1.42(s, 2H), 1.25(s, 2H), 1.03–0.79(m, 6H). NMR spectroscopy measurements were performed using a Bruker Avance III HD 300 MHz laser and a BBOF probe.

[0479] Preparation of compound 3-2,4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azin-1(7H)-yl)-N-((4-4-(((fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)benzenesulfonyl)benzamide

[0480] In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxalate-2,4,10-triazacyclo[7.5.0.0^[3,7]]tetracyclo-1(9),2,5,7-tetraen-10-yl]benzoic acid (80 mg, 0.13 mmol, 1 equivalent), DCM (3 mL), 4-[[(4-fluorooxy-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (42.6 mg, 0.13 mmol, 1.00 equivalent), EDCI (49.0 mg, 0.26 mmol, 2 equivalent), and DMAP (62.4 mg, 0.51 mmol, 4 equivalent) were added. The resulting solution was stirred overnight at 25 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC under the following conditions (Prep-HPLC-006): column, X Bridge PrepC18 OBD column, 19 x 150 mm 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O) and CH3CN (41.0% CH3CN increased to 61.0% in 6 min, maintained at 95.0% in 1 min, decreased to 41.0% in 1 min, and maintained at 41.0% in 1 min); detector, UV 210 nm. 17 mg (14.13%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexane-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(4-fluorooxy-4-yl)methyl]amino-3-nitrobenzene)benzenesulfonyl-2-[14-oxalate-2,4,10-triazacyclo[7.5.0.0^[3,7]]tetracyclo-1(9),2,5,7-tetraen-10-yl]benzamide was obtained as a yellow solid. LC-MS (ES, m / z): M+1 = 940, R, T = 1.583 min. Residence time was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: Water (0.05% TFA); Eluent B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile, 3.0 min; Oven temperature 40°C; Flow rate: 1.5 mL / min. 1 H NMR (300MHz, DMSO-d) 6,ppm) δ11.94(s,1H),11.25(s,1H),8.59(s,1H),8.48(d,J=2.3Hz,1H),7.66(d,J=9.1Hz,1H),7.47(d,J=8.9Hz ,1H),7.37(d,J=8.2Hz,2H),7.20(d,J=3.1Hz,1H),7.07(dd,J=8.9,3.8Hz,3H),6.94(s,1H),6.71(s,2H),6.1 3 (d, J = 3.1 Hz, 1H), 4.20 (d, J = 6.5 Hz, 2H), 3.80–3.70 (m, 3H), 3.68–3.60 (m, 1H), 3.58–3.45 (m, 4H), 3.25–3.05 (m, 4H), 2.83–2.69 (m, 2H), 2.33–2.10 (m, 6H), 1.98 (s, 4H), 1.84–1.68 (m, 4H), 1.49–1.35 (m, 2H), 0.95 (s, 6H). NMR spectroscopy measurements were performed using a Bruker Avance III HD 300 MHz laser and a BBOF probe.

[0481] Preparation of Compound 3-3: 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-(((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrrolo[2,3-b][1,4]azin-1(7H)-yl)benzamide

[0482] Synthesis of 4,4,4-trifluoro-3-hydroxybutyramide: In a 50-necked round-bottom flask, 500 mg of 4,4,4-trifluoro-3-hydroxybutyramide (2.7 mmol, 1 equivalent) and NH3 in MeOH (5 mL, 4.0 M) were added. The resulting solution was stirred at 60 °C for 16 hours, and the mixture was concentrated. 500 mg of 4,4,4-trifluoro-3-hydroxybutyramide was obtained as a white solid. 1 H NMR (300MHz, DMSO-d) 6, ppm) δ 7.62 (ds, 1H), 7.01 (ds, 1H), 3.36–6.34 (m, 1H), 4.27–4.40 (m, 1H), 2.39–2.36 (m, 2H). NMR spectroscopy measurements were performed using a Bruker Avance III HD 300 MHz spectrometer and a BBOF probe.

