TW202416963A - Egfr inhibitors and uses thereof - Google Patents

Abstract

Disclosed herein are compounds or pharmaceutically acceptable salts thereof that are useful as EGFR inhibitors. Also disclosed are pharmaceutical compositions comprising such compounds, and methods of using such compounds or compositions to treat EGFR-related disorder (e.g., cancers).

Description

EGFR inhibitor and its use

The present disclosure generally relates to novel compounds and pharmaceutically acceptable salts thereof that inhibit epidermal growth factor receptor (EGFR). The present disclosure also relates to pharmaceutical compositions comprising the compounds as active ingredients and the use of the compounds in treating EGFR-related diseases (including cancer).

Epidermal growth factor receptor (EGFR) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The EGFR family of receptor tyrosine kinases regulates cell proliferation, survival, adhesion, migration, and differentiation. Inhibition of EGFR activity has demonstrated potential therapeutic applicability in a wide range of pathological conditions. Certain cancers are characterized by EGFR mutations that result in increased cell proliferation. Currently available EGFR inhibitors include, for example, gefitinib and erlotinib as first-generation EGFR inhibitors and afatinib as a second-generation covalent EGFR inhibitor. Recently, the development of third-generation wild-type-retaining EGFR inhibitors such as WZ4002 and fourth-generation EGFR inhibitors has been reported. There remains a need for novel compounds that inhibit EGFR, which can be used as pharmacological tools and are of considerable interest as drugs for the treatment of EGFR-related disorders such as cancer.

Disclosed herein are novel compounds capable of inhibiting EGFR. Therefore, the compounds disclosed herein can be used to treat EGFR-related diseases such as cancer. In one aspect, the disclosure provides a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl; Ring B is selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl; ^L1 is selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl and a heteroalkynyl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl and the heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of a hydroxyl, a halogen, a cyano and an amino; ^L2 is selected from the group consisting of a bond, N(R ^A ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more ^RB ; wherein R ^A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; wherein each ^RB is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclo, aryl and heteroaryl; L ^wherein L is selected from the group consisting of: a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, and the heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl, a halogen, a cyano, and an amino group; ^L is selected from O, S, or N(R ^C ); wherein R ^C is selected from the group consisting of: hydrogen, an alkyl, an alkenyl, an alkynyl, a halogenated alkyl, a heteroalkyl, a heteroalkenyl, a heteroalkynyl, a cycloalkyl, a heterocyclo, an aryl, and a heteroaryl group; each R ¹ is independently selected from the group consisting of: a hydroxyl, a halogen, a cyano, an amino group, -N(R ^D ) ₂ , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more R ^E ; wherein each R ^D is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, -N( ^RF ) ₂ or ^-ORG ; wherein each ^RE is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, -N( ^RF ) ₂ , -alkyl-N( ^RF ) ₂ , -C(O) ^ORG , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino and alkyl; wherein each of ^RF and ^RG is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; each R ^R is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; ³ is selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo are optionally substituted with one or more groups independently selected from the group consisting of: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; m is an integer from 0 to 5; and n is an integer from 0 to 4. On the other hand, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: and On the other hand, the present disclosure provides a compound of formula (II): (II) or a pharmaceutically acceptable salt thereof, wherein: Ring A ¹ is a 7-12 membered cycloalkyl, a 7-12 membered heterocyclic group, a 7-12 membered aryl or a 7-12 membered heteroaryl; Ring B is selected from the group consisting of a cycloalkyl, a heterocyclic group, an aryl and a heteroaryl; L ¹ is selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl and a heteroalkynyl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl and the heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of a hydroxyl, a halogen, a cyano and an amino group; L ² is selected from the group consisting of a bond, an N(R ^A ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more ^RB ; wherein R ^A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; wherein each ^RB is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclo, aryl and heteroaryl; L ^wherein L is selected from the group consisting of: a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, and the heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl, a halogen, a cyano, and an amino group; ^L is selected from O, S, or N(R ^C ); wherein R ^C is selected from the group consisting of: hydrogen, an alkyl, an alkenyl, an alkynyl, a halogenated alkyl, a heteroalkyl, a heteroalkenyl, a heteroalkynyl, a cycloalkyl, a heterocyclo, an aryl, and a heteroaryl group; each R ¹ is independently selected from the group consisting of: a hydroxyl, a halogen, a cyano, an amino group, -N(R ^D ) ₂ , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more R ^E ; wherein each R ^D is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, -N( ^RF ) ₂ or ^-ORG ; wherein each ^RE is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, -N( ^RF ) ₂ , -alkyl-N( ^RF ) ₂ , -C(O) ^ORG , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino and alkyl; wherein each of ^RF and ^RG is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; each R ^R is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; each R ³ is selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; m is an integer from 0 to 5; n is an integer from 0 to 4; and p is an integer from 0 to 3. On the other hand, the present disclosure provides a compound of formula (III) (III) or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl; Ring ^B is 7-12 membered cycloalkyl, 7-12 membered heterocyclic, 7-12 membered aryl or 7-12 membered heteroaryl; L is selected ^from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl and a heteroalkynyl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl and the heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of a hydroxyl, a halogen, a cyano and an amino; L ^is selected from the group consisting of a bond, N(R ^A ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more ^RB ; wherein R ^A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; wherein each ^RB is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclo, aryl and heteroaryl; L ^wherein L is selected from the group consisting of: a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, and the heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl, a halogen, a cyano, and an amino group; ^L is selected from O, S, or N(R ^C ); wherein R ^C is selected from the group consisting of: hydrogen, an alkyl, an alkenyl, an alkynyl, a halogenated alkyl, a heteroalkyl, a heteroalkenyl, a heteroalkynyl, a cycloalkyl, a heterocyclo, an aryl, and a heteroaryl group; each R ¹ is independently selected from the group consisting of: a hydroxyl, a halogen, a cyano, an amino group, -N(R ^D ) ₂ , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more R ^E ; wherein each R ^D is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, -N( ^RF ) ₂ or ^-ORG ; wherein each ^RE is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, -N( ^RF ) ₂ , -alkyl-N( ^RF ) ₂ , -C(O) ^ORG , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino and alkyl; wherein each of ^RF and ^RG is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; each R ^R is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; each R ³ is selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; m is an integer from 0 to 5; n is an integer from 0 to 4; and p is an integer from 0 to 3. On the other hand, the disclosure provides a compound of formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl; Ring B is selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl; L ¹ is selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl and a heteroalkynyl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl and the heteroalkynyl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano and amino; L ²¹ is a 7-12 membered cycloalkyl or a 7-12 membered heterocyclic, wherein the cycloalkyl and heterocyclic are optionally substituted with one or more ^RB ; wherein each R ^B is independently selected from the group consisting of: hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclo, aryl and heteroaryl; ^L3 is selected from the group consisting of: bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of: hydroxyl, halogen, cyano and amino; ^L4 is selected from O, S or N (R ^C ); wherein R ^C is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogenated alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; each R ¹ is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, -N( ^RD ) ₂ , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more ^RE ; wherein each R ^D is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, -N( ^RF ) ₂ or ^-ORG ; wherein each ^RE is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, -N( ^RF ) ₂ , -alkyl-N( ^RF ) ₂ , -C(O) ^ORG , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino and alkyl; wherein each of ^RF and ^RG is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; each R ^R is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; ³ is selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo are optionally substituted with one or more groups independently selected from the group consisting of: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; m is an integer from 0 to 5; n is an integer from 0 to 4; and p is an integer from 0 to 3. On the other hand, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . On the other hand, the disclosure provides a kind of pharmaceutical composition, the pharmaceutical composition comprises the compound disclosed herein or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. In other aspects, the disclosure provides a kind of method for suppressing the EGFR activity in the subject in need, the method comprising applying an effective amount of the compound disclosed herein or its pharmaceutically acceptable salt or the pharmaceutical composition disclosed herein to the subject. In other aspects, the disclosure provides a kind of method for treating EGFR related conditions, the method comprising applying an effective amount of the compound disclosed herein or its pharmaceutically acceptable salt or the pharmaceutical composition disclosed herein to the subject in need. On the other hand, the disclosure provides the use of the compound disclosed herein or its pharmaceutically acceptable salt or the pharmaceutical composition disclosed herein in the preparation of a medicine for treating EGFR related conditions. In another aspect, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure for treating EGFR-related diseases.

Reference will now be made in detail to certain embodiments of the disclosure, embodiments of which are shown in the attached structures and formulas. Although the disclosure will be described in conjunction with the enumerated embodiments, it should be understood that the embodiments are not intended to limit the disclosure to those embodiments. On the contrary, the disclosure is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the disclosure as defined in the claims. Those skilled in the art will recognize many methods and materials that are similar or equivalent to the methods and materials described herein and that can be used in practicing the disclosure. The disclosure is in no way limited to the methods and materials described. In the event that one or more of the incorporated references and similar materials (including but not limited to defined terms, term usage, described techniques, etc.) are different from or contradictory to the present application, the disclosure shall prevail. All references, patents, and patent applications cited in this disclosure are hereby incorporated by reference in their entirety. It should be understood that certain features of the disclosure described in the context of separate embodiments for the sake of clarity may also be provided in combination in a single embodiment. Conversely, various features of the disclosure described in the context of a single embodiment for the sake of brevity may also be provided individually or in any suitable subcombination. It must be noted that, as used in the specification and the appended claims, the singular forms "a or an" and "the" include their plural forms unless the context clearly indicates otherwise. Thus, for example, a reference to "a compound" includes a plurality of compounds. Definitions Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed., inside cover, and specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry as well as specific functional moieties and reactivities are described in the following references: Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; LaEGFR, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1996. 1987; each of which is incorporated herein by reference in its entirety. Throughout this disclosure, linking substituents are described. Where a structure clearly requires a linking group, the Markush variable listed for that group is to be understood as the linking group. For example, if a structure requires a linking group and the Markush group definition for the variable lists "alkyl", it is to be understood that "alkyl" means a linking alkylene group. In any variable (e.g., R ⁱ) occurs more than once in any constituent or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if the indicated group is represented by 0 to 2 R ⁱPartially substituted, the group may be optionally replaced by up to two R ⁱPartial replacement, and R ⁱSelected independently from R at each occurrenceⁱ. Furthermore, combinations of substituents and/or variables are permitted, but only if such combinations result in stable compounds. As used herein, for convenience, a dash "-" is used in front of or at the end of a chemical group to indicate the point of attachment of a substituent. For example, -OH is attached through an oxygen atom; a chemical group may be depicted with one or more dashes or without one or more dashes without losing its general meaning. A wavy line drawn through a line in a structure indicates the point of attachment of a group. Unless chemically or structurally required, directionality does not indicate or imply the order in which the chemical groups are written or named. As used herein, a solid line from the center of a ring indicates that the point of attachment of a substituent on the ring can be at any ring atom. When substituents are listed without specifying the atom via which such substituents are bonded to the rest of the compound of a given formula, such substituents may be bonded via any atom in the formula. Combinations of substituents and/or variables are permitted, but only if such combinations result in stable compounds. Unless otherwise indicated herein, the recitation of numerical ranges is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated into the specification as if it were individually recited herein. As used herein, ranges include both limits of the range unless otherwise indicated. For example, the expressions "n is an integer between 1 and 6" and "n is an integer from 1 to 6" both mean "n is 1, 2, 3, 4, 5, or 6." As used herein, the term "compounds provided herein", or "compounds disclosed herein" or "compounds disclosed herein" refers to compounds of formula (I), (II), (III) and (IV) as well as specific compounds disclosed herein. As used herein, the term "C _ij" indicates a range of carbon atom numbers, where i and j are integers, and the range of carbon atom numbers includes the endpoints (i.e., i and j) and every integer point in between, and where j is greater than i. For example, C _1-6Indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms. In some embodiments, the term "C _1-12” indicates 1 to 12 carbon atoms, especially 1 to 10 carbon atoms, especially 1 to 8 carbon atoms, especially 1 to 6 carbon atoms, especially 1 to 5 carbon atoms, especially 1 to 4 carbon atoms, especially 1 to 3 carbon atoms or especially 1 to 2 carbon atoms. As used herein, the term "alkyl", whether used as part of another term or independently, refers to a saturated straight or branched chain alkyl group that may be optionally substituted independently by one or more substituents described below. The term "C _ij"Alkyl" refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 9 carbon atoms. In some embodiments, the alkyl group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C _1-10Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "C _1-6Examples of "alkyl" are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc. As used herein, the term "alkenyl", whether used as part of another term or independently, refers to a straight or branched chain alkyl group having at least one carbon-carbon double bond that may be optionally substituted independently with one or more substituents described herein and includes groups having "cis" orientation and "trans" orientation or alternatively "E" orientation and "Z" orientation. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms. In the formula, the alkenyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl group includes 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethylenyl or vinyl, propenyl (allyl), butenyl, pentenyl, 1-methyl-2-butene-1-yl, 5-hexenyl, etc. As used herein, the term "alkynyl", whether used as part of another term or independently, refers to a straight or branched alkyl group having at least one carbon-carbon triple bond that may be optionally independently substituted with one or more substituents described herein. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkynyl group includes 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like. As used herein, the term "amino" refers to -NH ₂The amino group may also be substituted by one or more groups such as alkyl, alkenyl, alkynyl, aryl, carbonyl or other amino groups. As used herein, the term "aryl", whether used as part of another term or independently, refers to monocyclic and polycyclic systems having a total of 5 to 20 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system includes 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, etc., which may carry one or more substituents. As used herein, the scope of the term "aryl" also includes groups in which an aromatic ring is fused to one or more additional rings. In the case of a polycyclic system, only one ring needs to be aromatic (e.g., 2,3-dihydroindole), but all rings can be aromatic (e.g., quinoline). The second ring can also be fused or bridged. Examples of polycyclic aryl groups include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthalimidyl, phenanthridinyl, or tetrahydronaphthyl, etc. The aryl group can be substituted at one or more ring positions with substituents as described above. As used herein, the term "cyano" refers to -CN. As used herein, the term "cycloalkyl", whether used as part of another term or by itself, refers to a monovalent non-aromatic saturated or partially unsaturated monocyclic and polycyclic system in which all ring atoms are carbon and the system includes at least three ring-forming carbon atoms. In some embodiments, the cycloalkyl group may contain 3 to 12 ring-forming carbon atoms, 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, 3 to 8 ring-forming carbon atoms, 3 to 7 ring-forming carbon atoms, 3 to 6 ring-forming carbon atoms, 3 to 5 ring-forming carbon atoms, 4 to 12 ring-forming carbon atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming carbon atoms, 4 to 8 ring-forming carbon atoms, 4 to 7 ring-forming carbon atoms, 4 to 6 ring-forming carbon atoms, 4 to 5 ring-forming carbon atoms. The cycloalkyl group may be saturated or partially unsaturated. The cycloalkyl group may be substituted. In some embodiments, the cycloalkyl group may be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group including at least one double or triple bond in its ring system. In some embodiments, the cycloalkyl group may be monocyclic or polycyclic. In the case of polycyclic systems, fused, spiro and bridged ring systems are included within the scope of this definition. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro[3.6]-decyl, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, etc. As used herein, the term "halogen" refers to an atom selected from fluorine (fluorine or fluoro), chlorine (chlorine or chloro), bromine (bromine or bromo) and iodine (iodine or iodo). As used herein, the term "heteroatom" refers to nitrogen, oxygen, sulfur, phosphorus, and includes any oxidized form of nitrogen, sulfur or phosphorus and any quaternized form of basic nitrogen (including N-oxide). As used herein, the term "heteroalkyl" refers to an alkyl group in which at least one of its carbon atoms is replaced by a heteroatom selected from N, O or S. The heteroalkyl group can be a carbon group or a heteroatom group (i.e., the heteroatom can appear in the middle or at the end of the group) and can be optionally substituted independently by one or more substituents described herein. The term "heteroalkyl" covers alkoxy and heteroalkoxy groups. As used herein, the term "heteroalkenyl" refers to an alkenyl group in which at least one of its carbon atoms is replaced by a heteroatom selected from N, O or S. The heteroalkenyl group may be a carbon group or a heteroatom group (i.e., the heteroatom may be present in the middle or at a terminal of the group), and may be optionally and independently substituted with one or more substituents described herein. As used herein, the term "heteroalkynyl" refers to an alkynyl group in which at least one of its carbon atoms is replaced by a heteroatom selected from N, O or S. The heteroalkynyl group may be a carbon group or a heteroatom group (i.e., the heteroatom may be present in the middle or at a terminal of the group), and may be optionally and independently substituted with one or more substituents described herein. As used herein, the term "heteroaryl", whether used as part of another term or independently, refers to an aryl group having one or more heteroatoms in addition to carbon atoms. Heteroaryl can be monocyclic. Examples of monocyclic heteroaryl include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, oxazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. Heteroaryl also includes polycyclic groups in which a heteroaromatic ring is fused to one or more aryl, cycloalkyl, or heterocyclic rings, wherein the connecting group or point of attachment is located on the heteroaromatic ring. Examples of polycyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo[1,3]dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, dihydroisoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, oxazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, etc. As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated carbocyclic group, wherein one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, etc., and the remaining ring atoms are carbon, wherein one or more ring atoms can be optionally independently substituted by one or more substituents. In some embodiments, the heterocyclic group is a saturated heterocyclic group. In some embodiments, the heterocyclic group is a partially unsaturated heterocyclic group having one or more double bonds in its ring system. In some embodiments, the heterocyclic group can include any oxidized form of carbon, nitrogen, sulfur or phosphorus and any quaternized form of basic nitrogen. "Heterocyclic" also includes groups in which the heterocyclic group is fused to a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic group. Where possible, the heterocyclic group can be carbon-linked or nitrogen-linked. In some embodiments, the heterocyclic group is carbon-linked. In some embodiments, the heterocyclic group is nitrogen-linked. For example, a group derived from pyrrole can be pyrrol-1-yl (nitrogen-linked) or pyrrol-3-yl (carbon-linked). Further, a group derived from imidazole can be imidazol-1-yl (nitrogen-linked) or imidazol-3-yl (carbon-linked). In some embodiments, the term "3- to 12-membered heterocyclic group" refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, sulfur or phosphorus. In the case of a polycyclic system, fused, spiro and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclic groups include, but are not limited to, oxacyclobutanyl, 1,1-dioxothiacyclobutanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, oxazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, oxazinonyl, pyrrolidinyl, triazinonyl, and the like. Examples of fused heterocyclic radicals include, but are not limited to, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothiophenyl, benzothiophene, benzothiazolyl ... oxazolyl, oxazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, hexahydro-1H-pyrrolizinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazol[4,3-a]pyridinyl, [1,2,3]triazol[4,3-a]pyridinyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, etc. Examples of spiroheterocyclic groups include, but are not limited to, spiropyranyl, spirooxazinyl, 2,6-diazaspiro[3.3]heptanyl, 2,5-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 5-oxa-2,8-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, and the like. Examples of bridged heterocyclic groups include, but are not limited to, morpholinyl, hexamethylenetetramine, 3-aza-bicyclo[3.1.0]hexane, 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 8-aza-bicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane, 3-azabicyclo[3.2.2]nonane, etc. As used herein, the term "hydroxyl" or "hydroxy" refers to -OH. As used herein, the term "partially unsaturated" refers to a group that includes at least one double or triple bond. The term "partially unsaturated" is intended to cover rings with multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties. As used herein, the term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. As used herein, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. It should be understood that "substituted" or "substituted by" includes the implicit proviso that such substitution is consistent with the allowed valencies of the substituted atom and that the substitution results in a stable or chemically feasible compound, e.g., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be the same or different at each position. Substitutions may include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halogen, halogenated alkyl, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazine, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. It will be understood by those skilled in the art that the substituents themselves may be substituted, if appropriate. Unless specifically stated as "unsubstituted," references to chemical moieties herein are to be understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants. As used herein, the term "substituted", whether preceded by the term "optionally", means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. It should be understood that "substituted" or "substituted by..." includes the implicit precondition that such substitution is consistent with the allowed valence of the substituted atom and that the substitution produces a stable or chemically feasible compound, for example, a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be the same or different at each position. It will be understood by those skilled in the art that the substituent itself may be substituted if appropriate. Unless specifically stated as "unsubstituted," references to chemical moieties herein are to be understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants. The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom. The isomer descriptors "R" and "S" are used as described herein to indicate the configuration of atoms relative to the core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68: 2193-2222 (1996)). Compounds In one aspect, the present disclosure provides compounds of formula (I): Formula (I) or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from the group consisting of: cycloalkyl, heterocyclic, aryl and heteroaryl; Ring B is selected from the group consisting of: cycloalkyl, heterocyclic, aryl and heteroaryl; L ¹Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ²Select from the group consisting of: key, N(R ^A), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted by one or more R ^BReplace; Where R ^ASelected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; wherein each R ^BIndependently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclo, aryl and heteroaryl; L ³Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ⁴Choose from O, S or N(R ^C)； Where R ^CSelected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogenated alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ¹Independently selected from the group consisting of: hydroxyl, halogen, cyano, amino, -N(R ^D) ₂, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted by one or more R ^EReplace; where each R ^DIndependently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano,  -N(R ^F) ₂OR ^G; where each R ^EIndependently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, -N(R ^F) ₂、-alkyl-N(R ^F) ₂、-C(O)OR ^G, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino and alkyl; wherein R ^Fand R ^GEach of R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ²Independently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; R ³Selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo are optionally substituted with one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; m is an integer from 0 to 5; and n is an integer from 0 to 4. In some embodiments, Ring A is aryl. In certain embodiments, Ring A is C _6-12Aryl, C _6-11Aryl, C _6-10Aryl, C _6-9Aryl or C _6-8Aryl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is heteroaryl. In some embodiments, Ring A is 5-12 membered heteroaryl, 5-11 membered heteroaryl, 5-10 membered heteroaryl, 5-9 membered heteroaryl, 5-8 membered heteroaryl, 5-7 membered heteroaryl or 5-6 membered heteroaryl. In some embodiments, Ring A is selected from the group consisting of furanyl, phenylthio, pyrrolyl, pyridyl, pyranyl, pyrimidinyl, oxazinyl, pyrazinyl and tetrahydroisoquinolinyl. In some embodiments, Ring A is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 and . In some embodiments, Ring B is aryl. In some embodiments, Ring B is C _6-12Aryl, C _6-11Aryl, C _6-10Aryl, C _6-9Aryl or C _6-8In some embodiments, ring B is phenyl. In some embodiments, ring B is heteroaryl. In some embodiments, ring B is 5-12 membered heteroaryl, 5-11 membered heteroaryl, 5-10 membered heteroaryl, 5-9 membered heteroaryl, 5-8 membered heteroaryl, 5-7 membered heteroaryl or 5-6 membered heteroaryl. In some embodiments, ring B is pyridyl or pyrazolyl. In some embodiments, ring B is selected from the group consisting of: 、 、 、 、 and . In some implementations, L ¹is a key. In some implementations, L ¹is an alkyl group. In certain embodiments, L ¹It is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, L ¹Choose from a group consisting of: 、 、 、 、 、 and , where L ¹*end and L ²connection. In some embodiments, L ²is a key. In some implementations, L ²It is N(R ^A), and R ^ASelected from alkyl or heterocyclic groups, wherein the alkyl or heterocyclic group is optionally substituted by one or more halogens or alkyl groups. In certain embodiments, L ²It is N(R ^A), and R ^Ais ethyl, difluoroethyl, trifluoroethyl or cyclohexane. In some embodiments, L ²is optionally represented by one or more R ^BSubstituted cycloalkyl. In certain embodiments, L ²It is C _3-10Cycloalkyl, C _3-9Cycloalkyl, C _3-8Cycloalkyl, C _3-7Cycloalkyl, C _3-6Cycloalkyl or C _3-5Cycloalkyl, each of which is optionally substituted by one or more R ^BReplace. In some embodiments, L ²is optionally represented by one or more R ^Breplaced . In some implementations, L ²is optionally represented by one or more R ^BSubstituted heterocyclic group. In certain embodiments, L ²is a heterocyclic group containing one or more heteroatoms selected from N, O or S. In certain embodiments, L ²is a 3-12-membered heterocyclic group, a 3-11-membered heterocyclic group, a 3-10-membered heterocyclic group or a 3-9-membered heterocyclic group, each of which is optionally substituted by one or more R ^BReplace. In some embodiments, L ²is a heterocyclic group selected from the group consisting of: 、 、 、 、 and , each of which is optionally represented by one or more R ^BReplacement, where L ²* end and L ³connection. In some embodiments, L ²is one or more R ^BSubstituted cycloalkyl or heterocyclic group, and R ^Bis an alkyl group. In certain embodiments, R ^BIt is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, R ^Bis methyl. In some embodiments, L ²Choose from a group consisting of: 、 、 、 、 、 、 、 、 、 、 、 and , where L ²*end and L ³connection. In some embodiments, L ³is an alkyl group. In some embodiments, L ³It is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, L ³is ethyl. In some embodiments, L ⁴is O or NH. In some embodiments, L ¹is the key, and L ²is a key or optionally replaced by one or more R ^BSubstituted heterocyclic group. In some embodiments, L ¹is an alkyl group, and L ²Yes key, N(R ^A) or optionally one or more R ^BSubstituted cycloalkyl. In some embodiments, -L ¹-L ²-L ³-L ⁴- is -alkyl-O-. In certain embodiments, -L ¹-L ²-L ³-L ⁴-Yes-(C _3-8Alkyl)-O-. In certain embodiments, -L ¹-L ²-L ³-L ⁴-Yes-CH ₂CH(CH ₃)(CH ₂) ₃-O- or    -CH ₂CH(CH ₂CH ₃)(CH ₂) ₃-O-. In some implementations, -L ¹-L ²-L ³-L ⁴-is-heterocyclic-alkyl-O-, wherein the heterocyclic group is optionally replaced by one or more R ^BReplace. In some embodiments, -L ¹-L ²-L ³-L ⁴- is -(5-10 membered heterocyclic group)-(C _1-6Alkyl)-O-, wherein the 5-10 membered heterocyclic group is optionally replaced by one or more R ^BReplace. In some embodiments, -L ¹-L ²-L ³-L ⁴-Choose from a group consisting of: 、 、 、 、 、 、 as well as . In some implementations, -L ¹-L ²-L ³-L ⁴- is - alkyl-N(R ^A)-alkyl-O-, where R ^ASelected from alkyl or heterocyclic groups, wherein the alkyl or heterocyclic group is optionally substituted by one or more halogens or alkyl groups. In certain embodiments, -L ¹-L ²-L ³-L ⁴-Yes-(C _1-6Alkyl)-N(R ^A)-(C _1-6Alkyl)-O-, where R ^ASelected from C _1-6Alkyl or 3- to 6-membered heterocyclic group, wherein the alkyl or heterocyclic group is optionally substituted by one or more halogens or C_1-6Alkyl substitution. In certain embodiments, -L ¹-L ²-L ³-L ⁴-yes 、 、 、 or . In some implementations, -L ¹-L ²-L ³-L ⁴-is-alkyl-cycloalkyl-alkyl-O-, wherein the cycloalkyl is optionally replaced by one or more R^BReplace. In some embodiments, -L ¹-L ²-L ³-L ⁴-Yes-(C _1-6Alkyl)-(C _3-6Cycloalkyl)-(C _1-6Alkyl)-O-, wherein the C _3-6The cycloalkyl group is optionally replaced by one or more R^BReplace. In some embodiments, -L ¹-L ²-L ³-L ⁴-yes . In some implementations, R ¹is hydroxyl and m is 1. In some embodiments, R ¹is a halogen and m is 1. In certain embodiments, R ¹is bromine or fluorine, and m is 1. In some embodiments, R ¹Yes-N(R ^D) ₂, and m is 1. In some embodiments, R ¹Yes-N(R ^D) ₂, and each R ^Dindependently hydrogen or optionally one or more independently selected from -N(R ^F) ₂OR ^GAn alkyl group substituted with a group. In certain embodiments, R ¹Yes-N(R ^D) ₂, and each R ^Dis arbitrarily selected by one or more independently selected from -N(R ^F) ₂or -OR ^GC _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, R ¹Yes-N(R ^D) ₂, and each R ^Dare independently methyl, methoxyethyl, N,N-dimethylaminoethyl, hydroxyethyl or N,N-dimethylaminopropyl. In some embodiments, R ¹is optionally represented by one or more R ^Esubstituted heterocyclic group, and m is 1. In certain embodiments, R ¹is optionally represented by one or more R ^Esubstituted 3- to 10-membered heterocyclic group, and m is 1. In certain embodiments, R ¹Choose from a group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and , each of which is optionally represented by one or more R ^EReplace. In some embodiments, R ^Eis a halogen. In certain embodiments, R ^Eis F. In some embodiments, each R ^EIndependently, it is a halogen, -N(R ^F) ₂、-alkyl-N(R ^F) ₂、-C(O)OR ^Gor an alkyl group optionally substituted with one or more halogens. In some embodiments, R ^Fand R ^GEach of R is independently an alkyl group. In certain embodiments, R ^Fand R ^GEach of them is independently C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, R ^Fand R ^GEach of them is independently C _1-3Alkyl. In certain embodiments, each R ^EIndependently selected from the group consisting of F, -N(CH ₃) ₂、-C _1-3Alkyl-N(CH ₃) ₂, -C(O)O(tert-butyl), methyl, ethyl or trifluoroethyl. In certain embodiments, R ^Eis a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are optionally substituted with one or more alkyl and/or halogen groups. In certain embodiments, R ^ESelected from cyclopropyl, morpholine, piperazine, oxacyclobutenyl or azocyclobutane, each of which is optionally substituted with one or more alkyl and/or halogen. In certain embodiments, R ^ESelected from cyclopropyl, morpholinyl, piperazinyl, oxacyclobutenyl or azocyclobutanyl, each of which is optionally substituted with one or more alkyl and/or halogen. In some embodiments, m is 2, R ¹One of them is a halogen, and the other R ¹is optionally represented by one or more R ^ESubstituted heterocyclic group. In certain embodiments, m is 2, R ¹One of them is a halogen, and the other R ¹is a heterocyclic group selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and , each of which is optionally represented by one or more R ^EReplace. In some embodiments, each R ^EIndependently selected from halogens,     -N(R ^F) ₂、-alkyl-N(R ^F) ₂、-C(O)OR ^Gor an alkyl group optionally substituted with one or more halogens. In some embodiments, R ¹Selected from the group consisting of: OH, F, Br, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and . In some implementations, R ²is a halogen, and n is 1 or 2. In certain embodiments, R ²is F. In some embodiments, R ²is an alkyl or cycloalkyl group, wherein the alkyl and cycloalkyl groups are optionally substituted with one or more or halogens. In certain embodiments, R²It is C _1-6Alkyl or C _3-6Cycloalkyl, wherein the C_1-6Alkyl and C _3-6The cycloalkyl group is optionally substituted with one or more halogens. In certain embodiments, R²is methyl, ethyl, cyclopropyl or trifluoroethyl. In some embodiments, R ³is an alkyl group or a cycloalkyl group. In certain embodiments, R ³It is C _1-6Alkyl or C _3-6Cycloalkyl. In certain embodiments, R ³is methyl, ethyl or cyclopropyl. In some embodiments, m is 0, 1 or 2. In some embodiments, n is 0 or 1. Exemplary compounds of formula (I) are described below. and . On the one hand, the present disclosure provides a compound of formula (II): (II) or a pharmaceutically acceptable salt thereof, wherein: Ring A ¹is a 7-12 membered cycloalkyl, a 7-12 membered heterocyclic group, a 7-12 membered aryl group or a 7-12 membered heteroaryl group; Ring B is selected from the group consisting of: cycloalkyl, heterocyclic group, aryl group and heteroaryl group; L ¹Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ²Select from the group consisting of: key, N(R ^A), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted by one or more R ^BReplace; Where R ^ASelected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; wherein each R ^BIndependently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclo, aryl and heteroaryl; L ³Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ⁴Choose from O, S or N(R ^C)； Where R ^CSelected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogenated alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ¹Independently selected from the group consisting of: hydroxyl, halogen, cyano, amino, -N(R ^D) ₂, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted by one or more R ^EReplace; where each R ^DIndependently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano,  -N(R ^F) ₂OR ^G; where each R ^EIndependently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, -N(R ^F) ₂、-alkyl-N(R ^F) ₂、-C(O)OR ^G, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino and alkyl; wherein R ^Fand R ^GEach of R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ²Independently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; Each R ³Selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo are optionally substituted with one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; m is an integer from 0 to 5; n is an integer from 0 to 4; and p is an integer from 0 to 3. In some embodiments, Ring A ¹is a 7-12 membered heteroaryl group. In certain embodiments, Ring A ¹is tetrahydroisoquinolinyl. In certain embodiments, Ring A ¹yes or . In some embodiments, Ring B is aryl. In some embodiments, Ring B is C _6-12Aryl, C _6-11Aryl, C _6-10Aryl, C _6-9Aryl or C _6-8Aryl. In some embodiments, Ring B is phenyl. In some embodiments, Ring B is heteroaryl. In some embodiments, Ring B is 5-12 membered heteroaryl, 5-11 membered heteroaryl, 5-10 membered heteroaryl, 5-9 membered heteroaryl, 5-8 membered heteroaryl, 5-7 membered heteroaryl or 5-12 membered heteroaryl. In some embodiments, Ring B is pyridyl or pyrazolyl. In some embodiments, Ring B is selected from the group consisting of: 、 、 、 、 and . In some implementations, L ¹is an alkyl group. In certain embodiments, L ¹It is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, wherein L ¹yes or , where L ¹*end and L ²connection. In some embodiments, L ²is a key. In some implementations, L ¹is an alkyl group, and L ²is a key. In some implementations, L ³is an alkyl group. In certain embodiments, L ³It is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, L ³is ethyl. In some embodiments, L ⁴is O or NH. In some embodiments, -L ¹-L ²-L ³-L ⁴- is -alkyl-O-. In certain embodiments, -L ¹-L ²-L ³-L ⁴-Yes-(C _3-8Alkyl)-O-. In certain embodiments, -L ¹-L ²-L ³-L ⁴-Yes-(CH ₂) ₅-O-, -CH ₂CH(CH ₃)(CH ₂) ₃-O- or -CH ₂CH(CH ₂CH ₃)(CH ₂) ₃-O-. In some embodiments, m is 0. In some embodiments, m is 1, and R ¹is optionally represented by one or more R ^ESubstituted alkyl. In certain embodiments, m is 1, and R ¹is optionally represented by one or more R ^ESubstituted C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, R ¹is optionally represented by one or more R ^Esubstituted ethyl. In some embodiments, R ^EYes-N(R ^F) ₂, and R ^Fis an alkyl group. In certain embodiments, R ^EYes-N(R ^F) ₂, and R ^FIt is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, R ^EYes-N(CH ₃) ₂. In some embodiments, m is 1, and R ¹is optionally represented by one or more R ^ESubstituted heterocyclic group. In certain embodiments, m is 1, and R ¹is a 3- to 10-membered heterocyclic group, a 3- to 9-membered heterocyclic group, a 3- to 8-membered heterocyclic group, a 3- to 7-membered heterocyclic group, a 3- to 6-membered heterocyclic group or a 3- to 5-membered heterocyclic group, each of which is optionally substituted by one or more R ^EReplace. In some embodiments, R ¹is an oxacyclobutane. In certain embodiments, R ¹yes . In some embodiments, n is 1. In some embodiments, R ²is an alkyl group. In certain embodiments, R ²It is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, R ²is methyl. In some embodiments, n is 1, and R ²is an alkyl group. In certain embodiments, n is 1, and R ²It is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, n is 1, and R ²is methyl. In some embodiments, yes . In some embodiments, p is 1. In some embodiments, R ³is an alkyl group. In certain embodiments, R ³It is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, R ³is methyl. In some embodiments, p is 1, and R ³is an alkyl group. In certain embodiments, p is 1, and R ³It is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, p is 1, and R ³is methyl. In some embodiments, yes . In some implementations, yes . In some embodiments, m is 0 or 1. In some embodiments, n is 1. In some embodiments, p is 1. On the other hand, the present disclosure provides a compound of formula (III): (III) or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl; Ring B ¹is a 7-12-membered cycloalkyl group, a 7-12-membered heterocyclic group, a 7-12-membered aryl group, or a 7-12-membered heteroaryl group; L ¹Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ²Select from the group consisting of: key, N(R ^A), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted by one or more R ^BReplace; Where R ^ASelected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; wherein each R ^BIndependently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclo, aryl and heteroaryl; L ³Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ⁴Choose from O, S or N(R ^C)； Where R ^CSelected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogenated alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ¹Independently selected from the group consisting of: hydroxyl, halogen, cyano, amino, -N(R ^D) ₂, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted by one or more R ^EReplace; where each R ^DIndependently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano,  -N(R ^F) ₂OR ^G; where each R ^EIndependently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, -N(R ^F) ₂、-alkyl-N(R ^F) ₂、-C(O)OR ^G, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino and alkyl; wherein R ^Fand R ^GEach of R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ²Independently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; Each R ³Selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo are optionally substituted with one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; m is an integer from 0 to 5; n is an integer from 0 to 4; and p is an integer from 0 to 3. In some embodiments, Ring A is aryl. In certain embodiments, Ring A is C _6-12Aryl, C _6-11Aryl, C _6-10Aryl, C _6-9Aryl or C _6-8Aryl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is heteroaryl. In some embodiments, Ring A is 5-12 membered heteroaryl, 5-11 membered heteroaryl, 5-10 membered heteroaryl, 5-9 membered heteroaryl, 5-8 membered heteroaryl, 5-7 membered heteroaryl or 5-6 membered heteroaryl. In some embodiments, Ring A is selected from the group consisting of furanyl, phenylthio, pyrrolyl, pyridyl, pyranyl, pyrimidinyl, oxazinyl, pyrazinyl and tetrahydroisoquinolinyl. In some embodiments, Ring B ¹is a 7-12 membered heteroaryl group. In certain embodiments, ring B ¹is pyrazolopyridinyl. In certain embodiments, ring B ¹yes . In some implementations, L ¹is a key. In some implementations, L ¹is an alkyl group. In certain embodiments, L ¹It is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, L ¹Choose from a group consisting of: 、 、 、 、 、 and , where L ¹*end and L ²connection. In some embodiments, L ²is a key. In some implementations, L ²It is N(R ^A), and R ^ASelected from alkyl or heterocyclic groups, wherein the alkyl or heterocyclic group is optionally substituted by one or more halogens or alkyl groups. In certain embodiments, L ²It is N(R ^A), and R ^Ais ethyl, difluoroethyl, trifluoroethyl or cyclohexane. In some embodiments, L ²is optionally represented by one or more R ^BSubstituted cycloalkyl. In certain embodiments, L ²It is C _3-10Cycloalkyl, C _3-9Cycloalkyl, C _3-8Cycloalkyl, C _3-7Cycloalkyl, C _3-6Cycloalkyl or C _3-5Cycloalkyl, each of which is optionally substituted by one or more R ^BReplace. In some embodiments, L ²is optionally represented by one or more R ^Breplaced . In some implementations, L ²is optionally represented by one or more R ^BSubstituted heterocyclic group. In certain embodiments, L ²is a heterocyclic group containing one or more heteroatoms selected from N, O or S. In certain embodiments, L ²is a 3-12-membered heterocyclic group, a 3-11-membered heterocyclic group, a 3-10-membered heterocyclic group or a 3-9-membered heterocyclic group, each of which is optionally substituted by one or more R ^BReplace. In some embodiments, L ²is a heterocyclic group selected from the group consisting of: 、 、 、 、 and , each of which is optionally represented by one or more R ^BReplacement, where L ²*end and L ³connection. In some embodiments, L ²is one or more R ^BSubstituted cycloalkyl or heterocyclic group, and R ^Bis an alkyl group. In certain embodiments, R ^BIt is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, R ^Bis methyl. In some embodiments, L ²Choose from a group consisting of: 、 、 、 、 、 、 、 、 、 、 、 and , where L ²* end and L ³connection. In some embodiments, L ³is an alkyl group. In some embodiments, L ³It is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, L ³is ethyl. In some embodiments, L ⁴is O or NH. In some embodiments, L ¹is the key, and L ²is a key or optionally replaced by one or more R ^BSubstituted heterocyclic group. In some embodiments, L ¹is an alkyl group, and L ²Yes key, N(R ^A) or optionally one or more R ^BSubstituted cycloalkyl. In some embodiments, -L ¹-L ²-L ³-L ⁴- is -alkyl-O-. In certain embodiments, -L ¹-L ²-L ³-L ⁴-Yes-(C _3-8Alkyl)-O-. In certain embodiments, -L ¹-L ²-L ³-L ⁴-Yes-(CH ₂) ₅-O-, -CH ₂CH(CH ₃)(CH ₂) ₃-O- or -CH ₂CH(CH ₂CH ₃)(CH ₂) ₃-O-. In some implementations, -L ¹-L ²-L ³-L ⁴-is-heterocyclic-alkyl   -O-, wherein the heterocyclic group is optionally replaced by one or more R^BReplace. In some embodiments, -L ¹-L ²-L ³-L ⁴- is -(5-10 membered heterocyclic group)-(C _1-6Alkyl)-O-, wherein the 5-10 membered heterocyclic group is optionally replaced by one or more R ^BReplace. In some embodiments, -L ¹-L ²-L ³-L ⁴-Choose from a group consisting of: 、 、 、 、 、 、 as well as . In some implementations, -L ¹-L ²-L ³-L ⁴- is - alkyl-N(R ^A)-alkyl-O-, where R ^ASelected from alkyl or heterocyclic groups, wherein the alkyl or heterocyclic group is optionally substituted by one or more halogens or alkyl groups. In certain embodiments, -L ¹-L ²-L ³-L ⁴-Yes-(C _1-6Alkyl)-N(R ^A)-(C _1-6Alkyl)-O-, where RA is selected from C _1-6Alkyl or 3- to 6-membered heterocyclic group, wherein the alkyl or heterocyclic group is optionally substituted by one or more halogens or C_1-6Alkyl substitution. In certain embodiments, -L ¹-L ²-L ³-L ⁴-yes 、 、 、 or . In some implementations, -L ¹-L ²-L ³-L ⁴-is-alkyl-cycloalkyl-alkyl-O-, wherein the cycloalkyl is optionally replaced by one or more R^BReplace. In some embodiments, -L ¹-L ²-L ³-L ⁴-Yes-(C _1-6Alkyl)-(C _3-6Cycloalkyl)-(C _1-6Alkyl)-O-, wherein the C _3-6The cycloalkyl group is optionally replaced by one or more R^BReplace. In some embodiments, -L ¹-L ²-L ³-L ⁴-yes . In some implementations, R ¹is a halogen and m is 1. In some embodiments, R ¹Yes-N(R ^D) ₂, and m is 1. In some embodiments, R ¹Yes-N(R ^D) ₂, and each R ^DIndependently is optionally selected by one or more independently selected from -N(R ^F) ₂OR ^GAn alkyl group substituted with a group. In certain embodiments, R ¹Yes-N(R ^D) ₂, and each R ^Dis arbitrarily selected by one or more independently selected from -N(R ^F) ₂OR ^GC _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, R ¹Yes-N(R ^D) ₂, and each R ^Dare independently methyl, methoxyethyl, N,N-dimethylaminoethyl or N,N-dimethylaminopropyl. In some embodiments, R ¹is optionally represented by one or more R ^Esubstituted heterocyclic group, and m is 1. In certain embodiments, R ¹is optionally represented by one or more R ^Esubstituted 3- to 10-membered heterocyclic group, and m is 1. In certain embodiments, R ¹Choose from a group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and , each of which is optionally represented by one or more R ^EReplace. In some embodiments, R ^Eis a halogen. In certain embodiments, R ^Eis F. In some embodiments, R ^EYes-N(R ^F) ₂、-alkyl-N(R ^F) ₂、 -C(O)OR ^GOr an alkyl group optionally substituted with one or more halogens. In some embodiments, R ^Fand R ^GEach of R is independently an alkyl group. In certain embodiments, R ^Fand R ^GEach of them is independently C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, R ^Fand R ^GEach of them is independently C _1-3Alkyl. In certain embodiments, R ^ESelect from the group consisting of:     -N(CH ₃) ₂、-C _1-3Alkyl-N(CH ₃) ₂, -C(O)O(tert-butyl), methyl, ethyl and trifluoroethyl. In certain embodiments, R ^Eis a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are optionally substituted with one or more alkyl and/or halogen groups. In certain embodiments, R ^ESelected from cyclopropyl, morpholinyl, piperazinyl, oxacyclobutane or azocyclobutane, each of which is optionally substituted with one or more alkyl and/or halogen. In certain embodiments, R ^ESelected from cyclopropyl, morpholinyl, piperazinyl, oxacyclobutane or azocyclobutane, each of which is optionally substituted with one or more alkyl and/or halogen. In certain embodiments, R ²is a halogen, and n is 1 or 2. In certain embodiments, R ²is F. In some embodiments, R ²is an alkyl or cycloalkyl group, wherein the alkyl and cycloalkyl groups are optionally substituted with one or more or halogens. In certain embodiments, R²It is C _1-6Alkyl or C _3-6Cycloalkyl, wherein the C_1-6Alkyl and C _3-6The cycloalkyl group is optionally substituted with one or more halogens. In certain embodiments, R²is methyl, ethyl, cyclopropyl or trifluoroethyl. In some embodiments, yes . In some implementations, R ³is an alkyl group or a cycloalkyl group. In certain embodiments, R ³It is C _1-6Alkyl or C _3-6Cycloalkyl. In certain embodiments, R ³is methyl, ethyl or cyclopropyl. In some embodiments, p is 1, and R ³is an alkyl group. In certain embodiments, p is 1, and R ³It is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, p is 1, and R ³is methyl. In some embodiments, yes . In some implementations, yes . In some embodiments, m is 0, 1 or 2. In some embodiments, n is 0 or 1. In some embodiments, p is 1. On the other hand, the present disclosure provides a compound of formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl; Ring B is selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl; L ¹Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ^{twenty one}is a 7-12 membered cycloalkyl or a 7-12 membered heterocyclic group, wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more R ^BReplace; where each R ^BIndependently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclo, aryl and heteroaryl; L ³Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ⁴Choose from O, S or N(R ^C)； Where R ^CSelected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogenated alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ¹Independently selected from the group consisting of: hydroxyl, halogen, cyano, amino, -N(R ^D) ₂, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted by one or more R ^EReplace; where each R ^DIndependently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano,  -N(R ^F) ₂OR ^G; where each R ^EIndependently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, -N(R ^F) ₂、-alkyl-N(R ^F) ₂、-C(O)OR ^G, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino and alkyl; wherein R ^Fand R ^GEach of R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ²Independently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; R ³Selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo are optionally substituted with one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; m is an integer from 0 to 5; n is an integer from 0 to 4; and p is an integer from 0 to 3. In some embodiments, Ring A is aryl. In certain embodiments, Ring A is C _6-12Aryl, C _6-11Aryl, C _6-10Aryl, C _6-9Aryl or C _6-8In some embodiments, Ring A is phenyl. In some embodiments, Ring A is heteroaryl. In some embodiments, Ring A is 5-12 membered heteroaryl, 5-11 membered heteroaryl, 5-10 membered heteroaryl, 5-9 membered heteroaryl, 5-8 membered heteroaryl, 5-7 membered heteroaryl or 5-6 membered heteroaryl. In some embodiments, Ring A is selected from the group consisting of furanyl, phenylthio, pyrrolyl, pyridyl, pyranyl, pyrimidinyl, oxazinyl, pyrazinyl and tetrahydroisoquinolinyl. In some embodiments, Ring B is aryl. In some embodiments, Ring B is C _6-12Aryl, C _6-11Aryl, C _6-10Aryl, C _6-9Aryl or C _6-8Aryl. In some embodiments, Ring B is phenyl. In some embodiments, Ring B is heteroaryl. In some embodiments, Ring B is 5-12 membered heteroaryl, 5-11 membered heteroaryl, 5-10 membered heteroaryl, 5-9 membered heteroaryl, 5-8 membered heteroaryl, 5-7 membered heteroaryl or 5-6 membered heteroaryl. In some embodiments, Ring B is pyridyl or pyrazolyl. In some embodiments, Ring B is selected from the group consisting of: 、 、 、 、 and . In some implementations, L ¹is a key. In some implementations, L ^{twenty one}is a 7-10 membered heterocyclic group containing one or more heteroatoms selected from N or O. In certain embodiments, L ^{twenty one}Choose from a group consisting of: 、 、 and , where L ^{twenty one}*end and L ³connection. In some embodiments, L ³is an alkyl group. In certain embodiments, L ³It is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, L ³is ethyl. In some embodiments, L ⁴is O or NH. In some embodiments, -L ¹-L ^{twenty one}-L ³-L ⁴-is-heterocyclic-alkyl-O-, wherein the heterocyclic group is optionally replaced by one or more R^BReplace. In some embodiments, -L ¹-L ^{twenty one}-L ³-L ⁴- is -(5-10 membered heterocyclic group)-(C _1-6Alkyl)-O-, wherein the 5-10 membered heterocyclic group is optionally replaced by one or more R ^BReplace. In some implementations, -L ¹-L ^{twenty one}-L ³-L ⁴-Choose from a group consisting of: 、 、 and . In some implementations, R ¹is a halogen and m is 1. In some embodiments, R ¹Yes-N(R ^D) ₂, and m is 1. In some embodiments, R ¹Yes-N(R ^D) ₂, and each R ^DIndependently is optionally selected by one or more independently selected from -N(R ^F) ₂OR ^GAn alkyl group substituted with a group. In certain embodiments, R ¹Yes-N(R ^D) ₂, and each R ^Dis arbitrarily selected by one or more independently selected from -N(R ^F) ₂OR ^GC _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, R ¹Yes-N(R ^D) ₂, and each R ^Dare independently methyl, methoxyethyl or N,N-dimethylaminopropyl. In some embodiments, R ¹is optionally represented by one or more R ^Esubstituted heterocyclic group, and m is 1. In certain embodiments, R ¹is optionally represented by one or more R ^Esubstituted 3- to 10-membered heterocyclic group, and m is 1. In certain embodiments, R ¹Choose from a group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and , each of which is optionally represented by one or more R ^EReplace. In some embodiments, R ^Eis a halogen. In certain embodiments, R ^Eis F. In some embodiments, R ^EYes-N(R ^F) ₂、-alkyl-N(R ^F) ₂、 -C(O)OR ^Gor an alkyl group optionally substituted with one or more halogens. In some embodiments, R ^Fand R ^GEach of R is independently an alkyl group. In certain embodiments, R ^Fand R ^GEach of them is independently C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, R ^Fand R ^GEach of them is independently C _1-3Alkyl. In certain embodiments, R ^ESelect from the group consisting of:     -N(CH ₃) ₂、-C _1-3Alkyl-N(CH ₃) ₂, -C(O)O(tert-butyl), methyl, ethyl and trifluoroethyl. In certain embodiments, R ^Eis a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are optionally substituted with one or more alkyl and/or halogen groups. In certain embodiments, R ^ESelected from cyclopropyl, morpholinyl, piperazinyl, oxacyclobutane or azocyclobutane, each of which is optionally substituted with one or more alkyl and/or halogen. In certain embodiments, R ^ESelected from cyclopropyl, morpholinyl, piperazinyl, oxacyclobutenyl or azocyclobutanyl, each of which is optionally substituted with one or more alkyl and/or halogen. In certain embodiments, R ¹Choose from a group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and . In some implementations, R ²is a halogen, and n is 1 or 2. In certain embodiments, R ²is F. In some embodiments, R ²is an alkyl or cycloalkyl group, wherein the alkyl and cycloalkyl groups are optionally substituted with one or more or halogens. In certain embodiments, R²It is C _1-6Alkyl or C _3-6Cycloalkyl, wherein the C_1-6Alkyl and C _3-6The cycloalkyl group is optionally substituted with one or more halogens. In certain embodiments, R²is methyl, ethyl, cyclopropyl or trifluoroethyl. In certain embodiments, R ²is methyl. In some embodiments, R ³is an alkyl group. In certain embodiments, R ³Each of them is independently C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, R ³is methyl. In some embodiments, p is 1, and R ³is an alkyl group. In certain embodiments, p is 1, and R ³It is C _1-6Alkyl, C _1-5Alkyl, C _1-4Alkyl, C _1-3Alkyl or C _1-2Alkyl. In certain embodiments, p is 1, and R ³is methyl. In some embodiments, yes . In some implementations, yes . In some embodiments, m is 1. In some embodiments, n is 1. In some embodiments, p is 1. Exemplary compounds of the present disclosure are described below. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . The compounds provided herein are described with reference to both general formulae and specific compounds. In addition, the compounds disclosed herein may exist in a variety of different forms or derivatives, including but not limited to prodrugs, active metabolic derivatives (active metabolites), solvates, pharmaceutically acceptable salts or isotope derivatives, all of which are within the scope of the present disclosure. As used herein, the term "prodrug" refers to a compound or a pharmaceutically acceptable salt thereof that produces the desired active compound when metabolized or converted by solvent decomposition under physiological conditions. Prodrugs include but are not limited to esters, amides, carbamates, carbonates, ureas, solvates or hydrates of active compounds. Typically, prodrugs are inactive or less active than active compounds, but can provide one or more advantageous handling, administration and/or metabolic properties. For example, some prodrugs are esters of active compounds; during metabolism, the ester group is cleaved to produce the active drug. In addition, some prodrugs are enzymatically activated to generate active compounds or compounds that generate active compounds after further chemical reactions. Prodrugs can be developed from prodrug forms to active forms in a single step, or can have one or more intermediate forms that may or may not be active themselves. The preparation and use of prodrugs are discussed in the following references: T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Volume 14 of the A.C.S. Symposium Series, Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; Prodrugs: Challenges and Rewards, eds. V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Springer Verlag New York, 1991. 2007, all of which are hereby incorporated by reference in their entirety. As used herein, the term "metabolite", e.g., active metabolite, overlaps with prodrugs as described above. Thus, such metabolites are pharmacologically active compounds or compounds that are further metabolized to pharmacologically active compounds that are derivatives produced by metabolic processes in the subject. For example, such metabolites can be produced by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound or salt or prodrug. Among them, the active metabolite is such a pharmacologically active derivative compound. For prodrugs, the prodrug compound is generally inactive or less active than the metabolite. For active metabolites, the parent compound can be an active compound or can be an inactive prodrug. Prodrugs and active metabolites can be identified using conventional techniques known in the art. See, e.g., Bertolini et al., 1997, J Med Chem 40:2011-2016; Shan et al., J Pharm Sci 86:756-757; Bagshawe, 1995, Drug Dev Res 34:220-230; Wermuth, supra. As used herein, the term "pharmaceutically acceptable" indicates that a substance or composition is chemically and/or toxicologically compatible with the other ingredients making up the formulation and/or the subject being treated. As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness of the free acid and base of the specified compound and are not biologically or otherwise undesirable. Pharmaceutically acceptable salt forms contemplated include, but are not limited to, monosalts, disalts, trisalts, tetrasalts, and the like. Pharmaceutically acceptable salts are nontoxic in the amounts and concentrations in which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical properties of the compound without interfering with its ability to exert its physiological effects. Useful changes in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of the drug. Pharmaceutically acceptable salts include acid addition salts, such as the following acid addition salts: sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylaminosulfonate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamate, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonate, fumaric acid and quinic acid. When an acidic functional group such as carboxylic acid or phenol is present, pharmaceutically acceptable salts also include base addition salts, such as base addition salts including benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines and zinc. See, e.g., Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts may be prepared using the appropriate corresponding base. Pharmaceutically acceptable salts may be prepared by standard techniques. For example, the free base form of the compound may be dissolved in a suitable solvent (e.g., an aqueous or aqueous-alcoholic solution containing an appropriate acid) and then isolated by evaporation of the solution. Thus, if a particular compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, or a pyranosyl acid such as glucuronic acid or galacturonic acid; an α-hydroxy acid such as citric acid or tartaric acid; an amino acid such as aspartic acid or glutamic acid; an aromatic acid such as benzoic acid or cinnamic acid; a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid; and the like. Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkali earth metal hydroxide, etc. Illustrative examples of suitable salts include organic salts derived from amino acids such as L-glycine, L-lysine and L-arginine; ammonia, primary, secondary and tertiary amines; and cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium. It is also understood that the compounds of the present disclosure may exist in non-solvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystalline forms or polycrystalline forms), and the present disclosure is intended to encompass all such forms. As used herein, the term "solvate" or "solvated form" refers to a solvent addition form that includes a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to capture a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the addition of one or more water molecules to a solid state in which the water retains its hydrogen bond as H ₂O molecular state of a substance to form a molecular combination. Examples of solvents that form solvates include but are not limited to water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The present disclosure is also intended to include all isotopic forms of the compounds provided herein. Isotopes of atoms include atoms with the same atomic number but different mass numbers. For example, unless otherwise stated, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine or iodine in the compounds of the present disclosure is meant to also include its isotopes, such as but not limited to ¹H. ²H. ³H. ¹¹C. ¹²C. ¹³C. ¹⁴C. ¹⁴N. ¹⁵N. ¹⁶O. ¹⁷O. ¹⁸O. ³¹P. ³²P. ³²S. ³³S. ³⁴S. ³⁶S. ¹⁷F. ¹⁸F. ¹⁹F. ³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, ¹²⁴I. ¹²⁷I and ¹³¹I. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes ¹²C and ¹³C. The compounds provided herein or their pharmaceutically acceptable salts may contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers and other stereoisomeric forms, which may be defined by absolute stereochemistry as (R)- or (S)- or (D)- or (L)- of amino acids, or by relative configuration as rel-(R)- or rel-(S)-. The present disclosure includes all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers may be prepared by chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Traditional techniques for preparing and separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When a compound is represented in its chiral form, it should be understood that the embodiments include but are not limited to specific diastereomers or enantiomerically enriched forms. Where chirality is not specified but exists, it should be understood that the embodiments are intended to include specific diastereomers or enantiomerically enriched forms; or racemic or non-scalemic mixtures of such compounds. The term "stereoisomer" refers to compounds containing the same atoms connected by the same bonds but with different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other. The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers in a ratio other than 1:1 is a "non-racemic" mixture. The term "diastereomer" refers to stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via low energy barriers. The presence and concentration of isomeric forms will depend on the environment in which the compound is located and may differ, for example, whether the compound is a solid or in an organic or aqueous solution. For example, proton tautomers (also called prototropic tautomers) include interconversions by proton migration, such as keto-enol, amide-imidic acid, lactam-lactimide, imine-enamine isomerizations, and cyclic forms in which protons can occupy two or more positions in heterocyclic systems. Valence tautomers include interconversions by reorganization of some of the bonding electrons. Tautomers may be in equilibrium or sterically locked into one form by appropriate substitution. Unless otherwise indicated, compounds disclosed herein that are identified by name or structure as a particular tautomeric form are intended to include other tautomeric forms. When the compounds provided herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise indicated, the compounds include both E and Z geometric isomers. Synthesis Methods The compounds provided herein can be prepared using any known organic synthesis technique and can be synthesized according to any of a number of possible synthetic routes. The reactions used to prepare the compounds disclosed herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with starting materials (reactants), intermediates or products at temperatures at which the reaction is carried out, e.g., temperatures that can range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a suitable solvent for a particular reaction step can be selected by a person skilled in the art. The preparation of the compounds disclosed herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by a person skilled in the art. The chemistry of protecting groups can be found in, for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, New York, (1999); P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003; and Peter G. M. Wuts, Greene's Protective Groups in Organic Synthesis, 5th ed., Wiley, 2014, which are incorporated herein by reference in their entirety. The reaction can be monitored according to any suitable method known in the art. For example, the reaction can be monitored by methods such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³ C), infrared spectroscopy, spectrophotometry (e.g., UV visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS) or thin layer chromatography (TLC) to monitor product formation. Those skilled in the art can purify the compound by various methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization" Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs "Journal of Combi. Chem. (Journal of Combi. Chem.) 2004, 6 (6), 874-883, the reference is incorporated herein by reference in its entirety) and normal phase silica gel chromatography. Pharmaceutical Compositions In another aspect, a pharmaceutical composition is provided, which comprises one or more compounds disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition disclosed herein comprises the first compound or its pharmaceutically acceptable salt provided herein and one or more other compounds of the same formula, but the first compound and the other compound are not the same molecule. On the other hand, a pharmaceutical composition is provided, which comprises one or more compounds disclosed herein or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition disclosed herein comprises a therapeutically effective amount of one or more compounds disclosed herein or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition disclosed herein comprises a therapeutically effective amount of one or more compounds disclosed herein or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient. As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition comprising the molecule or compound that treats, ameliorates, or prevents an identified disease or condition, or shows a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; the rate of administration; the treatment or combination of treatments selected for administration; and the judgment of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experiments within the skill and judgment of the clinician. As used herein, the term "drug composition" refers to a formulation comprising a molecule or compound disclosed herein in a form suitable for administration to a subject. The pharmaceutical composition comprises a composition suitable for oral administration, rectal administration, topical administration, parenteral administration (including subcutaneous, intramuscular and intravenous), sublingual administration, ocular administration, transdermal administration or nasal administration, but the most suitable route in any given case will depend on the nature and severity of the particular host and the condition to which the active ingredient is administered. The pharmaceutical composition can be conveniently presented in unit dosage form and can be prepared by any method well known in the pharmaceutical art. As used herein, the term "pharmaceutically acceptable excipient" means an excipient that can be used to prepare a generally safe, non-toxic and biologically and otherwise desirable pharmaceutical composition, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used herein, "pharmaceutically acceptable excipients" include one and more than one such excipients. The term "pharmaceutically acceptable excipients" also encompasses "pharmaceutically acceptable carriers" and "pharmaceutically acceptable diluents". The specific excipient used will depend on the means and purpose for which the compounds disclosed herein are applied. Solvents are typically selected based on solvents that are considered safe by those skilled in the art for administration to mammals, including humans. Typically, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and the like, and mixtures thereof. In some embodiments, suitable excipients may include buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzoyl chloride; benzethonium chloride; phenol, butyl alcohol, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; o-catechin; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulin; immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextran; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, coloring agents, sweeteners, aromas, flavoring agents and other known additives to provide the best presentation form of the drug (i.e., the compounds disclosed herein or their pharmaceutical compositions) or to assist in the manufacture of the drug product (i.e., the drug). The active pharmaceutical ingredient can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. ed. (1980). "Liposomes" are small vesicles comprising various types of lipids, phospholipids and/or surfactants that can be used to deliver drugs (such as the compounds disclosed herein and optionally chemotherapeutic agents) to mammals, including humans. The components of liposomes are usually arranged in a double layer, similar to the lipid arrangement of biological membranes. The pharmaceutical composition provided herein can be in a form that allows subjects, including but not limited to people, to use the composition and allows the composition to be formulated into any form compatible with the expected route of administration. A variety of approaches have been considered for the pharmaceutical composition provided herein, and therefore the pharmaceutical composition provided herein can be supplied in bulk or unit dosage form depending on the expected route of administration. For example, for oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, soft capsules and caplets can be acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions and solutions can be acceptable as liquid dosage forms. For injection, emulsions and suspensions may be acceptable as liquid dosage forms, and powders suitable for reconstitution with a suitable solution may be acceptable as solid dosage forms. For inhalation, solutions, sprays, dry powders and aerosols may be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches may be acceptable dosage forms. For vaginal administration, vaginal suppositories, tampons, creams, gels, pastes, foams and sprays may be acceptable dosage forms. In some embodiments, the disclosed pharmaceutical composition may be in the form of a formulation for oral administration. In certain embodiments, the pharmaceutical composition of the present disclosure may be in the form of a tablet formulation. Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl p-hydroxybenzoate; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or coated to modulate disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve stability and/or appearance, in either case using conventional coating agents and procedures well known in the art. In certain embodiments, the pharmaceutical compositions disclosed herein may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin; or in the form of soft gelatin capsules in which the active ingredient is mixed with water or oil, such as peanut oil, liquid paraffin or olive oil. In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension, which generally includes the active ingredient in the form of a fine powder and one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic; dispersants or wetting agents, such as lecithin or alkylene oxide and fatty acid. The aqueous suspension may also include one or more preservatives (e.g., ethyl or propyl paraben), antioxidants (e.g., ascorbic acid), coloring agents, flavoring agents, and/or sweeteners (e.g., sucrose, saccharin, or aspartame). In certain embodiments, the pharmaceutical compositions disclosed herein may be in the form of an oily suspension, which typically includes a suspended active ingredient in a vegetable oil (such as peanut oil, castor oil, olive oil, sesame oil, or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspension may also include a thickener, such as beeswax, hard wax, or cetyl alcohol. Sweeteners (such as those described above) and flavorings may be added to provide a palatable oral formulation. These compositions may be preserved by adding an antioxidant (such as ascorbic acid). In certain embodiments, the pharmaceutical compositions disclosed herein may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil; or a mineral oil, such as liquid paraffin; or a mixture of any of these oils. Suitable emulsifiers can be, for example, naturally occurring glues, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soybeans, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate) and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions can also include sweeteners, flavorings and preservatives. In certain embodiments, the pharmaceutical compositions provided herein can be in the form of syrups and elixirs, which can include sweeteners, such as glycerol, propylene glycol, sorbitol, aspartame or sucrose; softeners; preservatives; flavorings and/or coloring agents. In certain embodiments, the pharmaceutical compositions disclosed herein can be in the form of formulations for injection. In certain embodiments, the pharmaceutical composition disclosed herein can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. Such a suspension can be prepared using those suitable dispersants or wetting agents and suspending agents mentioned above according to known techniques. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenteral acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils can be used as solvents or suspension media conventionally. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can be used to prepare injectables. In some embodiments, the disclosed pharmaceutical composition can be in the form of a formulation for inhalation administration. In certain embodiments, the disclosed pharmaceutical composition can be in the form of an aqueous and non-aqueous (e.g., in a fluorocarbon propellant) aerosol, and the aqueous and non-aqueous aerosols include any suitable solvents and optionally other compounds, such as but not limited to stabilizers, antimicrobial agents, antioxidants, pH regulators, surfactants, bioavailability regulators and combinations thereof. Carriers and stabilizers vary with the requirements of the specific compound, but generally include non-ionic surfactants (Tween, Pluronic or polyethylene glycol), harmless proteins (such as serum albumin), sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of formulations for topical or transdermal administration. In certain embodiments, the pharmaceutical composition provided herein can be in the form of creams, ointments, gels and aqueous or oily solutions or suspensions, which can be prepared by mixing active ingredients with conventional local acceptable excipients, such as animal fat and vegetable fat, oil, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide or their mixtures. In certain embodiments, the pharmaceutical composition provided herein can be prepared for ophthalmic administration. In certain embodiments, the pharmaceutical composition provided herein can be in the form of ophthalmic formulations, such as eye ointments, powders, solutions, etc. In certain embodiments, ophthalmic formulations are prepared at a comfortable pH and an appropriate buffer system. In addition to those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the present disclosure. Such excipients and carriers are described in, for example, the following references: Remingtons Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991); Remington: The Science and Practice of Pharmacy, ed., University of the Sciences in Philadelphia, 21st ed., LWW (2005), which are incorporated herein by reference. The dosage regimen of the compounds provided herein will vary according to known factors, such as the pharmacodynamic characteristics of a particular agent and its mode and route of administration; the species, age, sex, health condition, physical condition and weight of the recipient; the nature and extent of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and liver function, and the desired effect. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. In some embodiments, the pharmaceutical composition of the present disclosure can be formulated so that 0.001 mg/kg body weight/day to 1000 mg/kg body weight/day can be administered, for example, 0.01 mg/kg body weight/day to 800 mg/kg body weight/day, 0.01 mg/kg body weight/day to 700 mg/kg body weight/day, 0.01 mg/kg body weight/day to 600 mg/kg body weight/day, 0.01 mg/kg body weight/day to 500 mg/kg body weight/day, 0.01 mg/kg body weight/day to 400 mg/kg body weight/day, 0.01 mg/kg body weight/day to 300 mg/kg body weight/day, 0.1 mg/kg body weight/day to 200 mg/kg body weight/day, 0.1 mg/kg body weight/day to 150 mg/kg body weight/day, 0.1 mg/kg body weight/day to 100 [00136] The present invention relates to a compound or a pharmaceutically acceptable salt thereof provided herein in an amount of 1 mg/kg body weight/day, 0.5 mg/kg body weight/day to 100 mg/kg body weight/day, 0.5 mg/kg body weight/day to 80 mg/kg body weight/day, 0.5 mg/kg body weight/day to 60 mg/kg body weight/day, 0.5 mg/kg body weight/day to 50 mg/kg body weight/day, 1 mg/kg body weight/day to 50 mg/kg body weight/day, 1 mg/kg body weight/day to 45 mg/kg body weight/day, 1 mg/kg body weight/day to 40 mg/kg body weight/day, 1 mg/kg body weight/day to 35 mg/kg body weight/day, 1 mg/kg body weight/day to 30 mg/kg body weight/day, 1 mg/kg body weight/day to 25 mg/kg body weight/day. In some cases, dosage levels below the lower limit of the aforementioned range may be sufficient, while in other cases, larger doses may be used without causing any harmful side effects, provided that such larger doses are first divided into several small doses for all-day administration. For additional information on the route of administration and dosage regimen, see "Comprehensive Medicinal Chemistry" Volume 5, Chapter 25.3 (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990, which reference is particularly incorporated herein by reference. In some embodiments, the disclosed pharmaceutical composition can be formulated into a single dosage form. The amount of the compound provided herein in a single dosage form will vary according to the subject being treated and the specific mode of administration. In some embodiments, dosage forms suitable for administration may contain about 1 mg to about 1000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1-95% by weight, based on the gross weight of the composition. In some embodiments, the pharmaceutical compositions disclosed herein may be formulated into short-acting, rapid-release, long-acting, and sustained-release forms. Therefore, the pharmaceutical formulations disclosed herein may also be formulated for controlled release or slow release. In some embodiments, a certain dose of the compound provided herein or the pharmaceutical composition provided herein is administered to a subject every day, every other day, every two days, every three days, once a week, twice a week, three times a week, or once every two weeks. If necessary, the effective daily dose of the active compound can be used as a single dose at appropriate intervals in a day, optionally in two, three, four, five, six or more subdoses administered in a unit dosage form. In some embodiments, a certain dose of the compound provided herein or the pharmaceutical composition provided herein is administered for 2 days, 3 days, 5 days, 7 days, 14 days, 21 days, 1 month, 2 months, 2.5 months, 3 months, 4 months, 5 months, 6 months or longer. In other aspects, veterinary compositions are also provided, comprising one or more molecules or compounds disclosed herein or pharmaceutically acceptable salts thereof and veterinary carriers. Veterinary carriers are materials that can be used for the purpose of administering the composition, and can be solid, liquid or gaseous materials that are otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions can be administered parenterally, orally or by any other desired route. Pharmaceutical compositions or veterinary compositions can be packaged in various ways depending on the method used to administer the drug. For example, a product for distribution can include a container in which a composition in an appropriate form is stored. Suitable containers are well known to those skilled in the art, and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include an anti-disassembly assembly to prevent easy access to the contents of the package. In addition, the container has a label placed thereon describing the contents of the container. The label may also include appropriate warnings. The composition may also be packaged in unit dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under freeze drying (lyophilization) conditions requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the types described previously. In some embodiments, the disclosed pharmaceutical composition comprising one or more compounds provided herein or pharmaceutically acceptable salts thereof further comprises one or more additional therapeutically active agents. The additional therapeutic agent has an activity that complements the compound provided herein, so that it does not adversely affect each other. Such agents are appropriately combined in an amount effective for the intended purpose. In certain embodiments, the additional therapeutic agent is selected from: EGFR TKI, EGFR antibody, MEK inhibitor, c-MET inhibitor, mitotic kinase inhibitor, immunotherapy, anti-angiogenic agent, apoptosis inducer, mTOR inhibitor, histone deacetylase inhibitor, IL6 inhibitor, JAK inhibitor. Examples of EGFR TKIs include, but are not limited to, for example, afatinib, erlotinib, gefitinib, lapatinib, dacomitinib, osimertinib, olmutinib, nazartinib, and AC0010. Examples of EGFR antibodies include, for example, cetuximab, panitumumab, and necitumumab. Examples of MEK inhibitors include trametinib, cobimetinib, binimetinib, selumetinib, and refametinib. Examples of c-MET inhibitors include, for example, savolitinib, cabozantinib, foretinib, and MET antibodies (such as emibetuzumab). Examples of mitotic kinase inhibitors include CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib. Examples of immunotherapeutic agents include immune checkpoint inhibitors, such as anti-CTLA4 mAb, anti-PD1 mAb, anti-PD-L1 mAb, anti-PD-L2 mAb, anti-LAG3 mAb, anti-TM3 mAb, preferably anti-PD1 mAb, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001, and immunomodulators, such as CD73 inhibitors or CD73 inhibitory antibodies. Examples of anti-angiogenic agents include, for example, bevacizumab, nintedanib. Examples of apoptosis inducers include Bcl-2 inhibitors (e.g., venetoclax, obatoclax, navitoclax), Mcl-1 inhibitors (e.g., AZD-5991, AMG-176, S-64315). Examples of mTOR inhibitors include, for example, rapamycin, temsirolimus, everolimus, ridaforolimus. Examples of histone deacetylase inhibitors include, for example, panobinostat, entinostat, romidepsin, and vorinostat. Examples of IL6 inhibitors include, for example, tocilizumab, siltuximab, olokizumab, elsilimomab, clazakizumab, sirukumab, levilimab, ARGX-109, FE301, FM101. Examples of JAK inhibitors include, for example, baricitinib, ruxolitinib, tofacitinib, oclacitinib, baricitinib, peficitinib, fedratinib, upadacitinib, filgotinib, delgocitinib, abrocitinib. One or more other therapeutic agents can be used simultaneously or sequentially with the compound provided herein. Sequential use includes use before or after the compound provided herein. In some embodiments, the one or more other therapeutic agents can be used in the same composition as the compound provided herein. In other embodiments, there can be a time interval between the use of the other therapeutic agent and the compound provided herein. In some embodiments, the use of the other therapeutic agent together with the compound provided herein can make it possible to reduce the dosage of other therapeutic agents and/or to use them at intervals with lower frequency. Methods for treatment The disclosed compound and the pharmaceutical composition comprising the compound can inhibit EGFR, and therefore can be used to inhibit the EGFR activity in a subject in need, and to prevent or treat EGFR-related diseases. In other aspects, the disclosure provides a method for treating EGFR related conditions, the method comprising administering an effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition to a subject in need thereof. As used herein, the term "treating/treatment" or "therapy" is intended to have its normal meaning, i.e., to treat a disease, to fully or partially alleviate one, some or all of its symptoms, or to correct or compensate for potential pathology, thereby achieving a useful or desired clinical outcome. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, relief of symptoms, reduction in extent of disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, improvement or alleviation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean prolonging survival as compared to expected survival if not receiving treatment. Situations in which treatment is needed include those already suffering from the condition or disorder as well as those susceptible to developing the condition or disorder or those in which the condition or disorder is to be prevented. As used herein, the term "preventing, prevention or prophylaxis" is intended to have its normal meaning and includes primary prevention for preventing the development of a disease and secondary prevention for preventing a disease from developing and temporarily or permanently protecting a patient from aggravation or deterioration of the disease or from developing new symptoms associated with the disease. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts and compositions can be used to treat a variety of EGFR-related conditions, including cancer, autoimmune diseases, and the like. In certain embodiments, the compounds provided herein or their pharmaceutically acceptable salts and compositions can be used to treat cancer, including lung cancer (e.g., non-small cell lung cancer), brain cancer, colorectal cancer, bladder cancer, urothelial carcinoma, breast cancer, prostate cancer, ovarian cancer, head and neck cancer, pancreatic cancer, gastric cancer and mesothelioma, including metastasis (particularly brain metastasis), and the like. In some embodiments, the compound or its pharmaceutically acceptable salt and composition provided herein can be used to treat autoimmune diseases, including rheumatoid arthritis, graft-versus-host disease, systemic lupus erythematosus (SLE), scleroderma, multiple sclerosis, diabetes, organ rejection, inflammatory bowel disease, psoriasis and other pains. The concentration and the application path of the subject will be different due to the EGFR related conditions to be treated. In some embodiments, the application is carried out by the route selected from the group consisting of: enteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreal injection, intravenous injection, intraarterial injection, oral, oral, sublingual, transdermal, topical, intratracheal, rectal, subcutaneous and ocular administration. The embodiments of various aspects provided by the present disclosure are also described in any of the following paragraphs. Embodiment 1: A compound of formula (I):(I) or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl; Ring B is selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl; L ¹Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ²Select from the group consisting of: key, N(R ^A), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted by one or more R ^BReplace; Where R ^ASelected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; wherein each R ^BIndependently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclo, aryl and heteroaryl; L ³Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ⁴Choose from O, S or N(R ^C)； Where R ^CSelected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogenated alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ¹Independently selected from the group consisting of: hydroxyl, halogen, cyano, amino, -N(R ^D) ₂, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted by one or more R ^EReplace; where each R ^DIndependently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano,  -N(R ^F) ₂OR ^G; where each R ^EIndependently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, -N(R ^F) ₂、-alkyl-N(R ^F) ₂、-C(O)OR ^G, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino and alkyl; wherein R ^Fand R ^GEach of R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ²Independently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; R ³Selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo are optionally substituted by one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; m is an integer from 0 to 5; and n is an integer from 0 to 4. Embodiment 2. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1, wherein Ring A is an aryl or heteroaryl group. Embodiment 3. The compound or pharmaceutically acceptable salt thereof according to Embodiment 2, wherein Ring A is selected from the group consisting of furanyl, phenylthio, pyrrolyl, phenyl, pyridyl, pyranyl, pyrimidyl, oxazinyl, pyrazinyl and tetrahydroisoquinolinyl. Embodiment 4. The compound or pharmaceutically acceptable salt thereof according to Embodiment 3, wherein Ring A is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 or and . Embodiment 5. The compound or pharmaceutically acceptable salt thereof according to Embodiment 1, wherein Ring B is an aryl group or a heteroaryl group. Embodiment 6. The compound or pharmaceutically acceptable salt thereof according to Embodiment 5, wherein Ring B is a phenyl group or a pyrazolyl group. Embodiment 7. The compound or pharmaceutically acceptable salt thereof according to Embodiment 6, wherein Ring B is 、 、 、 、 and . Implementation 8. The compound or a pharmaceutically acceptable salt thereof according to implementation 1, wherein L ¹is a bond. Implementation 9. A compound or a pharmaceutically acceptable salt thereof according to Implementation 8, wherein L ¹is an alkyl group. Embodiment 10. A compound according to Embodiment 9 or a pharmaceutically acceptable salt thereof, wherein L ¹Choose from a group consisting of: 、 、 、 、 、 and , where L ¹*end and L ²Connected. Implementation 11. The compound or a pharmaceutically acceptable salt thereof according to Implementation 1, wherein L ²is a bond. Implementation 12. A compound or a pharmaceutically acceptable salt thereof according to Implementation 1, wherein L ²It is N(R ^A), and R ^ASelected from alkyl or heterocyclic groups, wherein the alkyl or heterocyclic group is optionally substituted by one or more halogens or alkyl groups. Embodiment 13. A compound or a pharmaceutically acceptable salt thereof according to Embodiment 12, wherein R ^Ais ethyl, difluoroethyl, trifluoroethyl or oxacyclobutane. Implementation 14. A compound according to Implementation 1 or a pharmaceutically acceptable salt thereof, wherein L ²is optionally represented by one or more R ^BSubstituted cycloalkyl. Embodiment 15. A compound or a pharmaceutically acceptable salt thereof according to Embodiment 14, wherein L ²yes , which is optionally replaced by one or more R ^BReplacement. Implementation 16. A compound or a pharmaceutically acceptable salt thereof according to implementation 1, wherein L ²is optionally represented by one or more R ^BSubstituted heterocyclic group. Embodiment 17. A compound or a pharmaceutically acceptable salt thereof according to Embodiment 16, wherein the heterocyclic group is selected from the group consisting of: 、 、 、 、 and , each of which is optionally represented by one or more R ^BReplacement, where L ²*end and L ³connected. Implementation 18. A compound or a pharmaceutically acceptable salt thereof according to Implementation 16 or 17, wherein R ^Bis an alkyl group. Embodiment 19. A compound or a pharmaceutically acceptable salt thereof according to Embodiment 19, wherein R ^Bis methyl. Implementation 20. A compound or a pharmaceutically acceptable salt thereof according to implementation 1, wherein L ²Choose from a group consisting of: 、 、 、 、 、 、 、 、 、 、 、 and , where L ²*end and L ³connected. Implementation 21. A compound or a pharmaceutically acceptable salt thereof according to implementation 1, wherein L ³is an alkyl group. Embodiment 22. A compound or a pharmaceutically acceptable salt thereof according to Embodiment 21, wherein L ³is ethyl. Implementation 23. A compound or a pharmaceutically acceptable salt thereof according to Implementation 1, wherein L ⁴is O or NH. Implementation 24. A compound or a pharmaceutically acceptable salt thereof according to implementation 1, wherein L ¹is the key, and L ²is a key or optionally replaced by one or more R ^BSubstituted heterocyclic group. Embodiment 25. The compound or pharmaceutically acceptable salt thereof according to Embodiment 1, wherein L ¹is an alkyl group, and L ²Yes key, N(R ^A) or optionally one or more R ^BSubstituted cycloalkyl. Embodiment 26. A compound or a pharmaceutically acceptable salt thereof according to Embodiment 1, wherein R ¹is a halogen, and m is 1. Implementation 27. A compound or a pharmaceutically acceptable salt thereof according to Implementation 26, wherein R ¹is bromine. Implementation 28. A compound or a pharmaceutically acceptable salt thereof according to Implementation 1, wherein R ¹Yes-N(R ^D) ₂, and m is 1. Implementation 29. A compound or a pharmaceutically acceptable salt thereof according to implementation 28, wherein each R ^DIndependently is optionally selected by one or more independently selected from -N(R ^F) ₂OR ^Galkyl substituted with a group. Embodiment 30. A compound or a pharmaceutically acceptable salt thereof according to Embodiment 29, wherein each R ^Dare independently methyl, methoxyethyl or N,N-dimethylaminopropyl. Embodiment 31. A compound or a pharmaceutically acceptable salt thereof according to Embodiment 1, wherein R ¹is optionally represented by one or more R ^Esubstituted heterocyclic group, and m is 1. Embodiment 32. A compound or a pharmaceutically acceptable salt thereof according to Embodiment 31, wherein the heterocyclic group is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and , each of which is optionally represented by one or more R ^EReplacement. Implementation 33. A compound or a pharmaceutically acceptable salt thereof according to Implementation 31, wherein R ^Eis a halogen. Implementation 34. A compound or a pharmaceutically acceptable salt thereof according to Implementation 32, wherein R ^Eis F. Implementation 35. A compound or a pharmaceutically acceptable salt thereof according to implementation 31, wherein R ^EYes-N(R ^F) ₂、-alkyl-N(R ^F) ₂、    -C(O)OR ^GOr an alkyl group optionally substituted by one or more halogens. Embodiment 36. A compound according to Embodiment 35 or a pharmaceutically acceptable salt thereof, wherein R ^Fand R ^GEach of them is an alkyl group. Embodiment 37. A compound or a pharmaceutically acceptable salt thereof according to Embodiment 35, wherein R ^Fand R ^GEach of them is C _1-3Alkyl. Embodiment 38. A compound or a pharmaceutically acceptable salt thereof according to Embodiment 35, wherein R ^ESelect from the group consisting of: -N(CH ₃) ₂、-C _1-3Alkyl-N(CH ₃) ₂, -C(O)O(tert-butyl), methyl, ethyl or trifluoroethyl. Embodiment 39. A compound or a pharmaceutically acceptable salt thereof according to Embodiment 31, wherein R ^Eis a cycloalkyl or heterocyclic group, wherein the cycloalkyl and the heterocyclic group are optionally substituted by one or more alkyl or halogen groups. Embodiment 40. A compound according to Embodiment 39 or a pharmaceutically acceptable salt thereof, wherein R ^ESelected from cyclopropyl, morpholinyl, piperazinyl, oxadiazine or cyclobutane, each of which is optionally substituted by one or more alkyl or halogen groups. Embodiment 41. A compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein R ¹Choose from a group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and . Implementation 42. A compound or a pharmaceutically acceptable salt thereof according to implementation 1, wherein R ²is a halogen, and n is 1 or 2. Implementation 43. A compound or a pharmaceutically acceptable salt thereof according to implementation 42, wherein R ²is F. Implementation 44. A compound or a pharmaceutically acceptable salt thereof according to implementation 1, wherein R ²is an alkyl or cycloalkyl group, wherein the alkyl group and the cycloalkyl group are optionally substituted by one or more halogens. Embodiment 45. A compound according to Embodiment 44 or a pharmaceutically acceptable salt thereof, wherein R ²is methyl, ethyl, cyclopropyl or trifluoroethyl. Implementation 46. A compound or a pharmaceutically acceptable salt thereof according to Implementation 1, wherein R ³is an alkyl group or a cycloalkyl group. Embodiment 47. A compound or a pharmaceutically acceptable salt thereof according to Embodiment 46, wherein R ³is methyl, ethyl or cyclopropyl. Embodiment 48. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1, wherein m is 0, 1 or 2. Embodiment 49. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1, wherein n is 0 or 1. Embodiment 50. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1, wherein the compound is selected from the group consisting of: and . Embodiment 51. A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 50 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Embodiment 52. A method for inhibiting EGFR activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1 to 50 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to Embodiment 51. Embodiment 53. A method for treating an EGFR-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1 to 50 or a pharmaceutically acceptable salt thereof or administering to the subject a pharmaceutical composition according to Embodiment 51. Embodiment 54. The method according to Embodiment 53, wherein the EGFR-related disorder is an autoimmune disease or cancer. Embodiment 55. The method according to embodiment 54, wherein the cancer is selected from the group consisting of lung cancer, brain cancer, colorectal cancer, bladder cancer, urothelial cancer, breast cancer, prostate cancer, ovarian cancer, head and neck cancer, pancreatic cancer, gastric cancer and mesothelioma, including metastasis (especially brain metastasis), etc. Embodiment 56. The method according to any one of embodiments 53 to 55, wherein the compound is administered simultaneously, separately or sequentially with one or more additional therapeutic agents. Embodiment 57. The method according to embodiment 56, wherein the one or more additional therapeutic agents are selected from the group consisting of: EGFR TKI, EGFR antibody, MEK inhibitor, c-MET inhibitor, mitotic kinase inhibitor, immunotherapy agent, anti-angiogenic agent, apoptosis inducer, mTOR inhibitor, histone deacetylase inhibitor, IL6 inhibitor and JAK inhibitor. In addition, the embodiments of various aspects provided by the present disclosure are also described in any of the following paragraphs. Item 1. A compound of formula (II) (II) or a pharmaceutically acceptable salt thereof, wherein: Ring A ¹is a 7-12 membered cycloalkyl, a 7-12 membered heterocyclic group, a 7-12 membered aryl group or a 7-12 membered heteroaryl group; Ring B is selected from the group consisting of: cycloalkyl, heterocyclic group, aryl group and heteroaryl group; L ¹Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ²Select from the group consisting of: key, N(R ^A), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted by one or more R ^BReplace; Where R ^ASelected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; wherein each R ^BIndependently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclo, aryl and heteroaryl; L ³Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ⁴Choose from O, S or N(R ^C)； Where R ^CSelected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogenated alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ¹Independently selected from the group consisting of: hydroxyl, halogen, cyano, amino, -N(R ^D) ₂, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted by one or more R ^EReplace; where each R ^DIndependently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano,  -N(R ^F) ₂OR ^G; where each R ^EIndependently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, -N(R ^F) ₂、-alkyl-N(R ^F) ₂、-C(O)OR ^G, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino and alkyl; wherein R ^Fand R ^GEach of R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ²Independently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; Each R ³Selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclic, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclic are optionally substituted by one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; m is an integer from 0 to 5; n is an integer from 0 to 4; and p is an integer from 0 to 3. Item 2. A compound or a pharmaceutically acceptable salt thereof according to Project 1, wherein Ring A ¹is a 7-12 membered heteroaryl group. Item 3. A compound or a pharmaceutically acceptable salt thereof according to Project 2, wherein Ring A ¹is tetrahydroisoquinolinyl. Item 4. A compound or a pharmaceutically acceptable salt thereof according to Project 3, wherein Ring A ¹yes or . Item 5. A compound or a pharmaceutically acceptable salt thereof according to any of the foregoing projects, wherein m is 0. Item 6. A compound or a pharmaceutically acceptable salt thereof according to Project 1, wherein m is 1. Item 7. A compound or a pharmaceutically acceptable salt thereof according to Project 6, wherein R ¹is optionally replaced by one or more N(R ^F) ₂Substituted alkyl. Item 8. A compound or a pharmaceutically acceptable salt thereof according to Item 7, wherein R ¹is optionally replaced by one or more N(R ^F) ₂Substituted ethyl. Item 9. A compound or a pharmaceutically acceptable salt thereof according to Project 7 or 8, wherein R ^Fis an alkyl group. Item 10. A compound or a pharmaceutically acceptable salt thereof according to Project 9, wherein R ^Fis a methyl group. Item 11. A compound or a pharmaceutically acceptable salt thereof according to Project 6, wherein R ¹is a heterocyclic group. Item 12. A compound or a pharmaceutically acceptable salt thereof according to Project 11, wherein R ¹is an oxacyclobutane. Item 13. A compound or a pharmaceutically acceptable salt thereof according to Item 12, wherein R ¹yes . Item 14. A compound or a pharmaceutically acceptable salt thereof according to Project 1, wherein L ¹is an alkyl group. Item 15. A compound or a pharmaceutically acceptable salt thereof according to Item 14, wherein L ¹yes or , where L ¹*end and L ²Connected. Item 16. A compound or a pharmaceutically acceptable salt thereof according to Project 1, wherein L ²is a bond. Item 17. A compound or a pharmaceutically acceptable salt thereof according to Project 1, wherein L ³is an alkyl group. Item 18. A compound or a pharmaceutically acceptable salt thereof according to Project 11, wherein L ³is ethyl. Item 19. A compound or a pharmaceutically acceptable salt thereof according to Project 1, wherein L ⁴is O or NH. Item 20. A compound or a pharmaceutically acceptable salt thereof according to Item 1, wherein Ring B is an aryl group or a heteroaryl group. Item 21. A compound or a pharmaceutically acceptable salt thereof according to Item 20, wherein Ring B is a phenyl group, a pyridyl group or a pyrazolyl group. Item 22. A compound or a pharmaceutically acceptable salt thereof according to Item 21, wherein Ring B is selected from the group consisting of: 、 、 、 、 and . Item 23. A compound or a pharmaceutically acceptable salt thereof according to Item 1, wherein n is 1. Item 24. A compound or a pharmaceutically acceptable salt thereof according to Item 1, wherein R ²is an alkyl group. Item 25. A compound or a pharmaceutically acceptable salt thereof according to Item 24, wherein R ²is a methyl group. Item 26. A compound or a pharmaceutically acceptable salt thereof according to Project 1, wherein R ³is an alkyl group. Item 27. A compound or a pharmaceutically acceptable salt thereof according to Item 26, wherein R ³is methyl. Item 28. A compound according to Project 1 or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1. Item 29. A compound according to Project 1 or a pharmaceutically acceptable salt thereof, wherein n is 1. Item 30. A compound according to Project 1 or a pharmaceutically acceptable salt thereof, wherein p is 1. Item 31. A compound of formula (III): (III) or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl; Ring B ¹is a 7-12-membered cycloalkyl group, a 7-12-membered heterocyclic group, a 7-12-membered aryl group, or a 7-12-membered heteroaryl group; L ¹Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ²Select from the group consisting of: key, N(R ^A), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted by one or more R ^BReplace; Where R ^ASelected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; wherein each R ^BIndependently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclo, aryl and heteroaryl; L ³Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ⁴Choose from O, S or N(R ^C)； Where R ^CSelected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogenated alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ¹Independently selected from the group consisting of: hydroxyl, halogen, cyano, amino, -N(R ^D) ₂, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted by one or more R ^EReplace; where each R ^DIndependently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano,  -N(R ^F) ₂OR ^G; where each R ^EIndependently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, -N(R ^F) ₂、-alkyl-N(R ^F) ₂、-C(O)OR ^G, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino and alkyl; wherein R ^Fand R ^GEach of R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ²Independently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; Each R ³Selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo are optionally substituted by one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; m is an integer from 0 to 5; n is an integer from 0 to 4; and p is an integer from 0 to 3. Item 32. A compound or a pharmaceutically acceptable salt thereof according to Project 31, wherein Ring A is an aryl or heteroaryl group. Item 33. A compound or a pharmaceutically acceptable salt thereof according to Item 32, wherein Ring A is selected from the group consisting of furanyl, phenylthio, pyrrolyl, phenyl, pyridyl, pyranyl, pyrimidyl, oxazinyl, pyrazinyl and tetrahydroisoquinolinyl. Item 34. A compound or a pharmaceutically acceptable salt thereof according to Item 31, wherein m is 0. Item 35. A compound or a pharmaceutically acceptable salt thereof according to Item 31, wherein R ¹is a halogen, and m is 1. Item 36. A compound or a pharmaceutically acceptable salt thereof according to Item 35, wherein R ¹is bromine. Item 37. A compound or a pharmaceutically acceptable salt thereof according to Item 31, wherein R ¹Yes-N(R ^D) ₂, and m is 1. Item 38. A compound or a pharmaceutically acceptable salt thereof according to Item 37, wherein each R ^DIndependently is optionally selected by one or more independently selected from -N(R ^F) ₂OR ^G Item 39. A compound or a pharmaceutically acceptable salt thereof according to Item 38, wherein each R ^Dare independently methyl, methoxyethyl or N,N-dimethylaminopropyl. Item 40. A compound or a pharmaceutically acceptable salt thereof according to Project 31, wherein R ¹is optionally represented by one or more R ^Esubstituted heterocyclic group, and m is 1. Item 41. A compound or a pharmaceutically acceptable salt thereof according to Item 40, wherein the heterocyclic group is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and , each of which is optionally represented by one or more R ^ESubstituted. Item 42. A compound or a pharmaceutically acceptable salt thereof according to Item 40, wherein R ^Eis a halogen. Item 43. A compound or a pharmaceutically acceptable salt thereof according to Item 42, wherein R ^Eis F. Item 44. A compound or a pharmaceutically acceptable salt thereof according to Item 40, wherein R ^EYes-N(R ^F) ₂、-alkyl-N(R ^F) ₂、-C(O)OR ^GOr an alkyl group optionally substituted by one or more halogens. Item 45. A compound or a pharmaceutically acceptable salt thereof according to Item 44, wherein R ^Fand R ^GEach of them is an alkyl group. Item 46. A compound or a pharmaceutically acceptable salt thereof according to Item 45, wherein R ^Fand R ^GEach of them is C _1-3Alkyl. Item 47. A compound or a pharmaceutically acceptable salt thereof according to Item 44, wherein R ^ESelect from the group consisting of: -N(CH ₃) ₂、-C _1-3Alkyl-N(CH ₃) ₂, -C(O)O(tert-butyl), methyl, ethyl or trifluoroethyl. Item 48. A compound or a pharmaceutically acceptable salt thereof according to Project 40, wherein R ^Eis a cycloalkyl or heterocyclic group, wherein the cycloalkyl and the heterocyclic group are optionally substituted by one or more alkyl or halogen groups. Item 49. A compound or a pharmaceutically acceptable salt thereof according to Item 48, wherein R ^ESelected from cyclopropyl, morpholine, piperazine, oxacyclobutenyl or azocyclobutane, each of which is optionally substituted by one or more alkyl or halogen groups. Item 50. A compound or a pharmaceutically acceptable salt thereof according to Project 31, wherein R ¹Choose from a group consisting of 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and . Item 51. A compound or a pharmaceutically acceptable salt thereof according to Project 31, wherein Ring B ¹is a 7-12 membered heteroaryl group. Item 52. A compound or a pharmaceutically acceptable salt thereof according to Item 51, wherein Ring B ¹yes . Item 53. A compound or a pharmaceutically acceptable salt thereof according to Project 31, wherein R ²is a halogen, and n is 1 or 2. Item 54. A compound or a pharmaceutically acceptable salt thereof according to Item 53, wherein R ²is F. Item 55. A compound or a pharmaceutically acceptable salt thereof according to Project 31, wherein R ²is an alkyl group or a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are optionally substituted by one or more halogens. Item 56. A compound or a pharmaceutically acceptable salt thereof according to Item 55, wherein R ²is methyl, ethyl, cyclopropyl or trifluoroethyl. Item 57. A compound or a pharmaceutically acceptable salt thereof according to Project 31, wherein L ¹is an alkyl group. Item 58. A compound or a pharmaceutically acceptable salt thereof according to Item 57, wherein L ¹Is propyl. Item 59. A compound or a pharmaceutically acceptable salt thereof according to Project 31, wherein L ²is a bond. Item 60. A compound or a pharmaceutically acceptable salt thereof according to Project 31, wherein L ³is an alkyl group. Item 61. A compound or a pharmaceutically acceptable salt thereof according to Item 60, wherein L ³is ethyl. Item 62. A compound or a pharmaceutically acceptable salt thereof according to Project 31, wherein L ⁴is O or NH. Item 63. A compound or a pharmaceutically acceptable salt thereof according to Project 31, wherein R ³is an alkyl group. Item 64. A compound or a pharmaceutically acceptable salt thereof according to Item 63, wherein R ³is a methyl group. Item 65. A compound or a pharmaceutically acceptable salt thereof according to Project 31, wherein R ³is a halogen. Item 66. A compound or a pharmaceutically acceptable salt thereof according to Item 65, wherein R ³is Cl. Item 67. A compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein m is 0. Item 68. A compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein n is 0. Item 69. A compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein p is 1. Item 70. A compound of formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl; Ring B is selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl; L ¹Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ^{twenty one}is a 7-12 membered cycloalkyl or a 7-12 membered heterocyclic group, wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more R ^BReplace; where each R ^BIndependently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclo, aryl and heteroaryl; L ³Selected from the group consisting of: a bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group and a heteroalkynyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group and the heteroalkynyl group are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl group, a halogen group, a cyano group and an amino group; L ⁴Choose from O, S or N(R ^C)； Where R ^CSelected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogenated alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ¹Independently selected from the group consisting of: hydroxyl, halogen, cyano, amino, -N(R ^D) ₂, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted by one or more R ^EReplace; where each R ^DIndependently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano,  -N(R ^F) ₂OR ^G; where each R ^EIndependently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, -N(R ^F) ₂、-alkyl-N(R ^F) ₂、-C(O)OR ^G, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino and alkyl; wherein R ^Fand R ^GEach of R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; Each R ²Independently selected from the group consisting of: hydrogen, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; R ³Selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo are optionally substituted by one or more groups independently selected from: hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; m is an integer from 0 to 5; n is an integer from 0 to 4; and p is an integer from 0 to 3. Item 71. A compound or a pharmaceutically acceptable salt thereof according to Item 70, wherein Ring A is an aryl group. Item 72. A compound or a pharmaceutically acceptable salt thereof according to Item 71, wherein Ring A is a phenyl group. Item 73. A compound or a pharmaceutically acceptable salt thereof according to Item 70, wherein R ¹is a halogen, and m is 1. Item 74. A compound or a pharmaceutically acceptable salt thereof according to Item 73, wherein R ¹is bromine. Item 75. A compound or a pharmaceutically acceptable salt thereof according to Item 70, wherein R ¹Yes-N(R ^D) ₂, and m is 1. Item 76. A compound or a pharmaceutically acceptable salt thereof according to Item 75, wherein each R ^DIndependently is optionally selected by one or more independently selected from -N(R ^F) ₂OR ^G Item 77. A compound or a pharmaceutically acceptable salt thereof according to Item 76, wherein each R ^Dare independently methyl, methoxyethyl or N,N-dimethylaminopropyl. Item 78. A compound or a pharmaceutically acceptable salt thereof according to Item 70, wherein R ¹is optionally represented by one or more R ^Esubstituted heterocyclic group, and m is 1. Item 79. A compound or a pharmaceutically acceptable salt thereof according to Item 78, wherein the heterocyclic group is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and , each of which is optionally represented by one or more R ^ESubstituted. Item 80. A compound or a pharmaceutically acceptable salt thereof according to Project 78, wherein R ^Eis a halogen. Item 81. A compound or a pharmaceutically acceptable salt thereof according to Item 80, wherein R ^Eis F. Item 82. A compound or a pharmaceutically acceptable salt thereof according to Project 78, wherein R ^EYes-N(R ^F) ₂、-alkyl-N(R ^F) ₂、-C(O)OR ^GOr an alkyl group optionally substituted by one or more halogens. Item 83. A compound or a pharmaceutically acceptable salt thereof according to Item 82, wherein R ^Fand R ^GEach of which is an alkyl group. Item 84. A compound or a pharmaceutically acceptable salt thereof according to Item 83, wherein R ^Fand R ^GEach of them is C _1-3Alkyl. Item 85. A compound or a pharmaceutically acceptable salt thereof according to Item 82, wherein R ^ESelect from the group consisting of: -N(CH ₃) ₂、-C _1-3Alkyl-N(CH ₃) ₂, -C(O)O(tert-butyl), methyl, ethyl or trifluoroethyl. Item 86. A compound or a pharmaceutically acceptable salt thereof according to Project 78, wherein R ^Eis a cycloalkyl or heterocyclic group, wherein the cycloalkyl and the heterocyclic group are optionally substituted by one or more alkyl or halogen groups. Item 87. A compound or a pharmaceutically acceptable salt thereof according to Item 86, wherein R ^ESelected from cyclopropyl, morpholine, piperazine, oxacyclobutenyl or azocyclobutane, each of which is optionally substituted by one or more alkyl or halogen groups. Project 88 A compound or a pharmaceutically acceptable salt thereof according to Project 70, wherein R ¹Choose from a group consisting of 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and . Item 89. A compound or a pharmaceutically acceptable salt thereof according to Item 70, wherein Ring B is an aryl group or a heteroaryl group. Item 90. A compound or a pharmaceutically acceptable salt thereof according to Item 89, wherein Ring B is a phenyl group, a pyridyl group or a pyrazolyl group. Item 91. A compound or a pharmaceutically acceptable salt thereof according to Item 90, wherein Ring B is selected from the group consisting of: 、 、 、 、 and . Item 92. A compound or a pharmaceutically acceptable salt thereof according to Project 70, wherein L ¹is a bond. Item 93. A compound or a pharmaceutically acceptable salt thereof according to Project 70, wherein L ^{twenty one}is a 7-10 membered heterocyclic group containing one or more heteroatoms selected from N or O. Item 94. A compound or a pharmaceutically acceptable salt thereof according to Item 93, wherein L ^{twenty one}Choose from a group consisting of 、 、 and , where L ^{twenty one}*end and L ³connected. Item 95. A compound or a pharmaceutically acceptable salt thereof according to Project 70, wherein L ³is an alkyl group. Item 96. A compound or a pharmaceutically acceptable salt thereof according to Item 95, wherein L ³is ethyl. Item 97. A compound or a pharmaceutically acceptable salt thereof according to Project 70, wherein L ⁴is O or NH. Item 98. A compound or a pharmaceutically acceptable salt thereof according to Project 70, wherein R ¹is optionally represented by one or more R ^Esubstituted heterocyclic group, and m is 1. Item 99. A compound or a pharmaceutically acceptable salt thereof according to Project 70, wherein R ³is an alkyl group. Item 100. A compound or a pharmaceutically acceptable salt thereof according to Project 99, wherein R ³is methyl. Item 101. A compound or a pharmaceutically acceptable salt thereof according to Item 70, wherein m is 0 or 1. Item 102. A compound or a pharmaceutically acceptable salt thereof according to Item 70, wherein n is 1. Item 103. A compound or a pharmaceutically acceptable salt thereof according to Item 70, wherein p is 1. Item 104. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . Item 105. A pharmaceutical composition comprising a compound according to any one of Items 1 to 104 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Item 106. A method for inhibiting EGFR activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of Items 1 to 104 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to Item 105. Item 107. A method for treating an EGFR-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of Items 1 to 104 or a pharmaceutically acceptable salt thereof or administering to the subject a pharmaceutical composition according to Item 105. Item 108. The method according to Item 107, wherein the EGFR-related disorder is an autoimmune disease or cancer. Item 109. The method according to Item 108, wherein the cancer is selected from the group consisting of lung cancer, brain cancer, colorectal cancer, bladder cancer, urothelial cancer, breast cancer, prostate cancer, ovarian cancer, head and neck cancer, pancreatic cancer, gastric cancer and mesothelioma, including metastasis (especially brain metastasis), etc. Item 110. The method according to any one of Items 107 to 109, wherein the compound is administered simultaneously, separately or sequentially with one or more additional therapeutic agents. Item 111. A method according to Item 110, wherein the one or more additional therapeutic agents are selected from the group consisting of: EGFR TKI, EGFR antibody, MEK inhibitor, c-MET inhibitor, mitotic kinase inhibitor, immunotherapy agent, anti-angiogenic agent, apoptosis inducer, mTOR inhibitor, histone deacetylase inhibitor, IL6 inhibitor, JAK inhibitor. Examples The general method of the present disclosure is further explained below. The compounds of the present disclosure can be prepared by methods known in the art. The detailed preparation methods of the preferred compounds of the present disclosure are described below. However, these in no way limit the preparation methods of the compounds of the present disclosure. Synthesis Examples The following examples are included for illustrative purposes. The examples provided herein describe the synthesis of the compounds disclosed herein and the intermediates used to prepare the compounds. However, it should be understood that these examples do not limit the present disclosure and are intended only to illustrate methods for practicing the present disclosure. Those skilled in the art will recognize that the described chemical reactions can be easily adapted to prepare a variety of other compounds of the present disclosure, and that alternative methods for preparing the compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, non-exemplary compounds according to the present disclosure can be successfully synthesized by modifications that are obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art in addition to the described reagents and building blocks, and/or by routine modifications to reaction conditions. In addition, it will be understood by those skilled in the art that the various steps described herein or in separate batches of compounds can be combined. Alternatively, other reactions disclosed herein or known in the art will be considered applicable to the preparation of other compounds disclosed herein. Therefore, the following description is not intended to limit the scope of the disclosure, but is specified by the appended claims. Chemistry, Materials and General Methods Unless otherwise specified, all reagents and solvents are from commercial suppliers such as PharmaBlock, Bide Pharmatech, Shanghai Send Pharm, Aldrich, Sigma, etc., and can be used without further purification. Dry organic solvents (THF, DMF, 1,4-dioxane, etc.) were purchased from Anhui Senrise Technology, Beijing Innochem Science & Technology, and J & K Scientific and packaged in Sure/Seal bottles under nitrogen. All reactions involving air- or moisture-sensitive reagents were performed under nitrogen atmosphere. ¹H NMR spectra were recorded on a Bruker AV III HD 400 MHz, Bruker AV NEO 400 MHz spectrometer at ambient temperature. Chemical shifts are reported in parts per million (ppm, delta units). The data are reported as follows: chemical shift, number of protons and multiplicity (s = singlet, d = doublet, dd = double of doublets, dt = double of triplets, t = triplet, q = quartet, br = broad, m = multiplet). The reactions were monitored using LCMS (Shimadzu 20AD) with UV detection at 254 nm and low resonance electrospray mode (ESI). Most of the final compounds were purified to > 95% purity as determined by LCMS (3 min). The LCMS (3 minutes) method used the following: Shimadzu 20AD spectrometer, Shim-pack Scepter C18-120 3.3 * 33 mm, 3.0 um, 30°C, with a flow rate of 1.5 ml/min; solvent A was water + 6.5 mM NH ₄HCO ₃+ Hydrogen hydroxide (pH = 10), solvent B is acetonitrile; 0.0-1.7 minutes, 30% B-70% B; 1.7-2.3 minutes, 70% B-95% B; 2.3-2.8 minutes, 95% B; 2.8-3.0 minutes, 10% B. The flow from the UV detector was split (1:3) to the MS detector, which was configured with ESI as the ionization source. The CHIRAL method used the following: column: CHIRALPAK IC-3, 0.46 * 5 cm, 3 μm; at 25 ° C, the flow rate was 1.0 mL/min; methyl tert-butyl ether (0.2% diethylamine)/(ethanol/dichloromethane = 1/1) = 20/80. The SFC method used the following: Column: (R, R) -WHELK-01-Kromasil, 5 * 25 cm, 5 μm; Mobile phase A: CO ₂, mobile phase B: methanol/acetonitrile = 1/1. The abbreviations used in the synthesis of the compounds provided herein are listed below: Synthesis of intermediates Intermediate M1 2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-methylisoxonitrile Step 1. Preparation of 2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (M1-1). 2-Methyl-1H-pyrazol-3-one (100 g, 1019 mmol, 1 equiv) and K ₂CO ₃To a stirred solution of 2-(trimethylsilyl)ethoxymethyl chloride (352 g, 2548 mmol, 2.5 equiv) in acetonitrile (1000 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (254 g, 1528 mmol, 1.5 equiv) dropwise. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water (200 mL) at 0 °C, and the mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (3×500 mL) and purified by anhydrous Na ₂SO ₄Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with petroleum ether (200 mL) to give 130 g of 2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (M1-1) (55%) as a yellow solid. LCMS: m/z (ESI), [2M+H] ⁺=457.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.00 (9H, s), 0.80-0.85 (2H, m), 3.28 (3H, s), 3.40-3.50 (2H, m), 5.15 (2H, s), 5.29 (1H, d), 7.89 (1H, d). Step 2. Preparation of 4-iodo-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (M1-2). To a stirred mixture of 2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (47 g, 205.80 mmol, 1 equiv) in acetonitrile (400 mL) at 0 °C under nitrogen atmosphere was added N-iodosuccinimide (50.93 g, 226.39 mmol, 1.1 equiv). The resulting mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. The reaction was quenched with aqueous sodium thiosulfate solution (400 mL) at 0 °C, and the mixture was extracted with dichloromethane (3×300 mL). The combined organic layers were washed with brine (400 mL) and purified by anhydrous Na ₂SO ₄Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with petroleum ether (300 mL) to give 72 g of 4-iodo-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (M1-2) (97%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=354.95. ¹H NMR (DMSO-d ₆, 400 MHz) δ -0.04 (9H, s), 0.75-0.86 (2H, m), 3.32 (3H, s), 3.39-3.48 (2H, m), 5.13 (2H, s), 8.13 (1H, s). Step 3. Preparation of (6-chloro-4-(methoxycarbonyl)pyridin-2-yl)boronic acid (M1-3). A mixture of bis(pinacolato)diboron (11.5 g, 453.7 mmol, 1.3 equiv) in methyl tert-butyl ether (100 mL) was heated to 80°C and stirred for 0.5 h, then cooled to room temperature, and bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) (1.16 g, 17 mmol, 0.05 equiv) and 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine (1.4 g, 52 mmol, 0.15 equiv) were added. The mixture was stirred at 25°C for 0.5 h, then methyl 2-chloropyridine-4-carboxylate (60 g, 349 mmol, 1.00 equiv) was added, and stirred at 80°C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give 104 g of methyl 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-4-carboxylate (M1-3) (crude) as a brown oil. This crude material was used in the next step without purification. LCMS: m/z (ESI), [M+H] ⁺=216.05. Step 4. Preparation of methyl 2-chloro-6-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)isonicotinate (M1-4). Freshly prepared 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-4-carboxylic acid methyl ester (104 g crude, about 349 mmol, about 1 equiv), 4-iodo-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (M1-2, 124.30 g, 350.877 mmol, 1 equiv), bis(adamantan-1-yl)(butyl)phosphine (12.58 g, 35.088 mmol, 0.1 equiv), Cs ₂CO ₃(228.65 g, 701.754 mmol, 2 equiv) and Pd ₂(dba) ₃A mixture of (9.6 g, 10.4 mmol, 0.03 equiv) in toluene (600 mL) and water (150 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (800 mL), and the mixture was extracted with ethyl acetate (3×600 mL). The combined organic layers were washed with brine (3×500 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/4) to give 38 g of methyl 2-chloro-6-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)isonicotinate (M1-4) (25%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=398.05. Step 5. Preparation of methyl 2-methyl-6-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)isonicotinate (M1-5). Under nitrogen atmosphere at room temperature, methyl 2-chloro-6-(2-methyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)pyridine-4-carboxylate (38 g, 95 mmol, 1.00 equiv), Pd(dppf)Cl ₂(3677 mg, 5.02 mmol, 0.05 equiv), PCy ₃ ^.HBF ₄(10.5 g, 28.64 mmol, 0.3 equiv) and K ₂CO ₃To a stirred mixture of 1,4-dioxane (26.4 g, 190 mmol, 2 equiv) was added trimethyl-1,3,5,2,4,6-trioxatriborinane (23.9 g, 190 mmol, 2 equiv). The mixture was stirred at 100 °C for 2 h and then cooled to room temperature. The reaction was quenched with water (300 mL) and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×300 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/3) to give 34 g of methyl 2-methyl-6-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)isonicotinate (M1-5) (92%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=378.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.05 (9H, s), 0.80-0.90 (2H, m), 2.53 (3H, s), 3.41 (3H, s), 3.50 (2H, t), 3.89 (3H, s), 5.37 (2H, s), 7.44 (1H, d), 8.52-8.60 (2H, m). Step 6. Preparation of methyl 2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate (M1). A solution of methyl 2-methyl-6-(2-methyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)pyridine-4-carboxylate (34 g, 90 mmol, 1.00 equiv) and HCl in 1,4-dioxane (340 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was treated with saturated NaHCO₃(aqueous solution) solution (300 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×500 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to obtain 20 g of methyl 2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate (M1) (80%) as a red solid. LCMS: m/z (ESI), [M+H] ⁺=248.05. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.56 (3H, s), 3.48 (3H, s), 3.91 (3H, s), 7.31 (1H, s), 7.90-7.80 (2H, m). Intermediate M2 Methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate Step 1. Preparation of 5-bromo-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M2-1). At 0°C, 5-bromo-6-hydroxypyridine-3-carboxylic acid methyl ester (20 g, 86.19 mmol, 1 equivalent) was added to N, N-To the mixture in dimethylformamide (100 mL), NaH (60%) (4.14 g, 172.39 mmol, 2 eq.) was added. The mixture was stirred at 0 °C under nitrogen atmosphere for 60 min. CH ₃I (13.46 g, 94.81 mmol, 1.1 equiv) was added, and the mixture was stirred at 0 °C for 1 h. The reaction was quenched with water (1000 mL) at 0 °C, and the mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (500 mL) and purified by anhydrous Na ₂SO ₄Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with petroleum ether (200 mL) to give 19 g of methyl 5-bromo-1-methyl-6-oxopyridine-3-carboxylate (M2-1) (84%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺= 245.95. ¹H NMR (DMSO-d ₆, 400 MHz) δ 3.59 (3H, s), 3.81 (3H, s), 8.18 (1H, d), 8.62 (1H, d). Step 2. Preparation of (5-(methoxycarbonyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)boronic acid (M2-2). 5-Bromo-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (30 g, 121.92 mmol, 1 equivalent), Pd(dppf)Cl ₂ ^.CH ₂Cl ₂A mixture of (8.92 g, 12.2 mmol, 0.1 eq.), bis(pinacol)diboron (46.44 g, 182.88 mmol, 1.5 eq.) and KOAc (35.90 g, 365.76 mmol, 3 eq.) in 1,4-dioxane (600 mL) was stirred at 80 °C overnight under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction mixture was used directly in the next step without post-treatment. LCMS: m/z (ESI), [M+H] ⁺=212.00. Step 3. Preparation of methyl 1-methyl-5-(2-methyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-6-oxopyridine-3-carboxylate (M2-3). To the mixture freshly prepared by the reaction described above, 4-iodo-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (43 g, 121.37 mmol, 1.00 equiv), Pd(dppf)Cl ₂.CH ₂Cl ₂(7.91 g, 9.71 mmol, 0.08 equivalent), K ₂CO ₃(50.33 g, 364.14 mmol, 3 equiv.) and H ₂O (150 mL). The mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was cooled to room temperature, treated with water (200 mL), and extracted with dichloromethane (3×300 mL). The combined organic layers were washed with brine (500 mL) and purified by anhydrous Na ₂SO ₄Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/8) to obtain 30 g of 1-methyl-5-(2-methyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-6-oxopyridine-3-carboxylic acid methyl ester (M2-3) (62%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺= 394.10. ¹H NMR (DMSO-d ₆, 400 MHz) δ -0.06 (9H, s), 0.82 (2H, t), 3.37 (3H, s), 3.47 (2H, t), 3.60 (3H, s), 3.81 (3H, s), 5.33 (2H, s), 8.41 (1H, d), 8.85 (1H, s), 9.21 (1H, d). Step 4. Preparation of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2). A mixture of methyl 1-methyl-5-(2-methyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-6-oxopyridine-3-carboxylate (30 g, 76.23 mmol, 1 eq.) and HCl in 1,4-dioxane (50 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and treated with K ₂CO ₃Alkalize to pH 9. The resulting mixture was filtered and the filter cake was washed with dichloromethane (5×50 mL). The resulting solution was concentrated under reduced pressure. The residue was purified on a silica gel column eluted with dichloromethane/methanol (10/1) to give 15 g of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2) (74%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=264.10. ¹H NMR (DMSO-d ₆, 400 MHz) δ 3.52 (3H, s), 3.65 (3H, s), 3.83 (3H, s), 7.76 (1H, d), 8.09 (1H, s), 8.45 (1H, s), 13.34 (1H, s). Intermediate M3 (11 R)-16-bromo-5,11,26-trimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. (4 S)-4-benzyl-3-[(2 R)-2-methylpent-4-enyl]-1,3-oxazolidin-2-one (M3-1). In a nitrogen atmosphere at -78 ° C to (4 STo a stirred mixture of 4-benzyl-3-propionyl-1,3-oxazolidin-2-one (100 g, 428.69 mmol, 1 equiv) in tetrahydrofuran (640 mL) were added LiHMDS (471 mL, 471.56 mmol, 1.1 equiv) and allyl bromide (207.4 g, 1714.77 mmol, 4 equiv) dropwise in sequence. The resulting mixture was stirred at -50 °C under nitrogen atmosphere for 2 h and warmed to room temperature. The reaction mixture was treated with saturated NH₄Cl(aq) solution (1000 mL) and treated with CH ₂Cl ₂(3×400 mL) extraction. The combined organic layers were washed with brine (3×500 mL) and purified by anhydrous Na ₂SO ₄Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (40/1) to obtain 100 g (4 S)-4-benzyl-3-[(2 R)-2-methylpent-4-enyl]-1,3-oxazolidin-2-one (M3-1) (85%). LCMS: m/z (ESI), [M+H] ⁺=274.00. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.00-1.12 (3H, t), 2.08-2.49 (2H, m), 2.84-3.06 (2H, m), 3.64-3.78 (1H, m), 4.11-4.26 (1H, m), 4.29-4.39 (1H, m), 4.59-4.75 (1H, m), 4.98-5.18 (2H, m), 5.70-5.87 (1H, m), 7.13-7.38 (5H, m). Step 2. (2 R)-2-methylpent-4-enoic acid (M3-2) preparation. At 0℃, (4 S)-4-benzyl-3-[(2 R)-2-methylpent-4-enyl]-1,3-oxazolidin-2-one (M3-1, 100 g, 365.85 mmol, 1 equivalent) in tetrahydrofuran (800 mL) and H ₂Add LiOH to the stirred mixture in O (200 mL)^.H ₂O (46.05 g, 1097.56 mmol, 3 equiv.) and H ₂O ₂(30%) (114.30 mL, 4906 mmol, 13.4 equiv.). The resulting mixture was stirred at 0 °C for 3 h under a nitrogen atmosphere. The reaction was heated to 40 °C with Na ₂S ₂O ₃The solution (250 mL) was quenched, acidified to pH = 1 with HCl solution, and washed with CH₂Cl ₂(3×400 mL) extraction. The combined organic layers were washed with brine (3×500 mL) and purified by anhydrous Na ₂SO ₄Dry. After filtration, concentrate the filtrate under reduced pressure. The crude product is used directly in the next step without further purification. Step 3. (2 R)- N,N- Preparation of dibenzyl-2-methylpent-4-enamide (M3-3). In a nitrogen atmosphere at room temperature to (2 R)-2-methylpent-4-enoic acid (50 g, 219.02 mmol, 1 equivalent) and dibenzylamine (43.2 g, 219.022 mmol, 1 equivalent) were added to a stirred solution in dioxane (200 mL) N,N-diisopropylethylamine (56.6 g, 438.04 mmol, 2 equiv) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (99.94 g, 262.82 mmol, 1.2 equiv). The resulting mixture was stirred for 2 h. The reaction was quenched with water (1000 mL), and the mixture was washed with CH₂Cl ₂(3×300 mL) extraction. The combined organic layers were washed with brine (3×500 mL) and purified by anhydrous Na ₂SO ₄Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (40/1) to obtain 55.6 g (2 R)- N,N-Dibenzyl-2-methylpent-4-enamide (M3-3) (86%). LCMS: m/z (ESI), [M+H] ⁺=294.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.01 (3H, d), 1.94-2.39 (2H, m), 2.76-2.90 (1H, m), 4.35-4.67 (4H, m), 4.89-5.11 (2H, m), 5.58-5.81 (1H, m), 7.08-7.43 (10H, m). Step 4. (2 R)- N,N- Preparation of dibenzyl-5-hydroxy-2-methylpentylamide (M3-4). At 0°C, (2 R)- N,N-dibenzyl-2-methylpent-4-enamide (50 g, 170.41 mmol, 1 eq.) and 9-boraherobicyclo[3.3.1]nonane (852.05 mL, 426.02 mmol, 2.5 eq.) in tetrahydrofuran (60 mL) were added dropwise NaOH (10 M) (220 mL) and H ₂O ₂(30%) (151 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction was treated with Na ₂S ₂O ₄(aqueous solution) solution (500 mL) was quenched. The mixture was washed with CH ₂Cl ₂(3×500 mL) extraction, and the combined organic layers were purified by anhydrous Na ₂SO ₄Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/1) to obtain 42.5 g (2 R)- N,N-Dibenzyl-5-hydroxy-2-methylpentanamide (M3-4) (68%). LCMS: m/z (ESI), [M+H] ⁺=312.10. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.01 (3H, d), 1.24-1.43 (3H, m), 1.56-1.70 (1H, m), 2.60-2.80 (1H, m), 3.26-3.33 (2H, m), 4.30-4.42 (1H, m), 4.44-4.64 (4H, m), 7.15-7.23 (4H,m), 7.23-7.43 (6H, m). Step 5. (4 R)-5-(dibenzylamino)-4-methylpentan-1-ol (M3-5). At 0°C, LiAlH ₄(6.73 g, 177.41 mmol, 1.3 equiv.) was added to a stirred mixture of tetrahydrofuran (600 mL) (2R)- N,N-dibenzyl-5-hydroxy-2-methylpentanamide (42.5 g, 136.46 mmol, 1 eq.). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (7 mL) and 15 mL NaOH (w/w, 30%) at 0 °C and washed with anhydrous Na ₂SO ₄Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (10/1) to obtain 27.9 g (4 R)-5-(Dibenzylamino)-4-methylpentan-1-ol (M3-5) (68%). LCMS: m/z (ESI), [M+H] ⁺=298.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.81 (3H, d), 0.88-1.00 (1H, m), 1.13-1.46 (3H, m), 1.64-1.78 (1H, m), 2.03-2.27 (2H, m), 3.27- 3.39 (2H, m), 3.44 (2H, d), 3.49-3.59 (2H, d), 4.32 (1H, t), 7.18-7.26 (2H, m), 7.30-7.35 (8H, m). Step 6. (4 R)-5-amino-4-methylpentan-1-ol (M3-6). (4 RA mixture of )-5-(dibenzylamino)-4-methylpentan-1-ol (18 g, 60.51 mmol, 1 eq.) and Pd/C (1.29 g, 12.10 mmol, 0.2 eq.) in methanol (200 mL) was stirred at room temperature under a hydrogen atmosphere for 6 h. The resulting mixture was filtered, and the filter cake was washed with methanol (3×70 mL). The resulting solution was concentrated under reduced pressure to give 6.5 g (4 R)-5-amino-4-methylpentan-1-ol (M3-6) (91%).¹H NMR (DMSO-d ₆, 400 MHz) δ 0.83 (3H, d), 0.94-1.09 (2H, m), 1.25-1.54 (3H, m),2.26-2.49 (2H, m), 3.17 (1H, s), 3.37 (2H, t). Step 7. (4 RPreparation of )-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentan-1-ol (M3-7). 4-Bromo-2-fluoro-1-nitrobenzene (10.00 g, 45.46 mmol, 1 equivalent), K ₂CO ₃(12.56 g, 90.91 mmol, 2 equiv.) and (4 RA mixture of 5-amino-4-methylpentan-1-ol (6.39 g, 54.55 mmol, 1.2 equiv.) in acetonitrile (60 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature, treated with water (500 mL), and extracted with dichloromethane (3×500 mL). The combined organic layers were washed with brine (3×500 mL) and purified by anhydrous Na ₂SO ₄After filtration, the filtrate was concentrated under reduced pressure and purified by prep-TLC using petroleum ether/ethyl acetate (1/3) to obtain 11.7 g (4 R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentan-1-ol (M3-7) (81%). LCMS: m/z (ESI), [M+H] ⁺=319.00. ¹H NMR (400 MHz, DMSO-d ₆ ) δ 0.95 (3H, d), 1.14-1.27 (1H, m), 1.37-1.59 (3H, m), 1.77-1.88 (1H, m), 3.18-3.22 (1H, m), 3.24-3.34 (1H , m), 3.35-3.44 (2H, m), 4.39 (1H, t), 6.83-6.87 (1H, m), 7.26 (1H, d), 7.99 (1H, d), 8.20 (1H, t).Step 8. 5-(5-{[(4 RPreparation of methyl 5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M3-8). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 2.67 g, 10.09 mmol, 1 equiv) and triphenylphosphine (6.62 g, 25.22 mmol, 2.5 equiv) in tetrahydrofuran (60 mL) at 0°C under a nitrogen atmosphere were added diisopropyl azodicarboxylate (4.08 g, 20.18 mmol, 2 equiv) and (4 R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentan-1-ol (3.21 g, 10.09 mmol, 1 equiv). After stirring at room temperature for 5 h, the mixture was treated with water (500 mL) and extracted with dichloromethane (3×500 mL). The combined organic layers were washed with brine (3×500 mL) and purified by anhydrous Na ₂SO ₄Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC using petroleum ether/ethyl acetate (1/4) to obtain 2.72 g of 5-(5-{[(4 R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M3-8) (48%). LCMS: m/z (ESI), [M+H] ⁺=564.10. ¹H NMR (400 MHz, DMSO-d ₆ ) δ 0.97 (3H, d), 1.45-1.29 (1H, m), 1.60-1.64 (1H, m), 1.78-1.82 (1H, m), 1.86 (2H, s), 3.38-3.15 (2H, m ), 3.58 (3H, s), 3.68 (3H, s), 3.78 (3H, s), 3.96 (2H, t), 6.83-6.88 (1H, m), 7.26 (1H, d), 8.02-7.95 ( 2H, m), 8.14 (1H, d), 8.21 (1H, t), 8.43 (1H, d). Step 9. 5-(5-{[(4 RPreparation of methyl 5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M3-9). In a nitrogen atmosphere at 0 ° C, 5-(5-{[(4 R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (4.00 g, 7.11 mmol, 1 equiv) and ranyl nickel (200 mg, 2.33 mmol, 0.33 equiv) were added to a stirring mixture of methanol (40 mL) with NH ₂NH ₂ ^.H ₂O (712 mg, 14.22 mmol, 2 eq.). After stirring at room temperature for 3 h, the mixture was filtered and the filter cake was washed with methanol (3×200 mL). The organic solution was concentrated under reduced pressure and the residue was purified by prep-TLC eluting with dichloromethane/methanol (30/1) to give 3.65 g of 5-(5-{[(4 R)-5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M3-9) (96%). LCMS: m/z (ESI), [M+H] ⁺=533.95. Step 10. 5-(5-{[(4 RPreparation of methyl 4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M3-10). At room temperature, 5-(5-{[(4 RTo a stirred mixture of methyl 5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (3.00 g, 5.63 mmol, 1 equiv) in dichloromethane (40 mL) was added cyanogen bromide (895 mg, 8.45 mmol, 1.5 equiv). After stirring at room temperature for 2 h, the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC eluting with dichloromethane/methanol (20/1) to obtain 2.6 g of 5-(5-{[(4 R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M3-10) (83%). LCMS: m/z (ESI), [M+H] ⁺=559.05. Step 11. 5-(5-{[(4 R)-4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (M3-11). At room temperature, 5-(5-{[(4 RTo a stirred mixture of methyl 4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (3.71 g, 6.42 mmol, 1 eq.) in tetrahydrofuran (100 mL) was added LiOH (307 mg, 12.83 mmol, 2 eq.) in H ₂O (20 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (10% to 40% acetonitrile/water) to obtain 3.5 g of 5-(5-{[(4 R)-4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (M3-11) (97%). LCMS: m/z (ESI), [M+H] ⁺=545.15. Step 12. (11 R)-16-bromo-5,11,26-trimethyl-7-oxa-4,5,13, 20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (M3). At room temperature, 5-(5-{[(4 R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (1.2 g, 2.20 mmol, 1 equivalent) was added to the stirred mixture in dioxane (18 mL) N, N-diisopropylethylamine (0.85 g, 6.62 mmol, 3 equiv) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.26 g, 3.31 mmol, 1.5 equiv). After stirring at 60 °C for 3 h under nitrogen atmosphere, the reaction mixture was cooled to room temperature, treated with water (300 mL), and washed with CH₂Cl ₂(2×200 mL) extraction. The combined organic layers were washed with brine (3×300 mL) and purified by anhydrous Na ₂SO ₄Dry. After filtration, concentrate the filtrate under reduced pressure. The residue is subjected to prep-TLC using CH ₂Cl ₂/methanol (40/1) for purification to obtain 1.14 g (11 R)-16-bromo-5,11,26-trimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (M3) (98%). LCMS: m/z (ESI), [M+H] ⁺=525.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.81 (3H, d), 1.43 (1H, q), 1.91 (2H, d), 2.06-2.26 (1H, m), 2.78 (1H, br s), 3.62 (3H, s), 3.72 (3H, s), 3.89-4.00 (2H, m), 4.07-4.15 (1H, m), 4.31-4.38 (1H, m), 7.36 (1H, dd), 7.46 (1H, d), 7.88 (1H, d), 8.30 (1H, d), 8.35 (1H, s), 8.79 (1H, d), 12.67 (1H, s). Intermediates M4A and M4B 5-Bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer 1 (M4A) and isomer 2 (M4B) Step 1. Preparation of benzylbis(ethoxymethyl)amine (M4-1). Benzylamine (500 g, 4666 mmol, 1 equivalent), POM (840.62 g, 9332 mmol, 2 equivalents) and K ₂CO ₃(644.88 g, 4666. mmol, 1 eq.) in ethanol (1200 mL) was stirred at room temperature under nitrogen atmosphere for 16 h. The resulting mixture was filtered. The filter cake was washed with dichloromethane (3×200 mL), and the organic solution was concentrated under reduced pressure to give 1200 g of benzylbis(ethoxymethyl)amine (M4-1) (80%) as a yellow oil. This crude material was used in step 3 without further purification. ¹H NMR (DMSO- d ₆, 400 MHz) δ 1.01-1.19 (6H, m), 3.39-3.57 (3H, m), 3.90 (2H, t), 4.55-4.82 (4H, m), 7.27-7.39 (5H, m). Step 2. Preparation of 2-oxocyclopentane-1-carboxylic acid isopropyl ester (M4-2). 2-Oxocyclopentane-1-carboxylic acid ethyl ester (400 g, 2561 mmol, 1 equivalent) and DMAP (31.29 g, 256.11 mmol, 0.1 equivalent) were added to i-PrOH (500 mL) was stirred at 80 °C overnight under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified on a silica gel column eluted with petroleum ether/ethyl acetate (10/1) to give 400 g of 2-oxocyclopentane-1-carboxylic acid isopropyl ester (M4-2) (92%) as a yellow oil. LCMS: m/z (ESI), [M - H] ⁺=168.85. ¹H NMR (DMSO- d ₆, 400 MHz) δ 1.26 (6H, t), 1.80-1.92 (1H, m), 2.07-2.17 (1H, m), 2.25-2.35 (4H, m), 3.11 (1H, t), 5.00-5.10 (1H, m). Step 3. Preparation of 3-benzyl-8-oxo-3-azabicyclo[3.2.1]octane-1-carboxylic acid isopropyl ester (M4-3). A solution of benzylbis(methoxymethyl)amine (M4-1, 601.1 g, 3078.5 mmol, 2.62 equiv) in DMF (1.5 L) was treated with methyltrichlorosilane (400.4 g, 2679 mmol, 2.28 equiv) under nitrogen atmosphere at 0 °C for 10 min, followed by the slow addition of isopropyl 2-oxocyclopentane-1-carboxylate (M4-2, 200 g, 1175 mmol, 1 equiv) at 0 °C. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water (3 L) and treated with saturated NaHCO ₃(aqueous solution) solution (3 L) was alkalized to pH 7, and the mixture was extracted with ethyl acetate (3×2 L). The combined organic layers were washed with brine (3×2 L) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column eluting with petroleum ether:ethyl acetate (40/1) and concentrated under vacuum. The residue was further purified by Prep-HPLC by reverse phase flash chromatography using a C18 silica gel column. The fractions containing the desired compound were evaporated to dryness to give 110 g of 3-benzyl-8-oxo-3-azabicyclo[3.2.1]octane-1-carboxylic acid isopropyl ester (M4-3) (31%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=470.15. ¹H NMR (DMSO- d ₆, 400 MHz) δ 1.04-1.26 (6H, m), 1.84-1.96 (2H, m), 2.16-2.37 (3H, m), 2.45 (1H, d), 2.62 (1H, d), 2.94 (1H, d), 3.04 (1H, d), 3.65 (2H, s), 4.75-5.02 (1H, m), 7.13-7.48 (5H, m) Step 4. Preparation of 3-benzyl-8-[(4-methylbenzenesulfonylamino)imino]-3-azabicyclo[3.2.1]octane-1-carboxylic acid isopropyl ester (M4-4). A solution of 3-benzyl-8-oxo-3-azabicyclo[3.2.1]octane-1-carboxylic acid isopropyl ester (100 g, 331.8 mmol, 1 equivalent) in methanol (1 L) was added with TsNHNH in portions at 0°C under nitrogen atmosphere.₂(123.58 g, 663.5 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified on a silica gel column and eluted with petroleum ether/ethyl acetate (5/1) to give 80 g of 3-benzyl-8-[(4-methylbenzenesulfonylamide)imino]-3-azabicyclo[3.2.1]octane-1-carboxylic acid isopropyl ester (M4-4) (51%) as a white solid. ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.99-1.15 (6H, m), 1.57-1.85 (2H, m), 1.87-2.03 (1H, ddd), 2.02-2.13 (2H, m), 2.25 (1H, d), 2.39 (3H, s), 2.62-2.73 (1H, m),2.84(1H, d) 3.14-3.19 (1H, m), 3.06-3.10 (1H, m), 3.50 (2H, s), 4.75-4.91 (1H, m), 7.26-7.43 (7H, m), 7.67 (2H, d), 10.38 (1H, s). Step 5. Preparation of 3-benzyl-3-azabicyclo[3.2.1]octane-1-carboxylate (M4-5). To a stirred solution of 3-benzyl-8-[(4-methylbenzenesulfonylamide)imino]-3-azabicyclo[3.2.1]octane-1-carboxylic acid isopropyl ester (100 g, 212.95 mmol, 1 equivalent) in methanol (2 L) was added NaBH under nitrogen atmosphere at 0 °C.₄(120.8 g, 3194.20 mmol, 15 equiv.). The mixture was stirred at 80 °C overnight and then cooled to room temperature. The reaction was quenched with water (1 L), and the mixture was extracted with ethyl acetate (3×1 L). The combined organic layers were washed with brine (3×1 L), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography and eluted with petroleum ether/ethyl acetate (5/1) to give 33.0 g of 3-benzyl-3-azabicyclo[3.2.1]octane-1-carboxylic acid isopropyl ester (M4-5) (54%) as a colorless oil. LCMS: m/z (ESI), [M+H] ⁺=288.05. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.14 (6H, d), 1.41 (1H, d), 1.62-1.69 (2H, m), 1.70-1.90 (3H, m), 1.9-2.04 (1H, m), 2.12 (1H, d), 2.18 (1H, d), 2.58 (1H, d), 2.82 (1H, d), 3.50 (2H, d), 4.81-4.90 (1H, m), 7.06-7.51 (5H, m). Step 6. Preparation of 3-benzyl-3-azabicyclo[3.2.1]octane-1-carboxylic acid (M4-6). A mixture of 3-benzyl-3-azabicyclo[3.2.1]octane-1-carboxylic acid isopropyl ester (33.0 g, 114.82 mmol, 1 eq.) and LiOH (3.0 g, 126.30 mmol, 1.1 eq.) in ethanol (400 mL) was stirred at 80 °C for 2 days under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure to give 30 g of 3-benzyl-3-azabicyclo[3.2.1]octane-1-carboxylic acid (M4-6) (96%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=246.05. Step 7. NPreparation of tert-butyl-{3-benzyl-3-azabicyclo[3.2.1]octane-1-yl}carbamate (M4-7). A mixture of 3-benzyl-3-azabicyclo[3.2.1]octane-1-carboxylic acid (30 g, 110.06 mmol, 1 eq., 90%), DPPA (36.35 g, 132.07 mmol, 1.2 eq.) and triethylamine (33.41 g, 330.18 mmol, 3.0 eq.) in tetrahydrofuran (300 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. Toluene (500 mL) and t-BuOK (18.53 g, 165.09 mmol, 1.5 equiv). The mixture was stirred at 100 °C for 2 h under nitrogen atmosphere and then cooled to room temperature. The reaction was quenched with water (1 L), and the mixture was extracted with ethyl acetate (3×1 L). The combined organic layers were washed with brine (3×1 L), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (5/1) to give 15 g of a white solid.N-tert-butyl {3-benzyl-3-azabicyclo[3.2.1]octan-1-yl}carbamate (M4-7) (43%). LCMS: m/z (ESI), [M+H] ⁺=317.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.23 (9H, s), 1.38-1.60 (3H, m), 1.59-1.76 (2H, m), 1.75-2.25 (5H, m), 2.87 (1H, d), 3.38-3.56 (2H, m), 6.88 (1H, s), 7.17-7.37 (5H, m) Step 8. N- Preparation of tert-butyl {3-azabicyclo[3.2.1]oct-1-yl}carbamate (M4-8). NA mixture of tert-butyl-{3-benzyl-3-azabicyclo[3.2.1]octan-1-yl}carbamate (15 g, 47.40 mmol, 1 equiv) and Pd/C (7.57 g, 71.13 mmol, 1.50 equiv) in methanol (300 mL) was stirred at room temperature under hydrogen atmosphere for 2 h. The resulting mixture was filtered and the filter cake was washed with methanol (3×200 mL). The organic solution was concentrated under reduced pressure to obtain 10 g of a white solid.N-tert-Butyl {3-azabicyclo[3.2.1]octan-1-yl}carbamate (M4-8) (93%). This material was used in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺=227.10. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.36 (9H, d), 1.45-1.60 (2H, m), 1.60-1.75 (1H, m), 1.73-1.91 (1H, m), 1.93-2.00 (2H, m), 2.45 ( 2H, d), 2.76-2.89 (1H, m), 3.14-3.20 (1H, m), 6.73 (1H, d). Step 9. NPreparation of tert-butyl-(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.1]oct-1-yl)carbamate (M4-9). Freshly prepared N-tert-butyl {3-azabicyclo[3.2.1]oct-1-yl}carbamate (10 g, about 44 mmol, about 1 equivalent), (2-bromoethoxy)(tert-butyl)dimethylsilane (21.14 g, 88.37 mmol, 2 equivalents), NaI (13.25 g, 88.37 mmol, 2 equivalents) and K ₂CO ₃A mixture of (12.21 g, 88.37 mmol, 2 equiv) in DMF (160 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (300 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using a HPLC-HPLC system containing 0.1% NH₄HCO ₃of water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to obtain 12 g of a colorless oil.N-tert-Butyl (3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.1]oct-1-yl)carbamate (M4-9) (70%). LCMS: m/z (ESI), [M+H] ⁺= 385.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.00 (6H, s), 0.82 (9H, s), 0.85 (1H, s), 1.32 (9H, s), 1.37-1.48 (2H, m), 1.53-1.64 (2H, m), 1.91-2.05 (4H, m), 2.36-2.43 (2H, m), 2.54-2.57 (1H, m), 2.86-2.92 (1H, m), 3.61 (2H, t), 6.80 (1H, s). Step 10. Preparation of 2-(1-amino-3-azabicyclo[3.2.1]octan-3-yl)ethan-1-ol (M4-10). NA mixture of tert-butyl-(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.1]octan-1-yl)carbamate (12 g, 31.19 mmol, 1 equiv) in trifluoroacetic acid (28 mL) and dichloromethane (84 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product 2-(1-amino-3-azabicyclo[3.2.1]octan-3-yl)ethan-1-ol (M4-10) as an orange oil was used directly in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺= 285.15. Step 11. Preparation of 2-[1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl]ethanol (M4-11). 2-(1-amino-3-azabicyclo[3.2.1]octan-3-yl)ethan-1-ol (crude, M4-10), K ₂CO ₃A mixture of (21.56 g, 156.25 mmol, 5 equiv.) and 4-bromo-2-fluoro-1-nitrobenzene (20.53 g, 93.73 mmol, 3 equiv.) in DMSO (160 mL) was stirred at 120 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (300 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The crude product was purified by prep-HPLC using HPLC containing 0.1% NH₄HCO ₃of water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 12 g of 2-[1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl]ethanol (M4-11) (76%) as an orange semisolid. LCMS: m/z (ESI), [M+H] ⁺= 371.95. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.68 (3H, d), 1.82-1.85 (1H, m), 1.94 (1H, s), 2.12 (1H, d), 2.17 (1H, d), 2.21 (1H, s), 2.36 (1H, s), 2.49 (2H, d), 2.65-2.73 (1H, m), 3.10-3.20 (1H, m), 3.47-3.57 (2H, m), 4.36 (1H, t), 6.86-3.89 (1H, m), 7.21 (1H, d), 8.01 (1H, d), 8.31 (1H, s). Step 12. Preparation of methyl 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (M4-12). To a stirred mixture of 2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethanol (8 g, 21.61 mmol, 1 eq) and triphenylphosphine (17.00 g, 64.82 mmol, 3 eq) in tetrahydrofuran (500 mL) was added diisopropyl azodicarboxylate (12.23 g, 60.50 mmol, 2.8 eq) and methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (5.69 g, 21.61 mmol, 1 eq) slowly under nitrogen atmosphere at 0° C. The resulting mixture was stirred at 0° C. for 2 h under nitrogen atmosphere. The reaction was quenched with water (300 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/3) to give 9.5 g of 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M4-12) (71%) as an orange oil. LCMS: m/z (ESI), [M+H] ⁺=617.10. Step 13. Preparation of 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M4-13). To a mixture of methyl 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (10.5 g, 17.06 mmol, 1 eq) and ranyl nickel (2 g) in methanol (150 mL) was added hydrazine hydrate (2.19 g, 68.24 mmol, 1.5 eq) and stirred at 0 °C for 2 h under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with dichloromethane (3 x 200 mL). The organic solution was concentrated under reduced pressure. The residue was purified on a silica gel column using dichloromethane/methanol (10/1) to give 9.5 g of 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M4-13) (91%) as a brown oil. LCMS: m/z (ESI), [M+H] ⁺=585.20. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.45-1.60 (3H, m), 1.70-1.85 (2H, m), 1.95-2.17 (4H, m), 2.65-2.80 (3H, m), 3.09-3.15 (1H, m), 3.17 (2H, d), 3.57 (3H, s), 3.74 (3H, s), 3.79 (3H, s), 4.00-4.10 (3H, m), 4.52 (1H, s), 4.75 (2H, s), 6.44-6.50 (1H, m), 6.50-6.56 (1H, m), 6.64 (1H, d), 7.97 (1H, s), 8.10 (1H, d), 8.43 (1H, d). Step 14. Preparation of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M4-14). A solution of methyl 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (10 g, 17.08 mmol, 1 eq) and cyanogen bromide (2.17 g, 20.49 mmol, 1.20 eq) in ethanol (200 mL) was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, and the residue was purified on a silica gel column using dichloromethane/methanol (20/1) for elution to obtain 9.5 g of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M4-14) (91%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=612.05. Step 15. Preparation of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester, isomer 1 (M4-14A) and isomer 2 (M4-14B). Chiral chromatography was performed using a (R, R)-WHELK-01-Kromasil column (5 * 25 cm, 5 μm), CO ₂The racemic mixture of M4-14 (9 g, 14.74 mmol) was separated using methanol/acetonitrile (1/1) as mobile phase A and 3.6 g of isomer 1 (M4-14A, 41%) and 3.9 g of isomer 2 (M4-14B, 43%) as brown solids. SFC-HPLC, Rt (isomer 1) = 2.246 min, Rt (isomer 2) = 3.898 min. Step 16. Preparation of 5-(5-(2-(1-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (Isomer 1, M4-15A). To a stirred solution of 5-(5-(2-(1-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (isomer 1, M4-14A, 4 g, 6.55 mmol, 1 eq) in tetrahydrofuran (8 mL) was added LiOH (0.31 g, 13.10 mmol, 2 eq) in H ₂O (2 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure, and the residue was purified by Prep-HPLC by reversed phase flash chromatography using a C18 silica gel column eluting with water and acetonitrile. The fractions containing the desired compound were evaporated to dryness to give 3.6 g of 5-(5-(2-(1-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (Isomer 1, M4-15A) (92%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=598.05. Step 17. Preparation of 5-bromo-15,21-dimethyl-23-oxo-2,9,11,15,20,21, 26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (M4A). 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (M4-15A, 3.6 g, 6.03 mmol, 1 equivalent), N,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (3.44 g, 9.05 mmol, 1.5 equivalents) and N,N- A mixture of diisopropylethylamine (2.34 g, 18.10 mmol, 3 equiv.) in 1,4-dioxane (80 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (300 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using dichloromethane/methanol (20/1) to give 3.3 g of 5-bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (isomer 1, M4A) (94%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺= 580.00. SFC-HPLC, Rt=5.498, ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.56-1.81 (3H, m), 2.01 (1H, d), 2.42 (2H, d), 2.54 (1H, d), 2.63 (1H, s), 2.69-2.75 (1H, m), 3.09-3.20 (2H, m), 3.19-3.30 (1H, m), 3.63 (3H, s), 3.72 (3H, s), 4.54 (1H, t), 4.63 (1H, d), 7.36 (1H, d), 7.51 (1H, d), 7.82 (1H, d), 8.16 (1H, s), 8.30 (1H, d), 8.41 (1H, s), 8.81 (1H, d), 12.84 (1H, s). Step 18. Preparation of 5-(5-(2-(1-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (isomer 2, M4-15B). To a stirred solution of 5-(5-(2-(1-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (isomer 2, M4-14B, 4.2 g, 6.88 mmol, 1 eq.) in tetrahydrofuran (80 mL) was added LiOH (0.33 g, 13.76 mmol, 2 eq.) in H ₂O (20 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure, and the residue was further purified by Prep-HPLC by reversed phase flash chromatography using a C18 silica gel column eluting with water and acetonitrile. The fractions containing the desired compound were evaporated to dryness to give 3.8 g of 5-(5-(2-(1-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (isomer 2, M4-15B) (92%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=598.05. Step 19. Preparation of 5-bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21, 26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (isomer 2, M4B). 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (M4-15B, 3.8 g, 6.37 mmol, 1 equivalent), N,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (3.63 g, 9.56 mmol, 1.5 equivalents) and N,N- A solution of diisopropylethylamine (2.47 g, 19.11 mmol, 3 equivalents) in 1,4-dioxane (80 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (300 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using dichloromethane/methanol (20/1) to give 3.5 g of 5-bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (isomer 2, M4B) (94%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺= 580.00. SFC-HPLC, Rt=3.186, ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.55-1.76 (2H, m), 2.01 (1H, d), 2.39-2.47 (2H, m), 2.51-2.57 (1H, m), 2.61-2.65 (1H, m), 2.70-2.77 (2H, m), 3.09-3.18 (2H, m), 3.19-3.29 (1H, m), 3.63 (3H, s), 3.72 (3H, s), 4.54 (1H, t), 4.63 (1H, d), 7.36 (1H, dd), 7.51 (1H, d), 7.82 (1H, d), 8.16 (1H, s), 8.30 (1H, d), 8.41 (1H, s), 8.81 (1H, d), 12.84 (1H, s) Intermediate M5 5-Bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione Step 1. Preparation of ethyl 4-methylenecyclohexane-1-carboxylate (M5-1). To a mixture of methyltriphenylphosphonium bromide (314.81 g, 881.27 mmol, 1.5 equiv.) and potassium tert-butoxide (131.85 g, 1175.03 mmol, 2 equiv.) in tetrahydrofuran (500 mL) at 0°C was added ethyl 4-oxocyclohexane-1-carboxylate (100 g, 587.51 mmol, 1 equiv.). The mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was quenched with water (300 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (5/1) to give 80 g of ethyl 4-methylenecyclohexane-1-carboxylate (M5-1) (85%) as a yellow oil. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.18 (3H, t), 1.30-1.50 (2H, m), 1.80-1.95 (2H, m), 1.96-2.15 (2H, m), 2.15-2.35 (2H, m), 2.42-2.49 (1H, m), 4.04-4.08 (2H, m), 4.64 (2H, t). Step 2. Preparation of ethyl 1-(4-methylbenzenesulfonyl)-1-azaspiro[2.5]octane-6-carboxylate (M5-2). To a mixture of ethyl 4-methylenecyclohexane-1-carboxylate (80 g, 475.52 mmol, 1 eq.) and chloramine-T (216.50 g, 951.04 mmol, 2 eq.) in acetonitrile (800 mL) was added at 0°C.N,N,N-Trimethylphenylammonium dibromoethane (17.88 g, 47.55 mmol, 0.1 equiv). The mixture was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (5/1) to give 60 g of ethyl 1-(4-methylbenzenesulfonyl)-1-azaspiro[2.5]octane-6-carboxylate (M5-2) (33%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=338.05. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.18 (3H, t), 1.54-1.58 (1H, m), 1.58-1.72 (1H, m), 1.72-1.93 (4H, m), 2.40 (3H, s), 2.50-2.53(2H, m), 4.05-4.09 (2H, m), 7.43 (2H, d), 7.73-7.79 (2H, m). Step 3. Preparation of ethyl 4-[(benzylamino)methyl]-4-(4-methylbenzenesulfonylamide)cyclohexane-1-carboxylate (M5-3). A solution of ethyl 1-(4-methylbenzenesulfonyl)-1-azaspiro[2.5]octane-6-carboxylate (60 g, 177.81 mmol, 1 eq) and benzylamine (28.58 g, 266.72 mmol, 1.5 eq) in tetrahydrofuran (600 mL) was stirred at 80 °C for 2 days under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (1/1) to give 60 g of ethyl 4-[(benzylamino)methyl]-4-(4-methylbenzenesulfonamido)cyclohexane-1-carboxylate (M5-3) (75%) as a white oil. LCMS: m/z (ESI), [M+H] ⁺=445.20. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.15 (3H, t), 1.31-1.44 (2H, m), 1.48-1.76 (4H, m), 2.00 (1H, m), 2.21-2.30 (1H, m), 2.30 (2H, s), 2.33-2.37 (2H, m), 3.43 (2H, s), 4.02 (2H, m), 7.15-7.25 (3H, m), 7.25-7.36 (4H, m), 7.67-7.75 (2H, m). Step 4. Preparation of lithium 4-((benzylamino)methyl)-4-((4-methylphenyl)sulfonylamino)cyclohexane-1-carboxylate (M5-4). A mixture of ethyl 4-[(benzylamino)methyl]-4-(4-methylbenzenesulfonamido)cyclohexane-1-carboxylate (60 g, 134.95 mmol, 1 eq) and LiOH (6.46 g, 269.91 mmol, 2 eq) in ethanol (500 mL) was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give 57 g of lithium 4-((benzylamino)methyl)-4-((4-methylphenyl)sulfonamido)cyclohexane-1-carboxylate (M5-4) as a white solid. This material was used in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺=417.10. Step 5. N-{3-benzyl-4-oxo-3-azabicyclo[3.2.2]non-1-yl}-4-toluenesulfonamide (M5-5). N,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (77.03 g, 202.60 mmol, 1.5 equivalents), 4-((benzylamino)methyl)-4-((4-methylphenyl)sulfonylamino)cyclohexane-1-carboxylate lithium (57 g, about 135 mmol, about 1 equivalent) and N,N- A mixture of diisopropylethylamine (52.37 g, 405.21 mmol, 3 equivalents) in dichloromethane (150 mL) was stirred at room temperature overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (1/1) to obtain 50 g of a white solid.N-{3-Benzyl-4-oxo-3-azabicyclo[3.2.2]non-1-yl}-4-toluenesulfonamide (M5-5) (93%). LCMS: m/z (ESI), [M+H] ⁺= 399.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.64-1.74 (8H, m), 2.38 (3H, s), 3.18 (2H, s), 4.37 (2H, s), 7.01-7.19 (2H, m), 7.21-7.41 (5H, m), 7.48-7.56 (2H, m), 7.73 (1H, s) Step 6. NPreparation of -{3-benzyl-3-azabicyclo[3.2.2]non-1-yl}-4-toluenesulfonylamide methyl (M5-6). Add lithium aluminum hydroxide (7.62 g, 200.74 mmol, 2 equivalents) in tetrahydrofuran (400 mL) at 0°C.N-{3-benzyl-4-oxo-3-azabicyclo[3.2.2]non-1-yl}-4-toluenesulfonamide (40 g, 100.37 mmol, 1 equiv) was added and the mixture was stirred under nitrogen atmosphere for 2 h. The reaction was quenched with water (7 mL) and 15 mL NaOH (w/w, 30%) at 0 °C. The mixture was washed with anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/1) to obtain 20 g of a white solid.N-{3-Benzyl-3-azabicyclo[3.2.2]non-1-yl}-4-toluenesulfonamide (M5-6) (46%). LCMS: m/z (ESI), [M+H] ⁺=385.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.39-1.63 (6H, m), 1.71-1.77 (1H, m), 1.90-2.02 (2H, m), 2.36 (3H, s), 2.40 (2H, d), 2.64 (2H, s), 3.44 (2H, s), 7.18-7.31 (3H, m), 7.31-7.40 (4H, m), 7.39 (1H, s), 7.55-7.62 (2H, m). Step 7. N-{3-nitrobicyclo[3.2.2]non-1-yl}-4-toluenesulfonamide (M5-7). Pd/C (10%, 500 mg) and NA mixture of -{3-benzyl-3-azabicyclo[3.2.2]non-1-yl}-4-toluenesulfonamide (20 g, 52.01 mmol, 1 equiv) in methanol (200 mL) was stirred at room temperature under hydrogen pressure for 4 h. The resulting mixture was filtered. The filter cake was washed with methanol (3×70 mL), and the solution was concentrated under reduced pressure. The residue was purified on a silica gel column using dichloromethane/methanol (10/1) to give 15 g of white solid.N-{3-Azabicyclo[3.2.2]non-1-yl}-4-toluenesulfonamide (M5-7) (93%). LCMS: m/z (ESI), [M+H] ⁺=295.00. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.35-1.60 (6H, m), 1.63-1.69 (1H, m), 1.79-1.83 (2H, m), 2.37 (3H, s), 2.59 (2H, d), 2.80 (2H, s), 3.17 (1H, d), 7.29-7.41 (3H, m), 7.51-7.79 (2H, m). Step 8. N-(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]non-1-yl)-4-toluenesulfonamide (M5-8). N-{3-nitrobicyclo[3.2.2]non-1-yl}-4-toluenesulfonamide (15 g, 50.94 mmol, 1 equivalent), NaI (7.64 g, 50.94 mmol, 1 equivalent), K ₂CO ₃A mixture of (21.12 g, 152.84 mmol, 3 equiv.) and (2-bromoethoxy)(tert-butyl)dimethylsilane (14.63 g, 61.13 mmol, 1.2 equiv.) in dimethylformamide (150 mL) was stirred at 60 °C for 16 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (800 mL), and the mixture was extracted with ethyl acetate (3×600 mL). The combined organic layers were washed with brine (3×500 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using dichloromethane/methanol (10/1) to give 20 g of yellow solid.N-(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]non-1-yl)-4-toluenesulfonamide (M5-8) (78%). LCMS: m/z (ESI), [M+H] ⁺= 453.30. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.00 (6H, s), 0.83 (9H, s), 1.32-1.42 (2H, m), 1.44-1.54 (4H, m), 1.65-1.71 (1H, m), 1.80-1.90 (2H, m), 2.34 (3H, s), 2.38 (2H, t), 2.44 (2H, d), 2.65 (2H, s), 3.54 (2H, t), 7.32 (2H, d), 7.37 (1H, s), 7.59-7.76 (2H, m). Step 9. Preparation of 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (M5-9).NA mixture of -(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]non-1-yl)-4-toluenesulfonamide (5 g, 11.04 mmol, 1 eq.) and Mg (5.37 g, 220.88 mmol, 20 eq.) in methanol (200 mL) was stirred at 70 °C overnight under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was terminated by adding saturated NH₄Cl(aq) solution (300 mL) was quenched, and the mixture was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine (3×400 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using dichloromethane/methanol (5/1) to give 2.3 g of 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (M5-9) (60%) as a yellow oil. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.00 (6H, s), 0.82 (9H, s), 1.54-1.64 (4H, m), 1.79-1.83 (1H, m), 1.85-1.91 (2H, m), 2.42-2.52 (3H, m), 2.54 (2H, d), 2.60 (2H, s), 3.63 (2H, t). Step 10. N-(5-bromo-2-nitrophenyl)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (M5-10). 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (1 g, 3.35 mmol, 1 equivalent), 4-bromo-2-fluoro-1-nitrobenzene (1.84 g, 8.37 mmol, 2.5 equivalents) and K ₂CO ₃A mixture of (1.39 g, 10.05 mmol, 3 equiv.) in dimethyl sulfoxide (10 mL) was stirred at 120 °C for 4 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (5/1) to give 1.5 g of yellow oil.N-(5-bromo-2-nitrophenyl)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (M5-10) (85%). LCMS: m/z (ESI), [M+H]+=498.15. Step 11. Preparation of 2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]nonan-3-yl}ethanol (M5-11). NA solution of -(5-bromo-2-nitrophenyl)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (1.5 g, 3.00 mmol, 1 eq.) and tetrabutylammonium fluoride (1.57 g, 6.01 mmol, 2 eq.) in tetrahydrofuran (15 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was heated with saturated NaHCO₃(aqueous solution) solution (100 mL) was quenched, and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane/methanol (10/1) to give 1.2 g of 2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethanol (M5-11) (93%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺= 384.00. Step 12. Preparation of 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M5-12). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 0.66 g, 2.49 mmol, 0.8 eq.) and triphenylphosphine (2.46 g, 9.369 mmol, 3 eq.) in tetrahydrofuran (10 mL) at 0° C. were added diisopropyl azodicarboxylate (1.89 g, 9.36 mmol, 3 eq.) and methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (0.66 g, 2.49 mmol, 0.8 eq.). The mixture was stirred at 0° C. for 2 h under nitrogen atmosphere. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC and eluted with petroleum ether/ethyl acetate (1/1) to give 1.2 g of 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M5-12) (57%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=629.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.58-1.76 (9H, m), 2.56-2.79 (2H, m), 2.90 (4H, q), 3.56 (3H, s), 3.72 (6H, d), 4.13 (2H, t), 6.70-6.85 (1H, m), 7.01 (1H, d), 7.95-8.12 (4H, m), 8.28 (1H, d). Step 13. Preparation of 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M5-13). To a stirred mixture of ranyl nickel (0.90 g) and methyl 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (1.1 g, 1.74 mmol, 1 equiv) in methanol (8 mL) at 0°C under nitrogen atmosphere was added NH₂NH ₂.H ₂O (47 mg, 0.95 mmol, 2 eq.). The mixture was stirred at 0 °C for 1 h. The resulting mixture was filtered. The filter cake was washed with methanol (2×20 mL), and the solution was concentrated under reduced pressure. The residue was purified by Prep-TLC and eluted with dichloromethane/methanol (10/1) to give 910 mg of 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M5-13) (76%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺=599.20. Step 14. Preparation of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M5-14). A mixture of methyl 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (900 mg, 1.50 mmol, 1 eq) and BrCN (174 mg, 1.65 mmol, 1.1 eq) in ethanol (10 mL) was stirred under nitrogen atmosphere at room temperature for 2 h. The mixture was concentrated under vacuum. The residue was purified by Prep-TLC and eluted with dichloromethane/methanol (12/1) to give 640 mg of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M5-14) (68%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺=624.10. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.24 (1H, s), 1.78-1.95 (8H, m), 2.60-2.74 (2H, m), 2.85-2.95 (4H, m), 3.57 (3H, s), 3.71 (6H, d), 4.08-4.17 (2H, m), 5.95 (2H, s), 7.04 (2H, s), 7.47 (1H, s), 7.96 (1H, s), 8.12 (1H, ), 8.39 (1H, d). Step 15. Preparation of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (M5-15). 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (620 mg, 0.99 mmol, 1 eq.) and LiOH (28 mg, 1.19 mmol, 1.2 eq.) were dissolved in tetrahydrofuran/H ₂O (4 mL/1 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under vacuum to obtain 550 mg of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (M5-15) (90%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=610.10. Step 16. Preparation of 5-bromo-15,21-dimethyl-23-oxo-2,9,11,15,20,21, 26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]triacontriacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione (M5). 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (550 mg, 0.90 mmol, 1 equivalent), N,N,N,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (1027 mg, 2.70 mmol, 3 equivalents) and N,N- A mixture of diisopropylethylamine (174 mg, 1.35 mmol, 1.5 equiv.) in dioxane (6 mL) was stirred at 60 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by Prep-HPLC using an XBridge Prep OBD C18 column with 10 mmol/L NH₄HCO ₃of water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 500 mg of 5-bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontriacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione (M5) as a yellow solid (88%). LCMS: m/z (ESI), [M+H] ⁺=592.15. Synthesis Example Example A1 5,26-Dimethyl-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22, 26-heptaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. Preparation of 2-((2-((2-nitrophenyl)amino)ethyl)amino)ethan-1-ol (INT-A1-1). o-Fluoronitrobenzene (10 g, 70.871 mmol, 1 equivalent), K ₂CO ₃A mixture of (19.59 g, 141.742 mmol, 2 equiv) and aminoethylethanolamine (14.76 g, 141.742 mmol, 2 equiv) in ACN (300 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (800 mL), and the mixture was extracted with ethyl acetate (3×600 mL). The combined organic layers were washed with brine (3×500 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography and eluted with PE/EA (1:1) to give 8.5 g of 2-({2-[(2-nitrophenyl)amino]ethyl}amino)ethanol (INT-A1-1) (53%) as a yellow solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.99 (1H, s), 2.62 (2H, t), 2.84 (2H, t), 3.36-3.40 (2H, m), 3.44-3.49 (2H, m), 4.50 (1H, t), 6.65-3.71 (1H, m), 7.04-7.08 (1H, m), 7.54 (1H, m), 8.34-8.38 (1H, t), 8.04-8.08 (1H, m). Step 2. Preparation of 2-({2-[(2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethanol (INT-A1-2). 2-({2-[(2-nitrophenyl)amino]ethyl}amino)ethanol (INT-A1-1, 2 g, 8.879 mmol, 1 equivalent), N,N-Diisopropylethylamine (2.30 g, 17.758 mmol, 2 equivalents) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.47 g, 10.655 mmol, 1.2 equivalents) were added to N,N-The mixture in dimethylformamide (20 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (200 mL), and the mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (1/1) to give 2.19 g of 2-({2-[(2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethanol (INT-A1-2) (80%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=308.10. Step 3. Preparation of 1-methyl-5-{1-methyl-5-[2-({2-[(2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]pyrazol-4-yl}-6-oxopyridine-3-carboxylic acid methyl ester (INT-A1-3). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 0.56 g, 2.14 mmol, 1 eq) and triphenylphosphine (1.69 g, 6.44 mmol, 3 eq) in tetrahydrofuran (20 mL) at 0 °C under nitrogen atmosphere were added diisopropyl azodicarboxylate (1.30 g, 6.44 mmol, 3 eq) and 2-({2-[(2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethanol (0.66 g, 2.15 mmol, 1 eq). The mixture was stirred at 0 °C under nitrogen atmosphere for 2 h. The reaction was quenched with water (150 mL), and the mixture was extracted with dichloromethane (3×150 mL). The combined organic layers were washed with brine (3×150 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on Prep-TLC using petroleum ether/ethyl acetate (1/3) to give 1.15 g of 1-methyl-5-{1-methyl-5-[2-({2-[(2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]pyrazol-4-yl}-6-oxopyridine-3-carboxylic acid methyl ester (INT-A1-3) (96%) as an orange oil. LCMS: m/z (ESI), [M+H] ⁺=553.25. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 3.02 (2H, t), 3.12-3.19 (2H, m), 3.38-3.44 (2H, m), 3.50 (1H, s), 3.56 (3H, s), 3.67 (3H, s), 3.76 (3H, s), 4.03 (2H, t), 6.63-6.72 (1H, m), 6.97-7.05 (1H, m), 7.50-7.58 (1H, m), 7.62-7.68 (1H, m), 7.92 (1H, s), 8.01-8.06 (2H, m), 8.20 (1H, t), 8.37 (1H, d) Step 4. Preparation of methyl 5-{5-[2-({2-[(2-aminophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (INT-A1-4). To a stirred mixture of methyl 1-methyl-5-{1-methyl-5-[2-({2-[(2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]pyrazol-4-yl}-6-oxopyridine-3-carboxylate (1.1 g, 1.99 mmol, 1 eq) and ranyl nickel (0.85 g, 9.95 mmol, 5 eq) in methanol (30 mL) was added hydrazine hydrate (0.15 g, 2.98 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 0°C for 30 minutes under nitrogen atmosphere. The resulting mixture was filtered. The filter cake was washed with methanol (3×20 mL), and the solution was concentrated under reduced pressure to give 1 g of 5-{5-[2-({2-[(2-aminophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A1-4) (96%) as a brown solid. This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=523.10. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 2.95 (2H, t), 3.12 (2H, t), 3.17 (2H, d), 3.48 (2H, q), 3.57 (3H, s), 3.68 (3H, s), 3.79 (3H, s), 4.03 (2H, t), 4.36 (2H, s), 6.37-6.46 (2H, m), 7.51-7.59 (2H, m), 7.64-7.67 (1H, m), 7.94 (1H, s), 8.10 (1H, d), 8.45 (1H, d). Step 5. Preparation of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A1-5). 5-{5-[2-({2-[(2-aminophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (1 g, about 1.9 mmol, about 1 equivalent) and BrCN (0.24 g, 2.29 mmol, 1.2 equivalents) were mixed in CH₂CI ₂The mixture in 20 mL was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was separated by Prep-TLC using CH₂Cl ₂/methanol (40/1) for purification to obtain 1 g of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl] (2,2,2-trifluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A01-5) (95%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=548.25. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 3.04 (2H, t), 3.16 (2H, t), 3.50 (2H, q), 3.58 (3H, s), 3.65 (3H, s), 3.77 (3H, s), 3.98 (2H, t), 4.18 (2H, t), 7.07-7.21 (2H, m), 7.32 (1H, d), 7.40 (1H, d), 7.93 (1H, s), 8.04 (1H, d), 8.11 (2H, s), 8.46 (1H, d). Step 6. Preparation of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A1-6). 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (200 mg, 0.36 mmol, 1 equivalent) and LiOH.H ₂O (23 mg, 0.55 mmol, 1.5 equiv.) in tetrahydrofuran (4 mL) and H ₂The mixture in 400 mL was stirred at room temperature overnight under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 180 mg of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A1-6) (92%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=534.10. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 2.99 (2H, t), 3.28 (2H, t), 3.52 (6H, s), 3.67 (3H, s), 3.99 (2H, t), 4.18 (2H, t), 6.80-7.01 (4H, m), 7.05-7.14 (2H, m), 8.02 (1H, s), 8.09 (1H, d), 8.37 (1H, d) Step 7. 5,26-Dimethyl-10-(2,2,2-trifluoroethyl)-7-oxa-4,5, 10,13,20,22,26-heptaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. Preparation of 0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A1). 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (150 mg, 0.28 mmol, 1 equivalent), N,N,N,N-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (160 mg, 0.42 mmol, 1.5 equivalents) and N,N- A mixture of diisopropylethylamine (109 mg, 0.84 mmol, 3 equiv.) in 1,4-dioxane (5 mL) was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×150 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 29.5 mg of 5,26-dimethyl-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22, 26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A1) as a pink solid (20%). LCMS: m/z (ESI), [M+H] ⁺=516.20. ¹H NMR (DMSO, 400 MHz) δ 3.10 (2H, t), 3.27 (2H, t), 3.63 (3H, s), 3.59-3.69 (2H, m), 3.71 (3H, s), 4.19 (2H, t), 4.33 (2H, t), 7.18-7.31 (2H, m), 7.49-7.56 (1H, m), 7.70 (1H, d), 8.25 (1H, s), 8.29 (1H, d), 8.89 (1H, d), 12.55 (1H, s). ¹⁹F NMR (DMSO-d ₆ , 376 MHz) δ 69.23 (s). Example A2 5-cyclopropyl-26-methyl-16-(4-methylpiperazine-1-yl)-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclic [22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. Preparation of 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}amino)ethanol (INT-A2-1). 4-bromo-2-fluoro-1-nitrobenzene (2 g, 9.09 mmol, 1 equivalent), aminoethylethanolamine (1.42 g, 13.63 mmol, 1.5 equivalents) and K ₂CO ₃A mixture of (3 g, 27.27 mmol, 3 equiv.) in acetonitrile (20 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 2.1 g of 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}amino)ethanol (INT-A2-1) (72%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺= 306.00. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 2.64 (2H, t), 2.83 (2H, t), 3.18 (1H, d), 3.37-3.44 (2H, m), 3.48 (2H, q), 4.53 (1H, t), 6.83 (1H, d), 7.28 (1H, d), 7.99 (1H, d), 8.42 (1H, t). Step 2. Preparation of 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethanol (INT-A2-2). 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}amino)ethanol (INT-A2-1, 10 g, 32.87 mmol, 1 equivalent) and N,N-To a stirred mixture of diisopropylethylamine (12 g, 98.63 mmol, 3 equiv.) in dimethylformamide (100 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (11 g, 49.31 mmol, 1.5 equiv.). The mixture was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using petroleum ether/ethyl acetate (5/1) to give 3 g of 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethanol (INT-A2-2) (21%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=385.90 ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.76 (2H, t), 2.95 (2H, t), 3.40 (4H, d), 3.57-3.45 (2H, m), 4.55 (1H, t), 6.84 (1H, d), 7.27 (1H, d), 8.00 (1H, d), 8.30 (1H, t). Step 3. Preparation of 2-cyclopropylpyrazol-3-ol (INT-A2-3). A mixture of methyl (2E)-3-methoxyprop-2-enoate (1 g, 8.61 mmol, 1 eq.) and cyclopropylhydrazine (621 mg, 8.61 mmol, 1 eq.) in methanol (4 mL) was stirred at 80 °C under air atmosphere for 16 h. After cooling to room temperature, the reaction was heated with saturated NH₄Cl solution (300 mL) was quenched, and the mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine (3×300 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by reverse phase flash chromatography using 0% to 15% acetonitrile/water to give 200 mg of 2-cyclopropylpyrazol-3-ol (INT-A2-3) (18%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=125.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.08-0.93 (4H, m), 3.44-3.31 (1H, m), 5.64 (1H, d), 7.62 (1H, d). Step 4. Preparation of 2-cyclopropyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (INT-A2-4). 2-Cyclopropylpyrazol-3-ol (1.1 g, 8.86 mmol, 1 eq.) and 2-(trimethylsilyl)ethoxymethyl chloride (2.66 g, 15.95 mmol, 1.8 eq.) were added to 2-cyclopropylpyrazol-3-ol (1.1 g, 8.86 mmol, 1 eq.) at room temperature under a nitrogen atmosphere.N,N-Sodium hydride (0.85 g, 17.72 mmol, 2 eq., 60%) was added portionwise to the stirred mixture in dimethylformamide (10 mL). The mixture was stirred for 2 h. The reaction was heated with saturated NH₄Cl solution (300 mL) was quenched, and the mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine (3×300 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column eluting with dichloromethane/methanol (10:1). The product was further purified by reverse phase flash chromatography eluting with 0% to 100% acetonitrile/water to give 330 mg of 2-cyclopropyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (INT-A2-4) (15%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=255.20 Step 5. Preparation of 2-cyclopropyl-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (INT-A2-5). A mixture of 2-cyclopropyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (4.5 g, 17.69 mmol, 1 eq.) and NIS (5.97 g, 26.53 mmol, 1.5 eq.) in acetonitrile (50 mL) was stirred at 0 °C for 2 h under nitrogen atmosphere. The reaction was quenched by adding saturated sodium thiosulfate (aqueous solution) (100 mL), and the mixture was washed with CH ₂Cl ₂(3×50 mL) extraction. The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to obtain 5.5 g of 2-cyclopropyl-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (INT-A2-5) (82%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=380.95 Step 6. Preparation of 5-(2-cyclopropyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A2-6). Freshly prepared 5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-ylboronic acid (M2-2, 800 mg, 3.8 mmol, 1 equivalent), K ₂CO ₃(1.31 g, 9.48 mmol, 2.5 equivalents), Pd(dppf)Cl ₂(554 mg, 0.76 mmol, 0.2 equiv) and 2-cyclopropyl-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (1.73 g, 4.55 mmol, 1.2 equiv) in 1,4-dioxane (8 mL) and H ₂The mixture in 2% O (2 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with water (300 mL), and the mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/1) to give 1 g of methyl 5-(2-cyclopropyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A22-4) (92%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=420.05. Step 7. Preparation of 5-(1-cyclopropyl-5-hydroxypyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A2-7). A solution of 5-(2-cyclopropyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (750 mg, 1.79 mmol, 1 equivalent) in 1,4-dioxane (10 mL) containing HCl was stirred at 60 °C for 5 h under nitrogen atmosphere. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in methanol (10 mL) and treated with K ₂CO ₃Neutralize to pH 7. Filter the mixture. Wash the filter cake with methanol (2×5 mL). Concentrate the solution under reduced pressure to give 500 mg of methyl 5-(1-cyclopropyl-5-hydroxypyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A2-7) (96%) as a brown solid. This material was used in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺=290.05 Step 8. Preparation of 5-{5-[2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-cyclopropylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A2-8). To a mixture of methyl 5-(1-cyclopropyl-5-hydroxypyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (0.7 g, 2.42 mmol, 1 eq.) and triphenylphosphine (1.9 g, 7.26 mmol, 3 eq.) in tetrahydrofuran (20 mL) was added diisopropyl azodicarboxylate (1.4 g, 7.26 mmol, 3 eq.) and 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethanol (INT-A2-2, 0.9 g, 2.42 mmol, 1 eq.) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. Pass the residue through a C18 column using 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 400 mg of 5-{5-[2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-cyclopropylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A2-8) (25%) as an orange solid. LCMS: m/z (ESI), [M+H] ⁺=658.95. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.92-1.03 (2H, m), 0.99-1.10 (2H, m), 2.51 (3H, d), 3.04 (2H, t), 3.17 (2H, t), 3.44 (2H, q), 3.55-3.60 (3H, m), 3.77 (3H, s), 4.12-4.15 (2H, m), 6.80-6.83(1H, m), 7.23 (1H, d), 7.88 (1H, s), 7.94 (1H, d), 8.06 (1H, d), 8.25 (1H, t), 8.38 (1H, d). Step 9. Preparation of methyl 5-{5-[2-({2-[(2-amino-5-bromophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-cyclopropylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (INT-A2-9). To a mixture of methyl 5-{5-[2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-cyclopropylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (350 mg, 0.53 mmol, 1 eq) and ranyl nickel (365 mg, 4.26 mmol, 8 eq) in methanol (5 mL) was added hydrazine hydrate (98%) (40 mg, 0.80 mmol, 1.5 eq) under nitrogen atmosphere at 0 °C. The resulting mixture was stirred for 2 h and filtered. The filter cake was washed with methanol (3×50 mL), and the solution was concentrated under reduced pressure to give 300 mg of 5-{5-[2-({2-[(2-amino-5-bromophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-cyclopropylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A2-9) (about 90%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=627.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.91-1.03 (2H, m), 0.99-1.10 (2H, m), 2.98 (2H, t), 3.13-3.19 (4H, m), 3.51 (2H, q), 3.57 (3H, s), 3.79 (3H, s), 4.01-4.07 (3H, m), 4.12 (2H, t), 5.76 (1H, s), 6.38-6.58 (3H, m), 7.91 (1H, d), 8.13 (1H, d), 8.45 (1H, d). Step 10. Preparation of methyl 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-cyclopropylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A2-10). A mixture of methyl 5-{5-[2-({2-[(2-amino-5-bromophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-cyclopropylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (300 mg, 0.48 mmol, 1 eq) and BrCN (60 mg, 0.57 mmol, 1.2 eq) in dichloromethane (5 mL) was stirred under nitrogen atmosphere at room temperature for 2 h and concentrated under vacuum. The residue was purified on prep-TLC using dichloromethane/methanol (10/1) to give 300 mg of 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-cyclopropylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A2-10) (96%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=654.10. Step 11. Preparation of 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-cyclopropylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A2-11). 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-cyclopropylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (280 mg, 0.43 mmol, 1 equivalent) and LiOH ^.H ₂O (27 mg, 0.64 mmol, 1.5 eq.) in THF (4 mL) and H ₂The mixture in 4% O (1 mL) was stirred at room temperature for 2 h under nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 135 mg of 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-cyclopropylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A2-11) (49%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=638.10. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.90-1.03 (2H, m), 0.99-1.09 (2H, m), 3.01 (2H, t), 3.51 (3H, s), 3.53-3.63 (3H, m), 4.08 (2H, t), 4.23 (2H, t), 6.80-7.13 (3H, m), 7.19 (2H, s), 7.31 (1H, d), 7.97-8.05 (2H, m), 8.43 (1H, d) Step 12. Preparation of 16-bromo-5-cyclopropyl-26-methyl-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacos-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A2-12). 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-cyclopropylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (110 mg, 0.17 mmol, 1 equivalent), N,N-Diisopropylethylamine (67 mg, 0.52 mmol, 3 equivalents) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)urea hexafluorophosphate (98 mg, 0.26 mmol, 1.5 equiv) in 1,4-dioxane (5 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 60 mg of 16-bromo-5-cyclopropyl-26-methyl-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A2-12) (56%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=622.05. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.96-1.04 (2H, m), 1.08-1.35 (2H, m), 3.08-3.12 (2H, m), 3.28 (2H, q), 3.49-3.60 (1H, m), 3.62 (3H, s), 3.64-3.77 (2H, m), 4.21-4.33 (2H, m), 4.29 (2H, s), 7.36-7.38 (1H, m), 7.43 (1H, d), 8.09 (1H, d), 8.21 (1H, s), 8.30 (1H, d), 8.88 (1H, d), 12.63 (1H, s). Step 13. Preparation of 5-cyclopropyl-26-methyl-16-(4-methylpiperazin-1-yl)-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A2). 16-Bromo-5-cyclopropyl-26-methyl-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacos-1(28),2(6),3, 14,16,18, 20,24-octaene-23,27-dione (40 mg, 0.06 mmol, 1 eq.), 1-methylpiperazine (26 mg, 0.256 mmol, 4 eq.) and BrettPhos Pd G ₃To a mixture of 1,4-dioxane (5 mL) and 1,4-dioxane (18 mg, 0.02 mmol, 0.3 equiv.) was added LiHMDS (65 mg, 0.38 mmol, 6 equiv.). The mixture was stirred at 60 °C for 2 h and then cooled to room temperature. The reaction mixture was treated with NH₄Cl(aqueous) solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was passed through prep-HPLC using a Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 2.7 mg of 5-cyclopropyl-26-methyl-16-(4-methylpiperazin-1-yl)-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A2) as a white solid (6%). LCMS: m/z (ESI), [M+H] ⁺=640.35. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.96-1.04 (2H, m), 1.08-1.35 (2H, m), 2.25 (3H, s), 2.48-2.50 (4H, m), 3.04-3.15 (3H, m), 3.18 (4H, t), 3.57-3.64 (4H, m), 3.62 (3H, s), 4.24-4.29 (4H, m), 6.87 (1H, d), 7.23 (1H, s), 7.35 (1H, d), 8.21 (1H, s), 8.27 (1H, s), 8.89 (1H, s), 12.33 (1H, s). ¹⁹F NMR (DMSO-d ₆, 376 MHz) δ 69.26 (s). Example A3 5,26-Dimethyl-16-(4-methylpiperazine-1-yl)-10-(2,2,2-trifluoroethyl)-7-oxo-4,5,10,13,20,22,26-heptaazapentacyclic [22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. Preparation of methyl-5-{5-[2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (INT-A3-1). To a stirred mixture of triphenylphosphine (1324 mg, 5.04 mmol, 3 eq.) and methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 354 mg, 1.34 mmol, 0.8 eq.) in tetrahydrofuran (9 mL) at 0°C were added 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethanol (650 mg, 1.68 mmol, 1 eq.) and diisopropyl azodicarboxylate (1021 mg, 5.04 mmol, 3 eq.). The mixture was stirred at 0°C under nitrogen atmosphere for 1 h. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 550 mg of 5-{5-[2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A3-1) (36%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=630.85. ¹H NMR (DMSO-d ₆, 400 MHz) δ 3.01 (2H, t), 3.11 (2H, t), 3.31-3.45 (2H, m)3.49-3.54 (4H, m), 3.66 (3H, s), 3.76 (3H, s), 4.01 (2H, t), 5.73 (1H, s), 6.78-6.92 (1H, m), 7.20 (1H, d), 7.96-7.88 (2H, m), 8.00 (1H, d), 8.23 (1H, t), 8.33 (1H, d). Step 2. Preparation of 5-{5-[2-({2-[(2-amino-5-bromophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A3-2). To a stirred mixture of 5-{5-[2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (570 mg, 0.90 mmol, 1 eq.) and ranyl nickel (30 mg) in methanol (6 mL) was added NH ₂NH ₂ ^.H ₂O (57 mg, 1.80 mmol, 2 eq.). The mixture was stirred at 0 °C for 30 min under nitrogen atmosphere. The mixture was filtered. The filter cake was washed with methanol (3×30 mL), and the solution was concentrated under reduced pressure to give 270 mg of 5-{5-[2-({2-[(2-amino-5-bromophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A3-2) (42%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=601.05. Step 3. Preparation of 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A3-3). A mixture of 5-{5-[2-({2-[(2-amino-5-bromophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (240 mg, 0.39 mmol, 1 eq.) and BrCN (42 mg, 0.39 mmol, 1 eq.) in ethanol (6 mL) was stirred at 0°C for 1 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 120 mg of 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A3-3) (43%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=626.05 Step 4. Preparation of 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A3-4). To a stirred mixture of 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (100 mg, 0.16 mmol, 1 equivalent) in tetrahydrofuran (2 mL) was added LiOH ^.H ₂O (7.6 mg, 0.32 mmol, 2 eq.) of H ₂O (0.5 mL). The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 70 mg of 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A3-4) (68%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=612.00. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.98 (2H, t), 3.51 (3H, s), 3.57 (5H, t), 3.68 (3H, s), 3.99 (2H, t), 4.25 (2H, t), 7.06-6.97 (2H, m), 7.28 (2H, d), 7.33 (3H, s ), 7.98 (1H, d), 8.09 (1H, s), 8.47 (1H, d,). Step 5. Preparation of 16-bromo-5,26-dimethyl-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A3-5). 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (65 mg, 0.10 mmol, 1 equivalent) andN,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (60 mg, 0.15 mmol, 1.5 equivalents) was added to the stirred mixture in 1,4-dioxane (2 mL) N,N-diisopropylethylamine (41 mg, 0.31 mmol, 3 eq.) was added, and the mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 45 mg of 16-bromo-5,26-dimethyl-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6), 3,14,16,18,20,24-octaene-23,27-dione (INT-A3-5) (58%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=594.00. Step 6. Preparation of 5,26-dimethyl-16-(4-methylpiperazin-1-yl)-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (Example A3). 16-Bromo-5,26-dimethyl-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecano-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (50 mg, 0.08 mmol, 1 equivalent), BrettPhos Pd G ₃To a stirred mixture of 1,4-dioxane (2 mL) and piperazine, 1-methyl- (22 mg, 0.02 mmol, 0.3 equiv.) was added LiHMDS (0.48 mL, 0.48 mmol, 6 equiv.) dropwise. The mixture was stirred at 60 °C for 40 min under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (30 mL), and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to Prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 3.1 mg of 5,26-dimethyl-16-(4-methylpiperazin-1-yl)-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A3) as a yellow solid (5%). LCMS: m/z (ESI), [M+H] ⁺=614.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.26 (3H, s), 3.04-3.10 (2H, m), 3.18 (4H, t), 3.15-3.27 (5H, m), 3.58-3.64 (4H, m), 3.64-3.78 (5H, m), 4.17 (2H, t), 4.29 (2H, t), 6.85-6.89 (1H, m), 7.23 (1H, d), 7.35 (1H, d), 8.26 (2H, d), 8.88 (1H, d), 12.34 (1H, s). ¹⁹F NMR (DMSO-d ₆, 376 MHz) δ -69.31 (s). Example A4 10-(2,2-difluoroethyl)-16-{[2-(dimethylamino)ethyl](methyl)amino}-5,26-dimethyl-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclic[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione Step 1. Preparation of 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,-difluoroethyl)amino)ethanol (INT-A4-1). 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}amino)ethanol (2 g, 6.57 mmol, 1 equivalent), N,N- A mixture of diisopropylethylamine (2.55 g, 19.72 mmol, 3 equiv.) and 2,2-difluoroethyl trifluoromethanesulfonate (1.69 g, 7.89 mmol, 1.2 equiv.) in dimethylformamide (20 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (80 mL), and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 1.1 g of 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethanol (INT-A4-1) (43%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=366.00. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 2.71 (2H, t), 2.90 (2H, t), 2.99 (2H, t), 3.35-3.43 (2H, m), 3.46-3.64 (2H, m), 4.51 (1H, t), 5.87-6.18 (1H, m), 6.83-6.86 (1H, m), 7.27 (1H, d), 7.99 (1H, d), 8.33 (1H, t). Step 2. Preparation of 5-{5-[2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A4-2). To a mixture of triphenylphosphine (1.38 g, 5.29 mmol, 3 eq.) and methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 836 mg, 3.17 mmol, 1.8 eq.) in tetrahydrofuran (10 mL) at 0°C were added 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethanol (650 mg, 1.76 mmol, 1 eq.) and diisopropyl azodicarboxylate (1.07 g, 5.29 mmol, 3 eq.). The mixture was stirred at 0°C under nitrogen atmosphere for 1 h. The reaction was quenched with water (80 mL), and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/3) to give 400 mg of 5-{5-[2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A4-2) (33%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=613.00. Step 3. Preparation of 5-{5-[2-({2-[(2-amino-5-bromophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A4-3). To a stirred mixture of 5-{5-[2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (400 mg, 0.65 mmol, 1 eq.) and ranyl nickel (72 mg) in methanol (5 mL) was added hydrazine (41 mg, 1.30 mmol, 2 eq.) at 0°C. The mixture was stirred at 0°C for 30 minutes under nitrogen atmosphere. The resulting mixture was filtered. The filter cake was washed with methanol (3×10 mL), and the solution was concentrated under reduced pressure to give 300 mg of methyl-5-{5-[2-({2-[(2-amino-5-bromophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (INT-A4-3) (55%) as a brown solid. LCMS: m/z (ESI) , [M+H]+=583.05. Step 4. Preparation of methyl 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2-difluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A4-4). A mixture of methyl 5-{5-[2-({2-[(2-amino-5-bromophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (300 mg, 0.51 mmol, 1 eq.) and BrCN (54 mg, 0.51 mmol, 1 eq.) in ethanol (5 mL) was stirred under nitrogen atmosphere at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 250 mg of 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2-difluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A4-4) (71%) as a brown solid. LCMS: m/z (ESI), [M+H]+=608.05. Step 5. Preparation of 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2-difluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A4-5). To a stirred mixture of 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2-difluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (200 mg, 0.32 mmol, 1 equiv.) in tetrahydrofuran (4 mL) was added LiOH ^.H ₂O (19.6 mg, 0.82 mmol, 2.5 equiv) of H ₂O (1 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was passed through C18FLASH using a 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 175 mg of 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2-difluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A4-5) (80%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=594.10. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 2.90 (4H, t), 3.05 (4H, t), 3.27 (2H, d), 3.51 (6H, s), 3.68 (6H, s), 3.97 (4H, t), 4.24 (4H, t), 5.85-6.20 (1H, m), 7.06-6.97 (4H, m), 7.28 (4H, s), 7.32 (2H, d), 7.97 (2H, d), 8.08 (2H, s), 8.46 (1H, s), 8.47 (1H, s). Step 6. Preparation of 16-bromo-10-(2,2-difluoroethyl)-5,26-dimethyl-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A4-6). 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2-difluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (160 mg, 0.26 mmol, 1 equivalent), N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (153 mg, 0.40 mmol, 1.5 equivalents) andN,N- A mixture of diisopropylethylamine (104 mg, 0.80 mmol, 3 equiv.) in 1,4-dioxane (6 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (30 mL), and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×20 mL), purified by anhydrous Na ₂SO ₄The residue was purified by Prep-TLC eluting with dichloromethane/methanol (10/1) to give 130 mg of 16-bromo-10-(2,2-difluoroethyl)-5,26-dimethyl-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A4-6) (79%) as a brown solid. LCMS (EB237475-165): m/z (ESI), [M+H]+=576.00; Step 7. Preparation of 10-(2,2-difluoroethyl)-16-{[2-(dimethylamino)ethyl](methyl)amino}-5,26-dimethyl-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclic[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A4). 16-Bromo-10-(2,2-difluoroethyl)-5,26-dimethyl-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecano-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (100 mg, 0.17 mmol, 1 equivalent), BrettPhos Pd G ₃To a mixture of 2-(47 mg, 0.05 mmol, 0.3 eq.) and [2-(dimethylamino)ethyl](methyl)amine (70 mg, 0.69 mmol, 4 eq.) in 1,4-dioxane (3 mL) was added LiHMDS (0.7 mL, 1.02 mmol, 6 eq.) dropwise. The mixture was stirred at 60 °C under nitrogen atmosphere for 2 h and then cooled to room temperature. The reaction was heated with saturated NH₄Cl(aq) solution (5 mL) was quenched, and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃+0.1%NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 1.2 mg of 10-(2,2-difluoroethyl)-16-{[2-(dimethylamino)ethyl](methyl)amino}-5,26-dimethyl-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A4) as a yellow solid (1%). LCMS: m/z (ESI), [M+H] ⁺=598.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.19 (6H, s), 2.39 (2H, t), 2.96 (3H, s), 3.03 (2H, t), 3.11-3.52 (6H, m), 3.61 (3H, s), 3.73 (3H, s), 4.19 (2H, t), 4.28 (2H, t), 6.21 (1H, t), 6.64 (1H, d), 6.84 (1H, s), 7.31 (1H, d), 8.25 (2H, s), 8.87 (1H, s), 12.20 (1H, s). ¹⁹F NMR (DMSO-d ₆, 376 MHz) δ 119.603 (s). Example A5 5,26-Dimethyl-10-(oxacyclobutane-3-yl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. Preparation of 2-({2-[(2-nitrophenyl)amino]ethyl}(oxacyclobutan-3-yl)amino)ethanol (INT-A5-1). To a stirred mixture of 2-({2-[(2-nitrophenyl)amino]ethyl}amino)ethanol (1 g, 4.44 mmol, 1 eq), 3-oxacyclobutanone (383 mg, 5.33 mmol, 1.2 eq) and molecular sieves (20 mg) in dichloromethane (30 mL) was added sodium triacetoxyborohydride (1.88 g, 8.88 mmol, 2 eq) at room temperature. The mixture was stirred at room temperature for 12 h under nitrogen atmosphere. The reaction was quenched with water (80 mL), and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/1) to give 1.2 g of 2-({2-[(2-nitrophenyl)amino]ethyl}(oxadiazine-3-yl)amino)ethanol (INT-A5-1) (95%) as a red oil. LCMS: m/z (ESI), [M+H] ⁺=282.10. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.56-2.65(2H, m), 2.74-2.81(2H, m), 3.31-3.40(2H, m), 3.41-3.49(2H, m), 4.00-4.06(1H, m), 4.42-4.48(2H, m), 4.51-4.58(2H, m), 6.64-6.74(1H, m), 7.01-7.08(1H, m), 7.50-7.59(1H, m), 8.03-8.11(1H, m), 8.32(1H, t). Step 2. Preparation of methyl 1-methyl-5-{1-methyl-5-[2-({2-[(2-nitrophenyl)amino]ethyl}(oxacyclobutan-3-yl)amino)ethoxy]pyrazol-4-yl}-6-oxopyridine-3-carboxylate (INT-A5-2). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (308 mg, 1.17 mmol, 1.1 eq) and triphenylphosphine (839 mg, 3.20 mmol, 3 eq) in tetrahydrofuran (2 mL) at 0°C were added diisopropyl azodicarboxylate (647 mg, 3.20 mmol, 3 eq) and 2-({2-[(2-nitrophenyl)amino]ethyl}(oxacyclobutan-3-yl)amino)ethanol (300 mg, 1.07 mmol, 1 eq). The mixture was stirred at room temperature under nitrogen atmosphere for 12 h. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/1) to give 200 mg of 1-methyl-5-{1-methyl-5-[2-({2-[(2-nitrophenyl)amino]ethyl}(oxacyclobutan-3-yl)amino)ethoxy]pyrazol-4-yl}-6-oxopyridine-3-carboxylic acid methyl ester (INT-A5-2) (30%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺= 527.20. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.79-2.87(2H, m), 2.94-3.00(2H, m), 3.29-3.40(5H, m), 3.78(3H, s), 3.94-4.03(2H, m), 4.04-4.16(1H, m), 4.42-4.51(2H, m), 4.52-4.60(2H, m), 6.64-6.73(1H, m), 6.94-7.01(1H, m), 7.45-7.53(1H, m), 7.91(1H, s), 8.01-8.08(2H, m), 8.25(1H, t), 8.39(1H, d). Step 3. Preparation of 5-{5-[2-({2-[(2-aminophenyl)amino]ethyl}(oxacyclobutan-3-yl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A5-3). To a stirred mixture of 1-methyl-5-{1-methyl-5-[2-({2-[(2-nitrophenyl)amino]ethyl}(oxacyclobutan-3-yl)amino)ethoxy]pyrazol-4-yl}-6-oxopyridine-3-carboxylic acid methyl ester (150 mg, 0.29 mmol, 1 eq.) and ranyl nickel (30 mg, 0.35 mmol, 1.2 eq.) in methanol (30 mL) at 0°C was added NH ₂NH ₂.H ₂O (90 mg). The mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. The resulting mixture was filtered. The filter cake was washed with methanol (2×10 mL), and the solution was concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 120 mg of 5-{5-[2-({2-[(2-aminophenyl)amino]ethyl}(oxacyclobutan-3-yl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A5-3) (73%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=497.30. Step 4. Preparation of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](oxacyclobutan-3-yl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A5-4). A mixture of 5-{5-[2-({2-[(2-aminophenyl)amino]ethyl}(oxacyclobutan-3-yl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (120 mg, 0.24 mmol, 1 equiv.) and cyanogen bromide (38 mg, 0.36 mmol, 1.5 equiv.) in ethanol (10 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (5/1) to give 82 mg of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](oxacyclobutan-3-yl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A5-4) (65%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=522.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.77-2.86(2H, m), 2.99-3.07(2H, m), 3.57(3H, s), 3.68(3H, s), 3.77(3H, s), 3.91-3.98(2H, m), 3.98-4.11(3H, m), 4.29-4.36(2H, m), 4.43-4.50(2H, m), 6.39(2H, s), 6.78-6.85(1H, m), 6.87-6.95(1H, m), 7.04-7.14(1H, m), 7.93(1H, s), 8.08(1H, d), 8.45(1H, d). Step 5. Preparation of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](oxacyclobutan-3-yl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A5-5). A mixture of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](oxacyclobutan-3-yl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (82 mg, 0.16 mmol, 1 eq.) and lithium hydroxide (13 mg, 0.31 mmol, 2 eq.) in tetrahydrofuran (10 mL) and water (2.5 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was passed through C18FLASH using a 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 20 mg of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](oxacyclobutan-3-yl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A5-5) (24%) as a red solid. LCMS: m/z (ESI), [M+H] ⁺=508.25. Step 6. Preparation of 5,26-dimethyl-10-(oxacyclobutane-3-yl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octaconic-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A5). 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](oxacyclobutan-3-yl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (20 mg, 0.04 mmol, 1 equivalent), N, N-Diisopropylethylamine (15 mg, 0.12 mmol, 3 equivalents) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (22 mg, 0.06 mmol, 1.5 equiv.) in 1,4-dioxane (4 mL) was stirred at room temperature for 3 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC using an XBridge Prep OBD C18 column containing 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 8.8 mg of 5,26-dimethyl-10-(oxacyclobutane-3-yl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (Example A5) as a white solid (45%). LCMS: m/z (ESI), [M+H] ⁺=490.20. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.95-3.03(2H, m), 3.17-3.24(2H, m), 3.62(3H, s), 3.74(3H, s), 4.13-4.30(5H, m), 4.59-4.64(2H, m), 4.66-4.72(2H, m), 7.19-7.29(2H, m), 7.49-7.54(1H, m), 7.58-7.64(1H, m), 8.24(1H, s), 8.29(1H, d), 8.80(1H, d), 11.69(1H, s). Example A6 10-ethyl-5,12,26-trimethyl-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. NPreparation of tert-butyl-{1-[ethyl(2-hydroxyethyl)amino]propan-2-yl}carbamate (INT-A6-1). Ethylethanolamine (1 g, 11.21 mmol, 1 equivalent) and NTo a stirred mixture of tert-butyl-(1-bromopropan-2-yl)carbamate (3.2 g, 13.46 mmol, 1.2 equiv.) in acetonitrile (40 mL), add K ₂CO ₃(4.6 g, 33.65 mmol, 3 equiv.). The mixture was stirred at 60 °C overnight and cooled to room temperature. The reaction was quenched with water (50 mL), and the mixture was washed with CH₂Cl ₂(3×100 mL) extraction. The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC eluting with dichloromethane/methanol (10/1) to give 1 g of N-tert-Butyl{1-[ethyl(2-hydroxyethyl)amino]propan-2-yl}carbamate (INT-A6-1) (36%). ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.04 (3H, t), 1.14 (3H, d), 1.46 (9H, s), 2.32-2.47 (2H, m), 2.52-2.70 (4H, m), 3.50-3.63 (2H, m), 3.72-3.80 (1H, m), 4.45 (1H, brs). Step 2. Preparation of 2-[(2-aminopropyl)(ethyl)amino]ethanol (INT-A6-2). Add 2-[(2-aminopropyl)(ethyl)amino]ethanol to a 20 mL vial at room temperature.N-tert-butyl {1-[ethyl(2-hydroxyethyl)amino]propan-2-yl}carbamate (1 g, 4.05 mmol, 1 equiv) and 1,4-dioxane (10 mL) containing HCl. The mixture was stirred at room temperature for 10 h and concentrated under reduced pressure. The residue was treated with saturated NaHCO₃(aqueous solution) solution (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×40 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to give 0.59 g of 2-[(2-aminopropyl)(ethyl)amino]ethanol (INT-A6-2) as a yellow solid. This material was used in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺=146.15 Step 3. Preparation of 2-[ethyl({2-[(2-nitrophenyl)amino]propyl})amino]ethanol (INT-A6-3). To a stirred mixture of 2-[(2-aminopropyl)(ethyl)amino]ethanol (590 mg, about 4 mmol, about 1 equivalent) and o-fluoronitrobenzene (569 mg, 4.03 mmol, 1 equivalent) in acetonitrile (20 mL) was added K ₂CO ₃(1115 mg, 8.07 mmol, 2 eq.). The resulting mixture was stirred at 60 °C for 2 h and cooled to room temperature. The reaction was quenched with water (20 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (12/1) to give 640 mg of 2-[ethyl({2-[(2-nitrophenyl)amino]propyl})amino]ethanol (INT-A6-3) (59%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=268.10. ¹H NMR (CDCl ₃, 400 MHz) δ 1.16 (3H, t), 1.35 (3H, d), 2.34-3.01 (7H, m), 3.64-3.68 (2H, m), 6.68 (1H, t), 6.96 (1H, s), 7.47 (1H, t), 8.18-8.21 (2H, m). Step 4. Preparation of 5-(5-{2-[ethyl({2-[(2-nitrophenyl)amino]propyl})amino]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A6-4). To a stirred mixture of triphenylphosphine (1766 mg, 6.73 mmol, 3 eq.) and methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 590 mg, 2.24 mmol, 1 eq.) in tetrahydrofuran (20 mL) was added diisopropyl azodicarboxylate (1361 mg, 6.73 mmol, 3 eq.). The mixture was stirred at 0 °C for 0.5 h under nitrogen atmosphere. To the above mixture was added 2-[ethyl({2-[(2-nitrophenyl)amino]propyl})amino]ethanol (600 mg, 2.24 mmol, 1 eq.) in tetrahydrofuran (2 mL) at 0 °C over 2 min. The mixture was stirred at 0 °C for another 2 h. The reaction was quenched with water (20 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/3) to give 400 mg of 5-(5-{2-[ethyl({2-[(2-nitrophenyl)amino]propyl})amino]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A6-4) (34%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=513.20. ¹H NMR (methanol-d ₄, 400 MHz) δ 1.09 (3H, t), 1.23-1.31 (3H, m), 2.60-2.75 (3H, m), 2.84-2.95 (1H, m), 2.96-3.03 (1H, m), 3.66 (3H, s), 3.68 (3H, s), 3.80-3.92 (4H, m), 4.01 (2H, t), 6.42-6.62 (1H, m), 6.99 (1H, d), 7.39 (1H, d), 7.91 (1H, s), 8.05 (1H, d), 8.16 (1H, d), 8.35 (1H, d). Step 5. Preparation of methyl 5-{5-[2-({2-[(2-aminophenyl)amino]propyl}(ethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (INT-A6-5). To a stirred mixture of methyl 5-(5-{2-[ethyl({2-[(2-nitrophenyl)amino]propyl})amino]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (450 mg, 0.87 mmol, 1 eq) and ranyl nickel (50 mg) in methanol (5 mL) was added hydrazine hydrate (140 mg, 4.39 mmol, 5 eq) at 0°C. The mixture was stirred at room temperature under nitrogen atmosphere for 1 h and filtered. The filter cake was washed with methanol (3×20 mL), and the solution was concentrated under reduced pressure to give 260 mg of methyl 5-{5-[2-({2-[(2-aminophenyl)amino]propyl}(ethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (INT-A6-5) (61%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=483.10. Step 6. Preparation of dimethyl 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)propyl](ethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A6-6). A mixture of methyl 5-{5-[2-({2-[(2-aminophenyl)amino]propyl}(ethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (260 mg, 0.53 mmol, 1 eq.) and BrCN (114 mg, 1.07 mmol, 2 eq.) in ethanol (5 mL) was stirred at room temperature under a nitrogen atmosphere for 1 h and concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (20/1) to give 250 mg of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)propyl](ethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid dimethyl ester (INT-A6-6) (91%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=508.40. Step 7. Preparation of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)propyl](ethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A6-7). To a stirred solution of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)propyl](ethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (240 mg, 0.47 mmol, 1 equiv.) in tetrahydrofuran (6 mL) was added LiOH.H ₂O (33 mg, 1.41 mmol, 3 equiv) of H ₂O (1.5 mL). The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was purified by reverse flash chromatography using a C18 silica gel column using water and acetonitrile as mobile phases. The fractions containing the desired compound were evaporated to dryness to give 200 mg [5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)propyl](ethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A6-7) (85%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=494.40. Step 8. Preparation of 10-ethyl-5,12,26-trimethyl-7-oxa-4,5,10,13,20, 22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A6). 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)propyl](ethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (110 mg, 0.22 mmol, 1 equivalent) and N,N-Diisopropylethylamine (115 mg, 0.89 mmol, 4 equivalents) was added to the stirred mixture in 1,4-dioxane (6 mL) N, N, N, N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)uronium hexafluorophosphate (169 mg, 0.44 mmol, 2 equiv). The resulting mixture was stirred at 60 °C for 2 h, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (12/1) and by Prep-HPLC using an XBridge Shield RP18 OBD column with 0.1% NH₄HCO ₃and 0.1% NH ₃.H ₂O water and acetonitrile for further purification. The fractions containing the desired compound were evaporated to dryness to give 28.8 mg of 10-ethyl-5,12,26-trimethyl-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6), 3,14,16,18,20,24-octaene-23,27-dione (Example A6) (27%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=476.30. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.07 (3H, t), 1.62 (3H, d), 2.53-2.65 (2H, m), 2.75-2.82 (2H, m), 3.33-3.58 (2H, m), 3.62 (3H, s), 3.75 (3H, s), 4.09 (1H, s), 4.28-4.37 (1H, m), 5.15 (1H, s), 7.14-7.29 (2H, m), 7.47-7.60 (1H, m), 7.60-7.71 (1H, m), 8.17 (1H, s), 8.27 (1H, d), 8.88 (1H, d), 12.54 (1H, s). Example A7 10-ethyl-5,12,12,26-tetramethyl-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. NPreparation of tert-butyl-{1-[ethyl(2-hydroxyethyl)amino]-2-methylpropan-2-yl}carbamate (INT-A7-1).NA mixture of tert-butyl-(2-methyl-1-oxopropan-2-yl)carbamate (5 g, 26.70 mmol, 1 eq.), triethylamine (8 g, 80.11 mmol, 3 eq.) and ethylethanolamine (2.4 g, 26.70 mmol, 1.00 eq.) in dichloromethane (50 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. NaBH(OAc) was then added.₃(17 g, 80.11 mmol, 3 equiv.), and the mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction was quenched with water (300 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by passing through a C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to dryness to obtain 5 g of N-tert-butyl {1-[ethyl(2-hydroxyethyl)amino]-2-methylpropan-2-yl}carbamate (INT-A7-1) (72%). LCMS: m/z (ESI), [M+H] ⁺=261.10. ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.93 (3H, t), 1.13-1.14 (6H, s), 1.36-1.39 (9H, d), 2.49-2.53 (3H, m), 2.53-2.56 (3H, m), 3.42-3.43 (2H, m), 4.31 (1H, s), 6.25 (1H, s). Step 2. Preparation of 2-((2-amino-2-methylpropyl)(ethyl)amino)ethan-1-ol (INT-A7-2). NA mixture of tert-butyl-{1-[ethyl(2-hydroxyethyl)amino]-2-methylpropan-2-yl}carbamate (2 g, 3.84 mmol, 1 equiv) in trifluoroacetic acid (5 mL) and dichloromethane (15 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with saturated NaHCO₃(aqueous solution) solution (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×200 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to give 1.23 g of 2-((2-amino-2-methylpropyl)(ethyl)amino)ethan-1-ol (INT-A7-2) as a colorless oil. This material was used in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺=161.10. Step 3. Preparation of 2-[ethyl({2-methyl-2-[(2-nitrophenyl)amino]propyl})amino]ethanol (INT-A7-3). 2-[(2-amino-2-methylpropyl) (ethyl)amino]ethanol (2 g, 12.48 mmol, 1 equivalent), K ₂CO ₃A mixture of (5 g, 37.44 mmol, 3 equiv.) and o-fluoronitrobenzene (1.7 g, 12.48 mmol, 1 equiv.) in acetonitrile (20 mL) was stirred at 80 °C overnight under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (20/1) to give 1.2 g of 2-[ethyl({2-methyl-2-[(2-nitrophenyl)amino]propyl})amino]ethanol (INT-A7-3) (34%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=282.05. ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.97 (3H, t), 1.41 (6H, s), 2.62-2.66 (3H, m), 2.69 (2H, s), 3.17 (1H, d), 3.44-3.50 (2H, m), 4.37 (1H, t), 6.62-6.68 (1H, m), 7.26-7.33 (1H, m), 7.44-7.52 (1H, m), 8.04-8.10 (1H, m), 8.62-8.68 (1H, s). Step 4. Preparation of methyl 5-(5-(2-(ethyl(2-methyl-2-((2-nitrophenyl)amino)propyl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (INT-A7-4). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 281 mg, 1.06 mmol, 1 eq), triphenylphosphine (839 mg, 3.19 mmol, 3 eq) in tetrahydrofuran (10 mL) under nitrogen atmosphere at 0 °C were added diisopropyl azodicarboxylate (646 mg, 3.19 mmol, 3 eq) and 2-[ethyl({2-methyl-2-[(2-nitrophenyl)amino]propyl})amino]ethanol (300 mg, 1.06 mmol, 1 eq). The mixture was stirred for 1 h, treated with water (100 mL), and extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with brine (2×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (12/1) to give 230 mg of 5-(5-(2-(ethyl(2-methyl-2-((2-nitrophenyl)amino)propyl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A7-4) (41%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=527.20. ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.98 (3H, t), 1.39 (6H, s), 2.67-2.69 (2H, m), 2.74 (2H, s), 2.98 (2H, t), 3.56 (3H, s), 3.65 (3H, s), 3.77 (3H, s), 4.00 (2H, t), 5.77 (1H, s), 6.62-6.67 (1H, m), 7.23-7.28 (1H, d), 7.41-7.48 (1H, m), 7.90-7.93 (1H, s), 8.00-8.04 (2H, m), 8.40 (1H, d), 8.58 (1H, s) Step 5. Preparation of 5-{5-[2-({2-[(2-aminophenyl)amino]-2-methylpropyl} (ethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A7-5). To a stirred mixture of 5-(5-{2-[ethyl({2-methyl-2-[(2-nitrophenyl)amino]propyl})amino]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (230 mg, 0.44 mmol, 1 equiv.) and ranyl nickel (50 mg) in methanol (2 mL) was added NH ₂NH ₂ ^.H ₂O (22 mg, 0.44 mmol, 1 eq.). The mixture was stirred at 0 °C for 1 h. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (10/1) to give 110 mg of 5-{5-[2-({2-[(2-aminophenyl)amino]-2-methylpropyl}(ethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A7-5) (51%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=497.40. ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.97 (3H, t), 1.14 (6H, s), 2.62-2.69 (2H, m), 2.94 (2H, t), 3.18 (2H, d), 3.58 (3H, s), 3.67 (4H, s), 3.80 (3H, s), 4.00 (2H, t), 4.38 (5H, s), 4.47 (2H, s), 6.35-6.39 (2H, m), 6.47-6.54 (4H, m), 6.72 (1H, d), 7.96 (1H, s), 8.11 (1H, d), 8.46 (1H, d). Step 6. Preparation of methyl 5-(5-(2-((2-(2-amino-1H-benzo[d]imidazol-1-yl)-2-methylpropyl)(ethyl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (INT-A7-6). A mixture of methyl 5-{5-[2-({2-[(2-aminophenyl)amino]-2-methylpropyl}(ethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (200 mg, 0.40 mmol, 1 eq) and BrCN (51 mg, 0.48 mmol, 1.2 eq) in dichloromethane (5 mL) was stirred under nitrogen atmosphere at room temperature for 2 h and concentrated under vacuum. The residue was purified by prep-TLC using dichloromethane/methanol (12/1) to give 120 mg of 5-(5-(2-((2-(2-amino-1H-benzo[d]imidazol-1-yl)-2-methylpropyl)(ethyl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A7-6) (61%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=522.30. ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.82 (3H, t), 1.81 (6H, s), 2.44-2.48 (3H, m), 2.79 (2H, t), 3.02 (2H, s), 3.58 (6H, d), 3.78-3.82 (5H, m), 6.88 (1H, t), 6.99 (1H, t), 7.19 (1H, s), 7.55 (1H, d), 7.95 (1H, s), 8.05 (1H, d), 8.47 (1H, d) Step 7. Preparation of 5-(5-(2-((2-(2-amino-1H-benzo[d]imidazol-1-yl)-2-methylpropyl)(ethyl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (INT-A7-7). 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)-2-methylpropyl](ethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (120 mg, 0.23 mmol, 1 equiv) and LiOH ^.H ₂O (39 mg, 0.92 mmol, 4 equivalents) in tetrahydrofuran/H ₂O (2 mL/0.5 mL) was stirred at 40 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 65 mg of 5-(5-(2-((2-(2-amino-1H-benzo[d]imidazol-1-yl)-2-methylpropyl)(ethyl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (INT-A7-7) (56%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=508.15. ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.77 (3H, t), 1.79 (6H, s), 2.35-2,42 (3H, m), 2.67-2.69 (1H, m), 2.81 (2H, t), 2.99 (2H, s), 3.48 (3H, s), 3.56 (3H, s), 3.82 (2H, t), 6.30 (2H, s), 6.78 (1H, t), 6.86-6.93 (1H, m), 7.06-7.11 (1H, m), 7.46 (1H, d), 7.86 (1H, s), 7.96 (1H, s), 8.17 (1H, d) Step 8. Preparation of 10-ethyl-5,12,12,26-tetramethyl-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A7). 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)-2-methylpropyl](ethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (65 mg, 0.13 mmol, 1 equivalent), N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (97 mg, 0.25 mmol, 2 equivalents) andN,N- A mixture of diisopropylethylamine (33 mg, 0.25 mmol, 2 equiv.) in 1,4-dioxane (2 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (50 mL), and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 13.6 mg of 10-ethyl-5,12,12,26-tetramethyl-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A7) (22%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺= 490.20. ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.99 (3H, t), 1.94 (6H, s), 2.68 (2H, d), 3.08-3.22 (2H, m), 3.60-3.64 (5H, m), 3.73 (3H, s), 4.28 (2H, d), 7.17 (2H, t), 7.56-7.63 (1H, m), 7.83 (1H, d), 8.13 (1H, d), 8.29 (1H, d), 8.67 (1H, d), 12.93 (1H, s). Example A8 15,21-Dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazahexacyclo[24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(32),18(22),19-octaene-12,16-dione Step 1. Preparation of tert-butyl 3-((2-nitrophenyl)amino)azoloheptane-1-carboxylate (INT-A8-1). To a stirred mixture of o-fluoronitrobenzene (5 g, 35.43 mmol, 1 eq.) and tert-butyl 3-aminoazoloheptane-1-carboxylate (7.9 g, 37.20 mmol, 1.05 eq.) in acetonitrile (80 mL) was added K ₂CO ₃(9.7 g, 70.87 mmol, 2 eq.). The mixture was stirred at 80 °C for 3 h under nitrogen atmosphere and cooled to room temperature. The reaction was quenched with water (100 mL) and the mixture was washed with CH₂Cl ₂(3×100 mL) extraction. The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column and eluted with petroleum ether/ethyl acetate (10:1) to give 10.6 g of tert-butyl 3-[(2-nitrophenyl)amino]azanacycloheptane-1-carboxylate (INT-A8-1) (89%) as a brown oil. LCMS: m/z (ESI), [M+H] ⁺=336.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.37 (9H, d), 1.47-2.03 (6H, m), 3.34-3.49 (3H, m), 3.51-3.62 (1H, m), 3.93 (1H, s), 6.61-6.75 (1H, m), 7.20 (1H, m), 7.47-7.55 (1H, m), 7.97-8.22 (2H, m). Step 2. N- Preparation of (2-nitrophenyl) azacycloheptane-3-amine (INT-A8-2). A mixture of tert-butyl 3-[(2-nitrophenyl) amino] azacycloheptane-1-carboxylate (12 g, 35.77 mmol, 1 eq.) and HCl in 1,4-dioxane (100 mL) was stirred at room temperature for 1.5 h. The mixture was concentrated under reduced pressure and treated with CH₂Cl ₂(60 mL). The mixture was treated with saturated NaHCO₃(aqueous) solution (50 mL) and treated with CH ₂Cl ₂(3×100 mL) extraction. The combined organic layers were purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to obtain 8 g of yellow oil.N-(2-Nitrophenyl)azinecycloheptyl-3-amine (INT-A8-2). This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=236.20. Step 3. 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)- N-(2-nitrophenyl) azacycloheptyl-3-amine (INT-A8-3). To N-(2-nitrophenyl) azacycloheptyl-3-amine (1 g, 4.25 mmol, 1 equivalent) and (2-bromoethoxy)(tert-butyl)dimethylsilane (2.03 g, 8.50 mmol, 2 equivalents) were added to N, N-Dimethylformamide (15 mL) was added to the stirred mixture.₂CO ₃(1.17 g, 8.50 mmol, 2 equiv) and KI (1.41 g, 8.50 mmol, 2 equiv). The resulting mixture was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was washed with CH₂Cl ₂(3×100 mL) extraction. The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column and eluted with ethyl acetate/petroleum ether (1/10) to give 819 mg of 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}- N-(2-Nitrophenyl) azacycloheptyl-3-amine (INT-A8-3) (48%). LCMS: m/z (ESI), [M+H] ⁺=394.20. ¹H NMR (DMSO-d ₆, 400 MHz) δ -0.02 (6H, d), 0.81 (9H, s), 1.35-1.65 (3H, m), 1.65-1.85 (3H, m), 2.57-2.80 (3H, m), 2.81-3.03 (3H, m), 3.61-3.82 (2H, m), 3.93 (1H, s), 6.64-6.66 (1H, m), 7.04 (1H, d), 7.45-7.55 (1H, m), 8.02-8.09 (1H, m), 8.73 (1H, d). Step 4. Preparation of 2-(3-((2-nitrophenyl)amino)azoloheptan-1-yl)ethan-1-ol (INT-A8-4). To 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}- NTo a solution of -(2-nitrophenyl)azanidinecycloheptyl-3-amine (447 mg, 1.13 mmol, 1 eq.) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (593 mg, 2.272 mmol, 2 eq.). The mixture was stirred at room temperature for 2 h. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to give 447 mg of 2-{3-[(2-nitrophenyl)amino]azanacycloheptan-1-yl}ethanol (INT-A8-4) as a yellow oil. This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=280.05. Step 5. Preparation of 1-methyl-5-(1-methyl-5-(2-(3-((2-nitrophenyl)amino)azinecyclohept-1-yl)ethoxy)-1H-pyrazol-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A8-5). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 207 mg, 0.78 mmol, 1.1 eq.) and triphenylphosphine (563 mg, 2.14 mmol, 3 eq.) in tetrahydrofuran (10 mL) at 0° C. under nitrogen atmosphere were added diisopropyl azodicarboxylate (434 mg, 2.14 mmol, 3 eq.) and 2-{3-[(2-nitrophenyl)amino]azanacycloheptan-1-yl}ethanol (200 mg, 0.71 mmol, 1 eq.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using ethyl acetate to give 301 mg of 1-methyl-5-[1-methyl-5-(2-{3-[(2-nitrophenyl)amino]azanacyclohept-1-yl}ethoxy)pyrazol-4-yl]-6-oxopyridine-3-carboxylic acid methyl ester (INT-A8-5) (80%) as an orange solid. LCMS: m/z (ESI), [M+H] ⁺=525.30 ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.22-1.63 (7H, m), 2.45-2.68 (1H, m), 2.79-2.89 (2H, m), 2.95-3.05 (3H, m), 3.55 (3H, s), 3.68 (3H, s), 3.73 (3H, s), 4.05-4.10 (2H, m), 6.60-6.70 (1H, m), 6.95-7.09 (1H, m), 7.40-7.53 (1H,m), 7.94 (1H, s), 7.99-8.05 (2H, m), 8.32 (1H, d), 8.61 (1H, d) Step 6. Preparation of 5-(5-(2-(3-((2-aminophenyl)amino)azepan-1-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A8-6). To a stirred mixture of ranyl nickel (100 mg) and 1-methyl-5-[1-methyl-5-(2-{3-[(2-nitrophenyl)amino]azepan-1-yl}ethoxy)pyrazol-4-yl]-6-oxopyridine-3-carboxylic acid methyl ester (300 mg, 0.54 mmol, 1 equivalent) in methanol (10 mL) at 0°C was added NH ₂NH ₂ ^.H ₂O (84 mg, 0.28 mmol, 3 eq.). The mixture was stirred at room temperature for 2 h and filtered. The filter cake was washed with methanol (3×5 mL), and the solution was concentrated under reduced pressure. The residue was purified by Prep-TLC and eluted with dichloromethane/methanol (10/1) to give 89 mg of 5-[5-(2-{3-[(2-aminophenyl)amino]azanacyclohept-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A8-6) (44%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=495.30 Step 7. Preparation of 5-(5-(2-(3-(2-amino-1H-benzo[d]imidazol-1-yl)azanthene-1-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A8-7). 5-[5-(2-{3-[(2-aminophenyl)amino]azanthene-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (89 mg, 0.18 mmol, 1 equiv) and BrCN (20 mg, 0.19 mmol, 1.10 equiv) were mixed in CH ₂Cl ₂The mixture in 4% paraformaldehyde (5 mL) was stirred at room temperature for 5 h and concentrated under reduced pressure. The residue was purified by Prep-TLC and eluted with dichloromethane/methanol (10/1) to give 21 mg of 5-(5-{2-[3-(2-amino-1,3-benzodiazol-1-yl)azinecyclohept-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid dimethyl ester (INT-A8-7) (22%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=520.25 Step 8. Preparation of 5-(5-(2-(3-(2-amino-1H-benzo[d]imidazol-1-yl)azinecyclohept-1-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (INT-A8-8). To 5-(5-{2-[3-(2-amino-1,3-benzodiazol-1-yl)azinecyclohept-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (60 mg, 0.11 mmol, 1 equivalent) in tetrahydrofuran (4 mL) and H ₂Add LiOH.H O(1 mL) to the stirred mixture.₂O (8 mg, 0.34 mmol, 3 eq.). The resulting mixture was stirred at room temperature for 8 h and concentrated under reduced pressure. The mixture was purified by reverse flash chromatography using a C18 silica gel column using water and acetonitrile as mobile phases. The fractions containing the desired compound were evaporated to dryness to give 16.1 mg of 5-(5-{2-[3-(2-amino-1,3-benzodiazol-1-yl)azanylcyclohept-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A8-8) (42%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=506.20 Step 9. Preparation of 15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazahexacyclo[24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(32),18(22),19-octaene-12,16-dione (Example A8). To a stirred mixture of 5-(5-{2-[3-(2-amino-1,3-benzodiazol-1-yl)azanylcycloheptyl-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (15 mg, 0.03 mmol, 1 eq.) and N,N,N,N-tetramethyl-O-(7-azanylbenzotriazol-1-yl)uronium hexafluorophosphate (33 mg, 0.09 mmol, 3 eq.) in 1,4-dioxane (2 mL) was added N,N-Diisopropylethylamine (11 mg, 0.09 mmol, 3 equiv.). The resulting mixture was stirred at room temperature for 3 h and concentrated. The residue was subjected to Prep-HPLC using an XBridge Shield RP18 OBD column with 0.1% NH₄HCO ₃of water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 4 mg of 15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazahexacyclo[24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontidine-3,5,7,9,13,17(32), 18(22),19-octaene-12,16-dione (Example A8) as a white solid (27%). LCMS: m/z (ESI), [M+H] ⁺=488.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.65-2.03 (5H, m), 2.54-2.72 (1H, m), 2.72-3.03 (5H, m), 3.08-3.22 (1H, m), 3.63 (3H, s), 3.73 (3H, s), 3.80-3.94 (1H, m), 4.34-4.60 (1H, m), 5.14 (1H, s), 7.16-7.26 (2H, m), 7.50-7.57 (1H, m), 7.62 (1H, d), 8.27 (1H, d), 8.31 (1H, s), 8.98 (1H, s), 12.50 (1H, s). Example A9 15,21-Dimethyl-5-(morpholin-4-yl)-23-oxo-2,9,11,15,20,21, 26-heptaazaheptacyclic [24.4.1.1^{1,27}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione Step 1. Preparation of tert-butyl 1-[(5-bromo-2-nitrophenyl)amino]-6-azabicyclo[3.2.1]octane-6-carboxylate (INT-A9-1). tert-butyl 1-amino-6-azabicyclo[3.2.1]octane-6-carboxylate hydrochloride (1 g, 3.81 mmol, 1 equivalent), 4-bromo-2-fluoro-1-nitrobenzene (2.51 g, 11.42 mmol, 3 equivalents) and K ₂CO ₃(2.10 g, 15.22 mmol, 4 equiv.) in acetonitrile (20 mL) was stirred at 60 °C for 2 h. After cooling to room temperature, the reaction was treated with water (200 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (4/1) to give 1.25 g of tert-butyl 1-[(5-bromo-2-nitrophenyl)amino]-6-azabicyclo[3.2.1]octane-6-carboxylate (INT-A9-1) (77%) as a yellow solid. LCMS: m/z (ESI), [M+H - 56] ⁺=371.85. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.40-1.44 (10H, m), 1.48-1.75 (2H, m), 1.79-1.82 (1H, m), 1.98-2.00 (1H, m), 2.13-2.29 (3H, m), 3.23-3.33 (1H, m), 4.01-4.12 (2H, m), 6.92 (1H, d), 7.20 (1H, s), 8.03 (1H, d), 8.28 (1H, s). Step 2. N-Preparation of (5-bromo-2-nitrophenyl)-6-azabicyclo[3.2.1]octan-1-amine (INT-A9-2). To a stirred mixture of tert-butyl 1-[(5-bromo-2-nitrophenyl)amino]-6-azabicyclo[3.2.1]octane-6-carboxylate (1.28 g, 3.00 mmol, 1 eq.) in dichloromethane (10 mL) was added TFA (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was treated with saturated NaHCO ₃(aqueous solution) solution (200 mL) and extracted with dichloromethane (3×200 mL). The combined organic layers were washed with anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to give 950 mg of a pale yellow solid.N-(5-Bromo-2-nitrophenyl)-6-azabicyclo[3.2.1]octan-1-amine (INT-A9-2) (97%). LCMS: m/z (ESI), [M+H] ⁺= 327.90. ¹H NMR (CD ₃OD, 400 MHz) δ 1.51-1.64 (1H, m), 1.72-1.76 (2H, m), 1.80-1.95 (2H, m), 1.97 (1H, d), 2.21-2.33 (2H, m), 3.02-3.06 (1H, m), 3.54-3.65 (2H, m), 6.83-6.86 (1H, m), 7.14 (1H, d), 8.07 (1H, d). Step 3. N-(5-bromo-2-nitrophenyl)-6-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-6-azabicyclo[3.2.1]octan-1-amine (INT-A9-3) preparation.N-(5-Bromo-2-nitrophenyl)-6-azabicyclo[3.2.1]octan-1-amine (580 mg, 1.78 mmol, 1 equivalent), (2-bromoethoxy)(tert-butyl)dimethylsilane (850 mg, 3.56 mmol, 2 equivalents), NaI (533 mg, 3.56 mmol, 2 equivalents) and K ₂CO ₃(491 mg, 3.56 mmol, 2 equivalents) in N,N-The mixture in dimethylformamide (10 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was further purified by reverse phase flash chromatography using 20% to 100% acetonitrile/water to give 600 mg N-(5-Bromo-2-nitrophenyl)-6-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-6-azabicyclo[3.2.1]octan-1-amine (INT-A9-3) (69%). LCMS: m/z (ESI), [M+H] ⁺=484.51. ¹H NMR (CD ₃OD, 400 MHz) δ 0.11 (6H, d), 0.93 (9H, s), 1.38-1.57 (2H, m), 1.62-1.78 (2H, m), 1.83-1.86 (2H, m), 2.00 (1H, d), 2.28 (1H, d), 2.33-2.42 (1H, m), 2.91 (2H, t), 3.36-3.42 (2H, m), 3.79-3.83 (2H, m), 6.82-6.86 (1H, m), 7.09 (1H, d), 8.07 (1H, d). Step 4. Preparation of 2-{1-[(5-bromo-2-nitrophenyl)amino]-6-azabicyclo[3.2.1]octan-6-yl}ethanol (INT-A9-4). At room temperature,N-To a stirred mixture of (5-bromo-2-nitrophenyl)-6-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-6-azabicyclo[3.2.1]octan-1-amine (598 mg, 1.23 mmol, 1 equiv) in tetrahydrofuran (9 mL) was added tetrabutylammonium fluoride (2 mL, 1 M in tetrahydrofuran). After stirring at room temperature for 2 h, the reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (5×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to obtain 360 mg of 2-{1-[(5-bromo-2-nitrophenyl)amino]-6-azabicyclo[3.2.1]octan-6-yl}ethanol (INT-A9-4) (78%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺= 370.24. Step 5. Preparation of 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-6-azabicyclo[3.2.1]oct-6-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A9-5). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 268 mg, 1.02 mmol, 1 eq) and triphenylphosphine (714 mg, 2.72 mmol, 2.8 eq) in tetrahydrofuran (10 mL) at 0 °C under nitrogen atmosphere was added diisopropyl azodicarboxylate (491 mg, 2.43 mmol, 2.5 eq) followed by 2-{1-[(5-bromo-2-nitrophenyl)amino]-6-azabicyclo[3.2.1]octan-6-yl}ethanol (360 mg, 0.97 mmol, 1 eq) in tetrahydrofuran (3 mL). After stirring at 0°C for 30 minutes, the reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (1/9) to give 470 mg of 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-6-azabicyclo[3.2.1]octan-6-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A9-5) (78%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺=617.15. ¹H NMR (CD ₃OD, 400 MHz) δ 1.39-1.51 (1H, m), 1.62-1.74 (2H, m), 1.85 (3H, q), 2.24-2.28 (2H, m), 3.12-3.16 (2H, m), 3.18-3.25 (3H, m), 3.64 (3H, s), 3.79 (3H, s), 3.83 (3H, s), 4.12-4.16 (2H, m), 6.82-6.86 (1H, m), 7.06 (1H, d), 7.96 (1H, s), 8.08 (1H, d), 8.25-8.33 (2H, m) Step 6. Preparation of 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-6-azabicyclo[3.2.1]oct-6-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A9-6). To a stirred mixture of 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-6-azabicyclo[3.2.1]oct-6-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (460 mg, 0.75 mmol, 1 eq.) and ranyl nickel (128 mg, 1.49 mmol, 2 eq.) in methanol (20 mL) at 0°C was added NH ₂NH ₂ ^.H ₂O (187 mg, 3.74 mmol, 5 equiv). After stirring at room temperature for 2 h, the reaction mixture was quenched by adding water (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane/methanol (20/1) to give 370 mg of 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-6-azabicyclo[3.2.1]octan-6-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A9-6) (84%) as a reddish brown solid. LCMS: m/z (ESI), [M+H] ⁺=586.95. Step 7. Preparation of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-6-azabicyclo[3.2.1]oct-6-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A9-7). A mixture of methyl 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-6-azabicyclo[3.2.1]octan-6-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (340 mg, 0.58 mmol, 1 eq) and BrCN (92 mg, 0.87 mmol, 1.5 eq) in EtOH (5 mL) was stirred at room temperature for 4 h. The reaction was stirred by saturated NaHCO₃The solution (100 mL) was quenched and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using dichloromethane/methanol (20/1) to give 120 mg of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-6-azabicyclo[3.2.1]octan-6-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A9-7) (33%) as a reddish brown solid. LCMS: m/z (ESI), [M+H] ⁺=612.15. Step 8. Preparation of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-6-azabicyclo[3.2.1]oct-6-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A9-8). To a stirred solution of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-6-azabicyclo[3.2.1]octan-6-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (120 mg, 0.20 mmol, 1 eq.) in THF (4 mL) at room temperature was added LiOH (28 mg, 1.18 mmol, 6 eq.) in H ₂O (1 mL). The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using 20% to 100% acetonitrile/water elution to give 75 mg of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-6-azabicyclo[3.2.1]octan-6-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A9-8) (63%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺= 598.20. Step 9. Preparation of 5-bromo-15,21-dimethyl-23-oxo-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,27}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (INT-A9-9). To a stirred solution of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-6-azabicyclo[3.2.1]oct-6-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (70 mg, 0.12 mmol, 1 equiv) in dioxane (2 mL) was added at room temperature N,N-Diisopropylethylamine (45 mg, 0.35 mmol, 3 equivalents) and N,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (66 mg, 0.17 mmol, 1.5 equiv). After stirring at room temperature for 2 h, the reaction was quenched with water (80 mL), and the mixture was extracted with dichloromethane (2×80 mL). The combined organic layers were washed with brine (3×80 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC eluting with dichloromethane/methanol (20/1) to give 65 mg of 5-bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,27}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (INT-A9-9) (95%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺= 580.00. Step 10. Preparation of 15,21-dimethyl-5-(morpholin-4-yl)-23-oxo-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,27}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (Example A9). 5-Bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,27}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (50 mg, 0.09 mmol, 1 eq.), morpholine (30 mg, 0.34 mmol, 4 eq.) and BrettPhos Pd G ₃To a stirred mixture of 2-nitropropene (23 mg, 0.03 mmol, 0.3 equiv) in dioxane (3 mL) was added LiHMDS (0.34 mL, 0.34 mmol, 4 equiv) dropwise. The reaction mixture was stirred at 60 °C for 30 min. After cooling to room temperature, the reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 13 mg of 15,21-dimethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,27}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (Example A9) (25%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=585.35. ¹H NMR (CD ₃OD, 400 MHz) δ 1.63-1.69 (1H, m), 1.85-1.92 (2H, m), 2.02-2.08 (1H, m), 2.15 (1H, d), 2.26 (1H, q), 2.60-2.65 (1H, m), 2.82 (1H, d), 3.15-3.23 (4H, m), 3.39 (1H, m), 3.47-3.58 (2H, m), 3.68 (3H, s), 3.85 (3H, s), 3.90 (4H, t), 4.41-4.49 (3H, m), 4.61-4.68 (1H, m), 7.00 (1H, m), 7.25 (1H, d), 7.38 (1H, d), 8.20 (1H, s), 8.49 (1H, s), 9.05 (1H, d). Example A10 1,15,21-Trimethyl-5-(morpholin-4-yl)-23-oxo-2,9,11,15, 20,21,26-heptaazahexacyclo[24.3.1.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]tri-11-3,5,7,9,13,17(31),18(22),19-octaene-12,16-dione Step 1. Preparation of tert-butyl 3-((5-bromo-2-nitrophenyl)amino)-3-methylpiperidine-1-carboxylate (INT-A10-1). 4-bromo-2-fluoro-1-nitrobenzene (6.16 g, 27.99 mmol, 3 equivalents), K ₂CO ₃(3.8 g, 27.99 mmol, 3 equivalents) and tert-butyl 3-amino-3-methylpiperidine-1-carboxylate (2 g, 9.33 mmol, 1.00 equivalents) in N, N-The mixture in dimethylacetamide (40 mL) was stirred at 100 °C for 12 h under nitrogen atmosphere and then cooled to 25 °C. The reaction was quenched with water (300 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using petroleum ether/ethyl acetate (3/1) to give 3.5 g of tert-butyl 3-[(5-bromo-2-nitrophenyl)amino]-3-methylpiperidine-1-carboxylate (INT-A10-1) (91%) as a yellow oil. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.23 (9H, s), 1.44 (3H, s), 1.54 (2H, s), 1.64 (1H, s), 2.15 (1H, s), 2.78 (1H, s), 2.98 (1H , s), 3.88 (1H, s), 4.16-4.14 (1H, d), 6.86-6.93 (1H, m), 7.30 (1H, d), 8.04-7.98 (1H, d), 8.24 (1H, s ). Step 2. N-Preparation of (5-bromo-2-nitrophenyl)-3-methylpiperidin-3-amine (INT-A10-2). Trifluoroacetic acid (5 mL, 67.31 mmol, 7 equivalents) and tert-butyl 3-[(5-bromo-2-nitrophenyl)amino]-3-methylpiperidin-1-carboxylate (3.5 g, 8.44 mmol, 1 equivalent) were mixed in CH₂Cl ₂The mixture in 4% paraformaldehyde (15 mL) was stirred at room temperature under nitrogen atmosphere for 2 h and concentrated under reduced pressure. The residue was treated with saturated NaHCO₃(aqueous solution) (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to obtain 2.4 g of a yellow solid.N-(5-bromo-2-nitrophenyl)-3-methylpiperidin-3-amine (INT-A10-2) (89%). ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.51 (3H, s), 1.85-1.83 (3H, m), 2.03-2.0 (1H, t), 2.92-2.89 (1H, m), 3.09-3.05 (1H, d), 3.17-3.14 (1H, m), 3.85-3.82 (1H, d), 6.96-6.95 (1H, m), 7.34-7.31 (1H, d), 8.07-8.05 (1H, d), 8.18 (1H, s) Step 3. NPreparation of -(5-bromo-2-nitrophenyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methylpiperidin-3-amine (INT-A10-3). In a nitrogen atmosphere at 0°C to N-(5-bromo-2-nitrophenyl)-3-methylpiperidin-3-amine (1 g, 3.81 mmol, 1 equiv), 2-[(tert-butyldimethylsilyl)oxy]acetaldehyde (2 g, 15.27 mmol, 4 equiv) and trimethylamine (1.5 g, 15.27 mmol, 4 equiv) in CH ₂Cl ₂(50 mL) was added to the stirred mixture. ₃(1.6 g, 7.63 mmol, 2 equiv.). The mixture was stirred at room temperature for 2 h. The reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (5/2) to give 840 mg of yellow oil.N-(5-bromo-2-nitrophenyl)-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methylpiperidin-3-amine (INT-A10-3) (46%). ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.06 (6H, s), 0.86 (9H, s), 1.28-1.25 (1H, td), 1.39 (5H, s), 2.00-2.17 (2H, m), 2.23-2.20 (1H, d), 2.83-2.81 (1H, d), 2.93-2.9 (1H, d), 3.77-3.74(2H, td), 6.82-6.80 (1H, m), 7.22-7.19 (1H, d), 8.01-7.98 (1H, d), 8.78 (1H, s). Step 4. Preparation of 2-(3-((5-bromo-2-nitrophenyl)amino)-3-methylpiperidin-1-yl)ethan-1-ol (INT-A10-4).NA mixture of -(5-bromo-2-nitrophenyl)-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methylpiperidin-3-amine (700 mg, 1.48 mmol, 1 equiv) and tetrabutylammonium fluoride (774.7 mg, 2.96 mmol, 2.0 equiv) in tetrahydrofuran (7 mL) was stirred at room temperature under nitrogen atmosphere for 4 h. The reaction mixture was treated with water (30 mL) and extracted with dichloromethane (3×30 mL). The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-TLC using CH₂Cl ₂/methanol (12/1) for purification to obtain 500 mg of 2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylpiperidin-1-yl}ethanol (INT-A10-4) (94%) as a brown solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.19-1.16 (1H, t), 1.29-1.26 (1H, t), 1.41 (4H, s), 1.98-2.13 (3H, m), 2.25-2.23 (1H, d), 2.85-2.83 (2H, d), 3.59-3.57 (2H, t), 4.40-4.36 (1H, t), 6.83-6.80 (1H, d), 7.23-7.21 (1H, d), 8.03-8.01 (1H, d), 8.80 (1H, s). Step 5. Preparation of methyl 5-[5-(2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylpiperidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A10-5). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 350 mg, 1.33 mmol, 1 eq.) and triphenylphosphine (1046 mg, 3.99 mmol, 3 eq.) in tetrahydrofuran (10 mL) was added diisopropyl azodicarboxylate (806 mg, 3.99 mmol, 3 eq.) and 2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylpiperidin-1-yl}ethanol (523 mg, 1.463 mmol, 1.1 eq.) at 0 °C under nitrogen atmosphere. The mixture was stirred for 2 h. The reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by C18 FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to dryness to give 450 mg of 5-[5-(2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylpiperidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A10-5) (56%) as a yellow solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.41 (6H, s), 2.06-2.29 (3H, m), 2.74-2.94 (3H, m), 3.58 (3H, s), 3.69 (3H, s), 3.76 (3H, s), 4.10-4.06 (2H, m), 6.83-6.78 (1H, d), 7.23-7.20 (1H, d), 7.95 (1H, s), 8.01-7.98 (1H, d), 8.11-8.02 (1H, d), 8.44 (1H, d), 8.74 (1H, s). Step 6. Preparation of 5-(5-(2-(3-((2-amino-5-bromophenyl)amino)-3-methylpiperidin-1-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A10-6). 5-[5-(2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylpiperidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A10-5, 430 mg, 0.71 mmol, 1 equivalent), ranyl nickel (61 mg, 0.71 mmol, 1 equivalent) and NH ₂NH ₂ ^.H ₂A mixture of 1,4-dihydro-2-nitropropene (71 mg, 1.42 mmol, 2 equiv.) in methanol (6 mL) was stirred at 0 °C under nitrogen atmosphere for 0.5 h. The resulting mixture was filtered. The filter cake was washed with methanol (50 mL). The solution was concentrated under reduced pressure to give 340 mg of 5-[5-(2-{3-[(2-amino-5-bromophenyl)amino]-3-methylpiperidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A10-6) (83%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=573.20. Step 7. Preparation of 5-(5-(2-(3-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-3-methylpiperidin-1-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A10-7). A mixture of methyl 5-[5-(2-{3-[(2-amino-5-bromophenyl)amino]-3-methylpiperidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (340 mg, 0.59 mmol, 1 eq.) and BrCN (69 mg, 0.65 mmol, 1.1 eq.) in EtOH (5 mL) was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by prep-TLC using CH₂Cl ₂/methanol (12/1) for purification to obtain 300 mg of 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylpiperidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A10-7) (84%) as a brown solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.85-0.84 (1H, m), 0.98-1.09 (1H, m), 1.25-1.23 (4H, m), 1.49-1.47 (1H, m), 1.59 (4H, s), 2.20-2.07 (1H, m), 2.44-2.40 (1H, d), 2.79-2.67 (2H, m), 2.94-2.90 (1H, m), 3.15-3.12 (2H, m), 3.59 (3H, s), 3.71 (3H, s), 3.76 (3H, s), 4.21-4.06 (2H, m), 7.03-7.12 (2H, m), 7.35 (2H, s), 7.50-7.45 (1H, d), 7.95 (1H, s), 8.11-8.05 (1H, d), 8.47-8.45 (1H, d). Step 8. Preparation of 5-(5-(2-(3-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-3-methylpiperidin-1-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (INT-A10-8). 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylpiperidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (290 mg, 0.48 mmol, 1 equivalent) and LiOH ^.H ₂O (40 mg, 0.970 mmol, 2 eq.) in THF/H ₂O (2 mL/0.5 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 230 mg of 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylpiperidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A10-8) (81%) as a brown solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 1.21-1.31 (1H, m), 1.49 (1H, t), 1.58 (4H, s), 2.14 (1H, t), 2.42 (1H, d), 2.70-2.84 (2H, m), 2.87-2.98 (1H, m), 3.13 (1H, d), 3.50 (3H, s), 3.69 (3H, s), 4.04-4.17 (2H, m), 7.08 (2H, d), 7.48 (1H, s), 7.54 (2H, s), 7.88 (1H, s), 7.99 (1H, t), 8.18 (1H, d). Step 9. Preparation of 5-bromo-1,15,21-trimethyl-23-oxa-2,9,11,15,20,21,26-heptaazahexacyclo[24.3.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontene-3,5,7,9,13,17(31),18(22),19-octaene-12,16-dione (INT-A10-9). 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylpiperidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (230 mg, 0.39 mmol, 1 equivalent), N,N-Diisopropylethylamine (152.58 mg, 1.182 mmol, 3 equivalents) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (224.44 mg, 0.59 mmol, 1.5 eq.) in dioxane (5 mL) was stirred at 60° C. for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by P\prep-TLC using dichloromethane/methanol (10/1) to give 180 mg of 5-bromo-1,15,21-trimethyl-23-oxa-2,9,11,15,20,21,26-heptaazahexacyclo[24.3.1.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]triacontene-3,5,7,9,13,17(31),18(22),19-octaene-12,16-dione (INT-A10-9) (80%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=566.10. Step 10. Preparation of 1,15,21-trimethyl-5-(morpholin-4-yl)-23-oxo-2,9,11,15,20,21,26-heptaazahexacyclo[24.3.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontene-3,5,7,9,13,17(31),18(22),19-octaene-12,16-dione (Example A10). In a nitrogen atmosphere at room temperature, 5-bromo-1,15,21-trimethyl-23-oxa-2,9,11,15,20,21,26-heptaazahexacyclo[24.3.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tri-undecene-3,5,7,9,13,17(31),18(22),19-octaene-12,16-dione (90 mg, 0.16 mmol, 1 equivalent), BrettPhos Pd G ₃To a stirred mixture of 2-nitropropene (43 mg, 0.05 mmol, 0.3 equiv.) and morpholine (55 mg, 0.63 mmol, 4 equiv.) in dioxane (4 mL) was added LiHMDS (0.95 mL, 0.95 mmol, 6.0 equiv.). The mixture was stirred at 60 °C for 1 h, cooled to room temperature, treated with water (30 mL), and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃+ 0.1%NH ₃ ^.H ₂O was used for purification with water and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 12 mg of 1,15,21-trimethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazahexacyclo[24.3.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tri-undecene-3,5,7,9,13,17(31),18(22),19-octaene-12,16-dione (Example A10) as a white solid (13%). LCMS: m/z (ESI), [M+H] ⁺=573.50. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.89-1.85 (5H, m), 2.12-2.08 (1H, m), 2.30 (1H, s), 2.72-2.69 (1H, m), 2.92 (1H, d), 3.08-3.06 (3H, m), 3.29 (2H, s), 3.62 (3H, s), 3.72 (2H, s), 3.76-3.74 (3H, m), 4.62 (1H, t), 5.42-5.40 (1H, d), 6.93-6.90 (1H, m), 7.32 (1H, d), 7.48 (1H, d), 8.21-8.37 (1H, m), 8.74 (1H, d), 12.80 (1H, s). Example A11 5,13,27-Trimethyl-17-(morpholin-4-yl)-7-oxa-4,5,10,14,21,23,27-heptaazahexacyclo[23.3.1.1^{10,13}.0^{2,6}.0^{14,22}.0^{15, 20}]triazine-1(29),2(6),3,15,17,19,21,25-octaene-24,28-dione Step 1. Preparation of tert-butyl 3-[(5-bromo-2-nitrophenyl)amino]-3-methylpyrrolidine-1-carboxylate (INT-A11-1). 4-bromo-2-fluoro-1-nitrobenzene (2 g, 9.1 mmol, 3 equivalents), K ₂CO ₃A mixture of tert-butyl 3-amino-3-methylpyrrolidine-1-carboxylate (1.26 g, 9.09 mmol, 3 equiv.) and tert-butyl 3-amino-3-methylpyrrolidine-1-carboxylate (0.61 g, 3.03 mmol, 1 equiv.) in acetonitrile (20 mL) was stirred at 100 °C for 2 h under nitrogen atmosphere and cooled to room temperature. The reaction was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (4/1) to give 1.2 g of tert-butyl 3-[(5-bromo-2-nitrophenyl)amino]-3-methylpyrrolidine-1-carboxylate (INT-A11-1) (80%) as a yellow solid. LCMS: m/z (ES+), [M+H - 56] ⁺=344.00. Step 2. N-Preparation of (5-bromo-2-nitrophenyl)-3-methylpyrrolidin-3-amine (INT-A11-2). A mixture of tert-butyl 3-[(5-bromo-2-nitrophenyl)amino]-3-methylpyrrolidine-1-carboxylate (2.1 g, 5.25 mmol, 1 equiv) in trifluoroacetic acid (4 mL) and dichloromethane (16 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure and treated with saturated NaHCO₃(aqueous solution) solution (100 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 1.3 g of yellow solid.N-(5-bromo-2-nitrophenyl)-3-methylpyrrolidin-3-amine (INT-A11-2) (74%). LCMS: m/z (ES+), [M+H] ⁺=300.20. Step 3. NPreparation of -(5-bromo-2-nitrophenyl)-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methylpyrrolidin-3-amine (INT-A11-3). In a nitrogen atmosphere at room temperature to NTo a stirred solution of -(5-bromo-2-nitrophenyl)-3-methylpyrrolidin-3-amine (1.2 g, 4 mmol, 1 eq.) and 2-[(tert-butyldimethylsilyl)oxy]acetaldehyde (2.8 g, 16 mmol, 4 eq.) in dichloromethane (10 mL) were added trimethylamine (1.62 g, 16 mmol, 4 eq.) and NaBH(OAc) ₃(1.69 g, 8 mmol, 2 equiv.). The resulting mixture was stirred at 60 °C overnight and cooled to room temperature. The reaction was quenched with water (10 mL), and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×10 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O was purified using water and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 1.24 g of yellow oil.N-(5-bromo-2-nitrophenyl)-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methylpyrrolidin-3-amine (INT-A11-3) (61%). LCMS: m/z (ES+), [M+H] ⁺=458.50 Step 4. Preparation of 2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylpyrrolidin-1-yl}ethanol (INT-A11-4).NA mixture of -(5-bromo-2-nitrophenyl)-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methylpyrrolidin-3-amine (1.24 g, 2.71 mmol, 1 equiv) and tetrabutylammonium fluoride (1.41 g, 5.41 mmol, 2 equiv) in tetrahydrofuran (12 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was heated with saturated NaHCO₃(aqueous solution) solution (50 mL) was quenched at room temperature, and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 800 mg of 2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylpyrrolidin-1-yl}ethanol (INT-A11-4) (69%) as a yellow oil. LCMS: m/z (ES+), [M+H] ⁺= 344.00. Step 5. Preparation of 5-[5-(2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylpyrrolidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A11-5). To a stirred mixture of 2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylpyrrolidin-1-yl}ethanol (800 mg, 2.32 mmol, 1 eq) and triphenylphosphine (1829 mg, 7 mmol, 3 eq) in tetrahydrofuran (15 mL) was added methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 611 mg, 2.32 mmol, 1.0 eq) and diisopropyl azodicarboxylate (1410 mg, 7 mmol, 3 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 380 mg of 5-[5-(2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylpyrrolidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A11-5) (25%) as a yellow oil. LCMS: m/z (ES+), [M+H] ⁺=589.00. Step 6. Preparation of 5-[5-(2-{3-[(2-amino-5-bromophenyl)amino]-3-methylpyrrolidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A11-6). To a stirred mixture of 5-[5-(2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylpyrrolidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (380 mg, 0.65 mmol, 1 eq.) and ranyl nickel (55.23 mg, 0.65 mmol, 1 eq.) in methanol (6 mL) was added dropwise NH ₂NH ₂ ^.H ₂O (129.09 mg, 2.58 mmol, 4 equiv.). The resulting mixture was stirred at room temperature for 1.5 h. The reaction was quenched with water (30 mL), and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane/methanol (25/1) to give 240 mg of 5-[5-(2-{3-[(2-amino-5-bromophenyl)amino]-3-methylpyrrolidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A11-6) (67%) as a brown solid. LCMS: m/z (ES+), [M+H] ⁺=559.05. Step 7. Preparation of 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylpyrrolidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A11-7). To a stirred mixture of 5-[5-(2-{3-[(2-amino-5-bromophenyl)amino]-3-methylpyrrolidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (193 mg, 0.35 mmol, 1 eq.) in ethanol (10 mL) was added BrCN (40.19 mg, 0.38 mmol, 1.1 eq.) in portions at room temperature. The resulting mixture was stirred at 40 °C for 1 h. The mixture was cooled to room temperature. The reaction was quenched with water (30 mL), and the mixture was extracted with dichloromethane (3×30 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (12/1) to give 140 mg of 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylpyrrolidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A11-7) (69%) as a brown solid. LCMS: m/z (ES+), [M+H] ⁺=586.00. ¹H NMR (400 MHz, DMSO- d ₆) δ 1.24 (1H, s), 1.65 (3H, s), 2.35-2.48 (2H, m), 2.69-2.73 (1H, m), 2.80-2.90 (2H, m), 2.94-2.98 (1H, m), 3.18-3.22 (1H, m), 3.58 (3H, s), 3.75 (6H, d), 4.08-4.15 (2H, m), 6.52 (1H, s), 7.07 (1H, s), 7.43 (1H, s), 7.97 (1H, s), 8.13 (1H, d), 8.44 (1H, d). Step 8. Preparation of 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylpyrrolidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A11-8). 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylpyrrolidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (170 mg, 0.29 mmol, 1 equivalent) and LiOH ^.H ₂A mixture of O (50 mg, 1.16 mmol, 4 equiv.) in tetrahydrofuran (4 mL) and water (1 mL) was stirred at room temperature overnight under a nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 90 mg of 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylpyrrolidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A11-8) (54%) as a white solid. LCMS: m/z (ES+), [M+H] ⁺=572.35. Step 9. Preparation of 17-bromo-5,13,27-trimethyl-7-oxa-4,5,10,14,21, 23,27-heptaazahexacyclo[23.3.1.1^{10,13}.0^{2,6}.0^{14,22}. 0^{15,20}]triaconta-1(29),2(6),3,15,17,19,21,25-octaene-24,28-dione (INT-A11-9). 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylpyrrolidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (90 mg, 0.18 mmol, 1 equivalent), N,N-Diisopropylethylamine (45 mg, 0.35 mmol, 2 equivalents) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)urea hexafluorophosphate (133 mg, 0.35 mmol, 2 equiv.) in dioxane (3 mL) was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water (30 mL), and the mixture was extracted with dichloromethane (3×30 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (12/1) to give 70 mg of 17-bromo-5,13,27-trimethyl-7-oxa-4,5,10,14,21,23,27-heptaazahexacyclo[23.3.1.1^{10, 13}.0^{2,6}.0^{14,22}.0^{15,20}]triac-1(29),2(6),3,15,17, 19,21,25-octaene-24,28-dione (INT-A11-9) (72%) as a white solid. LCMS: m/z (ES+), [M+H] ⁺=554.00. Step 10. Preparation of 5,13,27-trimethyl-17-(morpholin-4-yl)-7-oxa-4,5, 10,14,21,23,27-heptaazahexacyclo[23.3.1.1^{10,13}.0^{2,6}.0^{14,22}.0^{15,20}]tris-1(29),2(6),3,15,17,19,21,25-octaene-24,28-dione (Example A11). To a stirred mixture of 17-bromo-5,13,27-trimethyl-7-oxa-4,5,10,14,21,23,27-heptaazahexacyclo[23.3.1.1^{10,13}.0^{2,6}.0^{14,22}.0^{15,20}]triaconta-1(29),2(6),3,15,17,19,21,25-octaene-24,28-dione (70 mg, 0.13 mmol, 1 eq), BrettPhos (35 mg, 0.065 mmol, 0.5 eq) and morpholine (35 mg, 0.40 mmol, 3.2 eq) in dioxane (5 mL) was added LiHMDS (2.5 mL, 2.5 mmol, 19 eq) dropwise at room temperature under nitrogen atmosphere. The mixture was stirred at 60 °C for 1 h under nitrogen atmosphere and then cooled to room temperature. The reaction was quenched with water (5 mL), and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×20 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 10.8 mg of 5,13,27-trimethyl-17-(morpholin-4-yl)-7-oxa-4,5,10,14,21,23,27-heptaazahexacyclo[23.3.1.1^{10,13}.0^{2,6}.0^{14,22}.0^{15,20}]triazine-1(29),2(6),3,15,17,19, 21,25-octaene-24,28-dione (Example A11) (15%) as an off-white solid. LCMS: m/z (ES+), [M+H] ⁺=559.20. ¹H NMR (DMSO- d ₆, 400 MHz) δ 1.65 (3H, s), 2.65-2.84 (3H, m), 2.97-3.03 (2H, m), 3.01-3.24 (4H, m), 3.31-3.37 (1H, m), 3.62 (3H, s), 3.75 (3H, s), 3.77-3.83 (5H, m), 4.14-4.20 (1H, m), 4.35-4.40 (1H, m), 5.16 (1H, d), 6.93 (1H, dd), 6.98 (1H, s), 7.45 (1H, d), 8.22 (1H, d), 8.31 (1H, s), 8.89 (1H, d), 12.63 (1H, s). Example A12 15,21,27,27-Tetramethyl-5-(morpholin-4-yl)-23-oxo-2,9,11,15, 20,21,26-heptaazahexacyclo[24.3.1.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]tri-11-3,5,7,9,13,17(31),18(22),19-octaene-12,16-dione Step 1. NPreparation of tert-butyl-(6,6-dimethylpiperidin-3-yl)carbamate (INT-A12-1).NA solution of tert-butyl-(6-oxopiperidin-3-yl)carbamate (4 g, 18.66 mmol, 1 eq.) in THF (50 mL) was treated with zirconium tetrachloride (10.44 g, 44.80 mmol, 2.4 eq.) at 10 °C under nitrogen atmosphere for 0.5 h, followed by the dropwise addition of CH ₃MgBr (28.94 g, 242.68 mmol, 13 equiv). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The reaction was quenched with water (500 mL), and the mixture was extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with brine (3×400 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by silica gel chromatography eluting with dichloromethane/methanol (30/1) to give 3.74 g of a yellow solid.N-(6,6-dimethylpiperidin-3-yl)carbamic acid tert-butyl ester (INT-A12-1) (87%). LCMS: m/z (ESI), [M+H] ⁺=229.05. Step 2. NPreparation of tert-butyl-(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-6,6-dimethylpiperidin-3-yl)carbamate (INT-A12-2). At room temperature,N-(6,6-dimethylpiperidin-3-yl)carbamic acid tert-butyl ester (INT-A12-1, 234 mg, 1.02 mmol, 1 equivalent) and K ₂CO ₃(354 mg, 2.56 mmol, 2.5 equiv) was added dropwise to a stirred mixture of (2-bromomethoxy)(tert-butyl)dimethylsilane (294 mg, 1.23 mmol, 1.2 equiv) in DMSO (10 mL). The reaction mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction mixture was treated with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (10/1) to give 128 mg of yellow oil.N-tert-Butyl (1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-6,6-dimethylpiperidin-3-yl)carbamate (INT-A12-2) (32%). LCMS: m/z (ESI), [M+H] ⁺=387.15. Step 3. Preparation of 2-(5-amino-2,2-dimethylpiperidin-1-yl)ethanol (INT-A12-3). NA solution of tert-butyl-(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-6,6-dimethylpiperidin-3-yl)carbamate (INT-A12-2, 20 g, 50 mmol, 1 equivalent) and trifluoroacetic acid (60 mL) in dichloromethane (200 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product 2-(5-amino-2,2-dimethylpiperidin-1-yl)ethanol (INT-A12-3) as a yellow oil was directly used in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺=173.00. Step 4. Preparation of 2-{5-[(5-bromo-2-nitrophenyl)amino]-2,2-dimethylpiperidin-1-yl}ethanol (INT-A12-4). 2-(5-amino-2,2-dimethylpiperidin-1-yl)ethanol (crude product, INT-A12-3), 4-bromo-2-fluoro-1-nitrobenzene (10.33 g, 60 mmol, 1.2 equivalents) and K ₂CO ₃(20.67 g, 52.24 mmol, 3 equiv.) in acetonitrile (150 mL) was stirred at 60 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (800 mL), and the mixture was extracted with ethyl acetate (3×600 mL). The combined organic layers were washed with brine (3×600 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (5/1) to give 9.3 g of 2-{5-[(5-bromo-2-nitrophenyl)amino]-2,2-dimethylpiperidin-1-yl}ethanol (INT-A12-4) (41%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=374.05. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.99 (3H, s), 1.05 (3H, s), 1.26-1.46 (2H, m), 1.63-1.70 (2H, m), 2.17-2.25 (1H, m), 2.50-2.60 (3H, m), 3.42 (2H, q), 3.86-3.92 (1H, m), 4.32 (1H, t), 6.76-7.82 (1H, m), 7.27 (1H, d), 8.00 (1H, d), 8.60 (1H, d). Step 5. Preparation of methyl 5-[5-(2-{5-[(5-bromo-2-nitrophenyl)amino]-2,2-dimethylpiperidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A12-5). A mixture of 2-{5-[(5-bromo-2-nitrophenyl)amino]-2,2-dimethylpiperidin-1-yl}ethanol (INT-A12-4, 350 mg, 0.94 mmol, 1 eq), methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 247 mg, 0.94 mmol, 1 eq) and 2-(tributyl-1^[5]-phosphinilidene)acetonitrile (1.13 g, 4.70 mmol, 5 eq) in toluene (8 mL) was stirred at 100 °C for 3 h. After cooling to room temperature, the reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by reverse phase flash chromatography using 10%-50% acetonitrile/water to give 350 mg of 5-[5-(2-{5-[(5-bromo-2-nitrophenyl)amino]-2,2-dimethylpiperidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A12-5) (60%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=617.20. Step 6. Preparation of 5-[5-(2-{5-[(2-amino-5-bromophenyl)amino]-2,2-dimethylpiperidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A12-6). A mixture of 5-[5-(2-{5-[(5-bromo-2-nitrophenyl)amino]-2,2-dimethylpiperidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A12-5, 400 mg, 0.64 mmol, 1 eq.), ranyl nickel (5 mg, 0.15 mmol, 0.5 eq.) and hydrazine (62 mg, 1.94 mmol, 3 eq.) in methanol (10 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (20/1) to give 350 mg of 5-[5-(2-{5-[(2-amino-5-bromophenyl)amino]-2,2-dimethylpiperidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A12-6) (91%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=589.35. Step 7. Preparation of 5-(5-{2-[5-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-2,2-dimethylpiperidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A12-7). A mixture of methyl 5-[5-(2-{5-[(2-amino-5-bromophenyl)amino]-2,2-dimethylpiperidin-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A12-6, 350 mg, 0.59 mmol, 1 eq.) and cyanogen bromide (69 mg, 0.65 mmol, 1.1 eq.) in EtOH (10 mL) was stirred at room temperature under nitrogen atmosphere for 3 h. The reaction mixture was treated with saturated NaHCO₃solution (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (20/1) to give 350 mg of 5-(5-{2-[5-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-2,2-dimethylpiperidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A12-7) (95%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=614.05. Step 8. Preparation of 5-(5-{2-[5-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-2,2-dimethylpiperidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A12-8). To a stirred solution of 5-(5-{2-[5-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-2,2-dimethylpiperidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A12-7, 240 mg, 0.39 mmol, 1 eq.) in tetrahydrofuran (4 mL) was added lithium hydroxide (28 mg, 1.17 mmol, 3 eq.) in H ₂O (1 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography using 10% to 40% acetonitrile/water elution to give 190 mg of 5-(5-{2-[5-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-2,2-dimethylpiperidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A12-8) (81%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=598.30. Step 9. Preparation of 5-bromo-15,21,27,27-tetramethyl-23-oxa-2,9,11,15,20,21,26-heptaazahexacyclo[24.3.1.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]triacontene-3,5,7,9,13,17(31),18(22),19-octaene-12,16-dione (INT-A12-9). 5-(5-{2-[5-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-2,2-dimethylpiperidin-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A12-8, 190 mg, 0.31 mmol, 1 equivalent), N,N-Diisopropylethylamine (82 mg, 0.63 mmol, 2 equivalents) and N,N,N,N-Tetramethyl- OA solution of -(7-azabenzotriazol-1-yl)urea hexafluorophosphate (181 mg, 0.47 mmol, 1.5 equiv) in dioxane (5 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (20/1) to give 100 mg of 5-bromo-15,21,27,27-tetramethyl-23-oxa-2,9,11,15,20,21,26-heptaazahexacyclo[24.3.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontene-3,5,7,9,13,17(31),18(22),19-octaene-12,16-dione (INT-A12-9) (27%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=580.35. Step 10. Preparation of 15,21,27,27-tetramethyl-5-(morpholin-4-yl)-23-oxo-2,9,11,15,20,21,26-heptaazahexacyclo[24.3.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontene-3,5,7,9,13,17(31),18(22),19-octaene-12,16-dione (Example A12). 5-Bromo-15,21,27,27-tetramethyl-23-oxa-2,9,11,15,20,21,26-heptaazahexacyclo[24.3.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontene-3,5,7,9,13,17(31),18(22),19-octaene-12,16-dione (INT-A12-9, 60 mg, 0.10 mmol, 1 equiv), morpholine (36 mg, 0.41 mmol, 4 equiv) and BrettPhos Pd G ₃To a stirred mixture of 46 mg, 0.05 mmol, 0.5 equiv.) in dioxane (3 mL) was added LiHMDS (0.5 mL, 0.51 mmol, 5 equiv.) dropwise. The reaction mixture was stirred at 60 °C under nitrogen atmosphere for 1 h. After cooling to room temperature, the reaction was heated with saturated NH₄Cl solution (50 mL), and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (18/1). The product was purified by prep-HPLC using an XBridge Shield RP18 OBD column containing 10 mmol/L NH₄HCO and 0.1% NH ₃ ^.H ₂The mixture was further purified by using water and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 8.9 mg of 515,21,27,27-tetramethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazahexacyclo[24.3.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tri-11-3,5,7,9,13,17(31), 18(22),19-octaene-12,16-dione (Example A12) as a white solid (14%). LCMS: m/z (ESI), [M+H] ⁺=587.40. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.12 (3H, s), 1.20-1.28 (1H, m), 1.30 (3H, s), 1.61-1.85 (2H, m), 2.17-2.29 (2H, m), 2.42 (1H, t), 3.05-3.18 (4H, m), 3.39-3.60 (3H, m), 3.62 (3H, s), 3.69 (3H, s), 3.78 (4H, t), 4.48-4.69 (2H, m), 6.87-6.94 (1H, m), 7.18 (1H, s), 7.43 (1H, d), 8.29 (1H, s), 8.37 (1H, s), 8.80 (1H, d), 11.81-12.75 (1H, m) Example A13 1,15,21-Trimethyl-5-(morpholin-4-yl)-23-oxo-2,9,11,15,20, 21,26-heptaazahexacyclo[24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18, 22}]triacontidine-3,5,7,9,13,17(32),18(22),19-octaene-12,16-dione Step 1. Preparation of 1-benzyl-3-methylazacycloheptan-3-ol (INT-A13-1). To a stirred mixture of 1-benzylazacycloheptan-3-one (3.0 g, 14.75 mmol, 1 eq.) in tetrahydrofuran (30 mL) was added MeMgBr (10.5 g, 88.54 mmol, 6 eq.) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred at 60 °C for 2 h. The reaction was heated with saturated NH₄Cl(aq) solution (300 mL) was quenched, and the mixture was extracted with dichloromethane (3×300 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to give 3.1 g of 1-benzyl-3-methylazacycloheptan-3-ol (INT-A13-1) as a brown oil. This material was used in the next reaction without purification. LCMS: m/z (ESI), [M+H] ⁺=220.05. Step 2. N- Preparation of (1-benzyl-3-methylazacycloheptan-3-yl)acetamide (INT-A13-2). To a stirred mixture of 1-benzyl-3-methylazacycloheptan-3-ol (3.1 g, about 14 mmol, about 1 equivalent) in acetonitrile (30 mL) was added dropwise fumed H ₂SO ₄(2.5 g, 14.13 mmol, 1 eq.). The mixture was stirred for 2 h. The reaction was quenched with water (300 mL) at room temperature. The mixture was treated with K ₂CO ₃Adjust to pH 9 and extract with dichloromethane (3×300 mL). Wash the combined organic layers with brine (3×300 mL) and precipitate with anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to obtain 1.1 g of a brown solid.N-(1-Benzyl-3-methylazacyclohept-3-yl)acetamide (INT-A13-2). ¹H NMR (400 MHz, DMSO-d ₆) δ 1.18 (3H, s), 1.35-1.67 (5H, m), 1.72 (3H, s), 1.90-2.00 (1H, m), 2.61 (1H, d), 2.87 (1H, d), 3.61 (2H, d), 7.20-7.37 (5H, m). Step 3. N-(3-methylazacycloheptyl-3-yl)acetamide (INT-A13-3). NA mixture of -(1-benzyl-3-methylazacyclohept-3-yl)acetamide (INT-A13-2, 1.1 g, 4.22 mmol, 1 eq.) and Pd/C (0.4 g, 4.22 mmol, 1 eq.) in methanol (10 mL) was stirred at room temperature overnight under nitrogen atmosphere. The mixture was filtered. The filter cake was washed with methanol (3×100 mL). The resulting solution was concentrated under reduced pressure. The crude product was directly used in the next step without further purification. ¹H NMR (400 MHz, DMSO-d ₆) δ 1.20 (3H, s), 1.32-1.58 (5H, m), 1.78 (3H, s), 1.90-2.10 (1H, m), 2.61 (1H, d), 2.65-2.77 (2H, m), 2.85 (1H, d), 7.23 (1H, s). Step 4. N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methylazinecyclohept-3-yl)acetamide (INT-A13-4). To N-(3-Methylazacyclohept-3-yl)acetamide (400 mg, about 2.3 mmol, 1 equivalent) and (2-bromoethoxy)(tert-butyl)dimethylsilane (1124 mg, 4.69 mmol, 2 equivalents) were added to N,N-Dimethylformamide (8 mL) was added to the stirred mixture.