Hot-melt extruded solid dispersion containing a Bcl2 inhibitor

Abstract

The pro-apoptotic solid dispersion is comprised of a Bcl-2 family protein inhibitor 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 process for preparing such a solid dispersion comprises subjecting the compound of Formula A, the water-soluble polymeric carrier, and the surfactant to an elevated temperature to provide an extrudable semi-solid mixture; extruding the semi-solid mixture; and cooling the resulting extrudate to provide a solid matrix comprising the polymeric carrier and the surfactant, and having the compound dispersed therein in an essentially amorphous form. The solid dispersion is suitable for oral administration to a subject in need thereof for the treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, e.g., cancer or an immune or autoimmune disease.

Description

[Technical Field]

[0001] Reference to related applications This application claims the benefit as of the filing date of U.S. Provisional Patent Application No. 62 / 980,700, filed on 24 February 2020, and U.S. Provisional Patent Application No. 63 / 053,565, filed on 17 July 2020, the entire contents of the aforementioned applications being incorporated herein by reference. Technical field The present invention relates to a solid dispersion containing an apoptosis inducer, a pharmaceutical dosage form containing the dispersion, a method for preparing the dispersion and dosage form, and a method for using it to treat diseases characterized by the overexpression of anti-apoptotic Bcl-2 family proteins. [Background technology]

[0002] Background of the Invention Apoptosis, or programmed cell death, is a conserved and controlled process that is the primary mechanism for eliminating senescent, damaged, and unwanted cells. The ability to block apoptotic signaling is a key feature of cancer and is therefore important for carcinogenesis, tumor maintenance, and chemotherapy resistance [Hanahan, D. & Weinberg, RA The hallmarks of cancer. Cell 100, 57-70 (2000)]. The dynamic binding interactions between prodeath proteins (e.g., BCL-2-related X protein (BAX), BCL-2 antagonist / killer 1 (BAK), BCL-2-related cell death agonist (BAD), BCL-2-like 11 (BIM), NOXA, and BCL-2 binding component 3 (PUMA)) and prosurvival proteins (BCL-2, BCL-XL, BCL-2-like 2 (BCL-W), myelocyte leukemia sequence 1 (MCL-1), and BCL-2-related protein A1 (BFL-1)) in the BCL-2 family regulate their involvement in programmed cell death. By altering the balance of these opposing axes, cancer cells can provide one means of interfering with normal apoptosis and gaining 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)].

[0003] BCL-2 was the first identified apoptosis regulator, originally cloned from the t(14;18) translocation breakpoint found in human B-cell lymphoma [Tsujimoto, Y., et al. Science 228, 1440-1443 (1985); Cleary, ML, et al. Cell 47, 19-28 (1986); Boise, LH et al. Cell 74, 597-608 (1993)]. This protein has since been shown to play a dominant role in the survival of several lymphoid malignancies [Vaux, DL, et al. pre-B cells. Nature 335, 440-442 (1988)]. Overexpression of BCL-2 family proteins has been associated with chemotherapy resistance, clinical outcomes, disease progression, overall prognosis, or a combination thereof in various cancers and immune system disorders. PCT / US2004 / 36770, disclosed as WO2005 / 049593, and PCT / US2004 / 37911, disclosed as WO2005 / 049594, describe the involvement of BCL-2 family proteins in bladder cancer, brain tumors, 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 derived lymphoid malignancies, malignant melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, splenic cancer, and others. The involvement of BCL-2 family proteins in immune and autoimmune diseases is described in Current Allergy and Asthma Reports 2003, 3, 378-384; British Journal of Hematology 2000, 110(3), 584-90; Hematology 2000, 95(4), 1283-92; and New England Journal of Medicine 2004 351(14), 1409-1418. The involvement of BCL-2 family proteins in arthritis is disclosed in WO2009 / 064938. The involvement of BCL-2 family proteins in bone marrow transplant rejection is disclosed in US2008-0182845A1. All of these are incorporated herein by reference.

[0004] Over the past decade, several BCL-2 inhibitors, including ABT-737, ABT-263, and ABT-199, have been identified and are progressing to human clinical trials for cancer treatment.

[0005] [ka]

[0006] ABT-737 was discovered through nuclear magnetic resonance (NMR)-based 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 BCL-2, Bcl-XL, and Bcl-w with anti-apoptotic activity, exhibiting affinities 2-3 orders of magnitude stronger than previously reported compounds. Mechanistic studies have revealed that ABT-737 does not directly initiate the apoptotic process, but rather enhances the effects of death signals, exhibiting synergistic cytotoxicity with chemotherapeutic agents and radiation. ABT-737 shows monophasic killing effects against lymphoma and small cell lung cancer cell lines and patient-derived primary cells, and in animal models, ABT-737 has been shown to improve survival rates, regress established tumors, and lead to high rates of cure. Unfortunately, ABT-737 is not orally bioavailable, and its low water solubility hinders the development of intravenous formulations.

[0007] As a result of extensive efforts by MedChem, the orally bioavailable 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 ​​of ≤0.5 nM, ≤1 nM, and ≤1 nM. ABT-263 showed an IC50 of 110 nM against the SCLCH146 cell line. 50In the H345 xenograft model, administration of ABT-263 at 100 mg / kg / day resulted in 80% TGI and at least 50% tumor volume reduction in 20% of treated tumors, demonstrating a significant antitumor effect. Oral monotherapy of ABT-263 completely regresses tumors in xenograft models of small cell lung cancer and acute lymphoblastic leukemia [Tse ​​C, et al. Cancer Res. 2008, 68(9), 3421-3428]. However, in clinical trials, BCL-XL inhibition by ABT-263 (navitoclax) induces a rapid, concentration-dependent decrease in circulating platelet count. This mechanism of thrombocytopenia is a dose-limiting toxicity of Navitoclax monotherapy in patients and also limits the ability to raise drug concentrations to a high efficacy range.

[0008] Therefore, BCL-2 selective (BCL-XL preserving) inhibitors can significantly reduce thrombocytopenia while maintaining efficacy in lymphoid malignancies. As a result, the therapeutic range is expanded, and greater BCL-2 suppression and clinical efficacy can be expected in BCL-2-dependent tumors. After extensive MedChem, ABT-199 (GDC-0199) was successfully developed [Andrew J Souers, et al, Nature Medicine, Volume 19, 22, p202, 2013]. ABT-199 is a BCL-2 selective inhibitor with a Ki <0.01nM, exhibiting more than 4800-fold selectivity for Bcl-xL and Bcl-w, and showing no activity against Mcl-1. ABT-199 is used in EC 50 At 8 nM, it potently inhibited RS4;11 cells. Furthermore, ABT-199 induced rapid apoptosis in RS4;11 cells, accompanied by cytochrome c release, caspase activation, and sub-G0 / G1 DNA accumulation. Quantitative immunoblotting revealed that sensitivity to ABT-199 was strongly correlated with BCL-2 expression, including in NHL, DLBCL, MCL, AML, and ALL cell lines. ABT-199 also inhibited mean EC2 50ABT-199 induces apoptosis in CLL with a 3.0 nM level. A single 100 mg / kg dose of ABT-199 causes up to 95% suppression of tumor growth and 152% delay of tumor growth in RS4;11 xenografts. ABT-199 inhibits xenograft growth either alone or in combination with bendamustine or other agents (DoHH2, Granta-519). Human Phase I and II data showed high efficacy of ABT-199 in CLL with 17p deletion, and it was approved by the FDA in 2016.

[0009] WO / 2017 / 132474, WO / 2019 / 040550, WO / 2019 / 040573, PCT / US2019 / 047404, and PCT / US2019 / 047403 disclose a novel class of BCL-2 inhibitors. When the aqueous solubility of Bcl-2 conjugated compounds is very low, prescribers face significant challenges in ensuring acceptable oral bioavailability, which is highly dependent on solubility in the aqueous medium of the gastrointestinal tract. This is also true when the binding affinity is very high. The challenges are further exacerbated when considering the need to provide an appropriate drug loading in the formulation so that a therapeutically effective dose can be administered in an acceptable amount.

[0010] Liquid formulations (including encapsulated liquids) may be useful for some drugs with low water solubility, provided that a suitable pharmaceutically acceptable solvent system (generally lipid-based) can be found without causing problems with solubility or storage stability. Another proposed approach for such drugs is solid dispersion, but this has its own set of challenges.

[0011] For various reasons, including patient compliance and taste masking, solid dosage forms are generally preferred over liquid forms. However, in most cases, oral solid dosage forms of drugs offer lower bioavailability than oral solutions of the drug.

[0012] Attempts have been made to improve the bioavailability of solid formulations by forming solid dispersions of drugs, or more specifically, solid solutions. Solid dispersions or solutions are preferred physical systems because, when brought into contact with a liquid medium such as gastric juice, their components readily form liquid solutions. This ease of dissolution is thought to be at least in part due to the fact that the energy required to dissolve components from a solid dispersion or solid solution is less than the energy required to dissolve components from a solid phase of crystals or microcrystals. However, it is important that the drug released from a solid dispersion or solid solution remains soluble in the aqueous fluids of the gastrointestinal tract; otherwise, the drug may precipitate in the gastrointestinal tract, resulting in low bioavailability.

[0013] International Patent Publication WO01 / 00175 relates to a mechanically stable pharmaceutical dosage form which is a solid solution of an active ingredient in an auxiliary matrix. The matrix comprises a homopolymer or copolymer of N-vinylpyrrolidone and a liquid or semi-solid surfactant.

[0014] International Patent Publication WO00 / 57854 relates to a mechanically stable pharmaceutical dosage form for oral administration comprising at least one active compound, at least one thermoplastic matrix-forming aid, and more than 10 wt% and up to 40% of a surface-active substance having a hydrophilic-lipophilic balance (HLB) value of 2 to 18, being liquid at 20°C, or having a dropping point between 20°C and 50°C.

[0015] U.S. Patent Application Publication No. 2005 / 0208082 relates to a solubilizing composition comprising a mixture of TPGS (α-tocopheryl polyethylene glycol succinate or vitamin E polyethylene glycol succinate) and linoleic acid. This solubilizing composition is used to disperse lipophilic substances in an aqueous phase.

[0016] Hot melt extrusion, which is increasingly being used to improve the bioavailability of hot melt extrusions, is a solvent-free, environmentally friendly process and has been said to have many advantages over conventional solid dosage forms in terms of robustness and versatility (Crowley et al. (2007) Drug Development and Industrial Pharmacy 33:908-926).

[0017] Hot-melt extrusion technology has been shown to significantly improve the pharmacokinetic properties of certain drugs compared to alternative formulations. See, for example, Klein et al. (2007) J. Acquir. Immune Defic. Syndr. 44:401-410.

[0018] Apoptosis-inducing agents targeting Bcl-2 family proteins such as Bcl-2 and Bcl-Xχ are best administered according to regimens that provide continuous, for example, daily, plasma concentration replenishment to maintain concentrations within the therapeutic range. This can be achieved by daily parenteral administration, such as intravenous (iv) or intraperitoneal (ip) administration. However, in clinical practice, especially for outpatients, daily parenteral administration is often impractical. To enhance the clinical utility of apoptosis-inducing agents, solid dosage forms with acceptable oral bioavailability are highly desirable, for example, as chemotherapeutic agents in cancer patients. Such dosage forms and regimens for their oral administration would represent a significant advance in the treatment of many types of cancer, including NHL, CLL, and ALL, and would facilitate combination therapy with other chemotherapy agents. [Overview of the Initiative]

[0019] One aspect of the present invention described herein relates to a form of formula (A) that is essentially amorphous (e.g., non-crystalline).

[0020] [ka]

[0021] (In the formula, Q4 is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or spiroheterocycle; Q5 is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or spiroheterocycle; R1, R2, R7, R8, R9, and R 10 are each independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, OR a SR a alkyl-Ra, NH(CH2)pRaR a C(O)R a S(O)R a SO2R<s 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[[ID=C2]] 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 ] wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl are optionally substituted with one or more R d ; R a R b R c R bb Rcc and R d is, independently, H, D, alkyl, spiroalkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, where said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally substituted with one or more of R e ; R e is, independently, H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; 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)​​​​​​​​​​​​​​​​​​​L1 is a bond, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, where said alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more R d ; L2 is a bond, or an alkyl in which one or more -L i - are optionally inserted between any two adjacent carbon atoms; -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 ), a divalent alkenyl group, a divalent alkynyl group, a divalent cycloalkyl group, a divalent heterocycloalkyl group, a divalent aryl group, a divalent heteroaryl group; The two R1 groups, together with the atoms to which they are attached, may optionally form one cycloalkyl or heterocycloalkyl, where said cycloalkyl or heterocycloalkyl of R1 may optionally be substituted with one or more R d ; The two R2 groups, together with the atoms to which they are attached, may optionally form one cycloalkyl or heterocycloalkyl, where said cycloalkyl or heterocycloalkyl of R2 may optionally be substituted with one or more R d ; The two R7 groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atom to which they are bonded, where the cycloalkyl or heterocycloalkyl group of R7 may optionally consist of one or more R groups. d It may also be replaced with; Two R's 10 The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R 10 The cycloalkyl or heterocycloalkyl in the above is optionally one or more R d It may also be replaced with; The R7 and L groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atom to which they are bonded, where the cycloalkyl or heterocycloalkyl group of R7 and L may optionally consist of one or more R groups. e It may also be replaced with; R b and R c The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R b and R c The cycloalkyl or heterocycloalkyl in the above is optionally one or more R e It may also be replaced with; Two R's d The groups, together with the atoms to which they are bonded, may optionally form a cycloalkyl or heterocycloalkyl group, where R d The cycloalkyl or heterocycloalkyl in the above is optionally one or more R e It may also be replaced with; Two R's e The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R eThe cycloalkyl or heterocycloalkyl group may optionally be substituted with one or more groups selected from H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; k, g, m, n, p, and q are each independently 0, 1, 2, 3, 4, or 5; s is either 0 or 1; and f is either 0 or 1. The compound or a pharmaceutically acceptable salt thereof The present invention provides a solid dispersion (such as one produced by hot-melt extrusion) 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, dispersed in a solid matrix.

[0022] Another aspect of the present invention described herein provides a solid in an orally administered dosage form comprising such a solid dispersion, together with one or more additional excipients. Another aspect of the present invention described herein provides a method for preparing the above-described solid dispersion. The method comprises the steps of (a) (i) a pharmaceutically active 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, being subjected to a raised temperature to provide an extruded semi-solid mixture:

[0023] [ka]

[0024] (In the formula, Q4 is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or spiroheterocycle; Q5 is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or spiroheterocycle; R1, R 2、 R7, R 8、 R9, and R 10 are each independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, 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 wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl are optionally substituted with one or more R d ; R a Rb , R c , R bb , R cc , and R d Each of these is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, where the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl are optionally one or more R e It has been replaced with; R e These are independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; 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 , a divalent alkenyl group, or a divalent alkynyl group; L is -L1-L2-; L1 is a bond, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, where the alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally one or more R d It has been replaced with; L2 is a bond, or one or more -L atoms between any two adjacent carbon atoms. i - is an alkyl group into which a hyphen is optionally inserted; -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 )-, a divalent alkenyl group, a divalent alkynyl group, a divalent cycloalkyl group, a divalent heterocycloalkyl group, a divalent aryl group, a divalent heteroaryl group; The two R1 groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atom to which they are bonded, where the cycloalkyl or heterocycloalkyl group of R1 may optionally consist of one or more R1 groups. d It may also be replaced with; The two R2 groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atom to which they are bonded, where the cycloalkyl or heterocycloalkyl group of R2 may optionally consist of one or more R groups.d It may also be replaced with; The two R7 groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atom to which they are bonded, where the cycloalkyl or heterocycloalkyl group of R7 may optionally consist of one or more R groups. d It may also be replaced with; Two R's 10 The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R 10 The cycloalkyl or heterocycloalkyl in the above is optionally one or more R d It may also be replaced with; The R7 and L groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atom to which they are bonded, where the cycloalkyl or heterocycloalkyl group of R7 and L may optionally consist of one or more R groups. e It may also be replaced with; R b and R c The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R b and R c The cycloalkyl or heterocycloalkyl in the above is optionally one or more R e It may also be replaced with; Two R's d The groups, together with the atoms to which they are bonded, may optionally form a cycloalkyl or heterocycloalkyl group, where R d The cycloalkyl or heterocycloalkyl in the above is optionally one or more R e It may also be replaced with; Two R's e The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R eThe cycloalkyl or heterocycloalkyl group may optionally be substituted with one or more groups selected from H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; k, g, m, n, p, and q are each independently 0, 1, 2, 3, 4, or 5; s is either 0 or 1; and f is either 0 or 1. (b) step of extruding the semi-solid mixture; and (c) The step of cooling the obtained extruded material to prepare a solid matrix comprising a polymer carrier and a surfactant (and optionally an antioxidant), wherein the compound or a salt thereof is dispersed therein in an essentially amorphous form.

[0025] In this specification, the term “molten” refers to a liquid or semi-solid (e.g., rubbery) state induced at a raised temperature in which the first component can be uniformly dispersed in a matrix containing the second component. Typically, the second (matrix) component, such as a polymer support, is in such a state, while other components, such as the compound of formula (A) or a salt thereof, dissolve in the molten and form a solution.

[0026] In this specification, the term “heated temperature” means a temperature above the softening point of the polymer support affected by other components, such as plasticizers or surfactants, if present. In certain embodiments, the heated temperature is about 100°C to about 200°C, about 125°C to about 175°C, or about 140°C to 160°C.

[0027] The preparation of the melt can be carried out in various ways. The mixing of the components can be carried out before, during or after the formation of the melt. For example, the components can first be mixed and then heated to form the melt; alternatively, mixing and melting can be carried out simultaneously. In certain embodiments, the polymer carrier is first melted, optionally together with a surfactant component, and then the API is added to the resulting melt. Usually, the melt is thoroughly mixed during heating to ensure homogeneous dispersion of the API.

[0028] Related aspects of the present invention provide a solid dispersion prepared by the above method. A further related aspect of the present invention provides an orally administrable pharmaceutical dosage form comprising the solid dispersion of the present invention.

[0029] Another aspect of the present invention is a method of treating a neoplastic, immune or autoimmune disease, comprising orally administering to a subject having the disease a therapeutically effective amount of the solid dispersion of the present invention or one or more solid dosage forms comprising such a dispersion.

[0030] Examples of neoplastic diseases include cancer. Specific exemplary types of cancer that can be treated according to the method are non-Hodgkin lymphoma (NHL). Another specific exemplary type of cancer that can be treated according to the method is chronic lymphocytic leukemia (CLL). Yet another specific exemplary type of cancer that can be treated according to the method of the present invention is, for example, acute lymphocytic leukemia (ALL) in pediatric patients.

[0031] The following provides additional embodiments of the present invention including specific aspects of the above embodiments. Any embodiment of the present invention, unless explicitly denied or inappropriate, includes the embodiment examples or embodiments described as examples in one aspect of the present invention and can be combined with any other embodiment of the present invention.

Mode for Carrying Out the Invention

[0032] Detailed description of the present invention The inventions described herein provide solid dispersions that contain an active ingredient in an essentially amorphous or noncrystalline form and are typically more soluble than those in a crystalline form.

[0033] In this specification, the term “solid dispersion” includes systems having small solid particles (e.g., essentially amorphous or non-crystalline particles) of one phase dispersed in another solid phase. More specifically, the solid dispersions of the present invention consist of particles of one or more active ingredients dispersed in a solid state in an inert carrier or matrix, and can be prepared by melting (e.g., hot melt extrusion or HME), solvent (e.g., spray drying), or a combination of melting and solvent methods. According to the present invention, hot melt extrusion as described herein is preferred.

[0034] In this specification, the term "amorphous form" means particles that do not have a clear structure, that is, particles that lack a crystalline structure. In this specification, the term “essentially amorphous” means, for example, that a degree of crystallinity of about 2% or less or about 1% or less is observed by X-ray diffraction analysis. In certain embodiments, no detectable degree of crystallinity is observed by either X-ray diffraction analysis or polarizing microscopy, or both. Where no detectable degree of crystallinity is observed, the solid dispersions described herein may be described additionally or alternatively as solid solutions.

[0035] Therefore, in one embodiment, the present invention provides a solid dispersion comprising a compound of formula (A).

[0036] [ka]

[0037] Here Q4 is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or spiroheterocyclyl.

[0038] Q5 is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or spiroheterocyclyl. R1, R2, R7, R8, R9, and R 10 These are, independently, H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, OR a , SR a Alkyl-Ra, NH(CH2)pRaR 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 Here, the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl may be any one or more R d It will be replaced by this.

[0039] R a , R b , R c , R bb , R cc , and R dEach of these is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, where the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl are optionally one or more R e It will be replaced by this.

[0040] R e Re is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, and Re is D, alkylo, halo, halo, halo, or halocarbonyl.

[0041] Z1 is a chemical 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 It is a divalent alkenyl group or a divalent alkynyl group.

[0042] L is -L1-L2-. L1 is a chemical bond, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, where the alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl can be any one or more R d It will be replaced by this.

[0043] L2 is a chemical bond, or one or more -L atoms between any two adjacent carbon atoms. i It is an alkyl group into which a hyphen is arbitrarily inserted. -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 )-, a divalent alkenyl group, a divalent alkynyl group, a divalent cycloalkyl group, a divalent heterocycloalkyl group, a divalent aryl group, a divalent heteroaryl group.

[0044] The two R1 groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atom to which they are bonded, where the cycloalkyl or heterocycloalkyl group of R1 may optionally consist of one or more R1 groups. d It may be replaced with .

[0045] The two R2 groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atom to which they are bonded, where the cycloalkyl or heterocycloalkyl group of R2 may optionally consist of one or more R groups. d It may be replaced with .

[0046] The two R7 groups, together with the atom to which they are bonded, may optionally form seven cycloalkyl or heterocycloalkyl groups, where the cycloalkyl or heterocycloalkyl groups of R7 may optionally consist of one or more R groups. d It may be replaced with .

[0047] Two R's 10 The groups, together with the atoms to which they are bonded, may optionally form a cycloalkyl or heterocycloalkyl group, where R 10 The cycloalkyl or heterocycloalkyl in the above is optionally one or more R d It may be replaced with .

[0048] The R7 and L groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atom to which they are bonded, where the cycloalkyl or heterocycloalkyl group of R7 and L may optionally consist of one or more R groups. e It may be replaced with .

[0049] R b and R c The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R b and R c The cycloalkyl or heterocycloalkyl in the above is optionally one or more R e It may be replaced with .

[0050] Two R's d The groups, together with the atoms to which they are bonded, may optionally form a single cycloalkyl or heterocycloalkyl group, where Rd The cycloalkyl or heterocycloalkyl in the above is optionally one or more R e It may be replaced with .

[0051] Two R's e The groups, together with the atoms to which they are bonded, may optionally form a cycloalkyl or heterocycloalkyl group, where R e The cycloalkyl or heterocycloalkyl group may optionally be substituted with one or more groups selected from H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.

[0052] k, g, m, n, p, and q are each independently 0, 1, 2, 3, 4, or 5. s is either 0 or 1. And f is either 0 or 1.

[0053] 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.

[0054] In a particular embodiment, the compound is represented by formula (A-1):

[0055] [ka]

[0056] In certain embodiments, the compound is represented by formula (A-2):

[0057] [ka]

[0058] In a particular embodiment, the compound is represented by formula (A-3):

[0059] [ka]

[0060] In a particular embodiment, the compound is selected from the group consisting of the following: (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazine-1(6H)-yl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazine-1(6H)-yl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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)piperazine-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-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)piperazine-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-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)piperazine-1-yl)-2-((5aS,8aR)-5a,6,8,8a-tetrahydrofluoro[3,4-b]pyrrolo[3',2':5,6]pyrido[3,2-e][1,4]oxazine-5(1H)-yl)benzamide, (R)-4-(4-((4'-chloro-2'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, (S)-N-((4-(((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)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (R)-N-((4-(((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)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-yl)benzamide, N-((4-((((R)-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)piperazine-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-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)piperazine-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-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)piperazine-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-yl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-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)piperazine-1-yl)-2-((S)-4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-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)piperazine-1-yl)-2-((R)-4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (S)-N-((4-(((1,4-dioxan-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)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)-N-(((S)-5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)-N-(((R)-5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)benzamide, N-(((R)-3-((S)-1,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)benzamide, N-(((S)-3-((S)-1,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)benzamide, N-(((R)-3-((S)-1,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, N-(((S)-3-((S)-1,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide.

[0061] In certain embodiments, the compound or salt is present in the solid dispersion in an equivalent amount of the parent compound, ranging from about 5 wt% to about 40 wt%. In this specification, the term "parent compound equivalent" includes the amount of a pharmaceutically acceptable salt of the parent compound in moles equal to the amount of the parent compound.

[0062] In certain embodiments, at least one polymer carrier is composed of homopolymers and copolymers of graft copolymers, oligos and polysaccharides and / or mixtures thereof from N-vinyl lactam, cellulose ester, cellulose ether, high molecular weight polyalkylene oxide, polyacrylate, polymethacrylate, polyacrylamide, vinyl acetate polymer, polyethylene glycol, polyvinylcaprolactam and polyvinyl acetate.

[0063] In certain embodiments, at least one polymer carrier comprises povidone, copovidone (such as KOLLIDON(R)VA64 type copovidone), HPMC, polyethylene glycol / polyvinyl caprolactam / polyvinyl acetate graft copolymer, and / or mixtures thereof. Optionally, at least one polymer carrier comprises, is essentially, or consists of KOLLIDON(R)VA64 type copovidone.

[0064] In certain embodiments, at least one surfactant is a nonionic surfactant. In certain embodiments, at least one surfactant is a nonionic surfactant. In certain embodiments, at least one surfactant includes polyoxyethylene glyceride, sorbitan fatty acid monoester, polysorbate (such as polysorbate 80 of the TWEEN® 80 brand or polyoxyethylene (20) sorbitan monooleate), α-tocopheryl polyethylene glycol succine (TPGS), and / or mixtures thereof.

[0065] In certain embodiments, at least one antioxidant may include ascorbic acid, ascorbate, bisulfite, metabisulfite, sulfite, curcumin, curcumin derivatives, ursolic acid, resveratrol, resveratrol derivatives, alpha-lipoic acid, thioglycerol, polyphenols, catatin, grape seed extract, green tea extract, citric acid, methionine, cysteine, glutathione, tocopherol, propyl gallate, sodium mercaptoacetate, sodium formaldehyde sulfoxylate, ascorbyl palmitate, butylhydroxyanisole, butylhydroxytoluene, lecithin, vitamin E, uric acid, and / or mixtures thereof.