[0483] Synthesis of 4-amino-1,1,1-trifluorobut-2-ol: In a 50 mL three-necked round-bottom flask, 500 mg of 4,4,4-trifluoro-3-hydroxybutyramide (3.2 mmol, 1 equivalent) and 10 mL of THF were added dropwise under ice bath conditions. LAH (242 mg, 6.4 mmol, 2.00 equivalent) was added gradually. The resulting solution was stirred at room temperature for 16 hours. After the reaction was complete, 0.24 mL of water was added to cool the reaction mixture. Then, 0.24 mL of NaOH (10% H₂O) and 0.72 mL of water were added continuously to the solution under ice bath conditions. The solid was filtered off. The resulting mixture was concentrated under vacuum. 380 mg (83.43%) of 4-amino-1,1,1-trifluorobut-2-ol was given as a colorless oil. 1 H NMR (300MHz, CDCL3) , ppm) 4.10–4.01 (m, 1H), 2.70–2.66 (m, 2H), 1.51–1.47 (m, 2H). NMR spectroscopy measurements were performed using a Bruker AvanceIII HD 300MHz spectrometer and a BBOF probe.

[0484] Synthesis of 4-methyl-N-(4,4,4-trifluoro-3-hydroxybutyl)benzenesulfonamide. In a 100 mL round-bottom flask, 4-amino-1,1,1-trifluorobut-2-ol (350 mg, 2.4 mmol, 1 equivalent), triethanolamine (480 mg, 4.8 mmol, 2.0 equivalent), and DCM (10 mL) were added, and TsCl (470 mg, 2.4 mmol, 1.0 equivalent) was added while in an ice bath. The resulting solution was stirred at room temperature for 4 hours and diluted with 50 mL of DCM. The resulting mixture was washed with 2 x 20 mL of water and 1 x 20 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solid was filtered off. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0-50%). 600 mg (82.52%) of 4-methyl-N-(4,4,4-trifluoro-3-hydroxybutyl)benzene-1-sulfonamide was obtained as a yellow solid. 1 H NMR (300MHz, DMSO-d) 6, ppm) δ 7.70-7.68 (m, 2H), 7.42-7.40 (m, 2H), 6.23-6.21 (m, 1H), 4.01-3.96 (m, 1H), 2.87-2.83 (m, 2H), 2.39 (s, 3H), 1.70-1.49 (m, 2H). NMR spectroscopy measurements were performed using a Bruker AvanceIII HD 300MHz spectrometer and a BBOF probe.

[0485] Synthesis of N-(3-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-oxy)-4,4,4-trifluorobutyl)-4-methylbenzenesulfonamide. In a 100 mL round-bottom flask, 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.9 mmol, 1 equivalent), 4-methyl-N-(4,4,4-trifluoro-3-hydroxybutyl)benzene-1-sulfonamide (310 mg, 1.0 mmol, 1.2 equivalent), Cs₂CO₃ (566 mg, 1.7 mmol, 2.0 equivalent), and 1,4-dioxane (10 mL) were added. The resulting solution was stirred in an oil bath at 90 °C for 16 h. The reaction mixture was cooled. The solid was filtered off. The resulting solution was diluted with 100 mL of DCM. The resulting mixture was washed with 5 x 50 mL of water and 1 x 50 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solid was filtered off. The resulting mixture was concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0-30%). 400 mg (73.95%) of N-[3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]-4,4,4-trifluorobutyl]-4-methylbenzene-1-sulfonamide was given as a pale yellow solid. 1 H NMR (300MHz, CDCL3) , ppm) 8.17 (bs, 1H), 7.76-7.73 (m, 2H), 7.29-7.27 (m, 3H), 6.51-6.50 (m, 1H), 5.93-5.91 (m, 1H), 5.75-5.72 (m, 2H), 5.63-5.58 (m, 1H), 3.60-3.57 (m, 2H), 3.34-3.32 (m, 1H), 3.13-3.11 (m, 1H), 2.46 (s, 3H), 2.31-2.29 (m, 1H), 2.10-2.07 (m, 1H), 1.00-0.85 (m, 2H), 0.01 (s, 9H). NMR spectroscopy measurements were performed using a Bruker AvanceIII HD 300MHz spectrometer and a BBOF probe.

[0486] Synthesis of 1-toluenesulfonyl-4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazacycloheptane: N-[3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]oxy]-4,4,4-trifluorobutyl]-4-methylbenzene-1-sulfonamide (700 mg, 1.13 mmol (1 equivalent), Cs₂CO₃ (1.1 g, 3.39 mmol, 3.00 equivalent), CuI (214 mg, 1.13 mmol, 1.0 equivalent), 2-isobutyrylcyclohexanol-1-one (80 mg, 0.56 mmol, 0.5 equivalent), and DMSO (10 mL) were placed in a 250 mL three-necked round-bottom flask, and nitrogen was blown in to maintain an inert atmosphere. The resulting solution was stirred in an oil bath at 120 °C for 24 hours. The resulting solution was diluted with 20 mL of water. The resulting solution was then diluted with 2x... Extracted with 50 mL of ethyl acetate. The resulting mixture was washed with 1 x 50 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0-30%). 350 mg (57.38%) of 1-toluenesulfonyl-4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyridine[2,3-b][1,4]oxazetane was obtained as a pale yellow solid. 1 H NMR (300MHz, CDCL3) , ppm) 8.19 (bs, 1H), 7.50-7.47 (m, 2H), 7.39 (s, 1H), 7.24-7.22 (m, 2H), 6.58-6.57 (m, 1H), 5.69-5.66 (m, 1H), 5.55-5.51 (m, 1H), 4.57-4.52 (m, 1H), 3.96-3.94 (m, 1H), 3.59-3.56 (m, 2H), 3.48-3.44 (m, 1H), 2.41 (s, 3H), 2.31-2.29 (m, 1H), 1.95-1.91 (m, 1H), 0.97-0.91 (m, 2H), 0.05 (s, 9H). NMR spectroscopy measurements were performed using a Bruker Avance III HD. Completed with a 300MHz and BBOF probe.

[0487] Synthesis of 4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyridine[2,3-b][1,4]oxazane: In a 250 mL three-necked round-bottom flask, Na (150 mg, 6.5 mmol, 1.0 equivalence), naphthalene (833 mg, 6.5 mmol, 10 equivalence), and DME (3 mL) were placed under N2. The reaction mixture was stirred at room temperature until Na and naphthalene were completely dissolved. A solution of 1-toluenesulfonyl-4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyridine[2,3-b][1,4]oxazetane (350 mg, 0.65 mmol, 1 equivalent) in THF (5 mL) was added at -78 °C. The resulting solution was stirred at -60 °C to -40 °C for 2–3 h until the starting material was completely consumed by TLC. The reaction was then stopped by adding 5 mL of NH4Cl at -10 °C. The resulting solution was extracted with 3 x 10 mL of ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was eluted on a silica gel column with ethyl acetate / petroleum ether (1 / 3). 220 mg (88%) of 4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrole[3',2':5,6]pyridine[2,3-b][1,4]oxazetane was obtained as a white solid.

[0488] Synthesis of methylmethyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-7-((2-(trimethyl)ethoxy)methyl)-3,4-dihydropyrrole[3',2':5,6]pyrido[2,3-b][1,4]oxazacycloheptan-1(7H)-yl)benzoate: 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1 [-en-1-yl]methyl]piperazin-1-yl)benzoate (1.2 g, 2.28 mmol, 4.00 equivalents), toluene (20 mL), 4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyridine[2,3-b][1,4]oxazetane (220 mg, 0.57 mmol, 1 equivalent), Cs₂CO₃ (923 mg, 2.84 mmol, 5 equivalents), XantPhos Pd 2G (250 mg, 0.46 mmol, 0.8 equivalents) were placed in a 100 mL three-necked round-bottom flask, and nitrogen was purged to maintain an inert atmosphere. The resulting solution was stirred overnight at 110 °C. The resulting solution was diluted with 30 mL of water. The resulting solution was extracted with 2 x 30 mL of ethyl acetate. The resulting mixture was washed with 1 x 30 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated on a silica gel column with ethyl acetate / petroleum ether (0-50%). 380 mg of crude (80.0%) 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-heptane-1(7H)-yl)benzoate was obtained as a yellow solid. LC-MS (ES, m / z): M+ = 838, R, T = 3.33 min. Residence time measurements were performed using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0, Poroshell HPH-C18, 2.7 μm; eluent A: water (0.05% NH4HCO3); eluent B: acetonitrile; linear gradient, from 5% acetonitrile to 100% acetoni...