[0066] In certain embodiments, at least one antioxidant comprises ascorbic acid or an ascorbate. In certain embodiments, at least one antioxidant is ascorbic acid or an ascorbate.

[0067] In certain embodiments, the solid dispersion further comprises at least one lubricant. In certain embodiments, at least one lubricant comprises colloidal silicon dioxide. In certain embodiments, the compound or salt is present in an amount of approximately 5 wt% to approximately 40 wt% of the parent compound equivalent, at least one polymer carrier is present in an amount of approximately 40 wt% to approximately 85 wt%, at least one surfactant is present in an amount of approximately 2.5% to approximately 20 wt%, and at least one antioxidant is present in an amount of approximately 0.25% to approximately 5 wt%.

[0068] In certain embodiments, the compound or salt is present in an amount of about 5 wt% to about 25 wt% of the parent compound equivalent (e.g., about 12-20%, about 15-20%, or about 18%), at least one polymeric carrier is present in an amount of about 50 wt% to about 80 wt% (e.g., about 60-80%, or about 70-80%), at least one surfactant is present in an amount of about 2.5 to about 15 wt% (e.g., about 5-10%, or about 7-9%), and at least one antioxidant is present in an amount of about 0.5 to about 2.5 wt% (e.g., about 0.5-2%, or about 0.5-1%).

[0069] In certain embodiments, the solid dispersion contains at least one disintegrant (such as 10-30 wt% croscarmellose sodium), at least one lubricant (such as 0.2-1.0 wt% stearyl fumarate sodium), and / or at least one coating (2-5 wt% opaly). (R) This also includes (for example, II85F92209-CNYellow).

[0070] In a particular embodiment, the compound is as follows: (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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)piperazine-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, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazine-1(6H)-yl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazine-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)piperazine-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-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)piperazine-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, (S)-N-((4-(((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)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (R)-N-((4-(((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)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-yl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-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)piperazine-1-yl)-2-((R)-4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, N-((4-(((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)piperazine-1-yl)-2-((S)-4-(trifluoromethyl)-3,4-dihydro-2H-pyrroliro[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide.

[0071] In certain embodiments, at least one polymer carrier is copovidone or vinylpyrrolidone-vinyl acetate copolymer (KOLLIDON (R) This refers to VA64 brand / type copovidone, etc. In this specification, "KOLLIDON" (R) The term "VA64" refers to a specific brand of copovidone used in the formulation of the present invention (i.e., KOLLIDON). (R) KOLLIDON (brand) has substantially the same physical, chemical, and / or biological properties as the original brand. (R)This refers to VA64 type copovidone. For simplicity, this term refers to a specific brand of copovidone used in the formulation of the present invention (i.e., KOLLIDON). (R) This includes, but is not limited to, the brand TWEEN (registered trademark). (R) 80 brands and other KOLLIDON (R) The same applies to products bearing other brand names or trademarks, such as branded products.

[0072] In certain embodiments, at least one surfactant is a polysorbate (such as a polysorbate 80 type surfactant). In certain embodiments, at least one antioxidant is ascorbic acid or sodium ascorbate.

[0073] In certain embodiments, the solid dispersion further comprises at least one lubricant. In certain embodiments, at least one lubricant comprises colloidal silicon dioxide. In certain embodiments, the solid dispersion is prepared using hot-melt extrusion (HME), or the solid dispersion is a hot-melt extrusion (HME) formulation.

[0074] In certain embodiments, the solid dispersion comprises one of the formulations of Examples 7-24 and 26-29, and the API is one of the compounds described herein, comprising one of the following compounds: (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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)piperazine-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, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazine-1(6H)-yl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazine-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)piperazine-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-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)piperazine-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, (S)-N-((4-(((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)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (R)-N-((4-(((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)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-yl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-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)piperazine-1-yl)-2-((R)-4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, N-((4-(((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)piperazine-1-yl)-2-((S)-4-(trifluoromethyl)-3,4-dihydro-2H-pyrroliro[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide.

[0075] In certain embodiments, the solid dispersion exhibits an AUC(0-t) value of at least approximately 25,000 to 150,000 h*ng / ml, at least approximately 30,000 to 100,000 h*ng / ml, at least approximately 40,000 to 80,000 h*ng / ml, or at least approximately 50,000 to 60,000 h*ng / ml when a 100 mg dose of the solid dispersion is force-administered to a 5 to 10 kg beagle dog.

[0076] Furthermore, the present invention provides a process for preparing a solid dispersion, comprising: (a) (i) a pharmaceutically active 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, which are extruded to provide a semi-solid mixture.

[0077] [ka]

[0078] Here Q4 is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or spiroheterocyclyl.

[0079] Q5 is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or spiroheterocyclyl. R1, R2, R7, R8, R9, and R10 These are, independently, H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, OR a , SR a Alkyl-Ra, NH(CH2)pRaR 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 Here, the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl may be any one or more R d It will be replaced by this.

[0080] R a、 R b , R c , R bb , R cc , and R d These are independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or It is a heteroaryl, where the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is any one or more R e It will be replaced by this.

[0081] R e Re is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, and Re is D, alkylo, halo, halo, halo, or halocarbonyl.

[0082] Z1 is a chemical 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 It is a divalent alkenyl group or a divalent alkynyl group.

[0083] L is -L1-L2-. L1 is a chemical bond, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, where the alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl may be one or more R d It will be replaced by this.

[0084] L2 is a chemical bond, or one or more -L atoms between any two adjacent carbon atoms. i It is an alkyl group into which a hyphen is arbitrarily inserted. 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)-, -N(R a )C(O)S-, -N(R a )C(O)N(R a )-, a divalent alkenyl group, a divalent alkynyl group, a divalent cycloalkyl group, a divalent heterocycloalkyl group, a divalent aryl group, a divalent heteroaryl group.

[0085] The two R1 groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atom to which they are bonded, where the cycloalkyl or heterocycloalkyl group of R1 may optionally consist of one or more R1 groups. d It may be replaced with .

[0086] The two R2 groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atom to which they are bonded, where the cycloalkyl or heterocycloalkyl group of R2 may optionally consist of one or more R groups. d It may be replaced with .

[0087] The two R7 groups, together with the atom to which they are bonded, may optionally form seven cycloalkyl or heterocycloalkyl groups, where the cycloalkyl or heterocycloalkyl groups of R7 may optionally consist of one or more R groups. d It may be replaced with .

[0088] Two R's 10 The groups, together with the atoms to which they are bonded, may optionally form a cycloalkyl or heterocycloalkyl group, where R 10 The cycloalkyl or heterocycloalkyl in the above is optionally one or more R d It may be replaced with .

[0089] The R7 and L groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atom to which they are bonded, where the cycloalkyl or heterocycloalkyl group of R7 and L may optionally consist of one or more R groups. e It may be replaced with .

[0090] R b and R c The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R b and R c The cycloalkyl or heterocycloalkyl in the above is optionally one or more R e It may be replaced with .

[0091] Two R's d The groups, together with the atoms to which they are bonded, may optionally form a single cycloalkyl or heterocycloalkyl group, where Rd The cycloalkyl or heterocycloalkyl in the above is optionally one or more R e It may be replaced with .

[0092] Two R's e The groups, together with the atoms to which they are bonded, may optionally form a cycloalkyl or heterocycloalkyl group, where R e The cycloalkyl or heterocycloalkyl group may optionally be substituted with one or more groups selected from H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.

[0093] k, g, m, n, p, and q are each independently 0, 1, 2, 3, 4, or 5. s is either 0 or 1. And f is either 0 or 1.

[0094] (b) Extrude the semi-solid mixture. and (c) To provide a solid matrix containing a polymer carrier and a surfactant, the obtained extruded material is cooled and the compound or a salt thereof is dispersed therein in an essentially amorphous form.

[0095] In a particular embodiment, the compound is represented by formula (A-1):

[0096] [ka]

[0097] In certain embodiments, the compound is represented by formula (A-2):

[0098] [ka]

[0099] In a particular embodiment, the compound is represented by formula (A-3):

[0100] [ka]

[0101] In certain embodiments, the API, polymer carrier, surfactant, and antioxidant are mixed together before being subjected to the aforementioned heating. In certain embodiments, the API, polymer carrier, surfactant, and antioxidant are mixed together while being subjected to heating.

[0102] In certain embodiments, the raised temperature is approximately 100°C to approximately 200°C. In certain embodiments, the raised temperature is approximately 125°C to 175°C, or approximately 140°C to 160°C.

[0103] In certain embodiments, the process further includes calendering the extruded material before or during cooling. In certain embodiments, the polymer carrier contains copovidone such as KOLLIDON(R)VA64 type copovidone.

[0104] In certain embodiments, the surfactant includes a polysorbate such as TWEEN® 80 type polysorbate 80. In certain embodiments, the antioxidant includes ascorbic acid or sodium ascorbate.

[0105] Furthermore, another aspect of the present invention provides an orally administered pharmaceutical dosage form comprising the solid dispersion of the present invention as described herein. Furthermore, another aspect of the present invention provides a method for treating a neoplastic, immune, or autoimmune disease, comprising orally administering a therapeutically effective amount of the solid dispersion of the present invention to a test subject having the disease.

[0106] In certain 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, gastric cancer, gastrointestinal (stomach, colon, duodenum) cancer, chronic lymphocytic leukemia, acute lymphocytic leukemia, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, testicular cancer. Hepatocellular carcinoma (liver and / or bile duct carcinoma), primary or secondary central nervous system tumors, primary or secondary brain tumors, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, lymphoma, lymphocytic lymphoma, lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, follicular lymphoma, T-cell or B-cell derived lymphoid malignancies, melanoma, multiple myeloma, oral cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer. Prostate cancer, small cell lung cancer, kidney and / or ureteral cancer, renal cell carcinoma, renal pelvis cancer, neoplastic central nervous system cancer, primary central nervous system lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, spleen cancer, bile duct cancer, fibrosarcoma, neuroblastoma, retinoblastoma, and combinations thereof.

[0107] In certain embodiments, the neoplastic disease is chronic lymphocytic leukemia or acute lymphocytic leukemia. In certain embodiments, the neoplastic disease is non-Hodgkin lymphoma or Hodgkin lymphoma.

[0108] In certain embodiments, the disease is an immune disease or an autoimmune disease. In certain embodiments, the solid dispersion is administered at an average therapeutic interval of about 6 hours to about 7 days, with the parent compound equivalent of the compound of formula A or a salt thereof being about 10 to about 1,000 mg per day.

[0109] In a particular embodiment, the compound is selected from the group consisting of the following: (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazine-1(6H)-yl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazine-1(6H)-yl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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)piperazine-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-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)piperazine-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-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)piperazine-1-yl)-2-((5aS,8aR)-5a,6,8,8a-tetrahydrofluoro[3,4-b]pyrrolo[3',2':5,6]pyrido[3,2-e][1,4]oxazine-5(1H)-yl)benzamide, (R)-4-(4-((4'-chloro-2'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, (S)-N-((4-(((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)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (R)-N-((4-(((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)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-yl)benzamide, N-((4-((((R)-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)piperazine-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-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)piperazine-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-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)piperazine-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-yl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-yl)benzamide, (S)-N-((4-(((1,4-dioxan-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)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)-N-(((S)-5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)-N-(((R)-5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)benzamide, N-(((R)-3-((S)-1,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)benzamide, N-(((S)-3-((S)-1,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)benzamide, N-(((R)-3-((S)-1,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, N-(((S)-3-((S)-1,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide.

[0110] The above describes general embodiments of the present invention; however, the following sections will describe various embodiments of the present invention in more detail. Part A: Chemical Synthesis In one embodiment, the pharmaceutically active ingredient (or API) present in the solid dispersion is a compound of formula (A).

[0111] In alternative embodiments, the API of the solid dispersion of the present invention is one selected from the compounds specifically identified in WO / 2017 / 132474, WO / 2019 / 040550, WO / 2019 / 040573, PCT / US2019 / 047404 and PCT / US2019 / 047403, and pharmaceutically acceptable salts of such compounds, regardless of whether these compounds are individually incorporated into Formula A, and exemplary procedures relating to the compounds and their synthesis in these examples are reproduced below.

[0112] In further embodiments, the API present in the solid dispersion is selected from the compound and its pharmaceutically acceptable salts, but such examples are limited to those individually included by Formula A. The entire disclosures of WO / 2017 / 132474, WO / 2019 / 040550, WO / 2019 / 040573, PCT / US2019 / 047404 and PCT / US2019 / 047403 are expressly incorporated herein by reference. A description of the synthesis of a representative compound is given below. Other compounds of Formula A can be prepared by substantially similar methods, as will be apparent to those skilled in the art. Where NMR data is shown, 1H spectra were obtained with an XL400 (400 MHz), with proton number, multiplicity, and binding constant (Hertz) shown in parentheses, reported in downfield ppm from Me4Si. Where HPLC data is presented, the analysis was performed using an Agilent 1100 system. Where LC / MS data is presented, the analysis was performed using an Applied Biosystems API-100 mass spectrometer and a Shimadzu SCL-10ALC column.

[0113] Preparation of INT-1:1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine Synthesis of 2-bromo-4,4-dimethylcyclohexa-1-encarbaldehyde 2: A solution of anhydrous chloroform (57 mL) and anhydrous N,N-dimethylformamide (9 mL) was cooled to ~3°C (internal temperature) under nitrogen, and phosphorus tribromide (10 mL, 0.1 mol) was applied dropwise at a rate that maintained the reaction at ~3°C. After the addition was complete, the reaction was slowly heated to ~10°C, and then the temperature was raised to 70°C and maintained there for 30 minutes. The reaction mixture 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 a solution of 4 M sodium acetate (53 ml) was slowly added. The pH of the obtained solution was adjusted to ~7 using a 5M NaOH solution, and the mixture was extracted with heptane (100 mL x 3). The combined organic fraction was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-bromo-4,4-dimethylcyclohexa-1-encarbaldehyde 2 (4 g, 49%) as a yellow oil.

[0114] Synthesis of 2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-encarbaldehyde 3: At room temperature, a degassed solution of 2-bromo-4,4-dimethylcyclohexa-1-encarbaldehyde 2 (5 g, 0.023 mol) and 4-chlorophenylboronic acid (3.6 g, 0.023 mol) in 1,4-dioxane (50 mL) was mixed with 2M Na2CO3 (20.4 ml) solution. The mixture was bubbling with nitrogen for 2 minutes, and PdCl2 (dppf) (0.5 g) was added. The reaction flask was heated to 120 °C and maintained for 3 hours. After this, the suspension was cooled to room temperature and filtered through Celite. The collected solid was further washed with dichloromethane, and the combined filtrate and washings were concentrated under reduced pressure. Purification by column chromatography on silica containing PE: 2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-encarbaldehyde 3 (3g, 53%) was obtained as a white solid at EA=20:1. MS: 249[M+H] + Synthesis of (2-(4-chlorophenyl)-4,4-dimethylcyclohexo-1-enyl)methanol 4: A solution of 2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-encarbaldehyde 3 (20 g, 80.6 mmol) in MeOH (100 mL) was cooled to 0°C, and NaBH4 (3.1 g, 80.6 mmol) was added by dispensing so that the reaction mixture would be maintained at 0-5°C. After addition, the mixture was stirred at 0°C for 1 hour. Water was slowly added to the mixture, extracted with EA (200 mL x 3), the organic layer was washed with brine and dry Na2SO4, filtered, and concentrated under reduced pressure to obtain (2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methanol 4 (15 g, 75%) as a white solid. MS: 233[M+H-H2O] + .

[0115] Synthesis of 1-(2-(bromomethyl)-5,5-dimethylcyclohexa-1-enyl)-4-chlorobenzene 5: A solution of (2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methanol 4 (15 g, 0.060 mol) and Et2O (300 ml) was cooled to 0°C. After adding phosphorus tribromide (7.5 mL) dropwise to the mixture, the mixture was stirred at 0°C for 1 hour and 90 minutes. After adding H2O to the reaction mixture, it was extracted with EA. The organic layer was washed with saturated NaHCO3 solution and brine, stabilized with Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-(2-(bromomethyl)-5,5-dimethylcyclohexa-1-enyl)-4-chlorobenzene 5 (18 g, 96%) as a colorless oil.

[0116] Synthesis of tert-butyl 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazine-1-carboxylate: 1-bromo-2-(bromomethyl)-5,5-dimethylcyclohexa-1-ene 5 (21 g, 0.067 mol) and tert-butylpiperazine-1-carboxylate (12.4 g, 0.067 mol) were mixed in dichloromethane (200 ml) with TEA (12.2 g, 0.12 mol) at room temperature. The reaction mixture was stirred for 2 hours and concentrated under reduced pressure to obtain the crude product. Purification by column chromatography on silica with a PE:EA ratio of 20:1 yielded tert-butyl 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazine-1-carboxylate 6 (21 g, 75%).

[0117] Synthesis of 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazine hydrogen chloride: 30 g, 0.072 mol of tert-butyl 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazine-1-carboxylate 6 was added to a 20 ml solution of MeOH with 50 ml of concentrated HCl. The reaction mixture was stirred for 24 hours and then concentrated under reduced pressure. A saturated solution of Na2CO3 was added to adjust the pH to ~8~9, and the mixture was extracted with dichloromethane (x2). The combined extract was washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The oily substance was treated with MeOH / HCl (g) (3M, 500 mL), stirred for 1 hour, and concentrated under reduced pressure to obtain product 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazine hydrogen chloride IM-14-1 (23 g, 83%). MS: 319[M+H] +1 HNMR (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).

[0118] INT-2: Preparation of 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide In a 500 mL three-necked RB flask equipped with a mechanical stirrer, 4-chloro-3-nitrobenzenesulfonamide (23.7 g, 100 mmol), DIPEA (12.9 g, 100 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (11.5 g, 100 mmol), and acetonitrile (200 mL) were added. The reaction mixture was adjusted to an internal temperature of 80°C and stirred for at least 12 hours. The product solution was cooled to 40°C and stirred for at least 1 hour until precipitation was observed. The product slurry was further cooled to 20°C. Water (80 mL) was slowly added over at least 1 hour, the mixture was cooled to 10°C and stirred for at least 2 hours, and then collected by filtration. The wet cake was washed with a 1:1 mixture of acetonitrile and water (40 mL). The wet cake was washed with water (80 mL) at 40°C for at least 1 hour, and then collected by filtration. The wet cake was washed with water (20 mL) and dried under vacuum at 75°C to obtain 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (24.5 g, 78%) as an orange solid. 1 HNMR (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. 2Hz, 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).

[0119] INT-3: Preparation of 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide In a 50 mL round-bottom flask, (4-fluorooxan-4-yl)methanamine hydrochloride (500 mg, 2.95 mmol, 1.00 equiv), 4-fluoro-3-nitrobenzene-1-sulfonamide (650 mg, 2.95 mmol, 1.00 equiv), tetrahydrofuran (15 mL), and Cs2CO3 (2.8 g, 8.59 mmol, 3.00 equiv) 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 applied to a silica gel column of ethyl acetate / petroleum ether (4:1). This yielded 650 mg (66%) of 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide 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). Preparation of INT-4: (S)-4-((1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamide Synthesis of (R)-1-chloro-3-(2-chloroethoxy)propan-2-ol: (R)-2-(chloromethyl)oxirane (500.0 g, 5.4 mol, 1.00 equiv) was slowly added to a stirred solution of 2-chloroethanol (870.0 g, 10.8 mol, 2.00 equiv) and BF3.Et2O (38.0 g, 27 mmol, 0.05 equiv) at 45°C. 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 × 300 mL), dried on magnesium sulfate, and concentrated to obtain a light brown liquid (R)-1-chloro-3-(2-chloroethoxy)propan-2-ol (800.0 g, quantified). 1H-NMR: (300 MHz, DMSO-d 6、 ppm)δ: 3.85-3.47 (m, 9H).

[0120] Synthesis of (R)-2-((2-chloroethoxy)methyl)oxirane. (R)-1-chloro-3-(2-chloroethoxy)propan-2-ol (800.0 g, crude product, 4.7 mol, 1.0 eq) was added dropwise to a stirred solution of NaOH (465.0 g, 11.6 mol, 2.5 eq) in 500 mL of water on an ice bath. Immediately after adding (R)-1-chloro-3-(2-chloroethoxy)propan-2-ol, the ice bath was removed. 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 × 50 mL), dried over sodium sulfate, and concentrated to obtain a light brown liquid (R)-2-((2-chloroethoxy)methyl)oxirane (400.0 g). H-NMR: (300MHz, CDCL3ppm)δ: 3.82~3.52(m, 5H), 3.40~3.35(m, 1H), 3.11~3.09(m, 1H), 2.75~2.73.

[0121] Synthesis of (S)-(1,4-dioxan-2-yl)methanol. (R)-2-((2-chloroethoxy)methyl)oxirane (400.0 g, 2.94 mol, 1.0 eq) was added to a solution of NaOH (294.0 g, 7.35 mol, 2.5 eq) in 2900 mL of water at room temperature. The reaction mixture was heated in an oil bath at 90°C for 2 hours. The resulting solution was cooled to room temperature and the pH was adjusted to 5 with HCl (6 M). The mixture was concentrated, and the residue was distilled under a vacuum pump (90-95°C, 0.1 kPa) to obtain colorless oil (S)-(1,4-dioxan-2-yl)methanol (110 g, 31.7%). 1H-NMR: (300 MHz, CDCl 3 ppm) δ: 3.85~3.42 (m, 9H), 2.15 (bs, 1H).

[0122] Synthesis of (R)-(1,4-dioxan-2-yl)methanesulfonate methyl. (S)-(1,4-dioxan-2-yl)methanol (50.0 g, 0.42 mol, 1.0 eq), TEA (63.6 g, 0.63 mol, 1.5 eq), and DCM (500 mL) were mixed in an ice bath, to which MsCl (48.1 g, 0.42 mol, 1.0 eq) 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 × 50 mL), the organic phase was dried over sodium sulfate, and concentrated to obtain a light brown oily substance, (R)-(1,4-dioxan-2-yl)methylmethanesulfonate (71.0 g, 83%). H-NMR: (300MHz, CDCL3ppm)δ: 4.23~4.20(m, 2H), 3.82~3.56(m, 6H), 3.50~3.40(m, 1H), 3.02(m, 3H).

[0123] Synthesis of (S)-(1,4-dioxan-2-yl)methanamine: In a 1000 mL autoclave, (R)-(1,4-dioxan-2-yl)methylmethanesulfonate (70.0 g, 0.36 mol, 1.0 eq) in NH3 solution was stirred with MeOH (7 M, 500 mL) at 80°C for 12 hours. The reaction mixture was cooled to room temperature and concentrated to obtain a light brown oily substance, (S)-(1,4-dioxan-2-yl)methaneamine (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).

[0124] Synthesis of (S)-4-((1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamide: (S)-(1,4-dioxan-2-yl)methanamine (25.0 g, 0.21 mol, 1.0 eq), 4-fluoro-3-nitrobenzenesulfonamide (46.0 g, 0.21 mol, 1.0 eq), and Cs2CO3 (137.3 g, 0.42 mol, 2.0 eq) 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 water (3500 mL) was added. The mixture was filtered, and the collected filtrate cake was dried in an oven to obtain yellow solid (S)-4-((1,4-dioxan-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).

[0125] INT-5: Preparation of 2-bromo-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)benzoic acid: In a 250 mL round-bottom flask, the solution from Example 1-1, i.e., 1-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-yl]methyl]piperazine (15.09 g, 47.32 mmol, 1.00 equiv) was dissolved in DMA (150 mL), and DIEA (12.9 g, 99.81 mmol, 2.00 equiv) and methyl 2-bromo-4-fluorobenzoic acid (11.6 g, 49.78 mmol, 1.00 equiv) were 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 quench 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 saline solution. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (0:1~1:5). This yielded 7 g (crude product) of methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazine-1-yl)benzoic acid as a yellow oily substance. LC-MS: (ES, m / z): M+1=533, 531. INT-6: Preparation of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide Synthesis of methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)piperazine-1-yl)benzoic acid: In a 20000 mL round-bottom flask, 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)piperazine dihydrochloride (600 g, 1.53 mol, 1 equiv), 2-bromo-4-fluorobenzoic acid (357 g, 1.53 mol, 1 equiv), DBU (319 g, 6.12 mol, 4 equiv), and DMSO (8000 mL) were added. The resulting solution was stirred at 70°C for 20 hours. LC-MS showed that the materials were completely consumed. The resulting mixture was cooled to R,T and added to water (32 L). The mixture was filtered, the filter cake was collected, the filter cake was washed with water (3000 mL x 3), and dried in an oven to obtain 740 g (Y: 91%) methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazin-1-yl)benzoic acid as a white solid. ¹H-NMR-PH-PHNW-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).

[0126] Synthesis of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazin-1-yl)benzoic acid. Methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazin-1-yl)benzoic acid (730 g, 1.37 mol, 1 equiv), LiOH (131.5 g, 5.48 mol, 4 equiv), and MeOH / THF / water (4500 mL / 3000 mL / 1000 mL) were added to a 20000 mL round-bottom flask. The resulting solution was stirred at 70°C for 16 hours. LC-MS showed that the materials were completely consumed. The resulting mixture was cooled to room temperature and concentrated. The residue was diluted with water (5000 mL), the mixture was adjusted to pH 3-5 with HCl (6 M), filtered, the filter cake was collected, and dried in an oven to obtain 650 g (Y: 93%) 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazin-1-yl)benzoic acid as a white solid. ¹H-NMR-PH-PHNW-4-55-400:(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), 3.7 6(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).

[0127] Synthesis of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide: In a 20000 mL round-bottom flask, 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa- 1-Enyl)methyl)piperazin-1-yl)benzoic acid (583g, 1.13mol, 1 equiv), DCM (10L), 3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (338g, 1.07mol, 0.95 equiv), EDCI (326g, 1.7mol, 1.5 equiv), and DMAP (551g, 4.52mol, 4 equiv) were added. The resulting solution was stirred overnight at 25°C. LCMS showed that the materials were completely consumed. Dilute hydrochloric acid (1.0M) (1000mL x 3), saturated sodium bicarbonate (1000mL x 3), and saline solution (1000mL x 1) were added to the resulting mixture, the organic phase was dried over Na2SO4, and filtered. The filtrate was concentrated to obtain 857 g of product (Y: 2-bromo-4-(4-(2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide as a pale brown-yellow solid (93%). LC-MS: (ES, m / z): M+1=814 / 816 / 818, R, T=2.01 min H-NMR-PH-PHNW-4-55-400: (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, 1 H), 7.05~7.02(m, 3H), 6.86~6.83(m, 1H), 3.87~3.82(m, 2H), 3.37~3.23(m , 8H), 2.92(s, 2H), 2.50~2.38(m, 4H), 2.22~2.20(m, 2H), 2.00~1.97(m, 2 H), 1.64~1.60(m, 2H), 1.48~1.46(m, 2H), 1.26~1.20(m, 2H), 0.97(s, 6H).

[0128] Preparation of compound 2-1:4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(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 In a 250 mL round-bottom flask, DIEA (12.9 g, 99.81 mmol, 2.00 equiv) dissolved in DMA (150 mL), 2-bromo-4-fluorobenzoic acid (11.6 g, 49.78 mmol, 1.00 equiv), and 1-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine (15.09 g, 47.32 mmol, 1.00 equiv) were 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 quench 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 saline solution. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (0:1~1:5). This yielded 7 g (crude product) of methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazine-1-yl)benzoic acid as a yellow oily substance. LC-MS (ES, m / z): M+1=533, 531. In a 40 mL round-bottom flask, combine 10 mL of dioxane (4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraene (175 mg, 0.57 mmol, 1.00 equiv), Cs2CO3 (560 mg, 1.72 mmol, 3.00 equiv), and xanthophos PdG2 (CAS: 1375325-77-1) (53 mg, 0.06 mmol, 0.10 equiv) and methyl 2-bromo-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methylpiperazine-1-yl)benzoate (334.7 mg, 0.63 mmol, 1.10 equiv) were added. The resulting solution was stirred at 110 degee for 2 hours. The reaction mixture was cooled to room temperature. The solids were filtered. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:3). This yielded 200 mg (46%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatrichloro[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl)benzoic acid as a yellow oily substance. LC-MS: (ES, m / z): M+1=756, R,T=1.252 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile: Linear gradient.

[0129] In a 50 mL round-bottom flask, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-(4-[ [2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazaltricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl) benzoic acid (200 mg, 0.26 mmol, 1.00 equiv) in tetrahydrofuran (20 mL), TBAF (3 mg, 0.01 mmol), and ethane-1,2-diamine (3 mL) were added. 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 quench the reaction. The obtained solution was extracted with 2 x 30 mL of ethyl acetate, and the organic layer was combined with it. The resulting mixture was washed with 2 x 30 mL of saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column of ethyl acetate / petroleum ether (0:1~1:2). This yielded 90 mg (54%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoatemethyl as a yellow solid. LC-MS (ES, m / z): M+1=626, R,T=1.052 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile: Linear gradient.

[0130] In an 8 mL round-bottom flask, methyl 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-yl]methyl)piperazin-1-yl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid (90 mg, 0.14 mmol, 1.00 equiv), tetrahydrofuran / MeOH / H2O (2 / 2 / 2 mL), and sodium hydroxide (23 mg, 0.57 mmol, 4.00 equiv) 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 quench 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 saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column of ethyl acetate / petroleum ether (0:1~1:1). This yielded 70 mg (80%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]tridecca-1,3(7),5,8-tetraen-10-yl]benzoic acid as a yellow solid.

[0131] LC-MS (ES, m / z): M+1=612, R,T=1.005 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 microm; Eluten A: Water (0.05% TFA); Eluten B: Acetonitrile: Linear gradient.

[0132] In an 8 mL round-bottom flask, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid (35 mg, 0.06 mmol, 1.00 equiv) was dissolved in dichloromethane (5 mL), and 4-dimethylaminopyridine (27.8 mg, 0.23 mmol, 4.00 equiv), 3-nitro-4-[(oxan-4-ylmethyl)amino]benzene-1-sulfonamide (21.7 mg, 0.07 mmol, 1.20 equiv), and EDCI (22 mg, 0.11 mmol, 2.00 equiv) were added. 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-bridgeRP18, 5um, 19*100mm; Mobile phase, 0.03%NH4HCO3&NH4OH,CH3CN (32%CH3CN, 52%, 6min); Detector, UV254nm. This yielded 28.3 mg of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-N-([3-nitro-4-[(oxan-4-ylmethyl)amino]benzene]sulfonyl)-2-[13-oxa-2,4,10-triazatriclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzamide as a yellow solid. LC-MS: (ES, m / z): M+1=909, R,T=1.52 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 microm; Eluten A: Water (0.05% TFA); Eluten 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 spectra were measured using a Bruker Avance III HD 300 MHz spectroscopy system with a BBOF probe.

[0133] Preparation of compound 2-2:4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide In an 8 mL round-bottom flask, 5 mL of dichloromethane containing 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[13oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid (35 mg, 0.06 mmol, 1.00 equiv), 4-dimethylaminopyridine (27.8 mg, 0.23 mmol, 4.00 equiv), EDCI (22 mg, 0.11 mmol, 2.00 equiv), and 4-amino-3-nitrobenzene-1-sulfonamide (22.7 mg, 0.07 mmol, 1.20 equiv) were added. 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, 5um, 19*100mm; Mobile phase: 0.03% NH4HCO3 & NH4OH, CH3CN (32% CH3CN, 52% in 6 min); Detector: UV 254nm. This yielded 26.2 mg (50%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-[13oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]-2-benzamide as a yellow solid. LC-MS results (ES, m / z): M+1=927, R,T=1.27 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 microm; Elutate A: Water (0.05% TFA); Elutate 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. 0Hz, 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 spectra were measured using a BrukerAvanceIII HD300MHz with a BBOF probe head.

[0134] Preparation of Compound 2-3: 4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyro[3',2',5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl-2,2,3,3-d4)-N-((4-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Synthesis of 4-[[2-(trimethylsilyl)ethoxy]methyl](12,12-2H2)-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-11-one: 4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-11-one (90 mg, 0.28 mmol, 1 equiv), D2O (1 mL), MeOD (1 mL), and Na2CO3 (89.6 mg, 0.85 mmol, 3.00 equiv) were added to an 8 mL vial. The resulting solution was stirred in an oil bath at 60°C for 48 hours. The obtained solution was extracted with 3 x 3 mL of dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This yielded 60 mg (66%) of 4-[[2-(trimethylsilyl)ethoxy]methyl](12,12-2H2)-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-11-1 as a yellow solid. LC-MS-PH-PHNW-4-34-1: (ES, m / z): M+1=322, retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 microm; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40°C; Flow rate: 1.5 mL / min. ¹H-NMR-PH-PHNW-4-34-2: (d-DMSO, 300 ppm): 7.44~7.41 (m, 2H), 6.43~6.42 (d, J=6Hz, 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).

[0135] Synthesis of 4-[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen: 4-[[2-(trimethylsilyl)ethoxy]methyl](12,12-2H2)-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-11-one (60 mg, 0.19 mmol, 1 equiv) and THF (3 mL) were added to an 8 mL vial. LiAlD4 (31.3 mg, 0.75 mmol, 3.99 equiv) was partially added at 0°C. The resulting solution was stirred overnight at room temperature. Subsequently, 1 mL of D2O was added to quench 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. This yielded 25 mg (43.28%) of 4-[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxa-2,4,10-triazatriclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraene 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).

[0136] Methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-(4-[[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl) Synthesis of benzoic acid: In an 8 mL vial, 4-[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-traene (25 mg, 0.08 mmol, 1 equiv), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylsilyl]methyl Chlohexa-1-en-1-yl]methyl]piperazin-1-yl)benzoic acid (55.9 mg, 0.11 mmol, 1.3 equiv), dioxane (5 mL), Cs2CO3 (52.6 mg, 0.16 mmol, 2 equiv), and chloro[9,9-dimethyl-4,5-bis(diphenylphosphinoxanthene)][2-amino-1,1-biphenyl-2-yl]palladium(II) (5 mg) were added. The resulting solution was stirred in an oil bath at 100°C for 2 hours. After the reaction was complete, the crude liquid and crude product were concentrated, and the residue was applied to a silica gel column of ethyl acetate / petroleum ether (0:1~1:1). This yielded 20 mg (32.56%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[4-[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxa-2,4,10-triazatrichloro[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl)benzoic acid as a yellow solid. Retention was measured using a reversed-phase column (C18).Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0137] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid. Methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[4-[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxa2,4,10-triazatriclo[7.4.0.0^[3,7]]trideca-1(9), (20 mg, 0.03 mmol, 1 equiv), THF (2 mL), TBAF (100 mg, 0.38 mmol, 14.54 equiv), and ethane-1,2-diamine (1 mL, 0.02 mmol, 0.63 equiv) were added to an 8 mL vial. The resulting solution was stirred overnight at 70°C. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column of ethyl acetate / petroleum ether (0:1~1:1). This yielded 12 mg (72.40%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a yellow solid. LC-MS-PH-PHNW-4-34-4:(ES, m / z):M+1=630. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0138] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid: In an 8 mL vial, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa- [SA-1-EN-1-yl]methyl)piperazin-1-yl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (12 mg, 0.02 mmol, 1 equiv), MeOH (1 mL), H2O (1 mL), THF (1 mL), and NaOH (3.0 mg, 0.08 mmol, 3.94 equiv) 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 HCl (1 mol / L). The reaction mixture was concentrated under vacuum. The residue was applied to a silica gel column and eluted with PE / EA (1:0-2:3). This yielded 9 mg (76.71%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatrichloro[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a white solid. LC-MS-PH-PHNW-4-34-5:(ES, m / z):M+1=616. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0139] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(4-fluorooxane-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide: In an 8 mL vial, add 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl) Radin-1-yl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid (9 mg, 0.01 mmol, 1 equiv), 4-[[(4-fluorooxan-4-yl)methyl]amino]-4-3-nitrobenzene-1-sulfonamide (6.3 mg, 0.02 mmol, 1.3 equiv), DCM (2 mL), DMAP (7.1 mg, 0.06 mmol, 3.98 equiv), and EDCI (5.6 mg, 0.03 mmol, 2 equiv) were added. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (10:1). This yielded 6 mg (44.10%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-N--3-nitrobenzenesulfonyl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide as a yellow solid. LC-MS-PH-PHNW-4-34-0:(ES, m / z):M+1=931. Retention was measured using a reversed-phase column (C18).Shimadzu LCMS2020; 50*3.0 Kinetex 2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40°C; Flow rate: 1.5 mL / min. ¹H-NMR-PH-PHNW-4-34-0: (d-DMSO, 300 ppm): 8.57(s, 1H), 8.37(s, 1H), 7.58~7.55(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, 6) H), 3.33(m, 3H), 2.76~2.73(m, 2H), 2.26~2.20(m, 6H), 1.98(m, 2H), 1.81~1.76(m, 5H), 1.41~1.39(m, 5H), 1.39(m, 4H), 0.91~0.88(m, 6H).

[0140] Preparation of compound 2-4:4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazine-1(6H)-yl)benzamide Synthesis of tert-butyl 1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-6-yloxy)propane-2-ylcarbamate. In a 250 mL round-bottom flask, tert-butyl 1-hydroxypropane-2-ylcarbamate (2.28 g, 13.05 mmol, 1.50 equiv), DMF (30 mL), and NaH (0.87 g, 21.75 mmol, 2.50 equiv) were added and stirred at 0°C for 10 minutes. 5-bromo-6-fluoro-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (3.0 g, 8.70 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature. The obtained solution was diluted with 200 mL of H2O. The obtained solution was extracted with 3 × 300 mL of ethyl acetate, and the organic layer was combined. The obtained mixture was washed with 1 × 200 mL of H2O and 1 × 200 mL of sodium chloride (aq). The obtained mixture was concentrated under vacuum. The residue was applied to a PE / EA (5:1) silica gel column. This yielded 2.2 g (50%) of tert-butyl 1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-6-yloxy)propan-2-ylcarbamate as a yellow oily substance. LC-MS-PH-PHNW-4-35-1(ES, m / z): LC-MS(M+1): 502; RT=1.50 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elution A: Water (0.05% TFA); Elution B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (2.0 min); Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0141] Synthesis of tert-butyl 2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-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]pyridine-6-yloxy)propan-2-ylcarbamate (2.2 g, 4.39 mmol, 1.00 equiv), dioxane (25 mL), Cs2CO3 (4.30 g, 13.17 mmol, 3.00 equiv), and X-phosPd3G (1.04 g, 1.317 mmol, 0.30 equiv) were added. The obtained solution was stirred overnight at 100°C under N2. The resulting mixture was concentrated under vacuum. The residue was applied to a PE / EA (3:1) silica gel column. This yielded 1.26 g (68%) of tert-butyl 2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H))carboxylate as a yellow oily substance. LC-MS-PH-PHNW-4-35-2(ES,m / z): LC-MS(M+1): 420;RT=1.84 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6uXB-ODS, 2.6μm; Elution A: Water (0.05% TFA); Elution B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (2.6 min); Oven temperature 40℃; Flow rate: 1.0 mL / min.

[0142] Synthesis of 2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,6-tetrahydropyrrolo-[3',2':5,6]pyrido[2,3-b][1,4]oxazine: In a 250 mL round-bottom flask, tert-butyl2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)carboxylate (1.26 g, 3.00 mmol, 1.00 equiv), DCM (15 mL), and ZnBr2 (10.0 g, 30 mmol, 10.0 equiv) were added. The resulting solution was diluted with 350 mL of NaHCO3. The resulting solution was extracted with 3 x 50 mL of DCM, and the organic layers were combined. The obtained mixture was washed with 1 x 50 mL of H2O and 1 x 50 mL of sodium chloride (aq). The obtained mixture was concentrated under vacuum. The residue was applied to a PE / EA (1:1) silica gel column. This yielded 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]oxazine as a yellow oily substance. LC-MS-THN-4-35-3(ES, m / z):LC-MS(M+1): 320; RT=1.54 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6uXB-ODS, 2.6μm; Elution A: Water (0.05% TFA); Elution B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (2.6 min); Oven temperature 40℃; Flow rate: 1.0 mL / min.

[0143] Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoic acid: In a 100 mL round-bottom flask, tert-butyl1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl) (Luoxy)propane-2-ylcarbamate (300 mg, 0.94 mmol, 1.00 equiv), dioxane (15 mL), Cs2CO3 (920 mg, 2.82 mmol, 3.00 equiv), xanthophos Pd2G (83 mg, 0.094 mmol, 0.10 equiv), and methyl 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 equiv) were added. The resulting solution was stirred overnight at 110°C under N2. The resulting mixture was concentrated under vacuum. The residue was applied to a PE / EA (5:1) silica gel column. This yielded 360 mg (50%) of methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3,2,3.5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)benzoic acid as a yellow oily substance. LC-MS-PH-PHNW-4-35-4(ES, m / z): LC-MS(M+1): 770; RT=1.56 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6uXB-ODS, 2.6μm; Elution A: Water (0.05% TFA); Elution B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (2.6 min); Oven temperature 40℃; Flow rate: 1.0 mL / min.

[0144] 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-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoate: In a 100 mL round-bottom flask, tert-butylmethyl 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]oxazin-1(6H)-yl)benzoate was added. Lahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)benzoic acid (300 mg, 0.39 mmol, 1.00 equiv), THF (10 mL), TBAF (3.0 g), and ethane-1,2-diamine (5 mL) were added. The resulting solution was stirred overnight at 60°C. The resulting mixture was concentrated under vacuum. The pH of this mixture was adjusted to <7 with 2N HCl. The resulting solution was extracted with 3 x 200 mL of EA and combined with the organic layer. The resulting mixture was washed with 1 x 10 mL of H2O and 1 x 10 mL of sodium chloride (aq). The resulting mixture was concentrated under vacuum. This yielded 120 mg (48%) of methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)benzoic acid as a yellow oily substance. LC-MS-PH-PHNW-4-35-5(ES, m / z): LC-MS(M+1): 640; RT=2.82 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u HPH-C18, 2.6 micrometers; Elutate A: Water (0.05% NH4HCO3); Elutate B: Methanol; Linear gradient from 10% acetonitrile to 98% acetonitrile (3.5 min); Oven temperature 40°C; Flow rate: 0.8 mL / min.

[0145] Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)benzoic acid. Methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)benzoic acid (70 mg, 0.11 mmol, 1.00 equiv), MeOH / H2O (5 / 5 mL), and NaOH (44 mg, 1.10 mmol, 10 equiv) were added to a 50 mL round-bottom flask. The resulting solution was stirred at 60 °C for 3 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (10:1). This yielded 50 mg (73%) of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)benzoic acid as a white solid. LC-MS-PH-PHNW-4-35-6(ES, m / z): LC-MS(M+1): 626; RT=2.45 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u HPH-C18, 2.6 micrometers; Elutate A: Water (0.05% NH4HCO3); Elutate B: Methanol; Linear gradient from 10% acetonitrile to 98% acetonitrile (3.5 min); Oven temperature 40°C; Flow rate: 0.8 mL / min.

[0146] 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 l)sulfonyl)-2-(2-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide: In a 50 mL round-bottom flask with one neck, combine 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]oxazine-1(6H)-yl)benzoic acid (40 mg, 0.064 mol, 1.00 equiv), DCM (4 mL), EDCI (49 mg, 0.256 mmol, 4.00 equiv), DMAP (16 mg, 0.128 mmol, 2.00 equiv), and 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide (28 mg, 0.0832 mol, 1.30 equiv) were added. The resulting solution was stirred overnight at 40°C. The resulting mixture was concentrated under vacuum. This yielded 2 mg (70%) of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazine-1(6H)-yl)benzamide as a yellow solid. LC-MS-PH-PHNW-4-35-0A(ES,m / z): LC-MS(M+1):941;RT=5.02min. Retention was measured using a reversed-phase column (C18).Shimadzu LCMS2020; 50*3.0 Kinetex2.6u Ascentis Express C18, 2.6μm; Elutate A: Water (0.05% TFA); Elutate B: Methanol; Linear gradient from 5% acetonitrile to 95% acetonitrile (7.0 min); Oven temperature 40℃; Flow rate: 1.0 mL / min.

[0147] Compound 2-5:(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazine-1(6H)-yl)benz Preparation of amides 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)amino)-3-nitrophenyl)sulfonyl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide Synthesis of 12-methyl-4-[7.4.0.0^[3,7]]-13-oxa-2,4,10-triazatricho(I)trideca-1(9),2,5,7-tetraen-11-one: 5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-6-ol (1.5 g, 5.37 mmol, 1 equiv), DMF (50 mL), and K2CO3 (2.2 g, 16.11 mmol, 3 equiv) were added to a 100 mL round-bottom flask. 2-chloropropanoyl chloride (1.4 g, 10.74 mmol, 2 equiv) was added dropwise at 0°C while stirring. The resulting solution was stirred overnight at room temperature. Then, 50 mL of water was added to quench the reaction. The resulting solution was extracted with 2 x 50 mL of ethyl acetate. The obtained mixture was washed with 2 x 50 mL of saline solution. The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:3). This yielded 500 mg (27.93%) of 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-11-one as a yellow solid. LC-MS-PH-PHNW-4-37-1:(ES, m / z): M+1=334, R,T=1.123 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate 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, 300ppm): 8.34(s, 1H), 7.63(d, J=3Hz, 1H), 7.42~7.28(m, 1H), 6.46(d, J=3Hz, 1H), 5.68(s, 2H), 4.92~4 .85(m, 1H), 3.63~3.53(m, 2H), 1.85~1.81(d, J=12Hz, 3H), 0.94~0.89(m, 2H), -0.154(s, 9H).NMR spectra were measured using a BrukerAvanceIIIHD300MHz probe head equipped with a BBOF probe head.

[0148] 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraene& (12R or S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7] Synthesis of ]trideca-1(9),2,5,7-tetraene (assumed) and (12S or R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraene (assumed): 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-trien-1one (500 mg, 1.50 mmol, 1 equivalent) and THF (20 mL) were added to a 100 mL three-necked round-bottom flask. Next, LiAlH4 (113.8 mg, 3.00 mmol, 2 equiv) was partially added at 0°C. The resulting solution was stirred overnight at room temperature. Then, 20 mL of water was added to quench the reaction. The solid was filtered. The resulting solution was extracted with 2 x 20 mL of ethyl acetate. The resulting mixture was washed with 2 x 20 mL of saline solution. The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:3). This yielded 450 mg (93%) of 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-triene as a yellow solid.

[0149] Crude product of 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraene (450 mg) was purified by Chiral-Prep-HPLC under the following conditions: (Shimadzu LC-20AT): Column, CHIRALPAKIC; Mobile phase A: n-hexane, Mobile phase B: ethanol; Detector, 220 nm. This yielded 200 mg (44%) of (12R or S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraene as a yellow solid (assumed).

[0150] This yielded 200 mg (44%) of (12S or R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraene as a yellow solid (assumed).

[0151] LC-MS-PH-PHNW-4-37-2: (ES, m / z): M+1=320, R, T=1.107min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature: 40°C; Flow rate: 1.5 mL / min.

[0152] 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).

[0153] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12R or S)-12-methyl-4-[7.4.0.0^[3,7]]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^3,7]trideca-1(9),2,4,10-triazatricyclotrideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical): In an 8 mL vial, (12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraene (200 mg, 0.63 mmol, 1 equiv), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1 [-en-1-yl]methyl]piperazin-1-yl)benzoic acid (399.6 mg, 0.75 mmol, 1.2 equiv), Cs2CO3 (611.9 mg, 1.88 mmol, 3 equiv), dioxane (5 mL), and chloro[9,9-dimethyl-4,5-bis(diphenylphosphinoxanthene)][2-amino-1,1-biphenyl-2-yl]palladium(II) (120 mg) were added. The resulting solution was stirred in an oil bath at 110°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column of ethyl acetate / petroleum ether (0:1~1:10). This yielded 250 mg (51.83%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12R or S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,4,10-trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a yellow solid (assumed).

[0154] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12R or S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical): In a 100 mL round-bottom flask, methyl 4-(4-[[2-(4-chlorophenyl)-4 ,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[7.4.0.0^[3,7]]-13-oxa-2,4,10-triazatrichotrideca-1(9),2 (250 mg, 0.32 mmol, 1 equiv), TBAF (3 g, 11.47 mmol, 35.36 equiv), THF (30 mL), and ethane-1,2-diamine (2 g, 33.28 mmol, 102.56 equiv) 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 quench 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 saline solution. The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:3). This yielded 90 mg (43%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12R or S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a yellow solid (assumed).H-NMR-PH-PHNW-4-37-50: (CDCl3、300ppm): 8.24(s、1H),7.89~7.86(d、J=9Hz、1H),7.32~7.24(m、6H),7.14 ~7.01(m、1H),6.97~6.94(m、2H),6.73~6.65(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)。

[0155] Synthesis (hypothetical) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12R or S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid. Methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12R or S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (90 mg, 0.14 mmol, 1 equiv), MeOH (1 mL), H2O (1 mL), THF (1 mL), and NaOH (22.5 mg, 0.56 mmol, 4 equiv) were added to an 8 mL vial. The resulting solution was stirred overnight in an oil bath at 60°C. The pH of the solution was adjusted to 5 with HCl (1 mol / L). The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (1:0-10:1). This yielded 80 mg (90%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12R or S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a yellow solid (assumed). LC-MS-PH-PHNW-4-37-60: (ES, m / z): M+1=626, R,T=1.035 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0156] Synthesis (hypothetical) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(4-fluorooxane-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)-2-[(12R or S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide: In an 8 mL vial, add 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazine-1-yl) Zin-1-yl)-2-[(12R or S)-12-methyl-13-oxa-2,4,10-triazatrichyro[7.4.0.0^[3,7]]tridecca-1(9),2,5,7-tetraen-10-yl)benzoin (90 mg, 0.14 mmol, 1 equiv), 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (57.5 mg, 0.17 mmol, 1.2 equiv), DCM (5 mL), DMAP (70.2 mg, 0.57 mmol, 4 equiv), and EDCI (55.1 mg, 0.29 mmol, 2.00 equiv) were added. 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% ACN, increased to 53.0% in 7 mins, held at 95.0% in 1 min, decreased to 48.0% in 1 min, held at 1 min) for 5 minutes; Detector: UV 254 nm. This yielded 28 mg (20%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazine-1-yl)-N-(4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)-2-[(12R or S)-12-methyl-13-oxa-2,4,10-triazatriclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide (hypothetical) as a yellow solid. A 19.8mg product was submitted (hypothetically).LC-MS-PH-PHNW-4-37-0: (ES, m / z): M+1=941, R,T=3.04 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 microm; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40℃; 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, 3H),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).

[0157] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12S or R)-12-methyl-4-[7.4.0.0^[3,7]]-13-oxa-2,4,10-triazatricyclo-1(9),2,2,5,7-tetraen-10-yl]benzoic acid (hypothetical): In an 8 mL vial, add (12S or R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-traene (200 mg, 0.63 mmol, 1 equiv), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa- [1-en-1-yl]methyl)piperazin-1-yl)benzoic acid (399.6 mg, 0.75 mmol, 1.2 equiv), Cs2CO3 (611.9 mg, 1.88 mmol, 3 equiv), dioxane (5 mL), and chloro[9,9-dimethyl-4,5-bis(diphenylphosphinoxanthene)][2-amino-1,1-biphenyl-2-yl]palladium(II) (120 mg) were added. The resulting solution was stirred in an oil bath at 110°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:10). This yielded 250 mg (51%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12S or R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,2,5,7-tetraen-10-yl]benzoic acid as a yellow solid (assumed).

[0158] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12S or R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical): In a 100 mL round-bottom flask, methyl 4-(4-[[2-(4-chlorophenyl) -4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[7.4.0.0^[3,7]]-13-oxa-2,4,10-triazatrichotrideca-1(9),2 (250 mg, 0.32 mmol, 1 equiv), TBAF (3 g, 11.47 mmol, 35.36 equiv), THF (30 mL), and ethane-1,2-diamine (2 g, 33.28 mmol, 102.56 equiv) 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 quench 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 saline solution. The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:3). This yielded 90 mg (43%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12S or R)-12-methyl l-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a yellow solid (assumed).

[0159] LC-MS-PH-PHNW-4-38-50: (ES, m / z): M+1=640, R,T=1.424 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 microm; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40℃; 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=9Hz, 1H), 7.32~7.24(m, 6H), 7.14~7.01(m, 1H), 6.97~6.94(m, 2H), 6.73~6.65(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).