Claims

1. A solid dispersion comprising a compound selected from: (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin- 1 -yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][l,4]oxazin-l(6H)-yl)-N-((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin- 1 -yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][l,4]oxazin-l(6H)-yl)-N-((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, N-((4-((((S)-l,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro- 5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((S)-3- methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][l,4]oxazin-l(6H)-yl)benzamide, N-((4-((((S)-l,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro- 5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((R)-3- methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][l,4]oxazin-l(6H)-yl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin- 1 -yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][l,4]oxazepin-l(7H)-yl)-N-((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, (S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2- (3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][l,4]oxazepin-l(7H)-yl)benzamide, and (R)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2- (3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][l,4]oxazepin-l(7H)-yl)benzamide, The compound or a pharmaceutically acceptable salt thereof is dispersed in a solid matrix comprising (a) copovidone VA64, (b) 80 Polysorbate 80 and optionally (c) ascorbic acid or sodium ascorbate in an amount of 0.5-2.5 wt.%; wherein the compound, or a pharmaceutically acceptable salt thereof, is present in an amount of 12% to 20% by weight of the equivalent of the parent compound, the copovidone VA64 is present in an amount of 60% to 80% by weight, and 80 Polysorbate 80 is present in an amount of 5% to 10% by weight.

2. The solid dispersion of claim 1, further comprising a glidant.

3. The solid dispersion of claim 2, wherein the glidant comprises colloidal silicon dioxide.

4. The solid dispersion of claim 1, wherein the compound or salt is present in an amount of 15-20% by weight of the equivalent of the parent compound.

5. The solid dispersion of claim 1, wherein the compound or salt is present in an amount of 18% by weight of the equivalent of the parent compound.

6. The solid dispersion of claim 1, wherein ascorbic acid or sodium ascorbate is present in an amount of 0.5-2% by weight.

7. The solid dispersion of claim 6, wherein ascorbic acid or sodium ascorbate is present in an amount of 0.5-1% by weight.

8. The solid dispersion of claim 1, further comprising a disintegrant, a lubricant, and / or a coating.

9. The solid dispersion of claim 8, wherein the lubricant is 0.2-1.0 wt% sodium stearyl fumarate.

10. The solid dispersion of claim 8, wherein the coating is 2-5 wt% of II 85F92209-CN Yellow.

11. The solid dispersion of claim 1, comprising a. 18% by weight of the compound, 74% by weight of copolyvione VA64, 7% by weight of Tween 80 and 1% by weight of silicon dioxide. TM 80 and 1% by weight of silicon dioxide. b. 12% by weight of the compound, 81% by weight of copolyvinalcone VA64, 5% by weight of Tween TM 80 and 1% by weight of silicon dioxide; c. 11.9% by weight of the compound, 79.2% by weight of copolyvione VA64, 6.9% by weight of Tween 80, 2% by weight of sodium dodecyl sulfate TM 80, 1% by weight of sodium ascorbate and 1% by weight of silicon dioxide; d.11.89 wt. % of the compound, 79.23 wt. % of copolyvione VA64, 6.93 wt. % of Tween TM 80, 0.9 wt. % of VC and 1.00 wt. % of silicon dioxide; e.12.00% by weight of the compound, 79.00% by weight of copolyvione VA64, 7.00% by weight of Tween TM 80. 1.0% by weight of VC and 1.00% by weight of silicon dioxide; f.14.00% by weight of the compound, 78.00% by weight of copolyvione VA64, 7.00% by weight of Tween 80 and 1.00% by weight of silicon dioxide. TM 80 and 1.00% by weight of silicon dioxide. g.14.00 percent by weight of the compound, 77.00 percent by weight of copolyvione VA64, 8.00 percent by weight of Tween 80, and 1.00 percent by weight of silicon dioxide. TM 80 and 1.00 percent by weight of silicon dioxide. h.14.00% by weight of the compound, 76.00% by weight of copolyvione VA64, 9.00% by weight of Tween TM 80and 1.00% by weight of silicon dioxide; i.16.00% by weight of the compound, 76.00% by weight of copolyvione VA64, 7.00% by weight of Tween 80 and 1.00% by weight of silicon dioxide. TM 80 and 1.00% by weight of silicon dioxide. j.16.00% by weight of the compound, 75.00% by weight of copolyvione VA64, 8.00% by weight of Tween TM 80 and 1.00% by weight of silicon dioxide; k.16.00% by weight of the compound, 74.00% by weight of copolyvione VA64, 9.00% by weight of Tween TM 80 and 1.00% by weight of silicon dioxide; l. 18.00% by weight of the compound, 74.00% by weight of copolyvione VA64, 7.00% by weight of Tween TM 80 and 1.00% by weight of silicon dioxide; m.18.00% by weight of the compound, 73.00% by weight of copolyvione VA64, 8.00% by weight of Tween TM 80 and 1.00% by weight of silicon dioxide; n.18.00 percent by weight of the compound, 72.00 percent by weight of copolyvione VA64, 9.00 percent by weight of Tween TM 80 and 1.00 percent by weight of silicon dioxide; o.20.00% by weight of the compound, 72.00% by weight of copolyvinal 64, 7.00% by weight of Tween TM 80 and 1.00% by weight of silicon dioxide; p.20.00% by weight of the compound, 71.00% by weight of copolyvinal 64, 8.00% by weight of Tween TM 80 and 1.00% by weight of silicon dioxide; q. 20.00% by weight of the compound, 70.00% by weight of copolyvione VA64, 9.00% by weight of Tween 80 and 1.00% by weight of silicon dioxide. TM 80 and 1.00% by weight of silicon dioxide. r.22.50% by weight of the compound, 69.50% by weight of copolyvione VA64, 7.00% by weight of Tween 80 and 1.00% by weight of silicon dioxide. TM 80 and 1.00% by weight of silicon dioxide. s. 15.00% by weight of the compound, 75.00% by weight of copolyvione VA64, 9.00% by weight of Tween 80 and 1.00% by weight of silicon dioxide. TM 80 and 1.00% by weight of silicon dioxide. t.12.00% by weight of the compound, 79.00% by weight of copolyvione VA64, 8.00% by weight of Tween 80 and 1.00% by weight of silicon dioxide. TM 80 and 1.00% by weight of silicon dioxide. u.15.00% by weight of the compound, 76.00% by weight of copolyvinal 64, 8.00% by weight of Tween TM 80 and 1.00% by weight of silicon dioxide; or v. 20.00% by weight of the compound, 71.00% by weight of copolyvione VA64, 8.00% by weight of Tween TM 80 and 1.00% by weight of silicon dioxide.