[0160] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12S or R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical): Methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12S or R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (90 mg, 0.14 mmol, 1 equiv), MeOH (1 mL), H2O (1 mL), THF (1 mL), and NaOH (22.5 mg, 0.56 mmol, 4.00 equiv) were added to an 8 mL vial. The resulting solution was stirred overnight in an oil bath at 60°C. The pH of the solution was adjusted to 5 with HCl (1 mol / L). The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with chloroform / methanol (1:0-10:1). This yielded 80 mg (90%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12S or R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a solid (assumed). LC-MS-PH-PHNW-4-38-60:(ES, m / z): M+1=626, R,T=1.039 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0161] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(4-fluorooxane-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)-2-[(12S or R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide (hypothetical): 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazine-1-yl)-2-[(12S or R)-12-methyl-13-oxa-2,4,10-triazatrichyro[7.4.0.0^[3,7]]tridecca-1(9),2,5,7-tetraen-10-yl]benzoic acid (90 mg, 0.14 mmol, 1 equiv), 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (57.5 mg, 0.17 mmol, 1.2 equiv), DCM (5 mL), DMAP (70.2 mg, 0.57 mmol, 4 equiv), and EDCI (55.1 mg, 0.29 mmol, 2 equiv) were added to an 8 mL vial. 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% ACN, up to 53.0% in 7 mins, retained at 95.0% in 1 min, up to 48.0% in 1 min, retained at 48.0% in 1 min), within 5 minutes; Detector, UV 254 nm. This yielded 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazine-1-yl)-N-(4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)-2-[(12S or R)-12-methyl-13-oxa-2,4,10-triazatrichlo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide as a yellow solid. 19.6 mg of the product was submitted (assumed).LC-MS-PH-PHNW-4-38-0: (ES, m / z): M+1=941, R,T=3.036 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 microm; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40℃; Flow rate: 1.5 mL / min. H-NMR-PH-PHNW-4-38-0: (d-DMSO, 300 ppm): 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, 1H), 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).

[0162] Compound 2-6:4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,3-dimethyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Synthesis of 12,12-dimethyl-4-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-11-one: In a 100 mL round-bottom flask, 5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-6-ol (1 g, 3.58 mmol, 1 equiv), CH3CN (20 mL), methyl 2-bromo-2-methylpropanoate (647.9 mg, 3.58 mmol, 1.0 equiv), and Cs2CO3 (1.7 g, 5.37 mmol, 1.5 equiv) were added. The resulting solution was stirred in an oil bath at 80°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:3). This yielded 270 mg (21%) of 12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-11-one as a pale yellow solid. LC-MS-PH-PHNW-4-40-2:(ES, m / z): M+1=348, R,T=1.164 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0163] Synthesis of 12,12-dimethyl-4--13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen: 12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-11-one (250 mg, 0.72 mmol, 1 equivalent) and THF (3 mL) were added to an 8 mL vial. Subsequently, LiAlH4 (54.6 mg, 1.44 mmol, 2 equivalents) was partially added at 0°C. The resulting solution was stirred overnight at room temperature. Then, 5 mL of water was added to quench the reaction. The solid was filtered. The resulting solution was extracted with 2 × 10 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:5). This yielded 140 mg (58%) of 12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraene as a yellow solid.

[0164] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-(12,12-dimethyl-4-[7.4.0.0^[3,7]]-13-oxa-2,4,10-triazatricyclo(I)trideca-1,3(7),5,8-tetraen-10-yl)benzoic acid: In an 8 mL vial, combine 12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7,4,0^[3,7]]trideca-1,3(7),5,8 -Tetraene (140 mg, 0.42 mmol, 1 equiv), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)benzoic acid (267.9 mg, 0.50 mmol, 1.2 equiv), Cs2CO3 (410.3 mg, 1.26 mmol, 3 equiv), dioxane (2 mL), and chloro[9,9-dimethyl-4,5-bis(diphenylphosphinoxanthene)][2-amino-1,1-biphenyl-2-yl]palladium(II) (80 mg) were added. The resulting solution was stirred in an oil bath at 110°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:3). This yielded 130 mg (39%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-(12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatrichloro[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl)benzoic acid as a yellow solid. LC-MS-PH-PHNW-4-40-4:(ES, m / z): M+1=784, R,T=1.331 min. Retention was measured using a reversed-phase column (C18).Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0165] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid: In a 40 mL vial, methyl 4-(4-[[2-(4-chlorophenyl)-4,4- Dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-(12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl)-13-oxa-2,4,10-triazatrichlo[7.4.0.0^[3,7]]trideca-1,3(7), (130 mg, 0.17 mmol, 1 equiv), TBAF (3 g), THF (10 mL), and ethane-1,2-diamine (2 g) were added. The resulting solution was stirred overnight in an oil bath at 60°C. Then, 10 mL of water was added to quench the reaction. The resulting solution was extracted with 2 × 10 mL of ethyl acetate. The resulting mixture was washed with 3 × 10 mL of saline solution. The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:3). This yielded 110 mg of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid (crude product) as a yellow solid. LC-MS-PH-PHNW-4-40-5:(ES, m / z): M+1=654, R,T=1.107 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0166] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid: In an 8 mL vial, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl) [Xa-1-en-1-yl]methyl)piperazin-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid (80 mg, 0.12 mmol, 1 equiv), MeOH (1 mL), THF (1 mL), H2O (1 mL), and NaOH (19.6 mg, 0.49 mmol, 4 equiv) 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 HCl (1 mol / L). The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (1:0-10:1). This yielded 60 mg (76.64%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]tridenca-1,3(7),5,8-tetraen-10-yl]benzoic acid as a yellow solid. LC-MS-PH-PHNW-4-40-6:(ES, m / z): M+1=640, R,T=1.359 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0167] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]-N-(4--3-nitrobenzenesulfonyl)benzamide: In an 8 mL vial, 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (37.5 mg, 0.11 mmol, 1.2 equiv), DCM (5 mL), 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid (60 mg, 0.09 mmol, 1 equiv), EDCI (35.9 mg, 0.19 mmol, 2 equiv), and DMAP (45.8 mg, 0.37 mmol, 4 equiv) were added. 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 up to 53.0% in 7 min, hold 95.0% in 1 min, down to 48.0% in 1 min with 5; Detector: UV 254 nm). This yielded 25 mg (27%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-yl]methyl)piperazin-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]-N-(4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)benzamide) as a yellow solid. 20.6 mg of the product was submitted. LC-MS-PH-PHNW-4-40-0:(ES, m / z): M+1=955, R,T=2.655 min.Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 microm; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40°C; Flow rate: 1.5 mL / min. ¹H-NMR-PH-PHNW-4-40-0:(d-DMSO, 300 ppm): 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).

[0168] Preparation of compound 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]oxazin-1(6H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-3-yl)methyl)amino)phenyl)sulfonyl)benzamide 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)methanamine (200 mg, 1.74 mmol, 1.00 equiv), THF (5 mL), 4-fluoro-3-nitrobenzene-1-sulfonamide (383 mg, 1.74 mmol, 1.00 equiv), and Cs2CO3 (1.134 g, 3.48 mmol, 2.00 equiv) were added. The resulting solution was stirred in an oil bath at 50°C for 3 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 1). This yielded 270 mg (49.3%) of 3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)benzenesulfonamide as a yellow solid. LC-MS-PH-PHNW-4-41-1: (ES, m / z): M+1=316, R,T=1.25 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-ODS, 2.6μm; Elutate A: Water (0.5% TFA); Elutate B: Acetonitrile (0.05% TFA); Linear gradient from 5% acetonitrile to 100% acetonitrile (2.6 min); Oven temperature 40℃; Flow rate: 1.0 mL / min.

[0169] Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-3-yl)methyl)amino)phenyl)sulfonyl)benzamide: In a 100 mL round-bottom flask, combine 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazine- 1-yl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid (50 mg, 0.00 equiv), EDCI in dichloromethane (5 mL) (63 mg, 0.328 mmol, 4.00 equiv), 4-dimethylaminopyridine (20 mg, 0.164 mmol, 2.00 equiv), and 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (26 mg, 0.082 mmol, 1.00 equiv) were added. 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, 5um, 19*100mm; Mobile phase: 0.03% NH4HCO3 & NH4OH, CH3CN (32% CH3CN, 52% in 6 min); Detector: UV 254nm. This purified the following compounds: 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl) methyl)piperazine-1-yl)-2-(2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)-N-((3-nitro-4-((((tetrahydro-2H-pyran-4-yl) methyl)amino)phenyl) 12.8 mg (17%) of sulfonyl 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.Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate 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) δ 12.40 (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, NMR spectra were measured using a BrukerAvanceIII HD300MHz with a BBOF probe head. (10.7Hz, 2H), 3.99-3.79(m, 3H), 3.70(s, 1H), 3.57(dd, J=18.5, 10.9Hz, 3H), 3.46-3.17(m, 7H), 2.80(s, 2H), 2.29(s, 3H), 2.21(s, 2H), 2.03(d, J=12.3Hz, 5H), 1.75-1.60(m, 4H), 1.44(d, J=8.7Hz, 3H), 1.28(s, 1H), 0.97(s, 6H), 0.87(s, 1H).

[0170] Compound 2-8:S)-4-(4-(4'-chloro-5,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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 Synthesis of 6-(tert-butoxy)-N-[2,3-b]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[pyridine-5-amine: In a 250 mL round-bottom flask, 300 mL of dioxane containing 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine (20.7 g, 60 mmol, 1.00 equiv), t-BuOK (20.5 g, 180 mmol, 3.00 equiv), xanthophos (6.9 g, 12 mmol, 0.20 equiv), Pd2(dba)3·CHCl3 (5.7 g, 0.10 equiv), and diphenylmethanimine (14.04 g, 78 mmol, 1.20 equiv) were added. The resulting solution was stirred overnight at 100°C. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:20). This yielded 15 g (crude product) of 6-(tert-butoxy)-N-(diphenylmethylidene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-5-amine as a white oil. LC-MS-PH-PHNW-4-7-9:(ES, m / z): M+1=500.

[0171] Synthesis of 5-amino-1-1H-pyrrolo[2,3-b]pyridine-6-ol hydrogen chloride: In a 500 mL round-bottom flask, 120 mL of dioxane, 15 g of 6-(tert-butoxy)-N-(diphenylmethylidene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-5-amine, and 30 mL of HCl / dioxane (4 M) were added. The resulting solution was stirred at room temperature for 5 hours. The resulting solution was diluted with 500 mL of ether. The solid was collected by filtration. This yielded 5 g (crude product) of 5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-6-ol hydrogen chloride as a red solid. Q-NMR indicated the possibility of conversion to three types of hydrogen chloride salts. LC-MS-PH-PHNW-4-10-1:(ES, m / z): M+1=280, R,T=0.811 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 microm; Eluten A: Water (0.05% TFA); Eluten B: Acetonitrile; Linear gradient: Synthesis of 12-methyl-4-[7.4.0.0^[3,7]]-13-oxa-2,4,10-triazatricho(I)trideca-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]pyridine-6-ol (1.5 g, 5.37 mmol, 1 equiv), DMF (50 mL), and K2CO3 (2.2 g, 16.11 mmol, 3 equiv) were added. 2-chloropropanoyl chloride (1.4 g, 10.74 mmol, 2 equiv) was added dropwise at 0°C while stirring. The resulting solution was stirred overnight at room temperature. Then, 50 mL of water was added to quench the reaction. The resulting solution was extracted with 2 x 50 mL of ethyl acetate. The obtained mixture was washed with 2 x 50 mL of saline solution. The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:3). This yielded 500 mg (27.93%) of 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-11-one as a yellow solid. LC-MS-PH-PHNW-4-37-1: (ES, m / z): M+1=334, R,T=1.123 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate 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, 300ppm): 8.34(s, 1H), 7.63(d, J=3Hz, 1H), 7.42~7.28(m, 1H), 6.46(d, J=3Hz, 1H), 5.68(s, 2H), 4.92~4 .85(m, 1H), 3.63~3.53(m, 2H), 1.85~1.81(d, J=12Hz, 3H), 0.94~0.89(m, 2H), -0.154(s, 9H).

[0172] 12-methyl-4--13-oxa-2,4,10-triazatricyclotrideca-1 (9),2,5,7-tetraene& (12 S)-12-methyl-4-[7.4.0.0^[3,7]]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1 (9),2,5,7-tetraene& (12 R)-12-methyl-4--13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1 (9),2,5, Synthesis of 7-tetraene: In a 100 mL three-necked round-bottom flask, 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-trien-1one (500 mg, 1.50 mmol, 1 equivalent) and THF (20 mL) were added. Subsequently, LiAlH4 (113.8 mg, 3.00 mmol, 2 equivalents) was partially added at 0°C. The resulting solution was stirred overnight at room temperature. Then, 20 mL of water was added to quench the reaction. The solid was filtered. The resulting solution was extracted with 2 x 20 mL of ethyl acetate. The resulting mixture was washed with 2 x 20 mL of saline solution. The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:3). This yielded 450 mg (93%) of 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-triene as a yellow solid.

[0173] The crude product of 12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraene (450 mg) was purified by Chiral-Prep-HPLC under the following conditions: (Shimadzu LC-20AT): Column, CHIRALPAKIC; Mobile phase A: n-hexane, Mobile phase B: ethanol; Detector, 220 nm. This yielded 200 mg (44%) of (12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraene as a yellow solid.

[0174] This yielded 200 mg (44%) of (12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraene as a yellow solid. LC-MS-PH-PHNW-4-37-2:(ES, m / z): M+1=320, R, T=1.107 min.

[0175] Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate 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).

[0176] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12S)-12-methyl-4-[7.4.0.0^[3,7]]-13-oxa-2,4,10-triazatricyclotrideca-1(9),2,4,10-triazatricyclo[7.4.0.0^3,7]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid: In an 8 mL vial, (12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^ [3,7]]trideca-1(9),2,5,7-tetraen (200 mg, 0.63 mmol, 1 equiv), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)benzoic acid (399.6 mg, 0.75 mmol, 1.2 equiv), Cs2CO3 (611.9 mg, 1.88 mmol, 3 equiv), dioxane (5 mL), and chloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-biphenyl-2-yl]palladium(II) (120 mg) were added. The resulting solution was stirred in an oil bath at 110°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:10). This yielded 250 mg (51.83%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,4,10-triazatricyclo[7.4.0.0^3,7]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a yellow solid.

[0177] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid. Methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazaltricyclo[7.4.0.0^[3,7]]trideca-1(9),2 (250 mg, 0.32 mmol, 1 equiv), TBAF (3 g, 11.47 mmol, 35.36 equiv), THF (30 mL), and ethane-1,2-diamine (2 g, 33.28 mmol, 102.56 equiv) were added to a 100 mL round-bottom flask. The resulting solution was stirred in an oil bath at 70°C for 12 hours. Then, 50 mL of water was added to quench the reaction. The obtained solution was extracted with 2 x 50 mL of ethyl acetate. The resulting mixture was washed with 3 x 50 mL of saline solution. The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:3). This yielded 90 mg (43%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]tridecca-1(9),2,5,7-tetraen-10-yl]benzoatemethyl as a yellow solid.H-NMR-PH-PHNW-4-37-50: (CDCl3、300ppm): 8.24(s、1H),7.89~7.86(d、J=9Hz、1H),7.32~7.24(m、6H),7.14 ~7.01(m、1H),6.97~6.94(m、2H),6.73~6.65(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)。

[0178] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid. Methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (90 mg, 0.14 mmol, 1 equiv), MeOH (1 mL), H2O (1 mL), THF (1 mL), and NaOH (22.5 mg, 0.56 mmol, 4 equiv) were added to an 8 mL vial. The resulting solution was stirred overnight in an oil bath at 60°C. The pH of the solution was adjusted to 5 with HCl (1 mol / L). The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (1:0-10:1). This yielded 80 mg (90%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a yellow solid. LC-MS: (ES, m / z): M+1=626, R,T=1.035 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile (3.5 min); Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0179] 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]oxazin-1(6H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide. In an 8 mL vial, add 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12R or S)-12-methyl-13-oxa-2,4,10-triazatrichyro[7.4.0.0^[3,7]]tridecca-1(9),2,5,7-tetraen-10-yl)benzoin (90 mg (0.14 mmol, 1 equiv), 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (57.5 mg, 0.17 mmol, 1.2 equiv), DCM (5 mL), DMAP (70.2 mg, 0.57 mmol, 4 equiv), and EDCI (55.1 mg, 0.29 mmol, 2.00 equiv) were added. 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% ACN, increased to 53.0% in 7 mins, held at 95.0% in 1 min, decreased to 48.0% in 1 min, held at 1 min) for 5 minutes; Detector: UV 254 nm. This yielded 22 mg (20%) 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]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamidite. LC-MS (ES, m / z): M+1=923, R,T=2.653 min. Retention was measured using a reversed-phase column (C18).Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elutate A: Water (0.05% TFA); Elutate 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).

[0180] Preparation of compound 2-9:(R)-4-(4-(4'-chloro-5,5,6-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 Synthesis of N-[(2R)-2-hydroxypropyl]-4-methylbenzene-1-sulfonamide: In a 250 mL round-bottom flask, (2R)-1-aminopropan-2-ol (5 g, 1 equiv), DCM (70 mL), and TsCl (12.67 g, 1 equiv) were added. Subsequently, TEA (7.41 g, 1.1 equiv) was added at 0°C. The resulting solution was stirred at 0°C for 3 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 1). This yielded 8 g of N-(2R)-2-hydroxypropyl]-4-methylbenzene-1-sulfonamide as a white solid. 1H NMR ((300 MHz, DMSO-d6, ppm): δ 7.74-7.63 (m, 2H), 7.52-7.34 (m, 3H), 4.66 (d, J = 4.7 Hz, 1H), 3.58 (qd, J = 6.3, 4.8 Hz, 1H), 2.73-2.50 (m, 2H), 2.39 (s, 3H), 0.99 (d, J = 6.2 Hz, 3H).

[0181] Synthesis of 2-bromo-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazine-1-yl)benzoic acid. In a 250 mL round-bottom flask, DIEA (12.9 g, 99.81 mmol, 2.00 equiv) dissolved in DMA (150 mL), 2-bromo-4-fluorobenzoic acid (11.6 g, 49.78 mmol, 1.00 equiv), and 1-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine (15.09 g, 47.32 mmol, 1.00 equiv) were 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 quench the reaction. The obtained solution was extracted with 3 x 100 mL of ethyl acetate, and the organic layer was combined with it. The resulting mixture was washed with 3 x 100 mL of saline solution. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:5). This yielded 7 g (crude product) of methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazine-1-yl)benzoic acid as a yellow oil. LC-MS: (ES, m / z): M+1=533, 531. Synthesis of N-[(2R)-2-[(5-bromo-1-[2,3-b]-1H-pyrrolo-pyridine-6-yl)oxy]propyl]-4-methylbenzene-1-sulfonamide: N-[(2R)-2-hydroxypropyl]-4-methylbenzene-1-sulfonamide (1 g, 1.5 equiv) and DMF (3 mL) were added to a 100 mL round-bottom flask. NaH (0.35 g, 3 equiv) was added at 0°C for 10 minutes. 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine (1 g, 1 equiv) was added at 0°C. The resulting solution was stirred at room temperature for 4 hours. Then, 20 mL of water was added to quench the reaction. The resulting solution was extracted with 3 x 50 mL of ethyl acetate, the organic layers were combined, and the mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 3). This yielded 400 mg of N-[(2R)-2-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-6-yl)oxy]propyl]-4-methylbenzene-1-sulfonamide as a yellow solid. 1 H-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).

[0182] Synthesis of (12R)-12-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraene: N-[(2R)-2-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-6-yl)oxy]propyl]-4-methylbenzene-1-sulfonamide (3.9 g, 1 equiv), dioxane (50 mL), t-BuXPhos3G (560 mg, 0.1 equiv), and Cs2O3 (6.9 g, 3 equiv) were added to a 100 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 90°C for 4 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 3). This yielded 3.3 g of (12R)-12-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-traene as a colorless oil. 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.

[0183] Synthesis of (12R)-12-methyl-4--13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraene: Na (1.31 g, 9.4 equiv) and naphthalene (0.76 g, 6 equiv) were added to a 100 mL three-necked round-bottom flask. DME (15 mL) was then added at room temperature over 30 minutes. To this, a solution of (12R)-12-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazaltricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraene (2.8g, 1 equiv) in THF (15mL) at -78°C was added. The resulting solution was stirred at room temperature for 3 hours. Then, 30mL of NH4Cl was added to quench the reaction. The resulting solution was extracted with 3 x 100mL of ethyl acetate, and the organic layers were combined and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 3). This yielded 1.4 g of (12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraene as a colorless oil. LC-MS (ES, m / z): 320[M+1] + RT=1.61min. Methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazaltricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl] Synthesis of benzoic acid: (12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-traene (1.178 G, 1 equiv), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-yl]methyl]piperazin-1-yl)benzoic acid (2.35 g, 1.2 equiv), dioxane (15 mg, 15 equiv), Cs2CO3 (3.62 g, 3 equiv), and xanthophos (328 mg, 0.1 equiv) were added to a 250 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 3). This yielded 3.2 g of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatrichloro[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a yellow solid. LC-MS (ES, m / z): 770[M+1] + RT=1.33min. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid: In a 250 mL round-bottom flask, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12R)-12-methyl-4-[ [2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7] [Trideca-1 (9),2,5,7-tetraen-10-yl] Benzoic acid (3.2g, 1 equiv), THF (50mL), TBAF (20g), and ethane-1,2-diamine (33g) were added. The resulting solution was stirred at 70°C for 5 hours. Then, 50mL of water was added to quench the reaction. The resulting solution was extracted with 3 x 100mL of ethyl acetate, and the organic layers were combined and concentrated. The residue was applied to a silica gel column with dichloromethane / methanol (10 / 1). This yielded 2.2 g of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]tridenca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a yellow solid. LC-MS-(ES,m / z): 640[M+1] + RT=2.51 min. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid: In a 250 mL round-bottom flask, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-yl]methyl)piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (2.2 g, 1 equiv) and MEOH / H2O / THF (10 mL / 10 mL / 10 mL) were added. The resulting solution was stirred at 60°C for 5 hours. The resulting mixture was concentrated. The resulting solution was extracted with 3 x 100 mL of dichloromethane, and the organic layers were combined and concentrated. The residue was applied to a silica gel column with dichloromethane / methanol (10 / 1). This yielded 1.6 g of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazine-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]tridenca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a yellow oil. LC-MS (ES, m / z): 626[M+1] + RT=2.47 min. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]-N-(3-nitro-4-benzenesulfonyl)benzamide: In a 250 mL round-bottom flask, combine 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1 (-yl)methyl)piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (1.6 g, 1 equiv), DCM (20 mL), 3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (890 mg, 1.2 equiv), DMAP (1.25 g, 4 equiv), and EDCI (980 mg, 2 equiv) were added. The resulting solution was stirred at room temperature for 14 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column with EA / DCM (1 / 10). This yielded 0.82 g of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-yl]methyl)piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)benzamide as a yellow solid. LC-MS (ES, m / z): 923 [M+1] + RT = 3.50 min. 1H NMR (300 MHz, CDCl3, ppm): δ 12.48 (s, 1H), 8.62 (d, J = 2.4 Hz, 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 = 2.9 Hz, 1H), 6.97-6.77 (m, 3H), 6.76-6.60 (m, 2H), 6.52 (s, 1H), 6.09 (d, J= 3.0 Hz, 1H), 4.88 (d, J = 7.7 Hz, 1H), 4.02 (dd, J = 11.8, 4.2 Hz, 2H), 3.55-3.34 (m, 4H), 3.32-3.14 (m, 5H), 3.08 (s, 1H), 2.77 (d, J = 9.6 Hz, 2H), 2.28 (s, 3H), 2.19 (s, 2H), 1.99 (d, J = 7.6 Hz, 4H), 1.72 (d, J = 12.7 Hz, 2H), 1.45 (ddd, J = 24.5, 12.3, 5.8 Hz, 6H), 0.94 (d, J = 2.1 Hz, 6H).

[0184] Preparation of compound 2-10:4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[13thia-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide In a 250 mL round-bottom flask, cysteamine hydrochloride (5.00 g, 44.014 mmol, 1.00 equiv), DCM (100.00 mL), TEA (13.36 g, 0.132 mmol, 3 equiv), and acetic anhydride (4.94 g, 0.048 mmol, 1.1 equiv) were added. The resulting solution was stirred overnight at room temperature. Then, 100 mL of water was added to quench the reaction. The resulting solution was extracted with 3 x 50 mL of ethyl acetate and dried over anhydrous sodium sulfate. The resulting solution was concentrated under vacuum. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (7:1). This yielded 7.2 g (crude product) of 2-acetamidoethanethiol as a pale yellow oily substance. 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).

[0185] In a 100 mL round-bottom flask, 2-acetamidoethanethiol (1.19 g, 9.985 mmol, 1.00 equiv), 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 equiv), and Cs2CO3 (9.76 g, 0.030 mmol, 3 equiv) 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 in a water / ice bath. Then, 50 mL of water was added to quench the reaction. The resulting solution was extracted with 3 x 50 mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated. This yielded 2 g (45.07%) of N-[2-[(5-bromo-1-[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridine-6-yl)sulfanyl]ethyl]acetamide as a yellow oily substance. LCMS-PH-PHNW-4-121-2 (ES, m / z):M+1:444 / 446. In a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, N-[2-[(5-bromo-1-[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridine-6-yl)sulfanyl]ethyl]acetamide (2.00 g, 0.004 mmol, 1.00 equiv), DMF (30 ml), Cs2CO3 (4.40 g, 0.013 mmol, 3 equiv), and BrettPhos Pd G3 pre-catalyst (0.61 mg, 0.001 mmol, 0.15 equiv) were added. The resulting solution was stirred overnight in an oil bath at 100°C. After cooling the reaction mixture to room temperature, 30 mL of water was added and the mixture was rapidly cooled. The resulting solution was extracted with 3 x 50 mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (5:2). The collected fractions were combined and concentrated. This yielded 670 mg (40.96%) of 1-(4-[[2-(trimethylsilyl)ethoxy]methyl)-13-thia-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-trien-10-yl)ethanone as a yellow oil. LCMS-PH-PHNW-4-121-3 (ES, m / z):M+1:364. 1-(4-[[2-(trimethylsilyl)ethoxy]methyl)-13-thia-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl)ethanone (600.00 mg, 1.650 mmol, 1.00 equiv), MeOH (10.00 mL), and NaOH (4M) (10.00 mL) were added to a 40 mL vial. The resulting solution was stirred overnight in an oil bath at 80°C. The resulting mixture was concentrated. The resulting solution was extracted with 3 x 30 L of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (3:1). The collected fractions were combined and concentrated. This yielded 410 mg (77.27%) of 4-[[2-(trimethylsilyl)ethoxy]methyl]-13-thia-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraene as a yellow oil. LC-MS-PH-PHNW-4-121-4:(ES, m / z): M+1:322.

[0186] In a 100 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, 4-[[2-(trimethylsilyl)ethoxy]methyl]-13-thia-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-triene (200.00 mg, 0.622 mmol, 1.00 equiv), 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1- (Iyl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)benzamide (1016.69 mg, 1.244 mmol, 2 equiv), DMF (20.00 mL), Cs2CO3 (608.04 mg, 1.866 mmol, 3 equiv), CuI (47.39 mg, 0.249 mmol, 0.4 equiv), and 1,10-phenanthroline (22.42 mg, 0.124 mmol, 0.2 equiv) were added. The resulting solution was stirred in an oil bath at 95°C for 4 hours. Then, 30 mL of water was added to quench the reaction. The solid was filtered off. The resulting solution was extracted with 3 x 20 mL of ethyl acetate concentrate. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (2:1). The collected fractions were combined and concentrated. This yielded 300 mg (45.59%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-13-thia-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl)benzamide as a yellow oil. LC-MS-PH-PHNW-4-121-5:(ES, m / z): M+1:1057.

[0187] In a 100 mL round-bottom flask, add 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino)-3-nitrobenzenesulfonyl)-2-(4-[[(2-methylsilyl)ethoxy]methyl]-13-thia-2,4,10-triazaltricyclo[7.4.0.0^[3,7] Trideca-1(9),2,5,7-tetraen-10-yl)benzamide (300.00 mg, 0.284 mmol, 1.00 equiv), THF (20.00 mL, 0.0284 mmol, 277 mmol, 0.98 equiv), TBAF (741.53 mg, 2.836 mmol, 10.00 equiv), and ethane-1,2-diamine (170.44 mg, 2.836 mmol, 10 equiv) were added. 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 XBridgePrepC18OBD19*150mm5um; Mobile phase, A: 0.1% HCl aqueous solution; B: ACN; Gradient: 24-95% B over 7.9 mins; Flow rate: 20 ml / min; Detector, 220 nm. This yielded 50 mg (18.29%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazine-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino)-3-nitrobenzenesulfonyl)-2-[13-thia-2,4,10-triazatriclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide hydrochloride as a yellow solid. LC-MS-PH-PHNW-4-121-0:(ES, m / z): M+1-HCl: 963.H-NMR-PH-PHNW-4-121-0: 1 H 1HNMR (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).

[0188] Preparation of compound 2-11:4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)benzamide In a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, 2-bromo-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)benzamide (1568.13 mg, 1.924 mmol, 1.30 equiv), 3,4-dihydro-2H-1,4-benzoxazine (200 mg, 1.480 mmol, 1.00 equiv), DMF (20.00 mL), CS2CO3 (1.45 g, 4.450 mmol, 3.01 equiv), CuI (112.00 mg, 0.588 mmol, 0.40 equiv) and 1,10-phenanthroline (53.30 mg, 0.296 mmol, 0.20 equiv) were added. The resulting solution was stirred in an oil bath at 90°C for 5 hours. The solid was filtered off. The resulting solution was extracted with 3 x 40 mL of ethyl acetate concentrate. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (5:1). The collected fractions were combined and concentrated. This yielded 100 mg (7.77%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-1,4-benzoxazine-4-yl)-N-(3-nitro-4-[(oxan-4-yl)methyl]amino]benzenesulfonyl)benzamide as a yellow solid. LC-MS-PH-PHNW-4-101-0:(ES, m / z): M+1: 869.H-NMR-PH-PHNW-4-101-0: 1HNMR (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).

[0189] Preparation of compound 2-12.4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-benzenesulfonyl]-2-[2H,3H-pyrido[4,3-b][1,4]oxazin-4-yl]benzamide In an 8 mL vial purged and maintained under an inert nitrogen atmosphere, 2-bromo-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-N-[3-nitro-4-[(oxan-4-ylmethyl)amino]benzenesulfonyl]benzamide (233.51 mg, 0.286 mmol, 1.30 equiv), DMF (4.00 mL), 2H,3H,4H-pyrido[4,3-b][1,4]oxazine (30.00 mg, 0.220 mmol, 1.00 equiv), 1,10-phenanthroline (7.94 mg, 0.044 mmol, 0.2 equiv), CuI (16.79 mg, 0.088 mmol, 0.4 equiv) and Cs2CO3 (215.37 mg, 0.661 mmol, 3 equiv) were added. The resulting solution was stirred in an oil bath at 95°C for 3 hours. The solids were filtered off. The resulting solution was quenched with 10 mL of water and extracted with 3 x 10 mL of ethyl acetate concentrate. The crude product was purified by Prep-HPLC under the following conditions (2#SHIMADZU(HPLC-01)): Column, SunFirePrepC18OBD column, 19*150 mm 5 μm 10 nm; mobile phase, water (0.1% HCl) and ACN (20% Phase B to 40% in 8 minutes); detector, UV=254 nm. This yielded 8 mg (4.17%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-[3-nitro-4-[(oxan-4-ylmethyl)amino]benzenesulfonyl]-2-[2H,3H-pyrido[4,3-b][1,4]oxazine-4-yl]benzamide as a yellow solid hydrochloride. LC-MS-PH-PHNW-4-104-0:(ES, m / z): M+1-HCl: 870.H-NMR-PH-PHNW-4-104-0: 1HNMR (300MHz, DMSO-d6) δ12.30 (s, 1H), δ10.37 (s, 1H), 8.64 (d, J=6.3 Hz, 1H), 8.43 (d, J=2.4 Hz, 1H), 7.88 (d, J=6.3 Hz, 1H), 7.80-7.65 (m, 1H), 7.54 (d, J=9.3 Hz, 1H), 7.42 (d, J=8.1 Hz, 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, 4.2 Hz, 4H), 3.66-3.56 (m, 4H), 3.29 (d, J=12.0 Hz, 6H), 2.76 (d, J=16.8 Hz, 2H), 2.42-2.24 (m, 4H), 2.06 (s, 2H), 1.95 (s, 1H), 1.66 (d, J=13.2 Hz, 2H), 1.49 (d, J=6.6 Hz, 2H), 1.40-1.21 (m, 2H), 0.97 (s, 6H).

[0190] Compound 2-13:4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)-N-(((S)-5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)benzamide and 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1, Preparation of 1'-biphenyl]-2-yl)methyl)piperazine-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 Synthesis of 3-bromo-4-chloro-5-nitrobenzenesulfonamide. 4-chloro-3-nitrobenzenesulfonamide (20.00 g, 84.520 mmol, 1.00 equiv) and H2SO4 (20.00 mL) were added to a 50 mL round-bottom flask. Next, NBS (22.56 g, 126.753 mmol, 1.50 equiv) was added in divided portions at 50°C. The resulting solution was stirred at 60°C for 2 hours, and the solution was diluted with 200 mL of cold H2O. The resulting solution was extracted with 3 × 30 mL of ethyl acetate. The resulting mixture was washed with 1 × 20 mL of H2O. The resulting mixture was washed with 1 × 20 mL of NaCl (aq.). The residue was applied to a silica gel column containing ethyl acetate and eluted with ethyl acetate / petroleum ether (1:3). This yielded 5 g (18.75%) of 3-bromo-4-chloro-5-nitrobenzenesulfonamide as a white solid. LC-MS-1:(ES, m / z): 312.9 [MH] Synthesis of 2-amino-2-(oxan-4-yl)ethanol: In a 100 mL round-bottom flask, amino(oxan-4-yl)acetic acid (4.00 g, 25.128 mmol, 1.00 equiv), THF (50.00 mL), and LiAlH4 (1.91 g, 50.324 mmol, 2.00 equiv) were added. The resulting solution was stirred in an oil bath at 60°C for 3 hours. Then, 10 mL of water was added to quench the reaction. The resulting mixture was concentrated. This yielded 6 g (crude) of 2-amino-2-(oxan-4-yl)ethanol as a white solid. LC-MS-21: (ES, m / z): 146.2 [M+H] + Synthesis of 3-bromo-4-[[2-hydroxy-1-(oxan-4-yl)ethyl]amino]-5-nitrobenzenesulfonamide: In a 100 mL round-bottom flask, 3-bromo-4-chloro-5-nitrobenzenesulfonamide (5.00 g, 15.847 mmol, 1.00 equiv), 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 equiv) were added. The resulting solution was stirred in an oil bath at 80°C for 48 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10:1). This yielded 1.2 g (17.85%) of 3-bromo-4-[[2-hydroxy-1-(oxan-4-yl)ethyl]amino]-5-nitrobenzenesulfonamide as a yellow solid. LC-MS-2:(ES, m / z): 424.1 [M+H] + .

[0191] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12 R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazaltricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid. In a 50 mL round-bottom flask, (12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen(500.00 mg, 1.565 mmol, 1.00 equiv), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)benzoic acid(832.48 mg, 1.565 mmol, 1.00 equiv), xanthophos Pd 2 G (138.82 (mg, 0.157 mmol, 0.10 equiv), Cs2CO3 (1529.77 mg, 4.695 mmol, 3.00 equiv), and dioxane (10.00 mL) were added. The resulting solution was stirred at 80°C for 14 hours, and the resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:3). This yielded 611 mg (50.67%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatrichloro[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a yellow solid. LC-MS-11:(ES, m / z):770.4 [M+H] + . Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid. Methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatriclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (300.00 mg, 0.389 mmol), ethane-1,2-diamine (0.20 mL), and TBAF in THF (1 ml, 2 M) were added to an 8 mL vial. The resulting solution was stirred in an oil bath at 70°C for 24 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1). This yielded 100 mg (40.12%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a white solid. LC-MS-11:(ES, m / z):640.3 [M+H] + . Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid. Methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12 R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (100.00 mg, 0.156 mmol, 1.00 equiv), NaOH (37.49 mg, 0.937 mmol, 6.00 equiv), MeOH (0.50 mL), dioxane (0.50 mL), and H2O (0.20 mL) were added to an 8 mL vial. The resulting solution was stirred in an oil bath and incubated at 70°C for 14 hours. The resulting mixture was concentrated. The obtained solution was diluted with 1 mL of H2O. The pH of the solution was adjusted to 6 with CH3COOH. The obtained mixture was concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10:1). This yielded 60 mg of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a brown solid. LC-MS-13:(ES, m / z):626.3 [M+H] + . Synthesis of 5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide. In a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, 3-bromo-4-[[2-hydroxy-1-(oxan-4-yl)ethyl]amino]-5-nitrobenzenesulfonamide (1.40 g, 3.300 mmol, 1.00 equiv), dioxane (20.00 mL), Pd2(dba)3 (604.34 mg, 0.660 mmol, 0.20 equiv), xanthophos (763.73 mg, 1.320 mmol, 0.40 equiv), and Cs2CO3 (3.23 g, 9.913 mmol, 3.00 equiv) were added. The resulting solution was stirred in an oil bath at 100°C for 2 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:1). This yielded 230 mg (20.30%) of 5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide as a yellow solid. LC-MS-3:(ES, m / z):342.1 [MH] - Synthesis of (3 S)-5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide and (3 R)-5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide. 5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide (150.00 mg) and DMF (10 ml) were added to a 50 mL round-bottom flask. This sample was purified by Chiral-Prep-HPLC under the following conditions (WATERS 2767): Column, CHIRALPAK IA, 250*20 mm, 5 μm; Mobile phase: A: o-hexane:DMC=3:1, 0.1% DEA), B: EtOH; Gradient: 10% B over 20 mins; Detector, 220 nm. This yielded 30 mg of (3S)-5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide as a yellow solid. This yielded 32 mg of (3R)-5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide as a yellow solid.

[0192] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12 R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]-N-[(3S)-5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-ylsulfonyl]benzamide hydrochloride: In an 8 mL vial, (3 S)-5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide(20 36.48 mg, 0.058 mmol, 1.00 equiv) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12 R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (36.48 mg, 0.058 mmol, 1.00 equiv), DCM (0.5 mL), EDC.HCl (22.33 mg, 0.116 mmol, 2.00 equiv), and DMAP (17.79 mg, 0.146 mmol, 2.50 equiv) were added. The resulting solution was stirred at room temperature for 14 hours. The resulting mixture was concentrated. The residue was purified by Prep-TLC with 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 um; Mobile phase, A: 0.1% HCl aqueous solution; B: ACN; Gradient: 38-58% B over 7 min; Flow rate: 20 ml / min; Detector, 220 nm.This yielded 10 mg (17.38%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12 R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]-N-[(3 S)-5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-ylsulfonyl]benzamide hydrochloride as a yellow solid. LC-MS-0 A:(ES, m / z): 951.4 [M-HCl+H]. +\ . 1 H NMR-0 A (300 MHz, DMSO, ppm): δ12.15 (s, 1 H), 10.86 (s, 1 H), 9.68 (s, 1 H), 8.78 (s, 1 H), 8.05-7.81 (m, 1 H), 7.58-7.31 (m, 1 H), 7.21-6.72 (m, 6 H), 6.70-6.40(m, 1 H), 6.02-5.81(m, 1 H), 4.61-4.11(m, 3 H), 3.92-3.78(m, 4 H), 3.65-3.61(m, 2 H), 3.38-3.13(m, 8 H), 2.90-2.72(m, 2 H), 2.30-2.21(m, 2 H), 2.13-1.94(m, 2 H), 1.92-1.51(m, 3 H), 1.51-1.23(m, 8 H), 0.96 (s, 6 H).

[0193] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4-methylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12 R)-12methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]-N-[(3 R)-5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-ylsulfonyl]benzamide hydrochloride. In an 8 mL vial, (3 R)-5-nitro-3-(oxan-4-yl)-3,4-dihydro-2 H-1,4-benzoxazine-7-sulfonamide (20.00 mg, 0.058 mmol, 1.00 equiv), 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12 R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (36.48 mg, 0.058 mmol, 1.00 equiv), DCM, EDCI (22.33 (mg, 0.116 mmol, 2.00 equiv) and DMAP (17.79 mg, 0.146 mmol, 2.50 equiv) were added. 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, XBridge Prep C18 OBD 19*150 mm 5 um; Mobile phase, A: 0.1% HCl aqueous solution; B: ACN; Gradient: 38-58% B over 7 minutes; Flow rate: 20 ml / min; Detector, 220 nm.This yielded 10.3 mg (18.16%) of 4-[(12 R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1 (9),2,5,7-tetraen-10-yl]-2-[(3 R)-5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-1,4-benzoxazine-7-ylsulfonyl]benzamide hydrochloride as a yellow solid. LC-MS-0B:(ES, m / z): 951.4 [M-HCl+H]. +.1 H NMR-0 B (300 MHz, DMSO, ppm): δ12.16 (s, 1 H), 10.89 (s, 1 H), 10.02 (s, 1 H), 8.78 (s, 1 H), 8.05-7.41 (m, 5 H), 7.21-6.52 (m, 6 H), 6.02-5.91 (m, 1 H), 4.61-4.21(m, 2 H), 4.15-3.78(m, 5 H), 3.71-3.65(m, 2 H), 3.38-3.13(m, 8 H), 2.88-2.72(m, 2 H), 2.35-2.30(m, 2 H), 2.13-1.94(m, 2 H), 1.92-1.59(m, 3 H), 1.51-1.23 (m, 8 H), 0.96 (s, 6 H).

[0194] Compounds 2-14: 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-[(3 S)-3-[(2 S)-1,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2 H-1,4-benzoxazine-7-ylsulfonyl]-2-[(12 R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide hydrochloride and 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-[(3 R) Preparation of -3-[(2 S)-1,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2 H-1,4-benzoxazine-7-ylsulfonyl]-2-[(12 R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide hydrochloride Synthesis of (2R)-1,4-dioxane-2-carbaldehyde: (2S)-1,4-dioxane-2-ylmethanol (2.36 g, 19.978 mmol, 1.00 equiv), CH3CN (50.00 mL, 1.218 mmol, 0.0 equiv), and IBX (9.51 g, 33.962 mmol, 1.70 equiv) were added to a 100 mL round-bottom flask and stirred. The resulting solution was stirred in an oil bath at 70°C for 4 hours. The solid was filtered. The resulting mixture was concentrated. This yielded 2.0 g (86.22%) of (2R)-1,4-dioxane-2-carbaldehyde as a colorless oil. 1H-NMR-1: 1 H NMR (300 MHz, CDCl3,ppm) δ 9.66 (s, 1H), 4.12-3.77 (m, 7H). Synthesis of 2-amino-2-[(2S)-1,4-dioxan-2-yl]acetonitrile: (2R)-1,4-dioxan-2-carbaldehyde (2.00 g, 17.224 mmol, 1.00 equiv) was added to a 100 mL pressure tank reactor. NH3 / MeOH (7M) (40.00 mL) was added. TMSCN (2.97 g, 29.970 mmol, 1.74 equiv) was added to this. The resulting solution was stirred overnight in an oil bath at 70°C. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (3:1). The collected fractions were combined and concentrated. This yielded 2.0 g (81.68%) of 2-amino-2-[(2S)-1,4-dioxan-2-yl]acetonitrile as a brown oil. LCMS-2 (ES, m / z): M+1: 143. Synthesis of amino((2S)-1,4-dioxan-2-yl)acetic acid: 2-amino-2-[(2S)-1,4-dioxan-2-yl]acetonitrile (2.00 g, 14.069 mmol, 1.00 equiv) and NaOH (4 M) (5.00 mL) were added to a 20 mL round-bottom flask. 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 recovered by filtration. This solid was dried in an oven under reduced pressure. This yielded 1.2 g (52.93%) of amino((2S)-1,4-dioxan-2-yl)acetic acid as a white solid. LCMS-3(ES, m / z):M+1:162. Synthesis of 2-amino-2-[(2S)-1,4-dioxan-2-yl]ethanol: In a 100 mL round-bottom flask, amino((2S)-1,4-dioxan-2-yl)acetic acid (1.20 g, 7.446 mmol, 1.00 equiv), THF (40.00 mL, 0.555 mmol, 0.07 equiv), and LiAlH4 (0.85 g, 22.396 mmol, 3.01 equiv) were added. The resulting solution was stirred in an oil bath at 60°C for 4 hours. The reaction was then quenched by adding 2.4 g of Na2SO4, 10H2O. The solid was filtered. The resulting mixture was concentrated. This yielded 1.8 g (crude product) of 2-amino-2-[(2S)-1,4-dioxan-2-yl]ethanol as a colorless oil. LCMS-4 (ES, m / z): M+1: 148. Synthesis of 3-bromo-4-([1-[(2 S)-1,4-dioxan-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 equiv), 2-amino-2-[(2 S)-1,4-dioxan-2-yl]ethanol (0.72 g, 0.005 mmol, 1.3 equiv), CH3CN (30.00 mL), and DIEA (1.46 g, 0.011 mmol, 3 equiv) were added. The resulting solution was stirred in an oil bath at 80°C for 48 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (9:1). The collected fractions were combined and concentrated. This yielded 120 mg (7.46%) of 3-bromo-4-([1-[(2 S)-1,4-dioxan-2-yl]-2-hydroxyethyl]amino)-5-nitrobenzenesulfonamide as a yellow solid. LCMS-5 (ES, m / z):M-1:424 Synthesis of (3 S)-3-[(2 S)-1,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide and (3 R)-3-[(2 S)-1,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide (assumed): In an 8 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen, 3-bromo-4-([1-[(2S)-1,4-dioxan-2-yl]-2-hydroxyethyl)amino)-5-nitrobenzenesulfonamide (120.00 mg, 0.282 mmol, 1.00 equiv), geosilica (8.00 mL), Cs2CO3 (229.32 (3S or 3R)-3-[(2S)-1,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide] was added as a yellow solid of 7 mg (7.20%). The resulting solution was stirred in an oil bath at 100°C for 8 hours. Then, water (8 mL) was added to quench the reaction. The resulting solution was extracted with 3 x 8 mL of ethyl acetate concentrate. The crude product was purified by Prep-HPLC under the following conditions: Column: X-bridge RP18, Mobile phase: 0.05% aqueous ammonia and CH3CN (from 45% CH3CN to 60% in 5 minutes), Detector: UV 254 nm. This yielded 7 mg (7.20%) of (3S or 3R)-3-[(2S)-1,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide as a yellow solid. This yielded 10 mg (10.29%) of (3R or 3S)-3-[(2S)-1,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide as a yellow solid. LC-MS-6:(ES, m / z): M-1:344.

[0195] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-[(3 S)-3-[(2 S)-1,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2 H-1,4-benzoxazine-7-ylsulfonyl]-2-[(12 R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide hydrochloride (hypothetical): In an 8 mL round-bottom flask, 4-(4-[[2-(4-chlorophenyl)-4, 4-Dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12 R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (12.69 mg, 0.020 mmol, 1.00 equiv), (3 S)-3-[(2 S)-1,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2 H-1,4-benzoxazine-7-sulfonamide (7.00 mg, 0.020 mmol, 1.00 equiv), DCM (5.00 mL), EDCI (7.77 mg, 0.041 mmol, 2.00 equiv), DMAP (7.43 mg, 0.061 mmol, 3.00 equiv) was added. 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 C 18 OBD column, 19*150 mm 5 um 10 nm; mobile phase, water (0.05% TFA) and ACN (38% B phase, up to 58% in 7 mins); detector, UV 254 nm. The collected solution was concentrated under vacuum to remove CH3CN, and the resulting solution was lyophilized (con.HCl (1 drop) added).This yielded 5 mg (24.92%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-[(3 S)-3-[(2 S)-1,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2 H-1,4-benzoxazine-7-ylsulfonyl]-2-[(12 R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide hydrochloride as a yellow solid. LC-MS-0A:(ES, m / z): M+1-HCl: 953. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-[(3 R)-3-[(2 S)-1,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2 H-1,4-benzoxazine-7-ylsulfonyl]-2-[(12 R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1 (9),2,5,7-tetraen-10-yl]benzamide hydrochloride (hypothetical): In an 8 mL round-bottom flask, (3 R)-3-[(2 S)-1,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2 H-1, 4-benzoxazine-7-sulfonamide (10.00 mg, 0.029 mmol, 1.00 equiv), 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(12 R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (18.13 mg, 0.029 mmol, 1.00 equiv), DCM (5.00 mL), EDCI (11.10 mg, 0.058 mmol, 2 equiv), and DMAP (14.15 mg, 0.116 mmol, 4 equiv) were added. 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 C 18 OBD Column, 19-150 mm 5 μm 10 nm; mobile phase, water (0.05% TFA) and ACN (38% B phase, up to 58% in 7 mins); detector, UV=254 nm. The collected solution was concentrated under vacuum to remove CH3CN, and the resulting solution was lyophilized (con.HCl (1 drop) added).This yielded 10 mg of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-[(3 R)-3-[(2 S)-1,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2 H-1,4-benzoxazine-7-ylsulfonyl]-2-[(12 R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1 (9),2,5,7-tetraen-10-yl]benzamide hydrochloride as a yellow solid. LC-MS-0B:(ES, m / z): M+1-HCl: 953; H-NMR-0B: 1 1H NMR (300 MHz, methanol-d 4, ppm) δ 8.01 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.25 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 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= 6.3 Hz, 2H), 1.51 (d, J = 6.3 Hz, 3H), 1.32 (s, 1H), 1.05 (s, 6H). Compound 2-15:4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2 S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[(11 S, 15 S)-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1 (9),2,5,7-tetraen-10-yl]benzamide (hypothetical) and 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2 S)-1, Preparation of 4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[(11 R, 15 R)-16-oxa-2,4,10-triazatetracyclo[7,7,0,0^[3,7],0^[11,15]]hexadeca-1 (9),2,5,7-tetraen-10-yl]benzamide (hypothetical): Synthesis of N-[(trans)-2-hydroxycyclopentyl]-4-methylbenzenesulfonamide: In a 250 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, (trans)-2-aminocyclopentan-1-ol (2.10 g, 20.761 mmol, 1.00 equiv), DCM (30.00 mL), and TEA (3.18 g, 31.426 mmol, 1.51 equiv) were added. Then, p-toluenesulfonyl chloride (4.35 g, 22.818 mmol, 1.10 equiv) was added gradually at 0°C, and the resulting solution was stirred at 25°C for 3 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1.5:1). This yielded 5 g (94.32%) of N-[(trans)-2-hydroxycyclopentyl]-4-methylbenzenesulfonamide as a pale yellow oil. 1¹H NMR (300 MHz, chloroform-d, ppm) δ 7.84-7.77 (m, 2H), 7.38-7.30 (m, 2H), 5.27 (s, 1H), 4.06 (dt, J=7.2, 6.3 Hz, 1H), 3.25 (q, J=7.7 Hz, 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).

[0196] Synthesis of N-[(trans)-2-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridine-6-yl)oxy]cyclopentyl]-4-methylbenzenesulfonamide: In a 250 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, N-[(trans)-2-hydroxycyclopentyl]-4-methylbenzenesulfonamide (5.00 g, 19.583 mmol, 1.30 equiv) and THF (50.00 mL) were added. NaH (1.81 g, 45.254 mmol, 3.01 equiv, 60%) was partially added at 0°C, and the resulting solution was stirred at 0°C for 0.5 hours. 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridine (5.19 g, 15.031 mmol, 1.00 equiv) was added at 0°C, and the resulting solution was stirred in an oil bath at 70°C for 2 hours. The reaction mixture was cooled to room temperature. The reaction was then quenched by the addition of aqueous NH4Cl. 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 saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:3). This yielded 4.8 g (55.00%) of N-[(trans)-2-[(5-bromo-1-[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridine-6-yl)oxy]cyclopentyl]-4-methylbenzenesulfonamide as a yellow oily substance. 1H NMR (300 MHz、、クロロホルム-d、ppm)δ8.00 (s、1 H)、7.56-7.47 (m、2 H)、7.19 (d、J=3.6 Hz、1 Hz、7.21-7.2 m). H)、6.42 (d、J=3.6 Hz、1 H)、5.70 (d、J=10.9 Hz、1 H)、5.49 (d、J=10.9 Hz、1 H)、5.33-5.20 (m、1 H=3.3.39) H)、2.31 (s、3 H)、1.93-1.63 (m、4 H)、1.01-0.93 (m、2 H)、0.89 (dd、J=7.0、1.5 Hz、2 H)、0.01 (s、9 H)、0.01 (s、9 H).