12. The solid dispersion of claim 1, wherein the compound is (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][l,4]oxazepin- l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; or a pharmaceutically acceptable salt thereof.

13. The solid dispersion of claim 12, wherein the compound or pharmaceutically acceptable salt thereof is present in an amount of 12% by weight of the equivalent of the parent compound; copovidone VA64 is 79% by weight; 80 Polysorbate 80 at 7% by weight; the antioxidant is 1% by weight; and the coating is 1% by weight. The solid dispersion further comprises a flow aid, the flow aid being silicon dioxide; wherein the silicon dioxide is 1% by weight.

14. A method for preparing the solid dispersion of claim 1, the method comprising: (a) subjecting to an elevated temperature: (i) an active pharmaceutical ingredient (API) comprising a compound selected from: (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin- 1 -yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin- 1 -yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-3-methyl- 2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide, N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-3-methyl- 2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)- 2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, (S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2- (3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrrolo[2,3-b][l,4]oxazepin-l(7H)-yl)benzamide, and (R)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2- (3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrrolo[2,3-b][l,4]oxazepin-l(7H)-yl)benzamide, (ii) a pharmaceutically acceptable water-soluble polymer carrier, wherein the pharmaceutically acceptable water-soluble polymer carrier is copovidone VA64, (iii) a pharmaceutically acceptable surface active agent; wherein the pharmaceutically acceptable surface active agent is 80 Polysorbate 80; and (iv) optionally a pharmaceutically acceptable antioxidant, wherein the pharmaceutically acceptable antioxidant is ascorbic acid or sodium ascorbate, (b) extruding the semi-solid mixture; and (c) cooling the resulting extrudate to provide a solid matrix comprising the polymer carrier and the surfactant and having the compound or salt thereof dispersed therein in substantially non-crystalline form.

15. The method of claim 14, wherein the compound, polymer carrier, surfactant, and antioxidant are mixed together prior to being subjected to the elevated temperature.

16. The method of claim 14, wherein the compound, polymer carrier, surfactant, and antioxidant are mixed together while being subjected to the elevated temperature.

17. The method of claim 14, wherein the elevated temperature is from 100 °C to 200 °C.

18. The method of claim 17, wherein the elevated temperature is from 125 °C to 175 °C.

19. The method of claim 17, wherein the elevated temperature is from 140 °C to 160 °C.

20. The method of claim 14, further comprising calendering the extrudate prior to or while cooling.

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