[0197] Synthesis of (trans)-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]Hexadeca-1 (9),2,5,7-tetraene: In a 100 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen, N-[(trans)-2-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridine-6-yl)oxy]cyclopentyl]-4-methylbenzenesulfonamide (2.90 g, 4.995 mmol, 1.00 equiv), DMF (30.00 mL), phen (902.00 (mg, 5.005 mmol, 1.00 equiv), CuI (952.00 mg, 4.999 mmol, 1.00 equiv), and K2CO3 (2.07 g, 14.978 mmol, 3.00 equiv) were added. 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 saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:3). This yielded 2.1 g (84.14%) of (trans)-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraene as a colorless oil. 1H NMR (300 MHz, Chloroform-d, ppm)δ 8.68 (s, 1H), 7.43 - 7.34 (m, 2H), 7.24 (d, J = 3.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 6.53 (d, J = 3.6 Hz, 1H), 5.54 (d, J = 1.4 Hz, 2H), 4.00 (td, J = 10.0, 7.6 Hz, 1H), 3.52 (t, J = 8.2 Hz, 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, 7.6 Hz, 1H), 0.97 - 0.86 (m, 2H), -0.05 (s, 9H)。

[0198] Synthesis of (11 S, 15 S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7] .0^[11,15]] hexadeca-1 (9),2,5,7-tetraene (hypothetical) and (11 R, 15 R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7] .0^[11,15]] hexadeca-1 (9),2,5,7-tetraene (hypothetical) in a 100 mL round-bottom flask, Mg (1.92 g, 78.996 mmol, 19.74 equiv), MeOH (20.00 mL) and (trans)-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10-triazatetracyclo[7,7,0^[3,7]0^[11,15]]hexadeca-1(9),2,5,7-traene (2.00 g, 4.002 mmol, 1.00 equiv) 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 of NaHCO3 and CH2Cl2. The solids were filtered and organic matter was separated. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to 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: DAIEL CHIRALPAK OD, 250*20 mm, 5 μm; Gradient: 20% within 15 min B; 220 nm. This yielded 360 mg (26.03%) of (11S,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraene (hypothetical) as a yellow oily substance.This yielded 400 mg (28.92%) of (11R,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraene (hypothetical) as a yellow oily substance. Peak 1: LC-MS (ES, m / z): M+1=346. 1 ¹H NMR (300 MHz, chloroform-d, ppm) δ 7.28 (s, 1 H), 7.15 (d, J=3.5 Hz, 1 H), 6.33 (d, J=3.5 Hz, 1 H), 5.56 (s, 2 H), 4.30-4.07 (m, 1 H), 3.55 (dd, J=8.8, 7.5 Hz, 2 H), 3.29 (dt, J=11.4, 7.5 Hz, 1 H), 2.37-2.19 (m, 1 H), 2.18-2.04 (m, 1 H), 2.04-1.79 (m, 3 H), 1.68-1.40 (m, 1 H), 0.90 (dd, J=8.7, 7.5 Hz, 2 H), -0.06 (s, 9 H). Peak 2: LC-MS (ES, m / z): M+1=346, 1 ¹H NMR (300 MHz, chloroform-d, ppm) δ 7.28 (s, 1 H), 7.15 (d, J=3.5 Hz, 1 H), 6.33 (d, J=3.5 Hz, 1 H), 5.56 (s, 2 H), 4.30-4.07 (m, 1 H), 3.55 (dd, J=8.8, 7.5 Hz, 2 H), 3.29 (dt, J=11.4, 7.5 Hz, 1 H), 2.37-2.19 (m, 1 H), 2.18-2.04 (m, 1 H), 2.04-1.79 (m, 3 H), 1.68-1.40 (m, 1 H), 0.90 (dd, J=8.7, 7.5 Hz, 2 H), -0.06 (s, 9 H).

[0199] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11S,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7] .0^[11,15]] hexa-1(9),2,5,7-terene-10-yl]benzoic acid (hypothetical): In a 40 mL vial purged and maintained under an inert atmosphere of nitrogen, (11S,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10-triazatetracyclo[7. 7.0.0^[3,7].0^[11,15]]Hexadeca-1 (9),2,5,7-tetraen (hypothetical) (340.00 mg, 0.984 mmol, 1.00 equiv), Toluene (15.00 mL), Methyl 2-bromo-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)benzoic acid (1.04 g, 1.955 mmol, 1.99 equiv), Pd2(dba)3.CHCl3 (204.00 mg, 0.197 mmol, 0.20 equiv), Xanthophos (228.00 mg, 0.394 mmol, 0.40 equiv), Cs2CO3 (961.00 (mg, 2.949 mmol, 3.00 equiv) was added. 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 applied to a silica gel column with ethyl acetate / petroleum ether (1:2).This yielded 630 mg (80.38%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexa-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical) as a yellow solid. LC-MS (ES, m / z): M+1=796.

[0200] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11 S, 15 S)-16-oxa-2, 4, 10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (assumed): In a 40 mL vial, methyl 4-(4-[ [2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[ (11 S, 15 S)-4-[ [2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2, 4, 10-Triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]Hexa-1(9),2,5,7-Tetraen-10-yl]benzoic acid (assumed) (630.00 mg, 0.791 mmol, 1.00 equiv), THF (10.00 mL, 1.0 M), ethylenediamine (1.30 g, 21.631 mmol, 27.35 equiv)TBAF were added. The resulting solution was stirred in an oil bath and incubated at 70°C for 8 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (2:1). This yielded 300 mg (56.93%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11 S, 15 S)-16-oxa-2,4,10-triazatetracyclo[7,7,0,0^[3,7],0^[11,15]]hexadeca-1 (9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical) as a yellow solid. LC-MS: (ES, m / z): M+1=666.

[0201] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11 S, 15 S)-16-oxa-2, 4, 10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1 (9),2,5,7-tetraen-10-yl]benzoic acid (assumed): In a 40 mL vial, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11 S, 15 S)-16-oxa-2, 4, 10-Triazatetracyclo[7,7,0,0^[3,7],0^[11,15]]hexadeca-1 (9),2,5,7-tetraen-10-yl]benzoic acid (300.00 mg, 0.450 mmol, 1.00 equiv), dioxane (5.00 mL), MeOH (5.00 mL), and NaOH (1.00 mL, 4.000 mmol, 8.88 equiv) were added. The resulting solution was stirred in an oil bath and incubated at 70°C for 4 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The pH of this solution was adjusted to 6-7 with HCl (2 mol / L). The resulting solution was extracted with 3 x 50 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 x 300 mL of saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-TLC with ethyl acetate. This yielded 130 mg (44.26%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11 S, 15 S)-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a white solid. LC-MS: (ES, m / z): M+1=652.

[0202] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[(11S,15S or 11R,15R)-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzamide (assumed): In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11S, 15 S)-16-oxa-2,4,10-triazatetracyclo[7,7,0,0^[3,7],0^[11,15]]hexadeca-1 (9),2,5,7-tetraen-10-yl]benzoic acid (50.00 mg, 0.077 mmol, 1.00 equiv), DCM (5.00 mL), 4-[[(2 S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonamide (24.00 mg, 0.076 mmol, 0.99 equiv), EDCI (30.00 mg, 0.156 mmol, 2.04 equiv), and DMAP (38.00 mg, 0.311 mmol, 4.06 equiv) were added. 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 shielded RP 18 OBD column, 5 μm, 19*150 mm; Mobile phase, water (0.05% NH3.H2O) and ACN (40% phase B, up to 70% in 7 mins); Detector, UV 254 / 220 nm.This yielded 25 mg (34.27%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[(11S,15S or 11R,15R)-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzamide as a yellow solid. LC-MS (ES, m / z): M+1=951. 1 H NMR (300 MHz, DMSO-d6, ppm)δ12.90 (s, 1 H), 11.21 (s, 1 H), 8.54 (s, 1 H), 8.35 (d, J=2.3 Hz, 1 H), 7.75 (d, J=8.6 Hz, 1 H), 7.46-7.30 (m, 3 H), 7.18-6.99 (m, 3 H), 6.93 (d, J=9.2 Hz, 1 H), 6.80 (s, 2 H), 6.49 (s, 1 H), 6.07-5.99 (m, 1 H), 4.33 (d, J=7.2 Hz, 1 H), 3.79 (dd, J=9.9, 5.9 Hz, 4H), 3.73-3.33 (m, 7H), 3.27 (d, J=13.6 Hz, 4 H), 3.12 (d, J=6.5 Hz, 1 H), 2.75 (s, 2 H), 2.20 (s, 6 H), 1.97 (s, 2 H), 1.83 (s, 2 H), 1.68 (s, 1 H), 1.40 (s, 3 H), 0.94 (d, J=2.2Hz, 6H).

[0203] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11 R, 15 R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7] .0^[11,15]] hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical) : In a 40 mL vial purged and maintained under an inert nitrogen atmosphere, (11R,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10-triazatetracyclo[7,7,0,0^][11,15]hexadeca-1(9),2,5,7-tetraen(Assumed) (400,00 mg, 1,158 mmol, 1.00 equiv), toluene (15 mL), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)benzoic acid (1.23 g, 2.312 mmol, 2.00 equiv), Pd2(dba)3.CHCl3(239.00 (mg, 0.231 mmol, 0.20 equiv), xanthophos (268.00 mg, 0.463 mmol, 0.40 equiv), and Cs2CO3 (1.13 g, 3.468 mmol, 3.00 equiv) were added. 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 applied to a silica gel column with ethyl acetate / petroleum ether (1:2). This yielded 680 mg (73.74%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11 R, 15 R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7] .0^[11,15]]hexa-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical) as a yellow solid.LC-MS (ES, m / z): M+1 = 796.

[0204] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11 R, 15 R)-16-oxa-2, 4, 10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (assumed): In a 40 mL vial, methyl 4-(4-[ [2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[ (11 R, 15 R)-4-[ [2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2, 4, 10-Triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]Hexa-1(9),2,5,7-Tetraen-10-yl]benzoic acid (assumed) (670.00 mg, 0.841 mmol, 1.00 equiv), THF (10.00 mL, 1.0 M), and ethylenediamine (1.30 g, 21.631 mmol, 25.72 equiv) TBAF were added. The resulting solution was stirred in an oil bath and incubated at 70°C for 8 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (2:1). This yielded 320 mg (57.10%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11 R, 15 R)-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical) as a yellow solid. LC-MS (ES, m / z): M+1=666.

[0205] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11 R, 15 R)-16-oxa-2, 4, 10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1 (9),2,5,7-tetraen-10-yl]benzoic acid (assumed): In a 40 mL vial, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11 R, 15 R)-16-oxa-2, 4, 10-Triazatetracyclo[7,7,0,0^[3,7],0^[11,15]]hexadeca-1 (9),2,5,7-tetraen-10-yl]benzoic acid (140.00 mg, 0.210 mmol, 1.00 equiv), dioxane (3.00 mL), MeOH (3.00 mL), and NaOH (0.60 mL, 2.400 mmol, 11.42 equiv) were added. The resulting solution was stirred in an oil bath and incubated at 70°C for 4 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The pH of this solution was adjusted to 6-7 with HCl (2 mol / L). The resulting solution was extracted with 3 x 50 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 x 300 mL of saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-TLC with ethyl acetate. This yielded 80 mg (58.37%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[ (11R,15R)-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical) as a white solid. LC-MS (ES, m / z): M+1=652.

[0206] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[(11R,15R or 11S,15S)-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzamide: In a 40 mL vial, combine 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11R,15 R) -16-oxa-2,4,10-triazatetracyclo[7,7,0,0^[3,7],0^[11,15]]hexadeca-1 (9),2,5,7-tetraen-10-yl]benzoic acid (20.00 mg, 0.031 mmol, 1.00 equiv), DCM (5.00 mL), 4-[[(2 S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonamide (9.70 mg, 0.031 mmol, 1.00 equiv), EDCI (12.00 mg, 0.063 mmol, 2.04 equiv), and DMAP (15.00 mg, 0.123 mmol, 4.00 equiv) were added. 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 shielded RP 18 OBD column, 5 μm, 19*150 mm; Mobile phase, water (0.05% NH3.H2O) and ACN (40% phase B, up to 70% in 7 mins); Detector, UV 254 / 220 nm.This yielded 4.7 mg (16.11%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[(11R,15R or 11S,15S)-16-oxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzamide as a yellow solid. LC-MS (ES, m / z): M+1=951. 1 H NMR (300 MHz, DMSO-d6, ppm)δ12.90 (s, 1 H), 11.21 (s, 1 H), 8.54 (s, 1 H), 8.35 (d, J=2.3 Hz, 1 H), 7.75 (d, J=8.6 Hz, 1 H), 7.46-7.30 (m, 3 H), 7.18-6.99 (m, 3 H), 6.93 (d, J=9.2 Hz, 1 H), 6.80 (s, 2 H), 6.49 (s, 1 H), 6.07-5.99 (m, 1 H), 4.33 (d, J=7.2 Hz, 1 H), 3.79 (dd, J=9.9, 5.9 Hz, 4H), 3.73-3.33 (m, 7H), 3.27 (d, J=13.6 Hz, 4 H), 3.12 (d, J=6.5 Hz, 1 H), 2.75 (s, 2 H), 2.20 (s, 6 H), 1.97 (s, 2 H), 1.83 (s, 2 H), 1.68 (s, 1 H), 1.40 (s, 3 H), 0.94 (d, J=2.2Hz, 6H).

[0207] Compound 2-16:4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11 R, 15 S)-13, 16dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]-N-(4-[[(2 S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)benzamide (hypothetical) and 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11 S, 15 R) Preparation of -13,16dioxa-2,4,10-triazatetracyclo[7,7,0,0^[3,7],0^[11,15]]hexadeca-1 (9),2,5,7-tetraen-10-yl]-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)benzamide (hypothetical): Synthesis of N-[(trans)-4-hydroxyoxolan-3-yl]-4-methylbenzenesulfonamide: In a 250 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, 3,6-dioxabicyclo[3.1.0]hexane (5.00 g, 58.079 mmol, 1.00 equiv), dioxane (100.00 mL), p-toluenesulfonamide (11.93 g, 69.681 mmol, 1.20 equiv), TEBAC (1.33 g, 5.833 mmol, 0.10 equiv), and K2CO3 (0.80 g, 5.788 mmol, 0.10 equiv) were added. The resulting solution was stirred in an oil bath at 90°C for 3 days. The reaction mixture was cooled to room temperature. The solids were filtered. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (2:1). This yielded 10.69 g (25.75%) of N-[(trans)-4-hydroxyoxolan-3-yl]-4-methylbenzenesulfonamide as a white solid. LC-MS: (ES, m / z): M+1=258.

[0208] Synthesis of N-[(trans)-4-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridine-6-yl)oxy]oxolan-3-yl]-4-methylbenzenesulfonamide: In a 250 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, N-[(trans)-4-hydroxyoxolan-3-yl]-4-methylbenzenesulfonamide (10.50 g, 14.691 mmol 1.30 equiv 36%) and THF (100 mL) were added. NaH (2.71 g, 67.756 mmol 6.01 equiv, 60%) was partially added 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 equiv) was added at 0°C, and 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 was added to quench the reaction. The resulting solution was extracted with 3 × 300 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 × 1500 mL of saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:2). This yielded 3 g (45.71%) of N-[(trans)-4-[(5-bromo-1-[ [2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridine-6-yl)oxy]oxolan-3-yl]-4-methylbenzenesulfonamide as a pale yellow oil. 1H NMR (300 MHz、クロロホルム-d、ppm)δ8.04 (s、1 H), 7.78-7.61 (m、2 H), 7.25-7.10 (m、3 H)、7.25-7.10 (m、3 H)、6.43 (d、3 Hz = 3.1 Hz). H)、5.67 (d、J=10.8 Hz、1 H)、5.60 (d、J=5.7 Hz、1 H)、5.49 (d、J=10.8 Hz、1 H)、5.40 (dt、J=6.1.1 Hz、1 Hz、1 H). (dd、J=10.5、5.9 Hz、1 H)、4.21-4.03 (m、1 H)、4.03-3.86 (m、2 H)、3.70-3.52 (m、3 H)、2.32 (s、3.9H) (ddt、J=10.6、5.5、2.6 Hz、2 H)、-0.02 (s、9 H)。

[0209] Synthesis of (trans)-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]Hexadeca-1 (9),2,5,7-tetraene: In a 250 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen, N-[(trans)(3S,4R)-4-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridine-6-yl)oxy]oxolan-3-yl]-4-methylbenzenesulfonamide (3.00 g, 5.149 mmol, 1.00 equiv), DMF (50.00 mL), phen (743.00 mg, 4.123 mmol, 0.80 equiv), CuI (785.00 mg, 4.122 mmol, 0.80 equiv), and K2CO3 (2.14 g, 15.484 mmol, 3.01 equiv) were added. 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 saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:2). This yielded 2.5 g (82.26%) of (trans)-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10-triazatetracyclo[7,7,0,0^[3,7],0^[11,15]]hexadeca-1(9),2,5,7-tetraene as a yellow oily substance. LC-MS: (ES, m / z) M+1=502. Synthesis of (11 S, 15 R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^ [3, 7] .0^ [11, 15]] hexadeca-1 (9),2,5,7-tetraene (hypothetical) and Synthesis of (11 R, 15 S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^ [3, 7] .0^ [11, 15]] hexadeca-1 (9),2,5,7-tetraene (hypothetical): In a 100 mL round-bottom flask, Mg (2.04 (Trans)-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraene (2.50 g, 4.236 mmol, 1.00 equiv, 85%) was added to MeOH (30.00 mL). 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 of NaHCO3 and CH2Cl2. The solids were filtered and the organic matter was separated. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to 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: DAIEL CHIRALPAK IA, 250*20 mm, 5 μm; Gradient: 12% B in 20 min; 220 nm. This yielded 350 mg (23.78%) of (11 R, 15 S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7] .0^[11,15]] hexadeca-1 (9),2,5,7-tetraene (hypothetical) as a yellow oily substance. And (11 S, 15 R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7] .0^[11,15]]Hexadeca-1 (9),2,5,7-tetraene (assumed) 400 mg (27.18%) was obtained as a yellow oily substance. Peak 1: LC-MS: (ES, m / z) M+1=348. 1 H NMR (300 MHz, chloroform-d, ppm) δ7.39 (s, 1 H), 7.21 (d, J=3.6 Hz, 1 H), 6.37 (d, J=3.6 Hz, 1 H), 5.57 (s, 2 H), 4.60 (dt, J=10.1, 7.6 Hz, 1 H), 4.39-4.22 (m, 2 H), 3.94 (dd, J=9.9, 7.9 Hz, 1 H), 3.86-3.69 (m, 2 H), 3.64-3.45 (m, 2 H), 0.91 (dd, J=8.8, 7.5 Hz, 2 H), -0.04 (s, 9 H). Peak 2: LC-MS: (ES, m / z) M+1=348. 1¹H NMR (300 MHz, chloroform-d, ppm) δ 7.39 (s, 1 H), 7.21 (d, J=3.6 Hz, 1 H), 6.37 (d, J=3.6 Hz, 1 H), 5.57 (s, 2 H), 4.60 (dt, J=10.1, 7.6 Hz, 1 H), 4.39-4.22 (m, 2 H), 3.94 (dd, J=9.9, 7.9 Hz, 1 H), 3.86-3.69 (m, 2 H), 3.64-3.45 (m, 2 H), 0.91 (dd, J=8.8, 7.5 Hz, 2 H), -0.04 (s, 9 H).

[0210] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11R,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7] .0^[11,15]]hexa-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical): In a 40 mL vial purged and maintained under an inert atmosphere of nitrogen, (11R,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10-triazatetracyclo[7. 7.0.0^[3,7].0^[11,15]]Hexadeca-1 (9),2,5,7-tetraen (assumed) (350.00 mg, 1.007 mmol, 1.00 equiv), Toluene (15.00 mL), Methyl 2-bromo-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)benzoic acid (1.07 g, 2.012 mmol, 2.00 equiv), Pd2(dba)3·CHCl3 (208.00 mg, 0.201 mmol, 0.20 equiv), Xanthophos (234.00 mg, 0.404 mmol, 0.40 equiv), Cs2CO3 (985.00 (mg, 3.023 mmol, 3.00 equiv) was added. 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 applied to a silica gel column with ethyl acetate / petroleum ether (1:2).This yielded 720 mg (89.52%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11 R, 15 S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7] .0^[11,15]]hexa-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical) as a yellow solid. LC-MS: (ES, m / z) M+1=798. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11 R, 15 S)-13, 16dioxa-2,4,10-triazatetracyclo[7,7,0,0^[3,7],0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical): Methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[(11R,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical) (720.00 mg, 0.902 mmol, 1.00 equiv), 1.0 M TBAF / THF (15.00 mL), and ethylenediamine (1.30 g, 21.631 mmol, 23.99 equiv) were added to a 40 mL vial. The resulting solution was stirred in an oil bath and incubated at 70°C for 8 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (2:1). This yielded 350 mg (58.09%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[ (11R,15S)-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical) as a pale yellow solid. LC-MS: (ES, m / z) M+1=668. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11 R, 15 S)-13, 16dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (assumed): In a 40 mL vial, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11 R, 15 S)-13, 16-Dioxa-2,4,10-Triazatetracyclo[7,7,0,0^[3,7],0^[11,15]]Hexadeca-1(9),2,5,7-Tetraen-10-yl]benzoic acid (150.00 mg, 0.224 mmol, 1.00 equiv), dioxane (3.00 mL), MeOH (3.00 mL), and NaOH (0.60 mL, 2.400 mmol, 10.69 equiv) were added. The resulting solution was stirred in an oil bath and incubated at 70°C for 4 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The pH of this solution was adjusted to 5-6 with HCl (2 mol / L). The resulting solution was extracted with 3 x 50 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 x 300 mL of saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-TLC with dichloromethane / methanol (10:1). This yielded 80 mg (54.48%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[ (11R,15S)-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical) as a white solid. LC-MS: (ES, m / z) M+1=654. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11 R, 15 S)-13, 16dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]-N-(4-[[(2 S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)benzamide (assumed): In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11 R, 15 S) -13,16-Dioxa-2,4,10-Triazatetracyclo[7,7,0,0^[3,7],0^[11,15]]Hexadeca-1(9),2,5,7-Tetraen-10-yl]benzoic acid (50.00 mg, 0.076 mmol, 1.00 equiv), DCM (5.00 mL), 4-[[(2 S)-1,4-Dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonamide (24.00 mg, 0.076 mmol, 0.99 equiv), EDCI (29.00 mg, 0.151 mmol, 1.98 equiv), and DMAP (37.00 mg, 0.303 mmol, 3.96 equiv) were added. 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, 5um, 19*150mm; Mobile phase: Water (0.05% NH3.H2O) and ACN (40% Phase B, to 70% in 7 min; Detector, UV 254 / 220 nm).This yielded 25 mg (34.31%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11 R, 15 S)-13, 16dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]-N-(4-[[(2 S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)benzamide (hypothetical) as a yellow solid. LC-MS: (ES, m / z) M+1=953. 1 H NMR (300 MHz, DMSO-d6, ppm) δ12.27 (s, 1 H), 11.05 (d, J=66.1 Hz, 1 H), 8.42 (d, J=30.6 Hz, 1 H), 8.32 (d, J=2.3 Hz, 1 H), 7.57 (s, 1 H), 7.36 (dd. H), 3.96-3.34 (m, 12 H), 3.19 (d, J=16.7 Hz, 4 H), 2.81-2.71 (m, 2 H), 2.24 (d, J=19.4 Hz, 6 H), 1.98 (s, 2 H), 1.41 (s, 2 H), 0.94 (s, 6 H).

[0211] Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11S,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7] .0^[11,15]]hexa-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical): In a 40 mL vial purged and maintained under an inert atmosphere of nitrogen, (11S,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10-triazatetracyclo[7. 7.0.0^[3,7].0^[11,15]]Hexadeca-1(9),2,5,7-tetraen (assumed) (400.00 mg, 1.151 mmol, 1.00 equiv), Toluene (15.00 mL), Methyl 2-bromo-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)benzoic acid (1.22 g, 2.294 mmol, 1.99 equiv), Pd2(dba)3·CHCl3 (237.00 mg, 0.229 mmol, 0.20 equiv), Xanthophos (266.00 mg, 0.460 mmol, 0.40 equiv), Cs2CO3 (1.12 g, 3.437 mmol, 2.99 equiv) was added. 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 applied to a silica gel column with ethyl acetate / petroleum ether (1:2).This yielded 820 mg (89.21%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11 S, 15 R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3, 7] .0^[11, 15]]hexa-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical) as a yellow solid. LC-MS: (ES, m / z) M+1=798. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11 S, 15 R)-13, 16dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (assumed): In a 40 mL vial, methyl 4-(4-[ [2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[ (11 S, 15 R)-4-[ [2-(trimethylsilyl)ethoxy]methyl]-13, 16-Dioxa-2,4,10-Triazatetracyclo[7.7.0.0^[3,7] .0^[11,15]]Hexa-1(9),2,5,7-Tetraen-10-yl]benzoic acid (assumed) (820.00 mg, 1.027 mmol, 1.00 equiv), TBAF in THF (15.00 mL), and ethylenediamine (1.30 g, 21.631 mmol, 21.06 equiv) were added. The resulting solution was stirred in an oil bath and incubated at 70°C for 8 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (2:1). This yielded 380 mg (55.37%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[ (11S,15R)-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (hypothetical) as a pale yellow solid. LC-MS: (ES, m / z) M+1=668. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11 S, 15 R)-13, 16dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (assumed): In a 40 mL vial, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11 S, 15 R)-13, 16-Dioxa-2,4,10-Triazatetracyclo[7,7,0,0^[3,7],0^[11,15]]Hexadeca-1(9),2,5,7-Tetraen-10-yl]benzoic acid (150.00 mg, 0.224 mmol, 1.00 equiv), dioxane (3.00 mL), MeOH (3.00 mL), and NaOH (0.60 mL, 2.400 mmol, 10.69 equiv) were added. The resulting solution was stirred in an oil bath and incubated at 70°C for 4 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The pH of this solution was adjusted to 5-6 with HCl (2 mol / L). The resulting solution was extracted with 3 x 50 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 x 300 mL of saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-TLC with dichloromethane / methanol (10:1). This yielded 80 mg (54.48%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[ (11S,15R)-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (assumed) as a white solid. LC-MS: (ES, m / z) M+1=654. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11 S, 15 R)-13, 16dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1 (9),2,5,7-tetraen-10-yl]-N-(4-[[(2 S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)benzamide (assumed): In a 40 mL vial, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11 S, 15 R) -13,16-dioxa-2,4,10-triazatetracyclo[7,7,0,0^[3,7],0^[11,15]]hexadeca-1 (9),2,5,7-tetraen-10-yl]benzoic acid (50.00 mg, 0.076 mmol, 1.00 equiv), DCM (5.00 mL), 4-[[(2 S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonamide (24.00 mg, 0.076 mmol, 0.99 equiv), EDCI (29.00 mg, 0.151 mmol, 1.98 equiv), and DMAP (37.00 mg, 0.303 mmol, 3.96 equiv) were added. 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, 5um, 19*150mm; Mobile phase: Water (0.05% NH3.H2O) and ACN (40% Phase B, to 70% in 7 min; Detector, UV 254 / 220 nm).This yielded 25 mg (34.31%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-[(11 S, 15 R)-13, 16-dioxa-2, 4, 10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1 (9),2, 5, 7-tetraen-10-yl]-N-(4-[[(2 S)-1, 4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)benzamide (hypothetical) as a yellow solid. LC-MS: (ES, m / z) M+1=953. 1 H NMR (300 MHz, DMSO-d6, ppm) δ12.27 (s, 1 H), 11.05 (d, J=66.1 Hz, 1 H), 8.42 (d, J=30.6 Hz, 1 H), 8.32 (d, J=2.3 Hz, 1 H), 7.57 (s, 1 H), 7.36 (dd. H), 3.96-3.34 (m, 12 H), 3.19 (d, J=16.7 Hz, 4 H), 2.81-2.71 (m, 2 H), 2.24 (d, J=19.4 Hz, 6 H), 1.98 (s, 2 H), 1.41 (s, 2 H), 0.94 (s, 6 H).

[0212] Preparation of compound 2-17: 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide Synthesis of (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: Ethyl vinyl ether (2000.00 g, 27777.778 mmol, 3.00 equiv) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (508.00 g, 9259.259 mmol, 1.00 equiv) were added to a 3 L four-necked round-bottom flask. This solution was cooled to 5°C in an ice / salt bath. Then, Pd(OAc)2 (10.39 g, 46.296 mmol, 0.005 equiv) was added partially at 0-5°C, and the resulting solution was stirred at room temperature for 18 hours. The resulting mixture was concentrated. The solution was then purified by rectification, and the solution was collected at 25 mmHg at 65-70 degrees Celsius to obtain 890 g of 2-[(Z,E mixture)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3-dioxolane (Y=50%, LCMS OK, Q-NMR=87%) as a pale yellow oily substance, yielding 1500 g (crude product). 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).

[0213] Synthesis of N-[(2R)-2-hydroxypropyl]acetamide: In a 250 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, (2R)-1-aminopropan-2-ol (10 g, 133.136 mmol, 1 equiv), DCM (100 mL), and TEA (16 g, 159.764 mmol, 1.2 equiv) were added. Next, a solution of acetyl acetate (13.6 g, 133.136 mmol, 1.0 equiv) 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 applied to a silica gel column with dichloromethane / methanol (100:5). This yielded 13.5 g (69.25%) of N-[(2R)-2-hydroxypropyl]acetamide as a yellow oil. LC-MS: (ES, m / z): M+1=118.

[0214] Synthesis of 4-([[(2S)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide: In a 100 mL round-bottom flask, 4-fluoro-3-nitrobenzene-1-sulfonamide (1.43 g, 0.007 mmol, 1 equiv), 1-[(2S)-1,4-dioxan-2-yl]methanamine hydrochloride (1 g, 6.510 mmol, 1 equiv), THF (30 mL), and Cs2CO3 (8.48 g, 0.026 mmol, 4 equiv) were added. The resulting solution was stirred overnight in an oil bath at 50°C. The solid was collected by filtration. This solid was dried in an oven under reduced pressure. This yielded 1.82 g (88.10%) of 4-([[(2S)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide as a yellow solid. LC-MS: (ES, m / z): M+1=318, R, T=0.741 min.

[0215] Synthesis of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)piperazine-1-yl)benzoatemethyl: In a 20000 mL round-bottom flask, 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-enyl)methyl)piperazine dihydrochloride (600 g, 1.53 mol, 1 equiv), methyl 2-bromo-4-fluorobenzoic acid (357 g, 1.53 mol, 1 equiv), DBU (319 g, 6.12 mol, 4 equiv), and DMSO (8000 mL) were added. The resulting solution was stirred at 70°C for 20 hours. LC-MS showed that the materials were completely consumed. The resulting mixture was cooled to room temperature and added to water (32 L). The mixture was filtered, the filter cake was collected, the filter cake was washed with water (3000 mL x 3), and dried in an oven to obtain 740 g (Y=91%) of methyl 2-bromo-4-(4-(2-(4-chlorophenyl)-4,4-dimethylcyclohexyl)methyl)piperazin-1-yl)benzoic acid as a white solid. ¹H-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).

[0216] Synthesis of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazin-1-yl)benzoic acid: Methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazin-1-yl)benzoic acid (730 g, 1.37 mol, 1 equiv), LiOH (131.5 g, 5.48 mol, 4 equiv), and MeOH / THF / water (4500 mL / 3000 mL / 1000 mL) were added to a 20000 mL round-bottom flask. The resulting solution was stirred at 70°C for 16 hours. LC-MS showed that the materials were completely consumed. The resulting mixture was cooled to room temperature and concentrated. The residue was diluted with water (5000 mL), the mixture was pH adjusted to 3-5 with HCl (6 M), then filtered, the filter cake was collected, and dried in an oven to obtain 650 g of product 2-bromo-4-(4-(2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazin-1-yl)benzoic acid as a white solid. ¹H-NMR-PH-PHNW-4-55-400:(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), 3.7 6(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).

[0217] Synthesis of 5-bromo-6-fluoropyridine-2-amine: In a 100 L four-necked round-bottom flask, 6-fluoropyridine-2-amine (4500.00 g, 40178.571 mmol, 1.00 equiv) and ACN (25000.00 mL) were added. Next, NBS (7100.00 g, 41764.706 mmol, 1.03 equiv) was partially added over 2 hours at 5-15°C, and the resulting solution was stirred at room temperature for 3 hours. The resulting solution was diluted with 50 L of water. The resulting solution was extracted with 2 x 32 L of ethyl acetate. The resulting mixture was washed with 10 L of saline solution. 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, and 6900 g (Y=90%) of 5-bromo-6-fluoropyridine-2-amine was given 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): δ7.63-7.71 (m, 1 H), 6.57 (s, 2 H), 6.27-631 (m, 1 H).

[0218] Synthesis of 5-bromo-6-fluoro-3-iodopyridine-2-amine: 5-bromo-6-fluoropyridine-2-amine (6500.00 g, 34219.531 mmol, 1.00 equiv) and AcOH (39000.00 mL) were added to a 100 L four-necked round-bottom flask. This solution was cooled to 15°C in a water / ice bath. Next, NIS (8470.00 g, 37641.484 mmol, 1.10 equiv) was partially added at 10-20°C, and the resulting solution was stirred at room temperature for 3 hours. The resulting solution was added to 100 L of water. The mixture was filtered, the filter cake was collected, the filter cake was washed with water (25 L x 3), and dried in an oven to obtain 9840 g (Y=85%) of 5-bromo-6-fluoro-3-iodopyridine-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): δ8.17-8.20 (m, 1 H), 6.69 (s, 2 H).

[0219] Synthesis of 5-bromo-3-(2-ethoxyvinyl)-6-fluoropyridine-2-amine: In a 20 L four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, 5-bromo-6-fluoro-3-iodopyridine-2-amine (855.00 g, 2705.696 mmol, 1.00 equiv), i-PrOH (10000.00 mL), 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3-dioxolane (1000.00 g, 5050.505 mmol, 1.87 equiv), K3PO4 (1720.00 g, 8113.207 mmol, 3.00 equiv), Ruphos (12.00 g, 27.060 mmol, 0.02 equiv) and Pd(OAc)2 (10.00 g, 44.643 mmol, 0.02 equiv) were added. The resulting solution was stirred in a liquid nitrogen bath at room temperature for 12 hours. The solids were filtered off. The filter cake was washed with 3 x 2 L DCM. The organic layer was collected and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:5). This was concentrated to obtain 680 g (80%) of 5-bromo-3-[(Z,E mixture)-2-ethoxyethenyl]-6-fluoropyridine-2-amine as a dark brown oil. LC-MS: (ES, m / z): M+1=261,263, RT=1.090 min.

[0220] Synthesis of 5-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine: In a 10 L four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, 5-bromo-3-[(E)-2-ethoxyethenyl]-6-fluoropyridine-2-amine (680.00 g, 2605.364 mmol, 1.00 equiv), EtOH (5000.00 mL), and HCl (1000.00 mL) were added. 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. This yielded 410 g (Y=75%) of 5-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine as a light brown solid. LC-MS: (ES, m / z): M+1=215,217, RT=0.993 min, H-NMR: (300 MHz, DMSO-d6, ppm): δ9.53 (BRS, 1 H), 8.19-8.22 (d, J=9.0 Hz, 1 H), 7.32-7.34 (m, 1 H), 6.50-6.52 (m, 1 H).

[0221] Synthesis of 5-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine: 5-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine (200.00 g, 930.232 mmol, 1.00 equiv) and DMF (2500.00 mL) were added to a 5 L four-necked round-bottom flask. This solution was cooled to 0°C in a water / ice bath. Next, NaH (75.00 g, 1860.464 mmol, 2.00 equv) was added in several portions at 0°C, and SEM-Cl (233.00 g, 1395.210 mmol, 1.50 equv) was added dropwise while stirring at °C, and the resulting solution was stirred at room temperature for 1 hour. The reaction was then quenched 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 combined with the organic layer. The resulting mixture was washed with 3 x 5 L of water. The resulting mixture was washed with 3 L of saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:20). This yielded 298 g (87%) of 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridine as a pale yellow oil. LC-MS: (ES, m / z): H-NMR (300 MHz, DMSO-d 6, ppm): δ8.46-8.49 (d, J=9.0 Hz, 1 H), 7.68-7.69 (m, 1 H), 6.57-6.58 (m, 1 H), 5.52-5.55 (m, 2 H), 345,347 3.47-1.435 3.60 (m, 2 H), 0.79-0.90 (m, 2 H), 0.01 (s, 9 H).

[0222] Synthesis of (R)-N-(2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-6-yloxy)propyl)acetamide: N-[(2R)-2-hydroxypropyl]acetamide (680 mg, 5.8 mmol, 2.00 equiv) and dioxane (10 mL) were added to a 50 mL round-bottom flask. NaH (348 mg, 8.7 mmol, 3 equiv) was partially added at 15°C. The resulting solution was stirred at RT for 10 minutes. A solution of 5-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1 g, 2.9 mmol, 1 equiv) in dioxane (5 mL) was added to this. The resulting solution was stirred in an oil bath at 80°C for 4 hours. The reaction mixture was cooled to room temperature, and 5 mL of water was added for rapid cooling. The resulting solution was extracted with 3 × 10 mL of ethyl acetate. The resulting mixture was washed with 3 × 5 mL of H2O. The resulting mixture was washed with 1 × 10 mL of NaCl(aq). This mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column with PE / EA (100:20). This yielded 880 mg (73%) of (R)-N-(2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-6-yloxy)propyl)acetamide as a white solid.

[0223] Synthesis of 1-[(12R)-4-(trimethylsilyl)ethoxy)methyl)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]ethane-1-one: In a 25 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen, (R)-N-(2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-6-yloxy)propyl)acetamide (500 mg, 1.13 mmol 1 equiv), dioxane (8 mL), Cs2CO3 (1.1 g, 3.4 mmol, 3 equiv), BrettPhos Pd G3 (102 mg, 0.11 mmol, A 0.10 equiv was obtained. The resulting solution was stirred in an oil bath at 80°C for 14 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (50:50). This yielded 300 mg (73.3%) of 1-[(12R)-4-(trimethylsilyl)ethoxy)methyl)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca 1(9),2,5,7-tetraen-10-yl]ethane-1-one as a pale yellow oil.

[0224] Synthesis of (12R)-4-(trimethylsilyl)ethoxy)methyl)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen: 1-[(12R)-4-(trimethylsilyl)ethoxy)methyl]-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]ethane-1-one (50 mg), methanol (0.5 mL), and NaOH / H2O (1 M, 0.5 ml) were added to an 8 mL vial. The resulting solution was stirred in an oil bath at 80°C for 14 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1). This yielded 15 mg (34%) of (12R)-4-(trimethylsilyl)ethoxy)methyl)-12-methyl-13-oxa-2,4,10-triazaltricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-triene as a brown oily substance.

[0225] 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[(12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazaltricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl] Synthesis of benzamide: In an 8 mL vial purged and maintained under an inert nitrogen atmosphere, (12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-triene (100.00 mg, 0.313 mmol, 1.00 equiv), 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)benzamide (255.79 mg, 0.313 mmol, 1.00 equiv), DMF (2.00 The following were added: (mL), CuI (23.84 mg, 0.125 mmol, 0.40 equiv), N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxamide (20.53 mg, 0.063 mmol, 0.20 equiv), and K2CO3 (129.78 mg, 0.939 mmol, 3.00 equiv). The resulting solution was stirred in an oil bath at 100°C for 4 hours. The resulting solution was diluted with 10 mL of H2O. The resulting solution was extracted with 3 x 5 mL of ethyl acetate. The resulting mixture was washed with 3 x 5 mL of H2O. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10:1).This yielded 220 mg (66.57%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2 S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[(12 R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazaltricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide as a yellow solid. LC-MS: (ES, m / z): 1055.5 [M +H]. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2 S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[(12 R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide: In a 25 mL round-bottom flask, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2 S) -1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[(12 R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazaltricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide (210.00 mg), ethane-1,2-diamine (1.00 mL), and TBAF were added. The resulting solution was stirred in an oil bath and incubated 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 with dichloromethane / methanol (100:5). This yielded 70 mg (38.02%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[ (12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide as a yellow solid. LC-MS: (ES, m / z): 925.4 [M +H]. 1H NMR (300 MHz, CDCl3, ppm): δ 12.38 (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), 2.91-2.79 (m, 2H), 2.40-2.17 (m, 6H), 2.10-2.02 (m, 2H), 1.70-1.61 (m, 3H), 0.97 (s, 6H).

[0226] Preparation of compound 2-18:4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[11-oxo-13-oxa-2,4,10-tridiazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide Synthesis of 5-bromo-6-fluoropyridine-2-amine. In a 5000 mL three-necked round-bottom flask, 6-fluoropyridine-2-amine (220 g, 2 mol, 1.00 equiv), CH3CN (2.0 L), and NBS (420 g, 2.2 mol, 1.20 equiv) were added. The resulting solution was stirred overnight at room temperature. Then, 2 L of water was added to quench the reaction. The resulting solution was extracted with 3 x 1 L of ethyl acetate, and the organic phase was 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 applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:5). This yielded 200 g (60%) of 5-bromo-6-fluoropyridine-2-amine as a white solid. LCMS: (ES, m / z): M+1:191, 193.

[0227] Synthesis of 5-bromo-6-fluoro-3-iodopyridine-2-amine. In a 2000 mL four-necked round-bottom flask, 200 g (1.05 mol, 1.00 equiv) of 5-bromo-6-fluoropyridine-2-amine dissolved in 1500 mL of AcOH and 200 g (1.15 mol, 1.10 equiv) of iodo(sulfanyl)amine (NIS) were added. The resulting solution was stirred overnight at room temperature. Then, 3000 mL of water was added to quench the reaction. The solid was collected by filtration and washed with Et2O. This yielded 170 g (50%) of 5-bromo-6-fluoro-3-iodopyridine-2-amine as a white solid. The organic phase was concentrated under vacuum to obtain 150 g of crude oil. 1 H-NMR: (CDCl3, 300MHz)δ: 7.98 (d, J=14.4 Hz, 1 H), 4.94~5.00 (bs, 2 H).

[0228] Synthesis of 5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridine-2-amine. In a 3000 mL three-necked round-bottom flask, 170 g, 536.45 mmol, 1.00 equiv of 5-bromo-6-fluoro-3-iodopyridine-2-amine dissolved in tetrahydrofuran (1500 mL), 10.2 g, 53.56 mmol, 0.10 equiv, 500 mL of TEA, dichloropalladium; bis(triphenylphosphan) (11.2 g, 15.96 mmol, 0.03 equiv), and ethyl(ethynyl)dimethylsilane (63 g, 561.27 mmol, 1.20 equiv) were added. The resulting solution was stirred at room temperature for 16 hours. Then, 2000 mL of water was added to quench the reaction. The obtained solution was extracted with 3 x 1000 mL of ethyl acetate, and the organic layer was combined with it. The resulting mixture was washed with 3 x 1000 mL of saline solution. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:1). This yielded 120 g (78%) of 5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridine-2-amine as a yellow oil. LC-MS (ES, m / z): M+1:289, 287.

[0229] Synthesis of N-[5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridine-2-yl]acetamide. In a 2000 mL four-necked round-bottom flask, 1000 mL of dichloromethane, a solution of 5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridine-2-amine (84 g, 292.48 mmol, 1.00 equiv), and pyridine (57.8 g, 730.72 mmol, 2.50 equiv) were added. Acetyl chloride (50.2 g, 639.51 mmol, 2.20 equiv) was added dropwise while stirring at 0°C. The resulting solution was stirred overnight at room temperature. Then, 1000 mL of water was added to quench the reaction. The resulting mixture was washed with 2 x 1000 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:10). This yielded 80 g (83%) of N-[5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridine-2-yl]acetamide as a white solid. LC-MS: (ES, m / z): M+1=331.

[0230] Synthesis of 5-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine. In a 2000 mL round-bottom flask, tetrahydrofuran (300 mL), N-[5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridine-2-yl]acetamide (80 g, 242.98 mmol, 1.00 equiv), and TBAF (1 M in tetrahydrofuran) (729 mL, 3.00 equiv) were added. The resulting solution was stirred at 70°C for 12 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. Then, 500 mL of water was added to quench the reaction. The resulting solution was extracted with 3 × 300 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 × 300 mL of saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petromomethic ether (0:1-4:1). This yielded 15 g (29%) of 5-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine as a white solid. LC-MS: (ES, m / z): M+1=213.

[0231] Synthesis of 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine. 5-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine (15 g, 69.76 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL) was added to a 250 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Sodium hydride (4.2 g, 175.00 mmol, 1.50 equiv) was added in divided portions at 0°C. After stirring for 0.5 hours, SEM-Cl (14 g, 84.34 mmol, 1.20 equiv) was added dropwise at 0°C while stirring. The resulting solution was reacted for a further 3 hours at room temperature with stirring. Subsequently, 300 mL of water was added to quench 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 3 x 200 mL of saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:10). This yielded 15 g (62%) of 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine as a yellow oil.

[0232] Synthesis of 6-(tert-butoxy)-N-(diphenylmethylidene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-5-amine. In a 250 mL round-bottom flask, 300 mL of dioxane containing 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine (20.7 g, 60 mmol, 1.00 equiv), t-BuOK (20.5 g, 180 mmol, 3.00 equiv), xanthophos (6.9 g, 12 mmol, 0.20 equiv), Pd2(dba)3·CHCl3 (5.7 g, 0.10 equiv), and diphenylmethanimine (14.04 g, 78 mmol, 1.20 equiv) were added. The resulting solution was stirred overnight at 100°C. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1 to 1:20). This yielded 15 g (crude product) of 6-(tert-butoxy)-N-(diphenylmethylidene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-5-amine as a white oily substance. LC-MS: (ES, m / z): M+1=500.

[0233] Synthesis of 5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-6-ol hydrogen chloride. In a 500 mL round-bottom flask, 120 mL of dioxane, 15 g of 6-(tert-butoxy)-N-(diphenylmethylidene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-5-amine, and 30 mL of HCl / dioxane (4 M) were added. The resulting solution was stirred at room temperature for 5 hours. The resulting solution was diluted with 500 mL of ether. The solid was collected by filtration. This yielded 5 g (crude product) of 5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-6-ol hydrogen chloride as a red solid. Q-NMR indicated that it may be converted to three different hydrogen chlorides. LC-MS: (ES, m / z): M+1=280.

[0234] Synthesis of 4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-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]pyridine-6-ol hydrogen chloride (5 g, 17.89 mmol, 1.00 equiv) and potassium carbonate (7.4 g, 53.54 mmol, 3.00 equiv) dissolved in N,N-dimethylformamide (100 mL) were added, and 2-chloroacetyl chloride (4 g, 35.42 mmol, 2.00 equiv) 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 quench the reaction. The resulting solution was extracted with 3 x 100 mL of ethyl acetate, and the organic layer was combined with it. The resulting mixture was washed with 3 x 100 mL of saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1~1:1). This yielded 2.5 g (44%) of 4-[[2-(trimethylsilyl)ethoxy]methyl]13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-11-one as a white solid. LC-MS: (ES, m / z): M+1=320.

[0235] Synthesis of methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazine-1-yl)benzoic acid. In a 20,000 mL round-bottom flask, 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazine dihydrochloride (60 g, 0.153 mol, 1 equiv), methino-2-bromo-4-fluorobenzoic acid (35.7 g, 0.153 mol, 1 equiv), DBU (31.9 g, 0.612 mol, 4 equiv), and DMSO (800 mL) were added. The resulting solution was stirred at 70°C for 20 hours. LC-MS showed that the materials were completely consumed. The resulting mixture was cooled to room temperature and added to water (3 L). The mixture was filtered, the filter cake was collected, the filter cake was washed with water (300 mL x 3), and dried in an oven to obtain 74 g (Y: 91%) methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazin-1-yl)benzoic acid as a white solid.

[0236] Synthesis of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazin-1-yl)benzoic acid. In a 2000 mL round-bottom flask, 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazin-1-yl)benzoic acid (73 g, 0.137 mol, 1 equiv), LiOH (13.15 g, 0.548 mol, 4 equiv), and MeOH / THF / water (450 mL / 300 mL / 100 mL) were added. The resulting solution was stirred at 70°C for 16 hours. LC-MS showed that the materials were completely consumed. The resulting mixture was cooled to room temperature and concentrated. The residue was diluted with water (500 mL), the mixture was pH adjusted to 3-5 with HCl (6 M), then filtered, the filter cake was collected and dried in an oven to obtain 65 g (Y: 93%) of the product 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazin-1-yl)benzoic acid as a white solid.

[0237] Synthesis of 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-N-(4-[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)benzamide. 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-enyl)methyl)piperazin-1-yl)benzoic acid (55 g, 0.107 mol, 1 equiv), DCM (1 L), (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (32 g, 0.102 mol, 0.95 equiv), EDCI (30.8 g, 0.161 mol, 1.5 equiv), and DMAP (52.2 g, 0.428 mol, 4 equiv) were added to a 2000 mL round-bottom flask. The resulting solution was stirred overnight at 25°C. LC-MS showed that the material was completely consumed. To the obtained mixture, dilute hydrochloric acid (1.0 M) (100 mL x 3), saturated sodium bicarbonate (100 mL x 3), and saline solution (100 mL x 1) were added. The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated, and 81 g of the product (Y: 93%) was obtained as a pale brownish-yellow solid. 2-Bromo-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)-N-(4-[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)benzamide was obtained as a brownish-yellow solid. LC-MS: (ES, m / z): M+1=816 / 819, RT=2.01 min. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-(11oxo-4-[ [2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazaltricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl)benzamide. In a 40 mL round-bottom flask, add 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)benzamide (214.89 mg, 0.263 mmol, 1.2 equiv), 4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-11-one (70.00 mg, 0.219 mmol, 1.00 equiv), 4,7-dimethoxy-1, 10-Phenanthroline (26.33 mg, 0.110 mmol, 0.5 equiv), Cs2CO3 (214.20 mg, 0.657 mmol, 3 equiv), dioxane (10.00 mL), and CuI (20.87 mg, 0.110 mmol, 0.5 equiv) were added. The resulting solution was stirred at 110°C for 3 hours, and the resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0:1 to 1:1).This yielded 200 mg (86.45%) of 44-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-(11oxo-4-[ [2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazaltricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl)benzamide as a crude yellow solid. LC-MS: (ES, m / z): M+1=1055.

[0238] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[11-oxo-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide. In a 40 mL round-bottom flask, combine 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(2 S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-(11oxo-4-[ [2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl) benzamide (200.00 mg, 0.189 mmol, 1.00 equiv), THF (10 mL), and ethylenediamine (227.71 (mg, 3.789 mmol, 20.00 equiv) and TBAF (990.65 mg, 3.789 mmol, 20 equiv) were added. The resulting solution was stirred at 70°C for 12 hours. Then, 10 mL of water was added to quench the reaction. The resulting solution was extracted with 2 x 10 mL of ethyl acetate concentrate.The crude product was purified by Prep-HPLC under the following conditions (Waters-2767): Column: X-bridge RP18, 5um, 19*100mm; Mobile phase: Water (0.03% HCl) and CH3CN (32% CH3CN, up to 52% in 6 minutes) containing 0.03% acid (acerbity); Detector: UV 254 nm. This revealed 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-N-(4-[[(2S)-1,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[ 11-oxo-13-oxa-2,4,10-triazaltricyclo[7. 4.0.0^[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide was obtained as a yellow solid in a concentration of 25 mg (14.26%). LC-MS: (ES, m / z): M+1=925. 1 H NMR (300 MHz, DMSO-d6) δ 11.32 (d, J = 7.2 Hz, 1H), 8.52 (s, 1H), 8.37 (dd, J = 4.6, 2.3 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 5.8 Hz, 1H), 7.11 (d, J = 8.3 Hz, 2H), 6.92 (d, J = 9.7 Hz, 2H), 6.60 (d, J = 1.8 Hz, 1H), 6.15 - 6.07 (m, 1H), 4.67 (d, J = 15.0 Hz, 1H), 4.36 (s, 1H), 3.98 - 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). Preparation of compound 3-1:4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl)benzoic acid: In a 100 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen, 2-bromo-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)benzoic acid (999.0 mg, 1.88 mmol, 4.00 equiv), toluene (20%) Add 4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7,5,0^[3,7]]tetradeca-1(9),2,5,7-tetraene (150 mg, 0.47 mmol, 1 equiv), Cs2CO3 (764.9 mg, 2.35 mmol, 5 equiv), and xanthophos Pd 2G (333.2 mg, 0.38 mmol, 0.8 equiv). Stir the resulting solution overnight at 110°C. Dilute the resulting solution with 300 mL of water. Extract the resulting solution with 2 × 100 mL of ethyl acetate. Wash the resulting mixture with 1 × 300 mL of saline solution. Dry the mixture over anhydrous sodium sulfate and concentrate under vacuum. Apply the residue to a silica gel column with ethyl acetate / petroleum ether (1:2). This yielded 200 mg (55.29%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatrichloro[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl)benzoic acid as a yellow solid. LC-MS: (ES, m / z): M+H=769, R,T=3.076 min. Retention was measured using a reversed-phase column (C18).Shimadzu LCMS 2020; 50×3.0 shim pack XR-ODS, 2.2μm; Elution A: Water (0.05% TFA); Elution B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile over 5.0 mins; Oven temperature 40℃; Flow rate: 1.5 mL / min.

[0239] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[14oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid: In a 40 mL vial, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl)-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-1(200 mg, 0.26 mmol, 1 equiv) of ethane-1,2-diamine (TAF, 3H2O, 2.5 g) and 24.96 mmol, 96.15 equiv) were added. The resulting solution was stirred in an oil bath at 70°C for two nights. The resulting solution was diluted with 200 mL of water. The resulting solution was extracted with 3 × 30 mL of ethyl acetate. The resulting mixture was washed with 2 × 200 mL of saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (2:1). This yielded 130 mg (78.22%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a pale yellow solid. LC-MS: (ES, m / z): M+H=639, R,T=1.388 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS 2020; 50×3.0 shim pack XR-ODS, 2.2μm; Elution A: Water (0.05% TFA); Elution B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile over 2.6 minutes; Oven temperature 40℃; Flow rate: 1.5 mL / min.

[0240] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid: In a 40 mL vial, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (130 mg, 0.20 mmol, 1 (equiv) of 10.00 mol / MeOH was added (6 mL), THF (6 mL), H2O (2 mL), and NaOH (81.2 mg, 2.03 mmol, 10.00 equiv). The resulting solution was stirred overnight in an oil bath at 60°C. The resulting mixture was concentrated under vacuum. The pH of this solution was adjusted to 5-6 with HCl (2 mol / L). The resulting solution was extracted with 2 x 50 mL of dichloromethane / MeOH (v:v=10:1). The resulting mixture was washed with 2 x 200 mL of saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This yielded 80 mg (62.92%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a pale yellow solid. LC-MS: (ES, m / z): M+H=625, R,T=1.336 min. Retention was measured using a reversed-phase column (C18). Shimadzu LCMS 2020; 50×3.0 shim pack XR-ODS, 2.2μm; Elution A: Water (0.05% TFA); Elution B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile over 2.6 minutes; Oven temperature 40℃; Flow rate: 1.5 mL / min.

[0241] 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(3-nitro-4-benzenesulfonyl)-2-[14oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5, Synthesis of 7-tetraen-10-yl]benzamide: In a 40 mL round-bottom flask, 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazine-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (50 mg, 0.08 mmol, 1 equiv), DCM (3 mL), 3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (25.2 mg, 0.08 mmol, 1.00 equiv), EDCI (30.6 mg, 0.16 mmol, 2 equiv), DMAP (39.0 mg, 0.32 mmol, 4 Equiv) was added. The resulting solution was stirred overnight at 25°C, and the resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (10:1). The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): Column: C18 reversed-phase column; Mobile phase: Water (10MMOL / L NH4HCO3 + 0.05% NH3.H2O) + CH3CN (20.0% CH3CN, max 90.0% in 30 min); Detector: UV 220 nm. This yielded 19.1 mg (25.90%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzamide as a yellow solid. LC-MS: (ES, m / z): M+1=923, R,T=3.463 min.Retention was measured using a reversed-phase column (C18). Shimadzu LCMS 2020; 50*3.0 Agilent Poroshell HPH-C 18, 2.7 μm; Elutate A: Water (0.05% aqueous ammonia); Elutate B: Acetonitrile; Linear gradient from 5% acetonitrile to 95% acetonitrile over 7.0 mins; Oven temperature 40°C; Flow rate: 1.5 mL / min. 1 1H NMR (300 MHz, DMSO-d 6, ppm) δ 11.91 (s, 1H), 11.26 (s, 1H), 8.56 (s, 1H), 8.47 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.20 (s, 1H), 7.07 (d, J = 8.3 Hz, 2H), 6.99 - 6.83 (m, 2H), 6.76 (d, J = 29.2 Hz, 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 spectra were measured using a Bruker AvanceIII HD 300 MHz with a BBOF probe head.

[0242] Preparation of Compound 3-2: 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-( (4-( ((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl)piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (80 mg, 0.13 mmol, 1 equiv), DCM (3 mL), 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (42.6 mg, 0.13 mmol, 1.00 equiv), EDCI (49.0 mg, 0.26 mmol, 2 equiv), and DMAP (62.4 mg, 0.51 mmol, 4 equiv) were added to a 40 mL vial. 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 prepared C 18 OBD column, 19 x 150 mm 5 μm; mobile phase, water (10 MMOL / L NH4HCO3 + 0.1% NH3H2O) and CH3CN (retaining 41.0% CH3CN to 61.0% in 6 mins, to 95.0% in 1 min, to 41.0% in 1 min, and to 41.0% in 1 min); detector, UV 210 nm. This yielded 17 mg (14.13%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)-N-(4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-10-ylbenzamide as a yellow solid. LC-MS: (ES, m / z): M+1=940, R,T=1.583 min. Retention was measured using a reversed-phase column (C18).Shimadzu LCMS2020; 50*3.0 Kinetex2.6uXB-C18, 2.6 micrometers; Elution A: Water (0.05% TFA); Elution B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile over 3.0 minutes; Oven temperature 40°C; Flow rate: 1.5 mL / min. 1 1H NMR (300 MHz, DMSO-d 6, ppm) δ 11.94 (s, 1H), 11.25 (s, 1H), 8.59 (s, 1H), 8.48 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 3.1 Hz, 1H), 7.07 (dd, J = 8.9, 3.8 Hz, 3H), 6.94 (s, 1H), 6.71 (s, 2H), 6.13 (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 spectra were measured using a Bruker AvanceIII HD 300 MHz with a BBOF probe head.

[0243] Preparation of compound 3-3:4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-yl)benzamide.

[0244] Synthesis of 4,4,4-trifluoro-3-hydroxybutanamide: Ethyl 4,4,4-trifluoro-3-hydroxybutanoate (500 mg, 2.7 mmol, 1 equiv) and NH3in MeOH (5 mL, 4.0 M) were added to a 50 mL round-bottom flask. The resulting solution was stirred at 60°C for 16 hours, and the resulting mixture was concentrated. This yielded 500 mg of 4,4,4-trifluoro-3-hydroxybutanamide as a white solid. 1 1H NMR (300 MHz, 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 spectra were measured using a Bruker AvanceIII HD 300 MHz with a BBOF probe head.

[0245] Synthesis of 4-amino-1,1,1-trifluorobutan-2-ol: 4,4,4-trifluoro-3-hydroxybutanamide (500 mg, 3.2 mmol, 1 equiv) and THF (10 mL) were placed in a 50 mL three-necked round-bottom flask. LAH (242 mg, 6.4 mmol, 2.00 equiv) was gradually added under ice bath conditions, followed by the addition of THF (10 mL). The resulting solution was stirred at room temperature for 16 hours. After the reaction was complete, 0.24 mL of water was added to the reaction mixture to quench it, and 0.24 mL of NaOH (10% in H2O) and 0.72 mL of water were sequentially added under ice bath conditions. The solid was filtered. The resulting mixture was concentrated under vacuum. This yielded 380 mg (83.43%) of 4-amino-1,1,1-trifluorobutan-2-ol as a colorless oil. 1 1H NMR (300 MHz, CDCL3) , ppm) 4.10-4.01 (m, 1H), 2.70-2.66 (m, 2H), 1.51-1.47 (m, 2H). NMR spectra were measured using a Bruker AvanceIII HD 300 MHz with a BBOF probe head.

[0246] Synthesis of 4-methyl-N-(4,4,4-trifluoro-3-hydroxybutyl)benzenesulfonamide. 4-amino-1,1,1-trifluorobutan-2-ol (350 mg, 2.4 mmol, 1 equiv), TEA (480 mg, 4.8 mmol, 2.0 equiv), and DCM (10 mL) were placed in a 100 mL round-bottom flask, and TsCl (470 mg, 2.4 mmol, 1.0 equiv) was added under ice bath. The resulting solution was diluted with 50 mL of DCM and stirred at room temperature for 4 hours. The resulting mixture was washed with 2 × 20 mL of water and 1 × 20 mL of saline solution. The mixture was dried over anhydrous sodium sulfate. The solid was filtered. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0-50%). This yielded 600 mg (82.52%) of 4-methyl-N-(4,4,4-trifluoro-3-hydroxybutyl)benzene-1-sulfonamide as a colorless oil. 1 1H NMR (300 MHz, 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 spectra were measured using a Bruker AvanceIII HD 300 MHz with a BBOF probe head.

[0247] Synthesis of N-(3-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-6-yloxy)-4,4,4-trifluorobutyl)-4-methylbenzenesulfonamide. 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.9 mmol, 1 equiv), 4-methyl-N-(4,4,4-trifluoro-3-hydroxybutyl)benzene-1-sulfonamide (310 mg, 1.0 mmol, 1.2 equiv), Cs2CO3 (566 mg, 1.7 mmol, 2.0 equiv), and 1,4-dioxane (10 mL) were added to a 100 mL round-bottom flask. The resulting solution was stirred in an oil bath at 90°C for 16 hours. The reaction mixture was cooled. The solid was filtered. 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 saline solution. The mixture was dried over anhydrous sodium sulfate. The solid was filtered. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0-30%). This yielded 400 mg (73.95%) of N-[3-[(5-bromo-1-[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-6-yl)oxy]-4,4,4-trifluorobutyl]-4-methylbenzene-1-sulfonamide as a pale yellow solid. 1 1H NMR (300 MHz, 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 spectra were measured using a Bruker AvanceIII HD 300 MHz probe head equipped with a BBOF probe head.

[0248] Synthesis of 1-tosyl-4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepane. In a 250 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, N-[3-[(5-bromo-1-[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine-6-yl)oxy]-4,4,4-trifluorobutyl]-4-methylbenzene-1-sulfonamide (700 mg, 1.13 mmol, 1 equiv), Cs2CO3 (1.1 g, 3.39 mmol, 3.00 equiv), CuI (214 mg, 1.13 mmol, 1.0 equiv), 2-isobutyrylcyclohexane-1-one (80 mg, 0.56 mmol, 0.5 equiv), and DMSO (10 mL) were added. 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 extracted with 2 x 50 mL of ethyl acetate. The resulting mixture was washed with 1 x 50 mL of saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0-30%). This yielded 350 mg (57.38%) of 1-tosyl-4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3', 2':5,6]pyrido[2,3-b][1,4]oxazepine as a pale yellow solid. 1 1H NMR (300 MHz, 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, 1 H), 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 spectra were measured using a Bruker AvanceIII HD 300 MHz with a BBOF probe head.

[0249] Synthesis of 4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepane. Sodium (150 mg, 6.5 mmol, 1.0 equiv), naphthalene (833 mg, 6.5 mmol, 10 equiv), and DME (3 ml) were added to a 250 mL three-necked round-bottom flask under a nitrogen atmosphere. The reaction mixture was stirred at room temperature until the Na and naphthalene were completely dissolved. To this, a solution of 1-tosyl-4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine (350 mg, 0.65 mmol, 1 equiv) dissolved in THF (5 mL) was added at -78 °C. The resulting solution was stirred at -60 °C to -40 °C for 2-3 hours until all the starting material consumed by TLC was gone. Then, the reaction was quenched 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 and concentrated under vacuum. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1 / 3). This yielded 220 mg (88%) of 4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3', 2':5,6]pyrido[2,3-b][1,4]oxazepine as a white solid.

[0250] Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-yl)benzoic acid. In a 100 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, methyl 2-bromo-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl)benzoic acid (1.2 g, 2.28 mmol, 4.00 equiv), toluene (20 mL), 4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine (220 mg, 0.57 mmol, 1 equiv), Cs2CO3 (923 mg, 2.84 mmol, 5 equiv), xanthophos Pd 2 G (250 (mg, 0.46 mmol, 0.8 equiv) was added. 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 × 30 mL of ethyl acetate. The resulting mixture was washed with 1 × 30 mL of saline solution. The mixture was dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0-50%). This yielded 380 mg of crude product (80.0%) of methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-yl)benzoic acid as a yellow solid. LC-MS: (ES, m / z): M+H=838, R,T=3.33 min. Retention was measured using a reversed-phase column (C18).Shimadzu LCMS 2020; 50 × 3.0 mm, Poroshell HPH-C 18, 2.7 μm; Elution A: Water (0.05% NH₄HCO₃); Elution B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile over 5.0 mins; Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0251] Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzoic acid. Methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3,2,2.5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzoic acid (380 mg, 0.45 mmol, 1 equiv), THF (20 mL), TBAF.3 H2O (708 mg, 2.25 mmol, 5 equiv), and ethane-1,2-diamine (540 mg, 9.0 mmol, 20 equiv) were added to a 40 mL vial. The resulting solution was stirred overnight in an oil bath at 70°C. The obtained solution was diluted with 20 mL of water. The obtained solution was extracted with 3 x 30 mL of ethyl acetate. The obtained mixture was washed with 2 x 20 mL of saline solution. The mixture was dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0-50%). This yielded 300 mg (93%) of methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3,2'.5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzoic acid as a pale yellow solid. 1 1H NMR (300 MHz, CDCL3) ,ppm) 10.78 (bs, 1H), 7.75-7.72 (m, 1H), 7.29-7.24 (m, 3H), 7.00-6.97 (m, 2H), 6.59-6.56 (m, 2H), 6.28-6.26 (m, 1H), 5.28-5.20 (m, 1H), 3.98-3.96 (m, 1H), 3.79-3.77 (m, 1H), 3.59 (s, 1H), 3.24-3.23 (m, 3H), 2.84 (m, 2H), 2.31-2.28 (m, 4H), 2.26-2.24 (m, 4H), 1.49-1.47 (m, 2H), 1.34-1.24 (m, 4H), 1.00 (s, 6H), 0.96-0.90 (m, 2H)。

[0252] Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzoic acid. Methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3,2'.5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzoic acid (200 mg, 0.28 mmol, 1 equiv), MeOH (6 mL), 1,4-dioxane (6 mL), H2O (2 mL), and NaOH (67 mg, 1.68 mmol, 6.00 equiv) were added to a 40 mL vial. The resulting solution was stirred overnight in an oil bath at 60°C. The resulting mixture was concentrated under vacuum. The pH of this solution was adjusted to 5-6 with HCl (2 mol / L). The resulting solution was extracted with 2 x 50 mL of dichloromethane / MeOH (v:v=10:1). The resulting mixture was washed with 2 x 200 mL of saline solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This yielded 157 mg (81.0%) of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzoic acid as a pale yellow solid. LC-MS (ES, m / z): M+H=694, R, T=2.43 min. Retention was measured using a reversed-phase column (C 18).Shimadzu LCMS 2020; 50 × 3.0 mm, Poroshell HPH-C 18, 2.7 μm; Elution A: Water (0.05% NH₄HCO₃); Elution B: Acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile over 5.0 mins; Oven temperature 40°C; Flow rate: 1.5 mL / min.

[0253] Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-yl)benzamide. In a 40 mL round-bottom flask, combine the following: 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3,2,2.5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzoic acid (57 mg, 0.08 mmol, 1 equiv), DCM (3 mL), 3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (25.2 mg, 0.08 mmol, 1.00 equiv), EDCI (30.6 mg, 0.16 mmol, 2 equiv), and DMAP (39.0 mg, 0.32 mmol, 4 equiv). The mixture was added. The resulting solution was stirred overnight at 25°C, and the resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (10:1). The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): Column: C18 reversed-phase column; Mobile phase: Water (10MMOL / L NH4HCO3 + 0.05% NH3.H2O) + CH3CN (20.0% C...

Claims

1. Formula (A) 【Chemistry 1】 (In the formula, R b , a , c , b , 2 , b , b , a , b , b , p , b , b , b , b , c , c , c , a , d , c , a , 2 , c , a , c , c , a , 2 , c , R 2 , R 7 , R 9 , and R 10 are each independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, OR a , SR a , alkyl - R a , NH(CH 2 ) p R a , C(O)R a , S(O)R a , SO 2 R 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 , SO 2 N(R b )R c , or N(R b )SO 2 R c and wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl are substituted with one or more R d ; R a , R b , R c , and R d Each of these is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, where the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl are arbitrarily one or more R e It has been replaced with; R e L is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; L is -L 1 -L 2 - and; L 1 R is a bond, alkenylene, alkylylene, cycloalkylene, cycloalkenylene, heterocycloalkylene, heterocycloalkenylene, arylene, or heteroarylene, where the alkenylene, alkylylene, cycloalkylene, cycloalkenylene, heterocycloalkylene, heterocycloalkenylene, arylene, or heteroarylene is any one or more R d It has been replaced with; L 2 This is a bond, or one or more -L atoms between any two adjacent carbon atoms. i - is an alkylene into which a hyphen is arbitrarily inserted; -L i - is N(R a )-, -O-, -S-, -C(O)-, -S(O 2 )-, -OC(O)-, -C(O)O-, -OSO 2 -, -S(O 2 )O-, -C(O)S-, -SC(O)-, -C(O)C(O)-, -C(O)N(R a )-,-N(R a )C(O)-,-S(O 2 )N(R a )-,-N(R a )S(O 2 )-, -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 ) - a divalent alkenylene group, a divalent alkylylene group, a divalent cycloalkylene group, a divalent heterocycloalkylene group, a divalent arylene group, a divalent heteroarylene group; Two R's 1 The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R 1 The cycloalkyl or heterocycloalkyl group may be any one or more R groups. d It is also fine if it is replaced with; Two R's 2 The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R 2 The cycloalkyl or heterocycloalkyl group may be any one or more R groups. d It is also fine if it is replaced with; Two R's 7 The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R 7 The cycloalkyl or heterocycloalkyl group may be any one or more R groups. d It is also fine if it is replaced with; Two R's 10 The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R 10 The cycloalkyl or heterocycloalkyl group may be any one or more R groups. d It is also fine if it is replaced with; R 7 The L groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atom to which they are bonded, where R 7 And the cycloalkyl or heterocycloalkyl of L may be any one or more R e It is also fine if it is replaced with; R b and R c The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R b and R c The cycloalkyl or heterocycloalkyl group may be any one or more R groups. e It is also fine if it is replaced with; Two Rs d The groups, together with the atoms to which they are attached, may optionally form one cycloalkyl or heterocycloalkyl, where the d cycloalkyl or heterocycloalkyl of R may optionally be substituted with one or more Rs e ; Two R's e The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R e The cycloalkyl or heterocycloalkyl group may optionally be substituted with one or more groups selected from H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; k, g, m, n, and p are each independently 0, 1, 2, 3, 4, or 5; and f is either 0 or 1. A compound or a pharmaceutically acceptable salt thereof A solid dispersion 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, dispersed in a solid matrix.

2. The compound is given by formula (A-1): 【Chemistry 2】 A solid dispersion according to claim 1, represented as shown in the image.

3. The compound is given by formula (A-2): 【Transformation 3】 The solid dispersion according to claim 2, as represented by [the specified method].

4. The compound is given by formula (A-3): 【Chemistry 4】 A solid dispersion according to claim 3, represented as shown in the image.

5. The compound, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-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)piperazine-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazine-1(6H)-yl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazine-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)piperazine-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-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)piperazine-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, (S)-N-((4-(((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)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (R)-N-((4-(((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)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-yl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-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)piperazine-1-yl)-2-((R)-4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, N-((4-(((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)piperazine-1-yl)-2-((S)-4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide A solid dispersion according to claim 1, selected from the group consisting of the following.

6. 1) The compound or salt is present in an amount equivalent to 5 wt% to 40 wt% of the parent compound; 2) Copovidone 60 / 40 is KOLLIDON (R) Contains VA64 type copovidone; 3) The nonionic surfactant includes polysorbate containing TWEEN® 80 brand polysorbate 80; and / or 4) The antioxidant contains ascorbic acid or ascorbate; The solid dispersion according to claim 1.

7. The solid dispersion according to claim 1, further comprising at least one lubricant, wherein the at least one lubricant comprises colloidal silicon dioxide.

8. 1) The compound or salt is present in an amount equivalent to 5% to 40% by weight of the parent compound; 2) At least one polymer support is present in an amount of 40% to 85% by weight; 3) At least one surfactant is present in an amount of 2.5% to 20% by weight; and 4) At least one antioxidant is present in an amount of 0.25% to 5% by weight; The solid dispersion according to claim 1.

9. The solid dispersion according to claim 1, further comprising at least one disintegrant, at least one lubricant, and / or at least one coating.

10. (1) The compound or salt is present in an amount equivalent to 12 to 20% by weight of the parent compound, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-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)piperazine-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazine-1(6H)-yl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazine-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)piperazine-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-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)piperazine-1-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, (S)-N-((4-(((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)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (R)-N-((4-(((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)piperazine-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-yl)benzamide, (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-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]oxazepine-1(7H)-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)piperazine-1-yl)-2-((R)-4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide, or N-((4-(((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)piperazine-1-yl)-2-((S)-4-(trifluoromethyl)-3,4-dihydro-2H-pyrroliro[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-1(7H)-yl)benzamide; 2) KOLLIDON containing at least one pharmaceutically acceptable water-soluble polymer carrier in an amount of 70-80% by weight. (R) Contains VA64 type copovidone; 3) A polysorbate of brand TWEEN® 80 containing at least one pharmaceutically acceptable nonionic surfactant in an amount of 7–9% by weight; 4) containing at least one pharmaceutically acceptable antioxidant present in an amount of 0.5 to 1% by weight of ascorbic acid or ascorbate; and 5) At least one lubricant comprises colloidal silicon dioxide; The solid dispersion according to claim 8.

11. When a 100 mg oral dose of the solid dispersion is force-administered to a 5-10 kg Beagle dog, the AUC is at least 25,000-150,000 h*ng / ml, at least 30,000-100,000 h*ng / ml, at least 40,000-80,000 h*ng / ml, or at least 50,000-60,000 h*ng / ml. (0-t) A solid dispersion according to claim 1, which shows a value.

12. The compound is (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; or a pharmaceutically acceptable salt thereof; The pharmaceutically acceptable water-soluble polymer carrier is copovidone VA64; The surfactant is polysorbate 80 of the TWEEN® 80 brand; and The antioxidant is ascorbic acid or ascorbate; The solid dispersion according to claim 1.

13. The compound or a pharmaceutically acceptable salt thereof is present in an amount equivalent to 12% by weight of the parent compound; Copovidone VA64 makes up 79% by weight; TWEEN® 80 brand polysorbate 80 is present in a quantity of 7% by weight; The antioxidant is 1% by weight; and The solid dispersion further contains a lubricant, the lubricant being silicon dioxide, and the silicon dioxide being 1% by weight; The solid dispersion according to claim 12.

14. (a) (i) A pharmaceutically active ingredient (API) comprising the compound of formula (A) or a pharmaceutically acceptable salt thereof, 【Transformation 5】 (In the formula, R 1 、R 2 、R 7 、R 9 、and R 10 are each independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, OR a 、SR a 、alkyl-R a 、NH(CH 2 ) p R a 、C(O)R a 、S(O)R a 、SO 2 R 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 、SO 2 N(R b )R c 、or N(R b )SO 2 R c and wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl are substituted with one or more R d ; R a , R b , R c , and R d Each of these is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, where the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl are arbitrarily one or more R e It has been replaced with; R e L is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; L is -L 1 -L 2 - and; L 1 R is a bond, alkenylene, alkylylene, cycloalkylene, cycloalkenylene, heterocycloalkylene, heterocycloalkenylene, arylene, or heteroarylene, where the alkenylene, alkylylene, cycloalkylene, cycloalkenylene, heterocycloalkylene, heterocycloalkenylene, arylene, or heteroarylene is any one or more R d It has been replaced with; L 2 This is a bond, or one or more -L atoms between any two adjacent carbon atoms. i - is an alkylene into which a hyphen is arbitrarily inserted; -L i - is N(R a )-, -O-, -S-, -C(O)-, -S(O 2 )-, -OC(O)-, -C(O)O-, -OSO 2 -, -S(O 2 )O-, -C(O)S-, -SC(O)-, -C(O)C(O)-, -C(O)N(R a )-,-N(R a )C(O)-,-S(O 2 )N(R a )-,-N(R a )S(O 2 )-, -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 ) - a divalent alkenylene group, a divalent alkylylene group, a divalent cycloalkylene group, a divalent heterocycloalkylene group, a divalent arylene group, a divalent heteroarylene group; Two R's 1 The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R 1 The cycloalkyl or heterocycloalkyl group may be any one or more R groups. d It is also fine if it is replaced with; Two R's 2 The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R 2 The cycloalkyl or heterocycloalkyl group may be any one or more R groups. d It is also fine if it is replaced with; Two R's 7 The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R 7 The cycloalkyl or heterocycloalkyl group may be any one or more R groups. d It is also fine if it is replaced with; Two R's 10 The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R 10 The cycloalkyl or heterocycloalkyl group may be any one or more R groups. d It is also fine if it is replaced with; R 7 The L groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atom to which they are bonded, where R 7 And the cycloalkyl or heterocycloalkyl of L may be any one or more R e It is also fine if it is replaced with; R b and R c The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R b and R c The cycloalkyl or heterocycloalkyl group may be any one or more R groups. e It is also fine if it is replaced with; Two R's d The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R d The cycloalkyl or heterocycloalkyl group may be any one or more R groups. e It is also fine if it is replaced with; Two R's e The groups may optionally form a cycloalkyl or heterocycloalkyl group together with the atoms to which they are bonded, where R e The cycloalkyl or heterocycloalkyl group may optionally be substituted with one or more groups selected from H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; k, g, m, n, and p are each independently 0, 1, 2, 3, 4, or 5; and f is either 0 or 1. (ii) A pharmaceutically acceptable water-soluble polymer carrier, (iii) pharmaceutically acceptable surfactants, and (iv) Optionally, pharmaceutically acceptable antioxidants, The step of subjecting to a raised temperature and providing an extruded semi-solid mixture: (b) the step of extruding a semi-solid mixture; and (c) Cooling the obtained extruded material to prepare a solid matrix comprising a polymer carrier and a surfactant, wherein a compound or a salt thereof is dispersed therein in an essentially amorphous form; A method for preparing the solid dispersion according to claim 1, including the above.

15. The method according to claim 14, wherein the API, polymer carrier, surfactant, and antioxidant are mixed together before or while being subjected to a raised temperature.

16. The method according to claim 14, wherein the raised temperature is 100°C to 200°C, 125°C to 175°C, or 140°C to 160°C.

17. The method according to claim 14, further comprising polishing the extruded material before or while it is being cooled.

18. An orally administered pharmaceutical preparation comprising a solid dispersion according to any one of claims 1 to 8.

19. A solid dispersion according to any one of claims 1 and 5 to 8, for treating a neoplastic disease, an immune disease, or an autoimmune disease.

20. A solid dispersion according to any one of claims 2 to 4 for treating a neoplastic disease, an immune disease, or an autoimmune disease.

21. The solid dispersion according to claim 20, administered at an equivalent dose of the parent compound of formula A-1 or a salt thereof, in an amount of 10 to 1,000 mg per day, with an average therapeutic interval of 6 hours to 7 days.

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