₂CO ₃(649.4 mg, 4.69 mmol, 2 eq.) and NaI (704 mg, 4.69 mmol, 2 eq.). The mixture was stirred at 60 °C for 2 h and then cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by C18FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to dryness to give 750 mg N-(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methylazacyclohept-3-yl)acetamide (INT-A13-4) (96%). ¹H NMR (400 MHz, DMSO-d ₆) δ 0.01 (6H, s), 0.83 (9H, s), 1.19 (3H, s), 1.28-1.62 (6H, m), 1.73 (3H, s), 1.86 (1H, d), 2.51-2.64 (5H, m), 2.72-2.80 (1H, m), 3.55-3.63 (2H, m). Step 5. Preparation of 2-(3-amino-3-methylazinocycloheptan-1-yl)ethanol (INT-A13-5). NA mixture of 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methylazacycloheptan-3-yl)acetamide (1.4 g, 4.26 mmol, 1 eq.) and HCl (6 M) (140 mL, 460.77 mmol, 108 eq.) was stirred at 100 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give 500 mg of 2-(3-amino-3-methylazacycloheptan-1-yl)ethanol (INT-A13-5) as a brown oil. ¹H NMR (400 MHz, DMSO-d ₆) δ 1.11-1.39 (3H, m), 1.48 (2H, d), 1.70 (1H, d), 1.76-2.08 (6H, m), 2.19 (1H, t), 3.18 (2H, t), 3.34-3.52 (1H, m), 3.52-3.95 (6H, m), 8.64 (2H, s). Step 6. Preparation of 2-(3-((5-bromo-2-nitrophenyl)amino)-3-methylazinocycloheptan-1-yl)ethanol (INT-A13-6). To a stirred mixture of 2-(3-amino-3-methylazinylcycloheptan-1-yl)ethanol (460 mg, 2.67 mmol, 1 eq) and 4-bromo-2-fluoro-1-nitrobenzene (1174 mg, 5.34 mmol, 2 eq) in acetonitrile (5 mL) was added K ₂CO ₃(738 mg, 5.34 mmol, 2 eq.). The mixture was stirred at 80 °C overnight and then cooled to room temperature. The reaction was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by silica gel chromatography using petroleum ether/ethyl acetate (1/10) to give 530 mg of 2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylazinocycloheptan-1-yl}ethanol (INT-A13-6) (53%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d ₆) δ 1.31-1.63 (7H, m), 1.64-1.77 (1H, m), 2.21 (1H, d), 2.58-2.86 (6H, m), 3.60 (2H, d), 4.44 (1H, t), 6.81 (1H, d), 7.41 (1H, d), 8.01 (1H, d), 9.07 (1H, s). Step 7. Preparation of 5-[5-(2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylazinocycloheptan-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A13-7). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 405 mg, 1.53 mmol, 1 eq.) and triphenylphosphine (1210 mg, 4.614 mmol, 3 eq.) in tetrahydrofuran (5 mL) was added diisopropyl azodicarboxylate (933 mg, 4.61 mmol, 3 eq.) and 2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylazanylcycloheptan-1-yl}ethanol (629 mg, 1.69 mmol, 1.1 eq.) at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 2 h. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to Prep-TLC using CH₂Cl ₂/methanol (10/1) for purification to obtain 550 mg of 5-[5-(2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylazinocyclohept-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A13-7) (57%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d ₆) δ 1.37 (3H, s), 1.44-1.50 (1H, m), 1.65-1.75 (1H, m), 2.17-2.25 (1H, m), 2.63-2.77 (2H, m), 2.83 (1H, s), 2.91 (1H, d), 3.10 (1H, d), 3.10-3.20 (1H, m), 3.33 (2H, s), 3.71 (6H, d), 4.06-4.22 (2H, m), 5.76 (1H, s), 6.80 (1H, d), 7.20-7.30 (2H, m), 7.33-7.50 (5H, m), 7.94 (1H, s), 7.98 (1H, d), 8.07 (1H, d), 8.40 (1H, d), 9.01 (1H, s). Step 8. Preparation of 5-(5-(2-(3-((2-amino-5-bromophenyl)amino)-3-methylazinocycloheptan-1-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A13-8). 5-[5-(2-{3-[(5-bromo-2-nitrophenyl)amino]-3-methylazinocyclohept-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (540 mg, 0.87 mmol, 1 equivalent), ranyl nickel (74 mg, 0.87 mmol, 1 equivalent) and NH ₂NH ₂ ^.H ₂A stirred mixture of 2-[4-[(2-amino-5-bromophenyl)amino]-3-methylazinocycloheptan-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A13-8) was stirred at 0 °C for 1 h under nitrogen atmosphere. The resulting mixture was filtered. The filter cake was washed with methanol (50 mL). The resulting solution was concentrated under reduced pressure to give 300 mg of 5-[5-(2-{3-[(2-amino-5-bromophenyl)amino]-3-methylazinocycloheptan-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A13-8) as a brown oil. This material was used in the next reaction without purification. LCMS: m/z (ESI), [M+H]+=589.20. Step 9. Preparation of methyl 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylazanol-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A13-9). A mixture of methyl 5-[5-(2-{3-[(2-amino-5-bromophenyl)amino]-3-methylazanol-1-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (280 mg, 0.47 mmol, 1 eq) and BrCN (50 mg, 0.47 mmol, 1 eq) in EtOH (4 mL) was stirred at 600° C. for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated by Prep-TLC using CH₂Cl ₂/methanol (10/1) for purification to obtain 210 mg of 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylazinocyclohept-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A13-9) (71%) as a brown oil. ¹H NMR (400 MHz, DMSO-d ₆) δ 1.19-1.23 (1H, m), 1.43-1.49 (1H, m), 1.60-1.64 (2H, m), 1.73-1.90 (5H, m), 2.65-2.81 (1H, m), 2.83-2.90 (1H, m), 2.90-3.05 (2H, m), 3.17 (3H, d), 3.55 (3H, s), 3.66 (3H, s), 3.74 (3H, s), 4.00-4.18 (3H, m), 6.95-7.11 (2H, m), 7.54 (1H, d), 7.70 (2H, s), 7.94 (1H, s), 8.06 (1H, d), 8.37 (1H, d). Step 10. Preparation of 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylazanyl-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A13-10). 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylazanyl-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (200 mg, 0.32 mmol, 1 eq.) and LiOH ^.H ₂O (27 mg, 0.65 mmol, 2 equivalents) in tetrahydrofuran/H ₂The mixture in 400 mL/mL was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by C18FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 150 mg of 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylazinocyclohept-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A13-10) (76%) as a brown solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 1.43-1.68 (2H, m), 1.81 (3H, d), 2.70-2.74 (1H, m), 2.82-3.02 (2H, m), 3.06-3.12 (1H, m), 3.38-3.44 (4H, m), 3.62 (2H, s), 3.97-4.10 (1H, m), 6.94-7.08 (1H, m), 7.54 (1H, d), 7.82 (1H, s), 7.88 (1H, s), 8.02 (1H, s), 8.16 (1H, d). Step 11. Preparation of 5-bromo-1,15,21-trimethyl-23-oxa-2,9,11,15,20, 21,26-heptaazahexacyclo[24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(32),18(22),19-octaene-12,16-dione (INT-A13-11). To a stirred mixture of 5-(5-{2-[3-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-methylazacyclohept-1-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (140 mg, 0.23 mmol, 1 eq.) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (133 mg, 0.35 mmol, 1.5 eq.) in dioxane (4 mL) was added under nitrogen atmosphere.N,N-Diisopropylethylamine (90 mg, 0.70 mmol, 3.0 equiv.). The resulting mixture was stirred at 60 °C for 2 h, cooled to room temperature, and concentrated under reduced pressure. The residue was treated with water (30 mL), and the mixture was extracted with dichloromethane (3×30 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to Prep-TLC using CH₂Cl ₂/methanol (12/1) for purification to obtain 100 mg of 5-bromo-1,15,21-trimethyl-23-oxa-2,9,11,15,20,21,26-heptaazahexacyclo[24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(32),18(22),19-octaene-12,16-dione (INT-A13-11) (73%) as a brown solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 1.23-1.29 (7H, m), 1.68-1.72 (2H, m), 1.78-1.86 (5H, m), 1.87-1.91 (1H, m), 2.02-2.13 (1H, m), 2.69 (3H, s), 3.10-3.21 (3H, m), 3.23 (1H, t), 3.41 (1H, d), 3.60-3.66 (4H, m), 3.72 (3H, s), 4.30-4.47 (3H, m), 7.35-7.44 (1H, m), 7.57 (1H, d), 7.69 (1H, d), 8.10 (1H, s), 8.30 (1H, d), 8.62 (1H, d), 13.06 (1H, s). Step 12. Preparation of 1,15,21-trimethyl-5-(morpholin-4-yl)-23-oxo-2,9, 11,15,20,21,26-heptaazahexacyclo[24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontidine-3,5,7,9,13,17(32),18(22),19-octaene-12,16-dione (Example A13). To 5-bromo-1,15,21-trimethyl-23-oxa-2,9,11,15,20,21,26-heptaazahexacyclo[24.4.1.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]triacontrine-3,5,7,9,13,17(32), 18(22),19-octaene-12,16-dione (90 mg, 0.15 mmol, 1 equivalent) and BrettPhos Pd G ₃To a stirred mixture of 1,4-dioxane (3 mL) and morpholine (54 mg, 0.62 mmol, 4 equiv.) (42 mg, 0.046 mmol, 0.3 equiv.) was added LiHMDS (0.93 mL, 0.93 mmol, 6 equiv.). The mixture was stirred at 60 °C for 1 h and then cooled to room temperature. The reaction was quenched with water (30 mL), and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to Prep-TLC using CH₂Cl ₂/methanol (25/1) for purification to obtain 25.8 mg of 1,15,21-trimethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazahexacyclo[24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(32),18(22),19-octaene-12,16-dione (A13) (28%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=587.40. ¹H NMR (400 MHz, DMSO-d ₆) δ 1.60-1.75 (3H, m) 1.80-1.88 (4H, s), 1.96-2.06 (1H, m), 2.57-2.67 (1H, m), 2.85-2.93 (1H, m), 2.95-3.09 (3H, m), 3.06-3.15 (2H, m), 3.21-3.29 (2H, m), 3.61 (3H, s), 3.70-3.80 (8H, m), 4.32 (1H, d), 4.39 (1H, t), 4.53 (1H, d), 6.94 (1H, d), 7.04 (1H, d), 7.49 (1H, d), 8.09 (1H, s), 8.26 (1H, d), 8.59 (1H, d), 12.85 (1H, s). Example A14 (11 R)-26-ethyl-5,11-dimethyl-16-(4-methylpiperazine-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. Preparation of 5-bromo-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A14-1). At 0°C, 5-bromo-6-hydroxypyridine-3-carboxylic acid methyl ester (10 g, 43.09 mmol, 1 equivalent) was added to N,NTo the stirred mixture in dimethylformamide (200 mL) was added NaH (3.45 g, 86.19 mmol, 2 eq., 60%). The reaction mixture was stirred at 60 °C for 30 min before the addition of ethyl iodide (10.08 g, 64.64 mmol, 1.5 eq.). The mixture was stirred for an additional 2 h at room temperature, treated with water (1 L), and extracted with ethyl acetate (3×1 L). The combined organic layers were washed with brine (3×1 L), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (3/1) to give 5 g of methyl 5-bromo-1-ethyl-6-oxopyridine-3-carboxylate (INT-A14-1) (37%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=261.90. ¹H NMR (400 MHz, DMSO-d ₆) δ 1.25 (3H, t), 3.81 (3H, s), 4.08 (2H, q), 8.17 (1H, d), 8.61 (1H, d) Step 2. Preparation of methyl-1-ethyl-5-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (INT-A14-2). 5-Bromo-1-ethyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A14-1, 2.0 g, 7.69 mmol, 1 equivalent), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (2.93 g, 11.53 mmol, 1.5 equivalent), Pd(dppf)Cl ₂A mixture of (0.56 g, 0.77 mmol, 0.1 eq.) and KOAc (2.26 g, 23.07 mmol, 3.0 eq.) in dioxane (25 mL) was stirred at 60 °C for 1 h under nitrogen atmosphere. The mixture was cooled to room temperature, followed by the addition of 4-iodo-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (2.72 g, 7.69 mmol, 1.0 eq.), Pd(dppf)Cl ₂(1.13 g, 1.54 mmol, 0.2 equivalent), K ₂CO ₃(3.19 g, 23.07 mmol, 3.0 equiv) and H ₂O (8 mL). The reaction mixture was stirred at 80 °C under nitrogen atmosphere for 2 h. After cooling to room temperature, the reaction was quenched with water (300 mL), and the mixture was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane/methanol (12/1) to give 1 g of methyl 1-ethyl-5-(2-methyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-6-oxopyridine-3-carboxylate (INT-A14-2) (31%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=408.15. ¹H NMR (400 MHz, DMSO-d ₆) δ 0.05 (9H, s), 0.78-0.86 (2H, m), 1.27 (3H, t), 3.37 (3H, s), 3.43-3.50 (2H, m), 3.82 (3H, s), 4.08-4.12 (2H, m), 5.32 (2H, s), 8.41 (1H, d), 8.87 (1H, s), 9.20 (1H, d). Step 3. Preparation of 1-ethyl-5-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A14-3). A mixture of methyl 1-ethyl-5-(2-methyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-6-oxopyridine-3-carboxylate (1.0 g, 2.45 mmol, 1 equiv) and HCl (10 mL, 4 M in 1,4-dioxane) was stirred at room temperature overnight. The mixture was concentrated under vacuum. The residue was washed with CH₂Cl ₂(20 mL) and saturated NaHCO ₃(aqueous solution) (50 mL). The resulting mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by reverse phase flash chromatography using 0% to 100% acetonitrile/water to give 520 mg of methyl 1-ethyl-5-(5-hydroxy-1-methylpyrazol-4-yl)-6-oxopyridine-3-carboxylate (INT-A14-3) (76%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=278.05. ¹H NMR (400 MHz, DMSO-d ₆) δ 1.29 (3H, t), 3.33 (3H, s), 3.84 (3H, s), 4.13-4.17 (2H, m), 7.96 (1H, s), 8.45 (2H, d), 12.72-13.41 (1H, br s). Step 4. Methyl-( RPreparation of )-5-(5-((5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-ethyl-6-oxopyridine-3-carboxylate (INT-A14-4). To a stirred mixture of 1-ethyl-5-(5-hydroxy-1-methylpyrazol-4-yl)-6-oxopyridine-3-carboxylic acid methyl ester (500 mg, 1.80 mmol, 1 equiv) and triphenylphosphine (1.41 g, 5.41 mmol, 3 equiv) in tetrahydrofuran (8 mL) at 0°C under nitrogen atmosphere were added diisopropyl azodicarboxylate (1.09 g, 5.41 mmol, 3 equiv) and (4 R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentan-1-ol (M3-7, 1.14 g, 3.60 mmol, 2.0 equiv.). The resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by reverse phase flash chromatography using 0% to 100% acetonitrile/water to give 370 mg of methyl-( R)-5-(5-((5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (INT-A14-4) (35%). LCMS: m/z (ESI), [M+H] ⁺=577.90. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.96 (3H, d), 1.27 (3H, t), 1.29-1.45 (1H, m), 1.58-1.64 (1H, m), 1.69-1.96 (3H, m), 3.16-3.27 (1H, m), 3.27-3.38 (1H, m), 3.68 (3H, s), 3.78 (3H, s), 3.96 (2H, t), 4.08 (2H, q), 6.80-6.86 (1H, m), 7.26 (1H, d), 7.95-8.02 (2H, m), 8.13 (1H, d), 8.21 (1H, t), 8.43 (1H, d) Step 5. ( RPreparation of methyl 5-(5-((5-((2-amino-5-bromophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (INT-A14-5). Raney nickel (53 mg, 0.62 mmol, 1 equivalent) and methyl-( R)-5-(5-((5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (INT-A14-4, 360 mg, 0.62 mmol, 1 equivalent) was added to a stirring mixture of methanol (5 mL) with NH ₂NH ₂ ^.H ₂O (62 mg, 1.25 mmol, 2 eq.). After stirring at 60 °C for 1 h, the resulting mixture was filtered and the organic solution was concentrated under reduced pressure to give 350 mg ( R)-5-(5-((5-((2-amino-5-bromophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A14-5). This material was used directly in the next reaction without purification. Step 6. Methyl-( RPreparation of methyl 5-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (INT-A14-6). Freshly prepared ( R)-5-(5-((5-((2-amino-5-bromophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (INT-A14-5, 350 mg) in alcohol (5 mL) was added BrCN (83 mg, 0.79 mmol, 1.5 equiv). After stirring at 60 °C for 1 h under nitrogen atmosphere, the mixture was concentrated under vacuum. The residue was purified by prep-TLC eluting with petroleum ether/ethyl acetate (5/1) to obtain 260 mg of methyl-( R)-5-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (INT-A14-6) (69%). LCMS: m/z (ESI), [M+H] ⁺=573.25. ¹1H NMR (DMSO-d ₆, 400 MHz) δ 0.83 (3H, d), 1.26 (3H, t), 1.28-1.40 (1H, m), 1.49-1.53 (1H, m), 1.67-1.71 (1H, m), 1.78-1.94 (1H, m), 1.96-2.02 (1H, m), 3.61 (3H, s), 3.79 (3H, s), 3.80-3.97 (4H, m), 4.08 (2H, q), 6.56 (2H, s), 7.04 (2H, d), 7.36 (1H, d), 7.99 (1H, s), 8.13 (1H, d), 8.45 (1H, d). Step 7. 5-(5-{[(4 RPreparation of 5-(5-{[(4 )-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-methylpyrazol-4-yl)-1-ethyl-6-oxopyridine-3-carboxylic acid (INT-A14-7).R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-methylpyrazol-4-yl)-1-ethyl-6-oxopyridine-3-carboxylic acid methyl ester (260 mg, 0.45 mmol, 1 equivalent) was added to a stirred mixture in THF (2 mL) containing LiOH ^.H ₂O (38 mg, 0.91 mmol, 2.0 equiv) of H ₂O (0.5 mL). After stirring at 60 °C for 30 minutes under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by reverse flash chromatography using 0% to 20% acetonitrile/water elution to give 160 mg 5-(5-{[(4 R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-methylpyrazol-4-yl)-1-ethyl-6-oxopyridine-3-carboxylic acid (INT-A14-7) (63%). LCMS: m/z (ESI), [M+H] ⁺= 559.15. Step 8. (11 R)-16-bromo-26-ethyl-5,11-dimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A14-8) was prepared by heating 5-(5-{[(4 R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-methylpyrazol-4-yl)-1-ethyl-6-oxopyridine-3-carboxylic acid (160 mg, 0.28 mmol, 1 equivalent) and N,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (163 mg, 0.43 mmol, 1.5 equivalents) was added to the stirred mixture in dioxane (2 mL) N,N-dDiisopropylethylamine (111 mg, 0.86 mmol, 3.0 equiv). The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC eluting with dichloromethane/methanol (12/1) to give 110 mg (11 R)-16-bromo-26-ethyl-5,11-dimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A14-8) (71%). LCMS: m/z (ESI), [M+H] ⁺= 541.05. Step 9. (11 R)-26-ethyl-5,11-dimethyl-16-(4-methylpiperazine-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A14). In a nitrogen atmosphere, (11 R)-16-bromo-26-ethyl-5,11-dimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (120 mg, 0.22 mmol, 1 equiv), 1-methylpiperazine (89 mg, 0.89 mmol, 4 equiv) and BrettPhos Pd G ₃(60 mg, 0.07 mmol, 0.3 equiv) in dioxane (5 mL) was added dropwise LiHMDS (223 mg, 1.33 mmol, 6 equiv). The reaction mixture was stirred at 60 °C for 30 min. After cooling to room temperature, the reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC eluting with dichloromethane/methanol (15/1) to give 50 mg (11 R)-26-ethyl-5,11-dimethyl-16-(4-methylpiperazin-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (Example A14) (39%). LCMS: m/z (ESI), [M+H] ⁺=559.35. ¹H NMR (400 MHz, DMSO-d ₆) δ 0.80-0.86 (4H, m), 1.13-1.34 (4H, m), 1.40-1.46 (2H, m), 1.91 (2H, d), 2.26-2.34 (5H, m), 2.80 (1H, s), 3.16 (4H, t), 3.72 (3H, s), 3.94 (2H, m), 4.05-4.18 (3H, m), 4.35 (1H, t), 6.82-6.88 (1H, m), 7.13 (1H, d), 7.36 (1H, d), 8.26 (1H, d), 8.35 (1H, s), 8.80 (1H, d), 12.35 (1H, s). Example A15 (11 R)-26-cyclopropyl-5,11-dimethyl-16-(4-methylpiperazine-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. Preparation of 5-bromo-1-cyclopropyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A15-1). 5-bromo-6-hydroxypyridine-3-carboxylic acid methyl ester (5 g, 21.55 mmol, 1 equivalent), cyclopropylboronic acid (4.07 g, 47.41 mmol, 2.2 equivalents), Cu(OAc) ₂A mixture of (4.31 g, 23.70 mmol, 1.1 equiv) and trimethylamine (4.36 g, 43.10 mmol, 2 equiv) in acetonitrile (100 mL) and ethanol (5 mL) was stirred at 80 °C for 12 h under nitrogen atmosphere. The mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (3×400 mL), and the resulting solution was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/1) to give 350 mg of 5-bromo-1-cyclopropyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A15-1) (30%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=271.90. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.90-0.97 (2H, m), 1.01-1.09 (2H, m), 3.38-3.42 (1H, m), 3.80 (3H, s), 8.17 (1H, d), 8.22 (1H, d). Step 2. Preparation of 1-cyclopropyl-5-(2-methyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-6-oxopyridine-3-carboxylic acid methyl ester (INT-A15-2). 5-Bromo-1-cyclopropyl-6-oxopyridine-3-carboxylic acid methyl ester (400 mg, 1.47 mmol, 1 equivalent) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (560 mg, 2.20 mmol, 1.5 equivalent), Pd(dppf)Cl ₂CH ₂Cl ₂A mixture of (239 mg, 0.29 mmol, 0.2 eq) and KOAc (432 mg, 4.41 mmol, 3 eq) in dioxane (8 mL) was stirred at 80 °C for 1 h under nitrogen atmosphere and then cooled to room temperature. To the above mixture were added 4-iodo-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (520.79 mg, 1.470 mmol, 1 eq), K ₂CO ₃(406 mg, 2.94 mmol, 2 equiv.) and water (2 mL). The resulting mixture was stirred at 80 °C for another 2 h. After cooling to room temperature, the reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (1/1) to give 210 mg of 1-methyl-5-(2-cyclopropyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-6-oxopyridine-3-carboxylic acid methyl ester (INT-A15-2) (34%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=420.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.06 (9H, s), 0.83 (2H, t), 0.89-0.95 (2H, m), 1.04-1.10 (2H, m), 3.24-3.26 (1H, m), 3.37 (3H, s), 3.45-3.50 (2H, m), 3.81(3H, d), 5.32 (2H, s), 8.06 (1H, d), 8.89 (1H, s), 9.18(1H, d). Step 3. Preparation of 1-cyclopropyl-5-(5-hydroxy-1-methylpyrazol-4-yl)-6-oxopyridine-3-carboxylic acid methyl ester (INT-A15-3). A solution of methyl 1-cyclopropyl-5-(2-methyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-6-oxopyridine-3-carboxylate (210 mg, 0.50 mmol, 1 eq.) and HCl (5 mL, 4 M in 1,4-dioxane) was stirred at room temperature for 6 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with CH₂Cl ₂(20 mL) and saturated NaHCO ₃(aqueous solution) (50 mL). The mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to give 190 mg of methyl 1-cyclopropyl-5-(5-hydroxy-1-methylpyrazol-4-yl)-6-oxopyridine-3-carboxylate (INT-A15-3), which was used directly in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺=290.00. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.95-1.00 (2H, m), 1.08-1.12 (2H, m), 3.45-3.49 (1H, m), 3.51 (3H, s), 3.83 (3H, s), 7.46-7.69 (1H, m), 8.03 (1H, s), 8.08 (1H, d), 8.38 (1H, d). Step 4. 5-(5-{[(4 RPreparation of methyl 1-cyclopropyl-5-(5-hydroxy-1-methylpyrazol-4-yl)-6-oxopyridine-3-carboxylate (INT-A15-4). To a solution of methyl 1-cyclopropyl-5-(5-hydroxy-1-methylpyrazol-4-yl)-6-oxopyridine-3-carboxylate (crude, 190 mg, 0.66 mmol, 1 eq) and triphenylphosphine (516 mg, 1.97 mmol, 3 eq) in tetrahydrofuran (10 mL) was added diisopropyl azodicarboxylate (398 mg, 1.97 mmol, 3 eq) and (4 R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentan-1-ol (208 mg, 0.66 mmol, 1 eq.). The resulting mixture was stirred at 0 °C for 3 h. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using ethyl acetate to give 135 mg of 5-(5-{[(4 R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-cyclopropyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A15-4) (33%). LCMS: m/z (ESI), [M+H] ⁺=589.90. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.85-1.00 (5H, m), 1.02-1.12 (2H, m), 1.15-1.30 (2H, m), 1.30-1.52 (1H, m), 1.53-1.96 (3H, m), 3.19-3.23 (1H, m), 3.38-3.42 (1H, m), 3.68 (3H, s), 3.77 (3H, s), 3.95 (2H, t), 6.80-6.86 (1H, m), 7.26 (1H, d), 7.97-8.01 (2H, m), 8.06 (1H, d), 8.11 (1H, d), 8.20 (1H, t) Step 5. 5-(5-{[(4 RPreparation of methyl 5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-cyclopropyl-6-oxopyridine-3-carboxylate (INT-A15-5). Raney nickel (60 mg, 0.70 mmol, 3 equivalents) and 5-(5-{[(4 RTo a mixture of methyl 5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-cyclopropyl-6-oxopyridine-3-carboxylate (135 mg, 0.2 mmol, 1 equiv) in methanol (3 mL) was added hydrazine hydrate (23 mg, 0.46 mmol, 2 equiv). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was filtered. The filter cake was washed with methanol (3×50 mL). The resulting solution was concentrated under reduced pressure. The residue was purified by Prep-TLC eluting with dichloromethane/methanol (16/1) to obtain 85 mg of 5-(5-{[(4 R)-5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-cyclopropyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A15-5) (65%). LCMS: m/z (ESI), [M+H] ⁺=558.05. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.80-1.12 (7H, m), 1.20-1.40 (2H, m), 1.52-1.95 (4H, m), 2.70-3.02 (2H, m), 3.68 (3H, s), 3.79 (3H, s), 3.96 (2H, t), 4.59-4.75 (3H, m), 6.41-6.54 (3H, m), 8.01 (1H, s), 8.09 (1H, d), 8.14 (1H, d) Step 6. 5-(5-{[(4 RPreparation of methyl 4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-methylpyrazol-4-yl)-1-cyclopropyl-6-oxopyridine-3-carboxylate (INT-A15-6). 5-(5-{[(4 RA mixture of methyl 5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-cyclopropyl-6-oxopyridine-3-carboxylate (85 mg, 0.15 mmol, 1 equiv) and cyanogen bromide (24 mg, 0.23 mmol, 1.5 equiv) in ethanol (18 mL) was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by Prep-TLC eluting with dichloromethane/methanol (12/1) to obtain 60 mg of 5-(5-{[(4 R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-methylpyrazol-4-yl)-1-cyclopropyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A15-6) (65%). LCMS: m/z (ESI), [M+H] ⁺=585.05. Step 7. 5-(5-{[(4 RPreparation of 5-(5-{[(4 RTo a mixture of methyl 4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-methylpyrazol-4-yl)-1-cyclopropyl-6-oxopyridine-3-carboxylate (70 mg, 0.12 mmol, 1 eq.) in tetrahydrofuran (4 mL) was added LiOH (11 mg, 0.48 mmol, 4 eq.) in water (1 mL). After stirring at room temperature for 2 h, the mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using 10% to 50% acetonitrile/water elution to give 50 mg of 5-(5-{[(4R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-methylpyrazol-4-yl)-1-cyclopropyl-6-oxopyridine-3-carboxylic acid (INT-A15-7) (73%) as an off-white solid. LCMS: m/z (ESI), [M+H] ⁺=569.25. Step 8. (11 R)-16-bromo-26-cyclopropyl-5,11-dimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A15-8). 5-(5-{[(4 R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-methylpyrazol-4-yl)-1-cyclopropyl-6-oxopyridine-3-carboxylic acid (60 mg, 0.10 mmol, 1 equivalent), N, N-Diisopropylethylamine (27 mg, 0.21 mmol, 2 equivalents) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)urea hexafluorophosphate (80 mg, 0.21 mmol, 2 equiv.) in 1,4-dioxane (1 mL, 11.80 mmol, 112 equiv.) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (25/1) to give 27 mg (11 R)-16-bromo-26-cyclopropyl-5,11-dimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A15-8) (46%). LCMS: m/z (ESI), [M+H] ⁺=553.10. Step 9. (11 R)-26-cyclopropyl-5,11-dimethyl-16-(4-methylpiperazine-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A15). In a nitrogen atmosphere, (11 R)-16-bromo-26-cyclopropyl-5,11-dimethyl-7-oxa-4,5,13, 20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (20 mg, 0.04 mmol, 1 equiv), 1-methylpiperazine (14.53 mg, 0.144 mmol, 4 equiv) and BrettPhos Pd G ₃(9.86 mg, 0.01 mmol, 0.3 eq.) was added dropwise to a stirred mixture of dioxane (1 mL) with LiHMDS (0.14 mL, 0.144 mmol, 4 eq.). The reaction mixture was stirred at 60 °C for 30 min. After cooling to room temperature, the reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by reverse phase flash chromatography eluting with 10% to 50% acetonitrile/water to give 8.6 mg (11 R)-26-cyclopropyl-5,11-dimethyl-16-(4-methylpiperazin-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A15) (41%). LCMS: m/z (ESI), [M+H] ⁺= 571.35. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.80 (3H, d), 0.87-0.89 (2H, m), 1.09-1.13 (2H, m), 1.42-1.48 (1H, m), 1.90-1.92 (2H, m), 2.18-2.28 (4H, m), 2.50 (4H, t), 2.78-2.82 (1H, m), 3.16 (4H, t), 3.42-3.46 (1H, m), 3.72 (3H, s), 3.87-3.94 (2H, m), 4.09 (1H, d), 4.33 (1H, t), 6.84-6.88 (1H, m), 7.14 (1H, d), 7.31-7.37 (1H, m), 8.04 (1H, d), 8.35 (1H, s), 8.77 (1H, d), 12.38 (1H, s). Example A16A and Example A16B 11-Ethyl-5,26-dimethyl-16-(4-methylpiperazin-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione, isomer 1 (Example A16A) and isomer 2 (Example A16B) Step 1. N, N- Preparation of dibenzylbutyramide (INT-A16-1). To a stirred mixture of butyric acid (10 g, 113.50 mmol, 1 eq.) and dibenzylamine (22.39 g, 113.50 mmol, 1 eq.) in 1,4-dioxane (100 mL) was added under nitrogen atmosphere at room temperature.N,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (64.73 g, 170.25 mmol, 1.5 equivalents) and N,N-diisopropylethylamine (44.01 g, 340.50 mmol, 3 equiv.). The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water (300 mL), and the mixture was washed with CH₂Cl ₂(3×300 mL) extraction. The combined organic layers were washed with brine (3×200 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by passing through a C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to dryness to give 25 g of N, N-Dibenzylbutyramide (INT-A16-1) (82%). LCMS: m/z (ESI), [M+H] ⁺=268.00. Step 2. N, N- Preparation of dibenzyl-2-ethylpent-4-enamide (INT-A16-2). In a nitrogen atmosphere at -78 °C to N, N-Dibenzylbutyramide (10 g, 37.40 mmol, 1 eq.) was added to a stirred mixture of tetrahydrofuran (100 mL) with LiHMDS (41.14 mL, 41.14 mmol, 1.1 eq.) and allyl bromide (6.79 g, 56.10 mmol, 1.5 eq.). The resulting mixture was stirred at -60 °C for 2 h under a nitrogen atmosphere and warmed to room temperature. The reaction was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by passing through a C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to dryness to obtain 8 g of N, N-Dibenzyl-2-ethylpent-4-enamide (INT-A16-2) (69%). LCMS: m/z (ESI), [M+H] ⁺= 308.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.75 (3H, t), 1.30-1.46 (1H, m), 1.46-1.63 (1H, m), 2.02-2.17 (1H, m), 2.21-2.31 (1H, m), 2.63- 2.79 (1H, m), 4.49-4.61 (4H, m), 4.86-5.07 (2H, m), 5.59-5.83 (1H, m), 7.12-7.49 (10H, m). Step 3. N, N- Preparation of dibenzyl-2-ethyl-5-hydroxypentanamide (INT-A16-3).N, NA mixture of 2-dibenzyl-2-ethylpent-4-enamide (6.0 g, 19.51 mmol, 1 eq.) and 9-boraherobicyclo[3.3.1]nonane (5.95 g, 48.79 mmol, 2.5 eq.) in THF (15 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. Then, NaOH (1.17 g, 29.27 mmol, 1.5 eq.) in H ₂O (1.50 mL, 83.33 mmol, 4.27 equiv) and H ₂O ₂(12.12 mL, 156.13 mmol, 8.0 equiv., 30%). The resulting mixture was stirred at room temperature for 2 h. The reaction was heated with saturated Na ₂S ₂O ₃The solution (100 mL) was quenched, and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by passing through a C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 5.0 g of N, N-Dibenzyl-2-ethyl-5-hydroxypentanamide (INT-A16-3) (79%). LCMS: m/z (ESI), [M+H] ⁺=326.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.75 (3H, t), 1.30-1.56 (6H, m), 2.60 (1H, t), 3.23-3.31 (2H, m), 4.56 (4H, d), 7.05-7.54 (10H, m). Step 4. Preparation of 4-[(dibenzylamino)methyl]hexan-1-ol (INT-A16-4). Under nitrogen atmosphere at 0 °C to N, N-dibenzyl-2-ethyl-5-hydroxypentanamide (5.0 g, 15.36 mmol, 1 equivalent) in tetrahydrofuran (50 mL) was added with LiAlH ₄(1.16 g, 30.73 mmol, 2.0 equiv). The resulting mixture was stirred at 0 °C for 2 h. The reaction was stirred at room temperature with water (1.2 mL) and H containing NaOH (387.12 mg, 9.679 mmol, 0.63 equiv).₂O (800 mg). The resulting mixture was filtered. The filter cake was washed with tetrahydrofuran (2×50 mL). The organic solution was concentrated under reduced pressure. The residue was purified by C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 3.0 g of 4-[(dibenzylamino)methyl]hexan-1-ol (INT-A16-4) (63%) as a colorless oil. LCMS: m/z (ESI), [M+H] ⁺=312.15. Step 5. Preparation of methyl 4-(aminomethyl)hexan-1-ol (INT-A16-5). A mixture of 4-[(dibenzylamino)methyl]hexan-1-ol (3.0 g, 9.63 mmol, 1 eq.) and Pd/C (0.31 g, 2.89 mmol, 0.3 eq.) in MeOH (50 mL) was stirred at 20 °C for 2 h under a hydrogen atmosphere. The mixture was filtered. The filter cake was washed with methanol (300 mL). The solution was concentrated under reduced pressure to give 1.2 g of 4-(aminomethyl)hexan-1-ol (INT-A16-5) as a colorless oil. This material was used in the next reaction without further purification. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.82 (3H, t), 1.0-1.44 (7H, m), 2.18-2.48 (2H, m), 3.37 (2H, t). Step 6. Preparation of 4-{[(5-bromo-2-nitrophenyl)amino]methyl}hexan-1-ol (INT-A16-6). 4-(Aminomethyl)hexan-1-ol (140 mg, 1.07 mmol, 1 eq.), 4-bromo-2-fluoro-1-nitrobenzene (234.72 mg, 1.07 mmol, 1.0 eq.) and K ₂CO ₃(294.91 mg, 2.13 mmol, 2.0 equiv) in acetonitrile (5.0 mL) was stirred at 60 °C overnight under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to dryness to give 300 mg of 4-{[(5-bromo-2-nitrophenyl)amino]methyl}hexan-1-ol (INT-A16-6) (85%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=330.90. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.90 (3H, t), 1.34-1.49 (6H, m), 1.60-1.70 (1H, m), 3.28 (2H, t), 3.39 (2H, d), 4.32-4.43 (1H, m), 6.84 (1H, d), 7.26 (1H, d), 7.99 (1H, d), 8.15 (1H, t) Step 7. Preparation of 5-{5-[(4-{[(5-bromo-2-nitrophenyl)amino]methyl}hexyl)oxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A16-7). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 262.29 mg, 0.99 mmol, 1.00 equiv) and triphenylphosphine (784.00 mg, 2.99 mmol, 3 equiv) in tetrahydrofuran (5 mL) under nitrogen atmosphere at 0° C. were added diisopropyl azodicarboxylate (604.41 mg, 2.99 mmol, 3 equiv) and 4-{[(5-bromo-2-nitrophenyl)amino]methyl}hexan-1-ol (330 mg, 0.99 mmol, 1.00 equiv). The resulting mixture was stirred at 0° C. under nitrogen atmosphere for 2 h. The reaction was quenched with water (50 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by C18 column using water and acetonitrile as mobile phase to obtain 500 mg of 5-{5-[(4-{[(5-bromo-2-nitrophenyl)amino]methyl}hexyl)oxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A16-7) (87%) as orange oil. LCMS: m/z (ESI), [M+H] ⁺=577.85. Step 8. Preparation of 5-{5-[(4-{[(2-amino-5-bromophenyl)amino]methyl}hexyl)oxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A16-8). A mixture of 5-{5-[(4-{[(5-bromo-2-nitrophenyl)amino]methyl}hexyl)oxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (400 mg, 0.69 mmol, 1 eq.), ranyl nickel (297.25 mg, 3.47 mmol, 5 eq.) and hydrazine hydrate (98%) (52.11 mg, 1.04 mmol, 1.5 eq.) in methanol (5 mL) was stirred at 0 °C for 2 h under nitrogen atmosphere. The resulting mixture was filtered. The filter cake was washed with methanol (3×30 mL). The solution was concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 300 mg of 5-{5-[(4-{[(2-amino-5-bromophenyl)amino]methyl}hexyl)oxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (INT-A16-8) (79%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=546.00. Step 9. Preparation of 5-[5-({4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]hexyl}oxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A16-9). 5-{5-[(4-{[(2-amino-5-bromophenyl)amino]methyl}hexyl)oxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (300 mg, 0.55 mmol, 1 equiv.) and BrCN (69.78 mg, 0.66 mmol, 1.2 equiv.) were mixed in CH₂Cl ₂The mixture in 4% paraformaldehyde (5 mL) was stirred at room temperature overnight under nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/3) to give 220 mg of 5-[5-({4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]hexyl}oxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A16-9) (90%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=572.95. Step 10. Preparation of 5-[5-({4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]hexyl}oxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A16-10). 5-[5-({4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]hexyl}oxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (170 mg, 0.23 mmol, 1 equivalent) and LiOH ^.H ₂O (24.96 mg, 0.55 mmol, 2.5 equiv.) in tetrahydrofuran (10 mL) and H ₂O (2.5 mL) was stirred at 20 ° C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 150 mg of 5-[5-({4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]hexyl}oxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A16-10) (87%) as an orange oil. LCMS: m/z (ESI), [M+H] ⁺=559.00. Step 11. Preparation of methyl 16-bromo-11-ethyl-5,26-dimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A16-11). 5-[5-({4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]hexyl}oxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (150 mg, 0.27 mmol, 1 equivalent), N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (204.63 mg, 0.54 mmol, 2.0 equivalent) andN,N- A mixture of diisopropylethylamine (104.33 mg, 0.81 mmol, 3.0 equiv.) in dioxane (5 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (30 mL), and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (5/1) to give 100 mg of 16-bromo-11-ethyl-5,26-dimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A16-11) (69%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺= 540.85. Step 12. Preparation of methyl 5-{5-[(4-{[(2-amino-5-bromophenyl)amino]methyl}hexyl)oxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (A16). 1-Methylpiperazine (83.56 mg, 0.85 mmol, 5.0 equivalent), 16-bromo-11-ethyl-5,26-dimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecanoic-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (90 mg, 0.17 mmol, 1.00 equivalent), BrettPhos Pd G ₃A mixture of (45.37 mg, 0.05 mmol, 0.3 equiv) and LiHMDS (1.00 mL, 1.00 mmol, 6.0 equiv) in dioxane (5.0 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was terminated by adding saturated NH₄Cl solution (30 mL) was quenched, and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (8/1) to give 2.0 mg of 11-ethyl-5,26-dimethyl-16-(4-methylpiperazin-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1. 0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16, 18,20,24-octaene-23,27-dione (A16) (2%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺=559.50. ¹H NMR (CD ₃OD, 400 MHz) δ 0.82 (3H, t), 1.17-1.47 (6H, m), 1.74 (2H, s), 2.08 (1H, s), 2.28 (1H, s), 2.71 (1H, d), 2.88 (3H, s), 3.43 (4H, s), 3.68 (3H, s), 3.77 (3H, s), 3.80-3.92 (2H, m), 4.04 (1H, s), 4.30 (1H, d), 4.42 (1H, d), 6.99 (1H, s), 7.01 (1H, s), 7.39 (1H, d), 8.24 (1H, s), 8.40 (1H, s), 8.87 (1H, s) Step 13. Preparation of 11-ethyl-5,26-dimethyl-16-(4-methylpiperazin-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione, isomer 1 (Example A16A) and isomer 2 (Example A16B). A racemic mixture of 11-ethyl-5,26-dimethyl-16-(4-methylpiperazin-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]octadecano-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (A16, 25 mg, 0.04 mmol) was purified by Prep-chiral-HPLC using a CHIRALPAK IG column (2*25 cm, 5 μm) with tert-butyl methyl ether containing 0.1% diethylamine as mobile phase A and EtOH/CH₂Cl ₂(1/1) was used as mobile phase B to separate, to obtain 1.8 mg of isomer 1 (Example A16A, 7%) and 2.2 mg of isomer 2 (Example A16B, 9%) as white solids. Isomer 1: LCMS: m/z (ESI), [M+H] ⁺=559.45. ¹H NMR (CD ₃OD, 400 MHz) δ 0.72-0.91 (3H, m), 1.16-1.45 (2H, m), 1.65-1.80 (2H, m), 2.03-2.12 (1H, m), 2.20-2.36 (1H, m), 2.60-2.74 (1H, m), 2.80 (4H, s), 3.15-3.26 (4H, m), 3.38 (4H, t), 3.56-3.71 (4H, m), 3.80 (3H, d), 4.00-4.06 (1H, m), 4.25-4.31 (1H, m), 4.39-4.46 (1H, m), 6.91 (1H, s), 7.02 (1H, d), 7.37 (1H, s), 8.12 (1H, s), 8.41 (1H, d), 8.83 (1H, s). Chiral-HPLC, Rt=4.108 min. Isomer 2: LCMS: m/z (ESI), [M+H] ⁺=559.35. ¹H NMR (CD ₃OD, 400 MHz) δ 0.72-0.91 (3H, m), 1.16-1.45 (2H, m), 1.65-1.80 (2H, m), 2.03-2.12 (1H, m), 2.20-2.36 (1H, m), 2.60-2.74 (1H, m), 2.80 (4H, s), 3.15-3.26 (4H, m), 3.38 (4H, t), 3.56-3.71 (4H, m), 3.80 (3H, d), 4.00-4.06 (1H, m), 4.25-4.31 (1H, m), 4.39-4.46 (1H, m), 6.83 (1H, s), 6.98 (1H, d), 7.35 (1H, s), 8.05 (1H, s), 8.41 (1H, d), 8.77 (1H, s). Chiral-HPLC, Rt=5.613 minutes. Example A18 5',26'-Dimethyl-16'-(4-methylpiperazine-1-yl)-7'-oxa-4',5',13',20',22',26'-hexaazaspiro[cyclopropane-1,11'-pentacyclic[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]twenty-eight]-1'(28'), 2'(6'),3',14',16',18',20',24'-octaene-23',27'-dione Step 1. Preparation of 3-(1-(((5-bromo-2-nitrophenyl)amino)methyl)cyclopropyl)propan-1-ol (INT-A18-1). 3-[1-(aminomethyl)cyclopropyl]propan-1-ol (500 mg, 3.87 mmol, 1 equivalent), K ₂CO ₃A mixture of (1069 mg, 7.74 mmol, 2 eq.) and 4-bromo-2-fluoro-1-nitrobenzene (936 mg, 4.25 mmol, 1.1 eq.) in acetonitrile (5 mL) was stirred at 60 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was loaded on a silica gel column and eluted with petroleum ether/ethyl acetate (5:1) to give 1.0 g of 3-(1-{[(5-bromo-2-nitrophenyl)amino]methyl}cyclopropyl)propan-1-ol (INT-A18-1) (78%) as a colorless oil. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.37-0.55 (4H, m), 1.31-1.44 (2H, m), 1.45-1.60 (2H, m), 3.25 (2H, d), 3.36-3.39 (2H, m), 4.45 (1H, s), 6.78-6.89 (1H, m), 7.26 (1H, d), 8.00 (1H, d), 8.08 (1H, t) Step 2. Preparation of methyl 5-(5-(3-(1-(((5-bromo-2-nitrophenyl)amino)methyl)cyclopropyl)propoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (INT-A18-2). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 700 mg, 2.66 mmol, 1 eq) and triphenylphosphine (2092 mg, 7.97 mmol, 3 eq) in tetrahydrofuran (10 mL) was added diisopropyl azodicarboxylate (1613 mg, 7.97 mmol, 3 eq) and 3-(1-{[(5-bromo-2-nitrophenyl)amino]methyl}cyclopropyl)propan-1-ol (875 mg, 2.66 mmol, 1 eq) at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 2 h. The reaction was quenched with water (80 mL) and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was loaded on a silica gel column and purified using petroleum ether/ethyl acetate (1/10) to give 700 mg of 5-{5-[3-(1-{[(5-bromo-2-nitrophenyl)amino]methyl}cyclopropyl)propoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A18-2) (45%) as a yellow oil. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.42-0.47 (m, 2H), 0.52 (2H, d), 1.50-1.58 (m, 2H), 1.80-1.88 (2H, m), 3.20-3.29 (2H, m), 3.57 (3H, s), 3.66 (3H, s), 3.77 (3H, s), 3.88-3.96 (2H, m), 6.79-6.84 (1H, m), 7.25 (1H, d), 7.55-7.66 (1H, m), 7.98 (1H, d), 8.07 (1H, d), 8.10 (1H, d), 8.42 (1H, d). Step 3. Preparation of 5-(5-(3-(1-(((2-amino-5-bromophenyl)amino)methyl)cyclopropyl)propoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A18-3). To a stirred mixture of 5-{5-[3-(1-{[(5-bromo-2-nitrophenyl)amino]methyl}cyclopropyl)propoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A18-2, 700 mg, 1.22 mmol, 1 equiv.) and ranyl nickel (50 mg) in methanol (10 mL) was added portionwise with NH ₂NH ₂ ^.H ₂O (122 mg, 2.43 mmol, 2 eq). The mixture was stirred at 0 °C for 1 h. The resulting mixture was filtered. The filter cake was washed with methanol (3×30 mL), and the solution was concentrated under vacuum. The residue was used directly in the next step. Step 4. Preparation of 5-(5-(3-(1-((2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)methyl)cyclopropyl)propoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A18-4). A mixture of methyl 5-{5-[3-(1-{[(2-amino-5-bromophenyl)amino]methyl}cyclopropyl)propoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (580 mg, 1.06 mmol, 1 eq) and BrCN (135 mg, 1.27 mmol, 1.2 eq) in ethanol (6 mL) was stirred under nitrogen atmosphere at room temperature for 2 h. The mixture was concentrated under vacuum. The residue was loaded on a silica gel column and purified using methylene chloride/methanol (12/1) elution to give 600 mg of 5-[5-(3-{1-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]cyclopropyl}propoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A18-4) (98%) as a brown solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.36 (2H, t), 0.45-0.54 (2H, m), 1.40-1.50 (2H, m), 1.78-1.88 (2H, m), 3.58 (3H, s), 3.65 (3H, s), 3.74 (3H, s), 3.88 (2H, t), 4.08 (2H, s), 6.65 (2H, s), 7.06 (2H, s), 7.35 (1H, s), 7.97 (1H, s), 8.08 (1H, d), 8.43 (1H, d) Step 5. Preparation of 5-(5-(3-(1-((2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)methyl)cyclopropyl)propoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (INT-A18-5). 5-[5-(3-{1-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]cyclopropyl}propoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (580 mg, 1.02 mmol, 1 equivalent) and LiOH ^.H ₂O (85 mg, 2.03 mmol, 2 equivalents) in tetrahydrofuran/H ₂O (0.8 mL/0.2 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was purified by C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 400 mg of 5-[5-(3-{1-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]cyclopropyl}propoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A18-5) (70%) as a brown solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.24-0.35 (2H, m), 0.42 (2H, t), 1.40-1.59 (2H, m), 1.89-1.96 (2H, m), 3.51 (3H, s), 3.63 (3H, s), 3.90 (2H, t), 4.17 (2H, s), 6.94 (2H, s), 7.02 (2H, d), 7.33-7.37 (1H, m),7.94(1H, s), 8.07 (1H, s), 8.38 (1H, d). Step 6. Preparation of 16'-bromo-5',26'-dimethyl-7'-oxa-4',5',13',20',22', 26'-hexaazaspiro[cyclopropane-1,11'-pentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadeca]-1'(28'),2'(6'),3',14',16',18',20',24'-octaene-23',27'-dione (INT-A18-6). Under nitrogen atmosphere at room temperature, 5-[5-(3-{1-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]cyclopropyl}propoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (330 mg, 0.59 mmol, 1 equivalent) andN,N,N,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (338 mg, 0.89 mmol, 1.5 equivalents) was added to a mixture of dioxane (5 mL)N,N-Diisopropylethylamine (230 mg, 1.78 mmol, 3 equiv.). The mixture was stirred at the temperature for 3 h. The reaction was quenched with water (80 mL), and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC and eluted with methylene dichloride/methanol (12/1) to give 300 mg of 16'-bromo-5',26'-dimethyl-7'-oxa-4',5',13',20',22',26'-hexaazaspiro[cyclopropane-1,11'-pentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadeca]-1'(28'), 2'(6'),3',14',16',18',20',24'-octaene-23',27'-dione (INT-A18-6) (93%) as a brown solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.39 (2H, t), 0.63 (2H, t), 1.78 (2H, s), 2.20-2.28 (2H, m), 3.10-3.18 (2H, m), 3.65 (3H, d), 3.73 (3H, s), 4.15-4.28 (2H, m), 7.34-7.51 (2H, m), 7.75 (1H, d), 8.24-8.36 (2H, m), 8.71 (1H, d), 12.82 (1H, s) Step 7. Preparation of 5',26'-dimethyl-16'-(4-methylpiperazin-1-yl)-7'-oxa-4',5',13',20',22',26'-hexaazaspiro[cyclopropane-1,11'-pentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octaconic]-1'(28'), 2'(6'),3',14',16',18',20',24'-octaene-23',27'-dione (Example A18). 16'-Bromo-5',26'-dimethyl-7'-oxa-4',5',13',20',22',26'-hexaazaspiro[cyclopropane-1,11'-pentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene]-1'(28'), 2'(6'),3',14',16',18',20',24'-octaene-23',27'-dione (100 mg, 0.18 mmol, 1 eq.), 1-methylpiperazine (74 mg, 0.74 mmol, 4.0 eq.) and BrettPhos Pd G ₃To a stirred mixture of 1,4-dioxane (4 mL) was added LiHMDS (1.12 mL, 1.12 mmol, 6 eq.). The mixture was stirred at 60 °C for 1 h and then cooled to room temperature. The reaction was heated with saturated NH₄Cl(aq) solution (20 mL) was quenched, and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC and eluted with methylene dichloride/methanol (12/1) to give 18 mg of 5',26'-dimethyl-16'-(4-methylpiperazin-1-yl)-7'-oxa-4',5',13',20',22',26'-hexaazaspiro[cyclopropane-1,11'-pentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octaconic]-1'(28'),2'(6'),3',14',16',18',20',24'-octaene-23',27'-dione (Example A18) as a white solid (17%). LCMS: m/z (ESI), [M+H] ⁺=557.35. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.35 (2H, t), 0.62 (2H, t), 1.73-1.81 (2H, m), 2.24 (5H, s), 2.45-2.49 (4H, m), 3.10-3.17 (4H, m), 3.62 (3H, s), 3.72 (3H, s), 4.18-4.29 (4H, m), 6.75-6.89 (1H, m), 6.95 (1H, d), 7.36 (1H, d), 8.29 (2H, d), 8.72 (1H, d), 12.51 (1H, s). Example A19 5,12,26-Trimethyl-16-(4-methylpiperazin-1-yl)-7-oxa-4,5, 13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. Preparation of 5-aminohexan-1-ol (INT-A19-1). 6-Hydroxy-hexan-2-one (1.0 g, 8.60 mmol, 1 equivalent), NH₄OAc (3.32 g, 43.04 mmol, 5.0 equiv) and NaBH ₃A mixture of CN (1.35 g, 21.52 mmol, 2.5 equiv.) in methanol (10 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. Pass the residue through C18FLASH using 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂Purification was performed using water with 0.04% O and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 2.5 g of 5-aminohexan-1-ol (INT-A19-1) (74%) as a colorless oil. LCMS: m/z (ESI), [M+H] ⁺=118.15. Step 2. Preparation of 5-((5-bromo-2-nitrophenyl)amino)hexan-1-ol (INT-A19-2). 5-aminohexan-1-ol (2.5 g, 21.33 mmol, 1 equivalent), K ₂CO ₃A mixture of (8.84 g, 63.99 mmol, 3 equiv.) and 4-bromo-2-fluoro-1-nitrobenzene (14.08 g, 63.99 mmol, 3 equiv.) in acetonitrile (80 mL) was stirred at 60 °C overnight under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (5/1) to give 3.1 g of 5-[(5-bromo-2-nitrophenyl)amino]hexan-1-ol (INT-A19-2) (42%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=319.05. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.18-1.26 (3H, m), 1.29-1.49 (4H, m), 1.50-1.68 (2H, m), 3.36-3.43 (2H, m), 3.81-3.90 (1H, m), 4.37 (1H, t), 6.78-6.86 (1H, m), 7.31 (1H, d), 7.94 (1H, d), 7.99 (1H, d). Step 3. Preparation of 5-(5-((5-((5-bromo-2-nitrophenyl)amino)hexyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (INT-A19-3). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 500 mg, 1.89 mmol, 1.00 equiv) and triphenylphosphine (1494 mg, 5.69 mmol, 3 equiv) in tetrahydrofuran (20 mL) was added diisopropyl azodicarboxylate (1152 mg, 5.69 mmol, 3 equiv) and 5-[(5-bromo-2-nitrophenyl)amino]hexan-1-ol (662 mg, 2.08 mmol, 1.1 equiv) in tetrahydrofuran (10 mL) at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for 2 h. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/1) to give 510 mg of 5-[5-({5-[(5-bromo-2-nitrophenyl)amino]hexyl}oxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A19-3) (47%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=564.05. Step 4. Preparation of 5-(5-((5-((2-amino-5-bromophenyl)amino)hexyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A19-4). To a stirred mixture of 5-[5-({5-[(5-bromo-2-nitrophenyl)amino]hexyl}oxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (490 mg, 0.87 mmol, 1 eq.) and ranyl nickel (599 mg, 6.96 mmol, 8 eq.) in methanol (5 mL) at 0°C was added hydrazine (87.23 mg, 1.742 mmol, 2.0 eq.). The mixture was stirred at 0 °C for 2 h under nitrogen atmosphere. The mixture was filtered. The filter cake was washed with methanol (3×50 mL), and the resulting solution was concentrated under reduced pressure to give 400 mg of 5-[5-({5-[(2-amino-5-bromophenyl)amino]hexyl}oxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A19-4) as a brown solid. This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=534.20. Step 5. Preparation of 5-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)hexyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A19-5). A mixture of 5-[5-({5-[(2-amino-5-bromophenyl)amino]hexyl}oxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (400 mg, 0.751 mmol, 1 eq.) and BrCN (95.49 mg, 0.901 mmol, 1.2 eq.) in ethanol (5 mL) was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water (20 mL), and the mixture was extracted with dichloromethane (3×30 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on Prep-TLC using dichloromethane/methanol (12/1) to give 320 mg of 5-(5-{[5-(2-amino-6-bromo-1,3-benzodiazol-1-yl)hexyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A19-5) (76%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=557.20. Step 6. Preparation of 5-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)hexyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (INT-A19-6). 5-(5-{[5-(2-amino-6-bromo-1,3-benzodiazol-1-yl)hexyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (300 mg, 0.54 mmol, 1 equivalent) and LiOH.H ₂A mixture of O (67 mg, 1.61 mmol, 3.0 equiv.) in tetrahydrofuran (4 mL) and water (1 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was passed through C18FLASH using a 10 mmol/L NH₄HCO ₃and 0.1% NH ₃.H ₂O and acetonitrile as the mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 260 mg of 5-(5-{[5-(2-amino-6-bromo-1,3-benzodiazol-1-yl)hexyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A19-6) (88%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=545.20. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.37-1.39 (3H, m), 1.60-1.84 (1H, m), 1.90-1.97 (1H, m), 3.51 (3H, s), 3.61 (3H, s), 3.80-3.83 (1H, m), 3.89-3.92 (1H, m), 4.69-4.73 (1H, m), 7.02-7.04 (2H, m), 7.11 (2H, s), 7.37 (1H, t), 8.01 (2H, d), 8.34 (1H, d) Step 7. Preparation of 16-bromo-5,12,26-trimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A19-7). 5-(5-{[5-(2-amino-6-bromo-1,3-benzodiazol-1-yl)hexyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (250 mg, 0.46 mmol, 1 equivalent), N, N, N, N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (262 mg, 0.69 mmol, 1.5 equivalents) and N, N- A mixture of diisopropylethylamine (178 mg, 1.38 mmol, 3.0 equiv.) in 1,4-dioxane (5 mL) was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water (20 mL), and the mixture was extracted with dichloromethane (3×30 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on Prep-TLC using dichloromethane/methanol (12/1) to give 170 mg of 16-bromo-5,12,26-trimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A19-7) (70%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=525.15. Step 8. Preparation of 5,12,26-trimethyl-16-(4-methylpiperazin-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A19). To a stirred mixture of 16-bromo-5,12,26-trimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (100 mg, 0.19 mmol, 1 eq), 1-methylpiperazine (76 mg, 0.76 mmol, 4 eq) and BrettPhos Pd G3 (51 mg, 0.06 mmol, 0.3 eq) in 1,4-dioxane (4 mL) was added LiHMDS (4 mL, 1.14 mmol, 6 eq) at room temperature under nitrogen atmosphere. The mixture was stirred at 60 °C for 1 h and cooled to room temperature. The reaction was heated with saturated NH₄Cl(aq) solution (10 mL) was quenched and the mixture was washed with CH₂Cl ₂(3×30 mL) extraction. The combined organic layers were purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was passed through prep-HPLC using an XBridge Shield RP18 OBD column using water 10 mmol/L NH₄HCO ₃and 0.1% NH ₃.H ₂O and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 11 mg of 5,12,26-trimethyl-16-(4-methylpiperazin-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A19) (10%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺= 545.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.54-1.62 (4H, m), 1.63-1.70 (1H, m), 1.73-1.79 (1H, m), 1.82-1.92 (1H, m), 2.12-2.20 (2H, m), 2.22-2.31 (1H, m), 2.38-2.45 (4H, m), 3.12-3.27 (4H, m), 3.31 (3H, s), 3.61 (3H, s), 3.71 (3H, s), 3.90-4.08 (1H, m), 4.23-4.27 (1H, m), 4.82-4.98 (1H, m), 6.87-6.86 (1H, m), 7.09 (1H, s), 7.35-7.32 (1H, m), 8.23-8.31 (2H, m), 8.89-8.86 (1H, m), 12.29 (1H, s). Example A20 (11 R)-11,26-dimethyl-16-(4-methylpiperazine-1-yl)-5-(2,2,2-trifluoroethyl)-7-oxo-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. Preparation of tert-butyl 4-(3-chloro-4-nitrophenyl)piperazine-1-carboxylate (INT-A20-1). 2-Chloro-4-fluoro-1-nitrobenzene (10 g, 56.967 mmol, 1 equivalent), K ₂CO ₃A mixture of tert-butyl piperazine-1-carboxylate (15.75 g, 113.934 mmol, 2 equiv.) and tert-butyl piperazine-1-carboxylate (11.67 g, 62.664 mmol, 1.1 equiv.) in acetonitrile (200 mL) was stirred at 60 °C overnight under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (800 mL), and the mixture was extracted with ethyl acetate (3×600 mL). The combined organic layers were washed with brine (3×500 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (1/1) to give 5.4 g of tert-butyl 4-(3-chloro-4-nitrophenyl)piperazine-1-carboxylate (INT-A20-1) (27%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=342.10. Step 2. ( RPreparation of tert-butyl 4-(3-((5-hydroxy-2-methylpentyl)amino)-4-nitrophenyl)piperazine-1-carboxylate (INT-A20-2). tert-butyl 4-(3-chloro-4-nitrophenyl)piperazine-1-carboxylate (1.4 g, 4.096 mmol, 1 equivalent), K ₂CO ₃(1132.20 mg, 8.192 mmol, 2 equiv.) and (4 R)-5-amino-4-methylpentan-1-ol (M3-6, 480.03 mg, 4.096 mmol, 1 equivalent) in N,N-The mixture in dimethylacetamide (15 mL) was stirred at 100 °C overnight under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/1) to give 730 mg of tert-butyl 4-(3-{[(2R)-5-hydroxy-2-methylpentyl]amino}-4-nitrophenyl)piperazine-1-carboxylate (INT-A20-2) (42%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=423.25. Step 3. Preparation of 2-(2,2,2-trifluoroethyl)pyrazol-3-ol (INT-A20-3). A mixture of (2E)-3-methoxyprop-2-enoic acid methyl ester (5 g, 43.06 mmol, 1 eq.) and (2,2,2-trifluoroethyl)hydrazine HCl salt (7.37 g, 64.59 mmol, 1.5 eq.) in methanol (20 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (200 mL), and the mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel column eluting with dichloromethane/methanol (20/1) to obtain 6 g of 2-(2,2,2-trifluoroethyl)pyrazol-3-ol (INT-A20-3) (83%) as a yellow solid. ¹H NMR (DMSO, 400 MHz) δ 4.71 (2H, q), 5.38 (1H, d), 7.25 (1H, s), 11.40 (1H, s) Step 4. Preparation of 2-(2,2,2-trifluoroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (INT-A20-4). 2-(2,2,2-trifluoroethyl)pyrazol-3-ol (6 g, 36.12 mmol, 1 eq.) and K ₂CO ₃(9.98 g, 72.24 mmol, 2 eq.) in acetonitrile (100 mL) was added SEM-Cl (12.04 g, 72.24 mmol, 2 eq.). The mixture was stirred at 0 °C for 2 h under nitrogen atmosphere. The reaction was quenched with water (200 mL), and the mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel column eluting with petroleum ether/ethyl acetate (1/3) to obtain 900 mg of 2-(2,2,2-trifluoroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (INT-A20-4) (8%) as a brown solid. ¹H NMR (DMSO, 400 MHz) δ 0.81 (2H, d), 1.06 (1H, t), 1.24 (1H, s), 3.18 (1H, d), 3.45 (2H, m), 4.64 (2H, q), 5.09 (2H, s), 5.44 (1H, d), 8.08 (1H, d) Step 5. Preparation of 4-iodo-2-(2,2,2-trifluoroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (INT-A20-5). To a mixture of 2-(2,2,2-trifluoroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (250 mg, 0.84 mmol, 1 eq.) in acetonitrile (5 mL) was added NIS (227 mg, 1.01 mmol, 1.2 eq.). The resulting mixture was stirred at 0 °C for 2 h under nitrogen atmosphere. The reaction was quenched with saturated sodium thiosulfate solution (aq.) (30 mL), and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel column eluting with petroleum ether/ethyl acetate (1/3) to give 200 mg of 4-iodo-2-(2,2,2-trifluoroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (INT-A20-5) (56%) as brown oil. ¹H NMR (DMSO, 400 MHz) δ -0.05 (9H, s), 0.74-0.87 (2H, m), 3.42-3.50 (2H, m), 4.72 (2H, q), 5.10 (2H, s), 8.35 (1H, s). Step 6. Preparation of 1-methyl-6-oxo-5-[3-oxo-2-(2,2,2-trifluoroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl]pyridine-3-carboxylic acid methyl ester (INT-A20-6). 5-Bromo-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (561 mg, 2.28 mmol mmol, 1 equivalent), Pd(dppf)Cl ₂ ^.CH ₂Cl ₂A mixture of (167 mg, 0.23 mmol, 0.1 eq), bis(pinacol)diboron (868 mg, 3.42 mmol, 1.5 eq) and KOAc (671 mg, 6.84 mmol, 3 eq) in 1,4-dioxane (6 mL) was stirred at 80 °C overnight under nitrogen atmosphere. The mixture was cooled to room temperature, and then 4-iodo-2-(2,2,2-trifluoroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (966 mg, 2.28 mmol, 1 eq), K ₂CO ₃(948 mg, 6.86 mmol, 3 equivalents), Pd(dppf)Cl ₂(167 mg, 0.23 mmol, 0.1 eq), 1,4-dioxane (10 mL) and H ₂O (5 mL). The reaction mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (50 mL), and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/5) to give 1 g of 1-methyl-6-oxo-5-[3-oxo-2-(2,2,2-trifluoroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl]pyridine-3-carboxylic acid methyl ester (INT-A20-6) (94%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=462.00. Step 7. Preparation of methyl 5-[5-hydroxy-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A20-7). A mixture of methyl 1-methyl-6-oxo-5-[3-oxo-2-(2,2,2-trifluoroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl]pyridine-3-carboxylate (1 g, 2.17 mmol, 1 eq.) and HCl in 1,4-dioxane (20 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was treated with saturated NaHCO ₃(aqueous solution) solution (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×200 mL) and purified by anhydrous Na ₂SO ₄Drying and concentrating under reduced pressure gave 700 mg of methyl 5-[5-hydroxy-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A20-7) (97%) as a brown solid. ¹H NMR (DMSO, 400 MHz) δ 3.67 (3H, s), 3.84 (3H, s), 4.78 (2H, q), 8.11 (1H, s), 8.33 (1H, s), 8.50 (1H, d). Step 8. 4-(3-{[(2 RPreparation of tert-butyl 5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-(2,2,2-trifluoroethyl)pyrazol-3-yl}oxy)-2-methylpentyl]amino}-4-nitrophenyl)piperazine-1-carboxylate (INT-A20-8). To a stirred solution of methyl 5-[5-hydroxy-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (970 mg, 2.93 mmol, 1.00 equiv) and triphenylphosphine (2.304 g, 8.78 mmol, 3 equiv) in tetrahydrofuran (15 mL) under nitrogen atmosphere at 0° C. was added tert-butyl 4-(3-{[(2R)-5-hydroxy-2-methylpentyl]amino}-4-nitrophenyl)piperazine-1-carboxylate (INT-A20-2, 1.237 g, 2.93 mmol, 1.00 equiv) and diisopropyl azodicarboxylate (1.776 g, 8.78 mmol, 3 equiv). The resulting mixture was stirred at 0° C. for 2 h under nitrogen atmosphere. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate to give 1.2 g of 4-(3-{[(2 R)-5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-(2,2,2-trifluoroethyl)pyrazol-3-yl}oxy)-2-methylpentyl]amino}-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (INT-A20-8) (55%). LCMS: m/z (ESI), [M+H] ⁺=736.25. Step 9. 4-(4-amino-3-{[(2 RPreparation of tert-butyl 5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-(2,2,2-trifluoroethyl)pyrazol-3-yl}oxy)-2-methylpentyl]amino}phenyl)piperazine-1-carboxylate (INT-A20-9). In a nitrogen atmosphere at 0 ° C, 4-(3-{[(2 RTo a stirred mixture of tert-butyl 5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-(2,2,2-trifluoroethyl)pyrazol-3-yl}oxy)-2-methylpentyl]amino}-4-nitrophenyl)piperazine-1-carboxylate (600 mg, 0.81 mmol, 1 eq.) and ranyl nickel (699 mg, 8.15 mmol, 10 eq.) in methanol (5 mL) was added hydrazine hydrate (61 mg, 1.22 mmol, 1.5 eq.). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was filtered. The filter cake was washed with methanol (3×30 mL), and the solution was concentrated under reduced pressure to obtain 575 mg of 4-(4-amino-3-{[(2 R)-5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-(2,2,2-trifluoroethyl)pyrazol-3-yl}oxy)-2-methylpentyl]amino}phenyl)piperazine-1-carboxylate (INT-A20-9). This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=706.45. Step 10. 4-{2-amino-3-[(2 RPreparation of tert-butyl 5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-(2,2,2-trifluoroethyl)pyrazol-3-yl}oxy)-2-methylpentyl]-1,3-benzodiazol-5-yl}piperazine-1-carboxylate (INT-A20-10). A solution of tert-butyl 4-(4-amino-3-{[(2R)-5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-(2,2,2-trifluoroethyl)pyrazol-3-yl}oxy)-2-methylpentyl]amino}phenyl)piperazine-1-carboxylate (600 mg, 0.85 mmol, 1 eq) and BrCN (108 mg, 1.02 mmol, 1.2 eq) in dichloromethane (8 mL) was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC eluting with dichloromethane/methanol (10/1) to give 180 mg of 4-{2-amino-3-[(2 R)-5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-(2,2,2-trifluoroethyl)pyrazol-3-yl}oxy)-2-methylpentyl]-1,3-benzodiazol-5-yl}piperazine-1-carboxylic acid tert-butyl ester (INT-A20-10) (29%). ¹H NMR (DMSO, 400 MHz) δ 0.81 (4H, d), 1.15-1.34 (4H, m), 1.36-1.48 (11H, m), 1.70-1.76 (1H, m), 1.85-1.91 (1H, m), 1.97-2.05 (1H, m), 2.93-2.99 (4H, m), 3.30-3.37 (3H, m), 3.55-3.63 (3H, m), 3.75-3.83 (3H, m), 3.82-3.98 (5H, m), 4.86-4.96 (2H, m), 5.77 (6H, s), 6.67-6.77 (1H, m), 6.90 (1H, s), 6.97-7.16 (3H, m), 8.03 (1H, s), 8.05 (1H, d), 8.52 (1H, d). Step 11. 5-(5-{[(4 R)-4-({2-amino-6-[4-(tert-butoxycarbonyl)piperazine-1-yl]-1,3-benzodiazol-1-yl}methyl)pentyl]oxy}-1-(2,2,2-trifluoroethyl)pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A20-11). 4-{2-amino-3-[(2 R)-5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-(2,2,2-trifluoroethyl)pyrazol-3-yl}oxy)-2-methylpentyl]-1,3-benzodiazol-5-yl}piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.20 mmol, 1 equivalent) and LiOH.H ₂O (13 mg, 0.31 mmol, 1.5 equivalents) in tetrahydrofuran (4 mL) and H ₂The mixture in 4% O (1 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography on a C18 silica gel column eluted with acetonitrile/water (0% to 100% gradient) to give 70 mg of 5-(5-{[(4 R)-4-({2-amino-6-[4-(tert-butoxycarbonyl)piperazine-1-yl]-1,3-benzodiazol-1-yl}methyl)pentyl]oxy}-1-(2,2,2-trifluoroethyl)pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A20-11) (47%). ¹H NMR (DMSO, 400 MHz) δ 0.76 (3H, d), 1.25 (1H, s), 1.42 (9H, s), 1.54-1.61 (1H, m), 1.70-1.76 (1H, m), 1.85-1.91 (1H, m), 1.97-2.05 (1H, s), 2.93-2.99 (4H, m), 3.30-3.37 (3H, m), 3.55-3.63 (3H, m), 3.75-3.83 (3H, m), 3.82-3.98 (5H, m), 4.88 (2H, m), 6.54 (2H, s), 6.60 (1H, q), 6.79 (1H, d), 6.96 (1H, d), 8.02 (1H, s), 8.04 (1H, d), 8.25 (1H, d). Step 12. Preparation of tert-butyl 4-[(11R)-11,26-dimethyl-23,27-dioxo-5-(2,2,2-trifluoroethyl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecano-1(28),2(6),3, 14,16,18,20,24-octan-16-yl]piperazine-1-carboxylate (INT-A20-12). N,N-diisopropylethylamine (27 mg, 0.21 mmol, 3 equivalents), 5-(5-{[(4R)-4-({2-amino-6-[4-(tert-butoxycarbonyl)piperazin-1-yl]-1,3-benzodiazol-1-yl}methyl)pentyl]oxy}-1-(2,2,2-trifluoroethyl)pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (50 mg, 0.07 mmol, 1 equivalent) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)urea hexafluorophosphate (40 mg, 0.10 mmol, 1.5 equiv.) in 1,4-dioxane (2 mL) was stirred at 60 °C overnight under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (30 mL), and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×20 mL), purified by anhydrous Na ₂SO ₄The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 48 mg of tert-butyl 4-[(11R)-11,26-dimethyl-23,27-dioxo-5-(2,2,2-trifluoroethyl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacos-1(28), 2(6),3,14,16,18,20,24-octan-16-yl]piperazine-1-carboxylate (INT-A20-12) (98%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=699.45. Step 13. (11 RPreparation of )-11,26-dimethyl-16-(piperazin-1-yl)-5-(2,2,2-trifluoroethyl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (INT-A20-13). A mixture of tert-butyl 4-[(11R)-11,26-dimethyl-23,27-dioxo-5-(2,2,2-trifluoroethyl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacos-1(28),2(6),3,14,16,18,20,24-octan-16-yl]piperazine-1-carboxylate (INT-A20-13 40 mg, 0.06 mmol, 1 eq.) and trifluoroacetic acid (0.5 mL) in dichloromethane (2 mL) was stirred under nitrogen atmosphere at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. Saturate the residue with NaHCO₃(aqueous solution) solution (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×200 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The crude product was used directly in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺=599.15. Step 14. (11 R)-11,26-dimethyl-16-(4-methylpiperazine-1-yl)-5-(2,2,2-trifluoroethyl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (Example A20). At room temperature, (11 RTo a stirred mixture of 1,1,26-dimethyl-16-(piperazin-1-yl)-5-(2,2,2-trifluoroethyl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacos-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (40 mg, 0.07 mmol, 1 eq), trimethylamine (20 mg, 0.20 mmol, 3 eq) and paraformaldehyde (6 mg, 0.06 mmol, 1 eq) in dichloromethane (2 mL) was added sodium acetyloxyborohydride (42 mg, 0.20 mmol, 3 eq). The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (5/1) to give 6.7 mg (11 R)-11,26-dimethyl-16-(4-methylpiperazine-1-yl)-5-(2,2,2-trifluoroethyl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A20) (16%). LCMS: m/z (ESI), [M+H] ⁺=613.30. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.77-0.89 (5H, m), 1.11-1.29 (9H, m), 1.40-1.50 (2H, m), 1.85-1.92 (2H, m), 2.15-2.21 (2H, m), 2.28 (3H, s), 2.75-2.80 (1H, m), 3.14-3.20 (3H, m), 3.63 (3H, s), 3.90-3.96 (2H, m), 4.07-4.11 (1H, m), 4.43-4.48 (1H, m), 4.93-5.00 (1H, m), 6.87 (1H, d), 7.14 (1H, s), 7.36 (1H, d), 8.31 (1H, d), 8.46 (1H, s), 8.73 (1H, d), 12.37 (1H, s) Example A21 (11 R)-5-ethyl-11,26-dimethyl-16-(4-methylpiperazine-1-yl)-7-oxo-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. Preparation of 2-ethylpyrazol-3-ol (INT-A21-1). A mixture of ethylhydrazine dihydrochloride (5.7 g, 43.06 mmol, 1 equivalent) and (2E)-3-methoxyprop-2-enoic acid methyl ester (5 g, 43.06 mmol, 1 equivalent) in methanol (50 mL) was stirred at 80 ° C overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (1/1) to obtain 4 g of 2-ethylpyrazol-3-ol (INT-A21-1) (82%) as a white solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.26 (3H, t), 3.94-3.98 (2H, m), 5.82 (1H, m), 7.48 (1H, d), 10.99 (1H, s). Step 2. Preparation of 2-ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (INT-A21-2). 2-Ethylpyrazol-3-ol (5 g, 44.59 mmol, 1 eq.), 2-(trimethylsilyl)ethoxymethyl chloride (11.15 g, 66.88 mmol, 1.5 eq.) and K ₂CO ₃A mixture of (15.41 g, 111.47 mmol, 2.5 equiv) in acetonitrile (50 mL) was stirred at room temperature under nitrogen atmosphere for 0.5 h. The reaction was quenched with water (500 mL), and the mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (3×500 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by silica gel chromatography using petroleum ether/ethyl acetate (1/1) to give 1.5 g of 2-ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (INT-A21-2) (13%) as a yellow oil. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.00 (9H, s), 0.79-0.84 (2H, m), 1.04 (3H, t), 3.38-3.47 (2H, m), 3.77 (2H, q), 5.08 (2H, s), 5.27 (1H, d), 7.89 (1H, d) Step 3. Preparation of 2-ethyl-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (INT-A21-3). 2-Ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (1.15 g, 4.74 mmol, 1 equivalent) and N-iodosuccinimide (1.28 g, 5.69 mmol, 1.2 equivalents) in acetonitrile (15 mL) was stirred at 0 °C for 3 h under nitrogen atmosphere. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (1/1) to give 1.9 g of 2-ethyl-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (INT-A21-3) (97%) as a yellow solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.03 (9H, s), 0.81 (2H, t), 1.05 (3H, t), 3.43 (2H, t), 3.83 (2H, q), 5.09 (2H, s), 8.17 (1H, s). Step 4. Preparation of 5-(2-ethyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A21-4). 5-Bromo-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (1.4 g, 5.69 mmol, 1 equivalent), bis(pinacol)diboron (1.73 g, 6.82 mmol, 1.2 equivalent), KOAc (1.4 g, 14.22 mmol, 2.5 equivalent) and Pd(dppf)Cl ₂A mixture of dichloromethane (0.46 g, 0.57 mmol, 0.1 eq.) in dioxane (16 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. 2-ethyl-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (1.7 g, 4.61 mmol, 0.9 eq.), Pd(dppf)Cl ₂Dichloromethane (0.28 g, 0.51 mmol, 0.1 equivalent), K ₂CO ₃(1.91 g, 13.82 mmol, 2.7 eq.) and H ₂O (4 mL), the reaction mixture was cooled to room temperature. The reaction was stirred at 80 °C for another 2 h under nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane/methanol (10/1) to obtain 1.6 g of ethyl 5-(2-ethyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A21-4) (76%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=408.10. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.05 (9H, s), 0.82 (2H, t), 1.10-1.13 (3H, m), 3.47 (2H, t), 3.60 (3H, s), 3.81 (3H, s), 3.89 (2H, q), 5.29 (2H, s), 8.43 (1H, d), 8.88 (1H, s), 9.21 (1H, d). Step 5. Preparation of 5-(1-ethyl-5-hydroxypyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A21-5). A solution of methyl 5-(2-ethyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (1.6 g, 3.92 mmol, 1 eq) and HCl (20 mL, 4 M in 1,4-dioxane) was stirred at room temperature for 2 h. The residue was treated with dichloromethane (30 mL) and K ₂CO ₃Work up. The mixture was filtered. The filter cake was washed with dichloromethane (3×20 mL). The resulting solution was concentrated under reduced pressure to give 640 mg of methyl 5-(1-ethyl-5-hydroxypyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A21-5) as a yellow solid. This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=278.00. Step 6. 5-(5-{[(4 RPreparation of methyl 5-(1-ethyl-5-hydroxypyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A21-6). A mixture of methyl 5-(1-ethyl-5-hydroxypyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (670 mg, 2.41 mmol, 1 eq.) and triphenylphosphine (1.58 g, 6.04 mmol, 2.5 eq.) in tetrahydrofuran (10 mL) was treated with diisopropyl azodicarboxylate (0.98 g, 4.83 mmol, 2 eq.) at 0°C under nitrogen atmosphere for 1 h, followed by the addition of (4 R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentan-1-ol (M3-7, 766 mg, 2.41 mmol, 1 equiv). After stirring for another 4 h at 0 °C under nitrogen atmosphere, the reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 720 mg of 5-(5-{[(4 R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentyl]oxy}-1-ethylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A21-6) (51%). LCMS: m/z (ESI), [M+H] ⁺=578.00. Step 7. 5-(5-{[(4 RPreparation of 5-(5-{[(4 )-5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}-1-ethylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A21-7).RA mixture of methyl 5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentyl]oxy}-1-ethylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (720 mg, 1.25 mmol, 1 equiv), ranyl nickel (54 mg, 0.62 mmol, 0.5 equiv) and hydrazine (120 mg, 3.74 mmol, 3 equiv) in methanol (15 mL) was stirred at room temperature for 2 h. The resulting mixture was filtered and the filter cake was washed with methanol (3×20 mL). The resulting solution was concentrated under reduced pressure to give 600 mg of 5-(5-{[(4 R)-5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}-1-ethylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A21-7). This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=546.20. Step 8. 5-(5-{[(4 RPreparation of methyl 4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-ethylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A21-8). 5-(5-{[(4 RA mixture of methyl 5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}-1-ethylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (600 mg, 1.10 mmol, 1 equiv) and cyanogen bromide (232 mg, 2.20 mmol, 2 equiv) in ethanol (15 mL) was stirred at room temperature for 2 h and concentrated. The residue was purified by silica gel chromatography using dichloromethane/methanol (10/1) to give 400 mg of 5-(5-{[(4 R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-ethylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A21-8) (63%). LCMS: m/z (ESI), [M+H] ⁺=573.30. Step 9. 5-(5-{[(4 RPreparation of 5-(5-{[(4 RTo a stirred mixture of methyl 4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-ethylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (700 mg, 1.22 mmol, 1 eq.) in tetrahydrofuran (15 mL) was added LiOH (58 mg, 2.45 mmol, 2 eq.) in H ₂O (3 mL). The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using 10% to 50% acetonitrile/water to give 600 mg of 5-(5-{[(4 R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-ethylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A21-9) (87%). LCMS: m/z (ESI), [M+H] ⁺=559.30. Step 10. (11 R)-16-bromo-5-ethyl-11,26-dimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A21-10). 5-(5-{[(4 R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-ethylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (460 mg, 0.82 mmol, 1 equivalent), N,N,N,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (627 mg, 1.65 mmol, 2 equivalents) and N, N- A mixture of diisopropylethylamine (213 mg, 1.65 mmol, 2 equiv.) in dioxane (10 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC eluting with dichloromethane/methanol (15/1) to give 430 mg (11 R)-16-bromo-5-ethyl-11,26-dimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (INT-A21-10) (96%). LCMS: m/z (ESI), [M+H] ⁺=541.00. Step 11. (11 R)-5-ethyl-11,26-dimethyl-16-(4-methylpiperazine-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A21). In a nitrogen atmosphere at room temperature to (11 R)-16-bromo-5-ethyl-11,26-dimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (100 mg, 0.18 mmol, 1 equivalent), BrettPhos Pd G ₃To a mixture of 1,4-dioxane (5 mL) and 1-methylpiperazine (84.02 mg, 0.09 mmol, 0.5 eq.) was added LiHMDS (1.1 mL, 1.11 mmol, 6 eq.) dropwise. The reaction mixture was stirred at 60 °C for 30 min. After cooling to room temperature, the reaction was heated with saturated NH₄Cl solution (100 mL) was quenched, and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (18/1) to give 29 mg (11 R)-5-ethyl-11,26-dimethyl-16-(4-methylpiperazine-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A21) (28%). LCMS: m/z (ESI), [M+H] ⁺=559.35. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.80 (3H, d), 1.37 (3H, t), 1.45 (1H, t), 1.90 (2H, d), 2.17-2.25 (4H, m), 2.51 (4H, t), 2.79 (1H, s), 3.15 (4H, t), 3.61 (3H, s), 3.86-4.13 (5H, m), 4.36-4.40 (1H, m), 6.86 (1H, d), 7.12 (1H, d), 7.35 (1H, d), 8.26 (1H, d), 8.37 (1H, s), 8.78 (1H, d), 12.35 (1H, s). Example A22 (11 R)-5-cyclopropyl-11,26-dimethyl-16-(4-methylpiperazine-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. 5-(5-{[(4 RPreparation of methyl 5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentyl]oxy}-1-cyclopropylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A22-1). To a stirred mixture of methyl 5-(1-cyclopropyl-5-hydroxypyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-2-7, 750 mg, 2.59 mmol, 1 eq) and triphenylphosphine (1360 mg, 5.19 mmol, 2 eq) in tetrahydrofuran (10 mL) at 0°C, diisopropyl azodicarboxylate (1048 mg, 5.19 mmol, 2 eq) and (4 R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentan-1-ol (M3-7, 905 mg, 2.85 mmol, 1.1 equiv). The resulting mixture was stirred at 0 °C for 2 h under a nitrogen atmosphere. The reaction was quenched with water (30 mL), and the mixture was extracted with dichloromethane (3×30 mL). The combined organic layers were purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/1) to give 700 mg of 5-(5-{[(4 R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentyl]oxy}-1-cyclopropylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A22-1) (45%). LCMS: m/z (ESI), [M+H] ⁺=590.10 Step 2. 5-(5-{[(4 RPreparation of methyl 5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}-1-cyclopropylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A22-2). At 0°C, 5-(5-{[(4 R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentyl]oxy}-1-cyclopropylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (700 mg, 1.19 mmol, 1 equiv) and ranyl nickel (51 mg, 0.60 mmol, 0.5 equiv) were added to a stirring mixture of methanol (15 mL) with NH ₂NH ₂.H ₂O (90 mg, 1.79 mmol, 1.5 equiv). The mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. The mixture was filtered. The filter cake was washed with methanol (2×20 mL). The resulting solution was concentrated under reduced pressure. The residue was purified on a silica gel column using dichloromethane/methanol (10/1) to obtain 570 mg 5-(5-{[(4 R)-5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}-1-cyclopropylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A22-2) (85%). LCMS: m/z (ESI), [M+H] ⁺=560.40 Step 3. 5-(5-{[(4 RPreparation of methyl 4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-cyclopropylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A22-3). 5-(5-{[(4 RA mixture of methyl 5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}-1-cyclopropylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (570 mg, 1.02 mmol, 1 eq.) and BrCN (162 mg, 1.53 mmol, 1.5 eq.) in ethanol (5 mL) was stirred at room temperature for 2 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was purified on a silica gel column using dichloromethane/methanol (10/1) for elution to obtain 550 mg of 5-(5-{[(4 R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-cyclopropylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A22-3) (92%). LCMS: m/z (ESI), [M+H] ⁺=585.15 Step 4. 5-(5-{[(4 RPreparation of 5-(5-{[(4 )-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-cyclopropylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A22-4).RTo a stirred mixture of methyl 4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-cyclopropylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (480 mg, 0.823 mmol, 1 eq.) in tetrahydrofuran (20 mL) was added LiOH (78.81 mg, 3.292 mmol, 4 eq.) and H ₂O (5 mL). The resulting mixture was stirred at 60 °C for 30 min. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using 10% to 40% acetonitrile/water elution to give 380 mg of 5-(5-{[(4 R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-cyclopropylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A22-4) (81%). LCMS: m/z (ESI), [M+H] ⁺= 571.00. Step 5. (11 R)-16-bromo-5-cyclopropyl-11,26-dimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A22-5). 5-(5-{[(4 R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1-cyclopropylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (375 mg, 0.66 mmol, 1 equivalent), N, N-Diisopropylethylamine (255 mg, 1.98 mmol, 3 equiv.) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)urea hexafluorophosphate (375 mg, 0.98 mmol, 1.5 equiv.) in 1,4-dioxane (10 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and saturated with NH₄Cl(aqueous solution) (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column eluting with dichloromethane/methanol (10/1) to give 330 mg (11 R)-16-bromo-5-cyclopropyl-11,26-dimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A22-5) (90%). LCMS: m/z (ESI), [M+H] ⁺= 553.10. Step 6. (11 R)-5-cyclopropyl-11,26-dimethyl-16-(4-methylpiperazine-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A22). In a nitrogen atmosphere at room temperature to (11 R)-16-bromo-5-cyclopropyl-11,26-dimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (90 mg, 0.16 mmol, 1 equivalent), BrettPhos Pd G ₃To a stirred mixture of 4-(44 mg, 0.05 mmol, 0.3 eq.) and 1-methylpiperazine (49 mg, 0.49 mmol, 3 eq.) in 1,4-dioxane (9 mL) was added LiHMDS (2.7 mL, 2.7 mmol, 16.9 eq.). The mixture was stirred at 60 °C for 30 min under nitrogen atmosphere and cooled to room temperature. The reaction was heated with saturated NH₄Cl(aq) solution (30 mL) was quenched, and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using dichloromethane/methanol (15/1) to give 24.7 mg of the title compound (Example A22) as an off-white solid (26%). LCMS: m/z (ESI), [M+H] ⁺=571.40. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.81 (3H, d), 0.971.06 (4H, m), 1.37-1.54 (1H, m), 1.83-2.03 (2H, m), 2.17-2.23 (1H, m), 2.24 (3H, s), 2.50 (4H, t), 2.82 (1H, br s), 3.15 (4H, br s), 3.53-3.60 (1H, m), 3.61 (3H, s), 3.85-4.20 (3H, m), 4.30-4.47 (1H, m), 6.86 (1H, dd), 7.13 (1H, d), 7.35 (1H, d), 8.26 (1H, d), 8.30 (1H, s), 8.84 (1H, d), 12.35 (1H, s). Example A23 (11 R)-15-chloro-5,11,26-trimethyl-16-(4-methylpiperazine-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. (4 RPreparation of )-5-[(2-chloro-3-fluoro-6-nitrophenyl)amino]-4-methylpentan-1-ol (INT-A23-1). 2-Chloro-1,3-difluoro-4-nitrobenzene (1.73 g, 8.96 mmol, 1.05 equivalents) and (4 R)-5-amino-4-methylpentan-1-ol (M3-6, 1 g, 8.53 mmol, 1 equivalent) was added in portions to a stirred mixture in acetonitrile (25 mL) with K ₂CO ₃(2.36 g, 17.06 mmol, 2 eq.). The mixture was stirred at 60 °C for 2 h under nitrogen atmosphere and cooled to room temperature. The reaction was quenched with water (100 mL) and the mixture was washed with CH₂Cl ₂(3×100 mL) extraction. The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (3/1) to give 2 g (4 R)-5-[(2-chloro-3-fluoro-6-nitrophenyl)amino]-4-methylpentan-1-ol (INT-A23-1) (80%). LCMS: m/z (ESI), [M+H] ⁺=290.95. ¹H NMR (DMSO-d6, 400 MHz) δ 0.82 (3H, d), 1.01 - 1.30 (2H, m), 1.31-1.72 (3H, m), 2.78-2.89 (1H, m), 2.94-3.09 (1H, m), 3.33 (2H, d), 4.37 (1H, t), 6.59 (1H, t), 7.22 (1H, d), 7.76 (1H, d). Step 2. 4-(2-chloro-3-{[(2 RPreparation of tert-butyl 5-hydroxy-2-methylpentyl]amino}-4-nitrophenyl)piperazine-1-carboxylate (INT-A23-2). At room temperature, (4 R)-5-[(2-chloro-3-fluoro-6-nitrophenyl)amino]-4-methylpentan-1-ol (2 g, 6.87 mmol, 1 eq.) and tert-butyl piperazine-1-carboxylate (2.56 g, 13.75 mmol, 2 eq.) were added dropwise to a stirred mixture in dimethyl sulfoxide (30 mL).N,N-Diisopropylethylamine (1.78 g, 13.75 mmol, 2 equiv.). The mixture was stirred at 120 °C for 4 h under nitrogen atmosphere and cooled to room temperature. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (10/1) to give 3.1 g of 4-(2-chloro-3-{[(2 R)-5-hydroxy-2-methylpentyl]amino}-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (INT-A23-2) (98%). LCMS: m/z (ESI), [M+H] ⁺=457.15. Step 3. 4-(2-chloro-3-{[(2 RPreparation of tert-butyl 5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}-4-nitrophenyl)piperazine-1-carboxylate (INT-A23-3). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 576.04 mg, 1.09 mmol, 1 eq.) and triphenylphosphine (1.7 g, 3.28 mmol, 3 eq.) in tetrahydrofuran (10 mL) at 0°C were added diisopropyl azodicarboxylate (1.3 g, 3.28 mmol, 3 eq.) and 4-(2-chloro-3-{[(2 R)-5-hydroxy-2-methylpentyl]amino}-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (1 g, 1.09 mmol, 1 equiv). The mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC and eluted with dichloromethane/methanol (25/1) to give 1.1 g of 4-(2-chloro-3-{[(2 R)-5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (INT-A23-3) (66%). LCMS: m/z (ESI), [M+H] ⁺=702.15. Step 4. 4-(4-amino-2-chloro-3-{[(2 RPreparation of tert-butyl 5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}phenyl)piperazine-1-carboxylate (INT-A23-4). Raney nickel (500 mg) and 4-(2-chloro-3-{[(2 R)-tert-butyl 5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}-4-nitrophenyl)piperazine-1-carboxylate (1.1 g, 1.56 mmol, 1 equivalent) was added to a stirring mixture of NH ₂NH ₂ ^.H ₂O (235.26 mg, 4.69 mmol, 3 equiv.). The mixture was stirred at 0 °C for 1 h and filtered. The filter cake was washed with methanol (2×20 mL). The resulting solution was concentrated under reduced pressure. The residue was purified by Prep-TLC and eluted with dichloromethane/methanol (10/1) to give 610 mg of 4-(4-amino-2-chloro-3-{[(2 R)-5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}phenyl)piperazine-1-carboxylic acid tert-butyl ester (INT-A23-4) (52%). LCMS: m/z (ESI), [M+H] ⁺=672.20. ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.95 (3H, d), 1.95-1.25 (1H, m), 1.36-1.45 (11H, m), 1.59-1.75 (2H, m), 2.65-2.78 (5H, m), 2.81 (1H, d), 3.57 (4H, s), 3.62-3.76 (7H, m), 3.81 (1H, d), 3.92 (2H, t), 5.76 (3H, s), 6.49-6.59 (2H, m), 7.58-7.69 (1H, m), 8.00 (1H, s), 8.14 (1H, d), 8.45 (1H, d). Step 5. 4-{2-amino-4-chloro-3-[(2 RPreparation of tert-butyl 5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]-1,3-benzodiazol-5-yl}piperazine-1-carboxylate (INT-A23-5). 4-(4-amino-2-chloro-3-{[(2 RA mixture of tert-butyl 5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}phenyl)piperazine-1-carboxylate (600 mg, 0.89 mmol, 1 eq.) and BrCN (94.54 mg, 0.89 mmol, 1 eq.) in ethanol (8 mL) was stirred at room temperature for 2 h under nitrogen atmosphere and concentrated under vacuum. The residue was purified by Prep-TLC and eluted with dichloromethane/methanol (12/1) to give 480 mg of 4-{2-amino-4-chloro-3-[(2 R)-5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]-1,3-benzodiazol-5-yl}piperazine-1-carboxylic acid tert-butyl ester (INT-A23-5) (76%). LCMS: m/z (ESI), [M+H] ⁺=697.20. ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.01 (5H, s), 1.24 (2H, s), 1.78-1.92 (8H, m), 2.60-2.79 (2H, m), 2.81-2.95 (4H, m), 3.17 (3H, d), 3.57 (3H, s), 3.71 (6H, d), 4.01-4.22 (2H, m), 5.95 (2H, s), 7.04 (2H, s), 7.47 (1H, s), 7.96 (1H, s), 8.12 (1H, d), 8.39 (1H, d). Step 6 and Step 7. 4-[(11 RPreparation of tert-butyl 1-(28),2(6),3,14,16,18,20,24-octan-16-yl)piperazine-1-carboxylate (INT-A23-7). 4-{2-amino-4-chloro-3-[(2 R)-tert-butyl 5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]-1,3-benzodiazol-5-yl}piperazine-1-carboxylate (INT-A23-5, 450 mg, 0.76 mmol, 1 equiv) and LiOH (18 mg, 0.71 mmol, 1.2 equiv) in tetrahydrofuran/H ₂O (2 mL/1 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under vacuum. To the residue was added N,N,N,N-Tetramethyl- O-(7-Azabenzotriazole-1-yl)urea hexafluorophosphate (166.96 mg, 0.44 mmol, 1.5 equivalents)) , N,N-Diisopropylethylamine (113.51 mg, 0.87 mmol, 3 equivalents) and 1,4-dioxane (6 mL). The mixture was stirred under nitrogen atmosphere for 3 h. The mixture was treated with water (10 mL), extracted with ethyl acetate (3×10 mL), and washed with anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC and eluted with methylene dichloride/methanol (12/1) to give 160 mg 4-[(11 R)-15-chloro-5,11,26-trimethyl-23,27-dioxo-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecano-1(28),2(6),3,14,16,18,20,24-octan-16-yl]piperazine-1-carboxylic acid tert-butyl ester (INT-A23-7) (78%). LCMS: m/z (ESI), [M+H] ⁺=665.15. Step 8. (11 R)-15-chloro-5,11,26-trimethyl-16-(piperazine-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A23). 4-[(11 R)-15-chloro-5,11,26-trimethyl-23,27-dioxo-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecano-1(28),2(6),3,14,16,18,20,24-octan-16-yl]piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.22 mmol, 1 equivalent) in trifluoroacetic acid (1 mL) and CH ₂Cl ₂The mixture in (4 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was concentrated under reduced pressure. The residue was treated with saturated NaHCO₃Solution treatment and CH ₂Cl ₂(3×10 mL) extraction. The combined organic layers were washed with brine (3×10 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC and eluted with methylene dichloride/methanol (12/1) to give 13.5 mg (11 R)-15-chloro-5,11,26-trimethyl-16-(piperazine-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (Example A23) (56%). LCMS: m/z (ESI), [M+H] ⁺=565.35. ¹H NMR (DMSO-d ₆, 400 MHz) δ1.23-1.32 (3H, m), 1.52-1.59 (2H, m), 1.73 (1H, s), 1.95 (1H, s), 2.12-2.19 (1H, m), 2.89-2.97 (9H, m), 3.62-3.69 (3H, m), 3.71-3.76 (3H, m), 3.90 (1H, s), 4.19 (1H, m), 4.32-4.39 (1H, m), 4.70-4.79 (1H, m), 7.09-7.27 (1H, m), 7.50 (1H, d), 8.28-8.45 (2H, m), 8.65-8.76 (1H, m). Example A25 (11 R)-5,11,26-trimethyl-16-(4-methylpiperazine-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. Preparation of 1-(3-chloro-4-nitrophenyl)-4-methylpiperazine (INT-A25-1). 2-Chloro-4-fluoro-1-nitrobenzene (4 g, 22.79 mmol, 1 equivalent) and 1-methylpiperazine-(2.28 g, 22.79 mmol, 1 equivalent) and K ₂CO ₃(6.3 g, 45.57 mmol, 2 equiv.) in acetonitrile (60 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature, treated with water (100 mL), and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/1) to give 5.6 g of 1-(3-chloro-4-nitrophenyl)-4-methylpiperazine (INT-A25-1) (96%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=256.05. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.22 (3H, s), 2.41 (4H, t), 3.45 (4H, t), 7.00-7.03 (1H, m), 7.10 (1H, d), 8.02 (1H, d). Step 2. (4 RPreparation of )-4-methyl-5-{[5-(4-methylpiperazine-1-yl)-2-nitrophenyl]amino}pentan-1-ol (INT-A25-1). 1-(3-chloro-4-nitrophenyl)-4-methylpiperazine (1.5 g, 5.87 mmol, 1 equivalent), K ₂CO ₃(1.62 g, 11.73 mmol, 2 equiv.) and (4 R)-5-amino-4-methylpentan-1-ol (M3-6, 0.82 g, 7.04 mmol, 1.2 equivalents) in N,N-The mixture in dimethylformamide (10 mL) was stirred at 120 °C for 16 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, treated with water (80 mL), and extracted with dichloromethane (3×70 mL). The combined organic layers were washed with brine (3×500 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC eluting with petroleum ether/ethyl acetate (1/1) to give 1.5 g (4 R)-4-methyl-5-{[5-(4-methylpiperazine-1-yl)-2-nitrophenyl]amino}pentan-1-ol (INT-A25-2) (76%). LCMS: m/z (ESI), [M+H] ⁺=337.15. Step 3. 1-methyl-5-(1-methyl-5-{[(4 RPreparation of methyl 5-{[5-(4-methylpiperazine-1-yl)-2-nitrophenyl]amino}pentyl]oxy}pyrazol-4-yl)-6-oxopyridine-3-carboxylate (INT-A25-3). To a stirred mixture of triphenylphosphine (1.57 g, 5.97 mmol, 3 equiv.) and methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 498.05 mg, 1.89 mmol, 0.95 equiv.) in tetrahydrofuran (20 mL) was added (4 R)-4-methyl-5-{[5-(4-methylpiperazin-1-yl)-2-nitrophenyl]amino}pentan-1-ol (670 mg, 1.99 mmol, 1 equiv) and diisopropyl azodicarboxylate (1.21 g, 5.97 mmol, 3 equiv). The mixture was stirred at room temperature for 2 h, treated with water (80 mL), and extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with water (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column eluting with dichloromethane/methanol (35/1) to give 500 mg of 1-methyl-5-(1-methyl-5-{[(4R)-4-methyl-5-{[5-(4-methylpiperazin-1-yl)-2-nitrophenyl]amino}pentyl]oxy}pyrazol-4-yl)-6-oxopyridine-3-carboxylic acid methyl ester (INT-A25-3) (43%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺=582.20. Step 4. 5-(5-{[(4 RPreparation of methyl 5-{[2-amino-5-(4-methylpiperazine-1-yl)phenyl]amino}-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A25-4). In a nitrogen atmosphere at 0 ° C, 1-methyl-5-(1-methyl-5-{[(4 RTo a stirred mixture of methyl 4-(4-methyl-5-{[5-(4-methylpiperazin-1-yl)-2-nitrophenyl]amino}pentyl]oxy}pyrazol-4-yl)-6-oxopyridine-3-carboxylate (700 mg, 1.20 mmol, 1 eq.) in methanol (6 mL) were added Ranyl nickel (349.52 mg, 4.08 mmol, 3.4 eq.) and NH ₂NH ₂ ^.H ₂O (90.37 mg, 1.80 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for 1 h, treated with water (20 mL), and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with water (3×10 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to obtain 510 mg of 5-(5-{[(4 R)-5-{[2-amino-5-(4-methylpiperazin-1-yl)phenyl]amino}-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A25-4) (77%). This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=552.25. Step 5. 5-(5-{[(4 RPreparation of methyl 4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A25-5). In a nitrogen atmosphere, 5-(5-{[(4 RTo a stirred mixture of methyl 2-(2-{[2-amino-5-(4-methylpiperazin-1-yl)phenyl]amino}-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (480 mg, 0.87 mmol, 1 equiv) in dichloromethane (8 mL) was added cyanogen bromide (138.24 mg, 1.30 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h, treated with water (20 mL), and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane/methanol (15/1) to give 170 mg of 5-(5-{[(4 R)-4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A25-5) (34%). LCMS: m/z (ESI), [M+H] ⁺=577.40. Step 6. 5-(5-{[(4 R)-4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A25-6). At room temperature, 5-(5-{[(4 RTo a stirred mixture of methyl 4-{[2-amino-6-(4-methylpiperazin-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (140 mg, 0.24 mmol, 1 eq.) in tetrahydrofuran (4 mL) was added water (0.3 mL) containing LiOH (11.63 mg, 0.49 mmol, 2 eq.). The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography eluting with acetonitrile/water (0% to 100%) to give 37 mg of 5-(5-{[(4 R)-4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A25-6) (27%). LCMS: m/z (ESI), [M+H] ⁺=563.35. Step 7. (11 R)-5,11,26-trimethyl-16-(4-methylpiperazine-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A25). At room temperature, 5-(5-{[(4 R)-4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (34 mg, 0.06 mmol, 1 equivalent) was added to the stirred mixture in dioxane (3 mL) N,N-Diisopropylethylamine (23 mg, 0.18 mmol, 3 equivalents ) and N,N,N,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (34 mg, 0.09 mmol, 1.5 equiv). The resulting mixture was stirred at 60 °C for 1 h under a nitrogen atmosphere, cooled to room temperature, and concentrated under reduced pressure. The residue was passed through Prep-HPLC using an XBridge Shield RP18 OBD column containing 10 mmol/L NH₄HCO ₃of water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 14.4 mg (11 R)-5,11,26-trimethyl-16-(4-methylpiperazin-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (Example A25) (43%). LCMS: m/z (ESI), [M+H] ⁺=545.35. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.81 (3H, d), 1.44 (1H, q), 1.92 (2H, d), 2.12-2.25 (1H, m), 2.25 (3H, s), 2.50 (4H, t), 2.80 (1H, br s), 3.16 (4H, t), 3.62 (3H, s), 3.72 (3H, s), 3.88-3.99 (2H, m), 4.10 (1H, d), 4.33-4.38 (1H, m), 6.86 (1H, dd), 7.13 (1H, d), 7.36 (1H, d), 8.27 (1H, d), 8.36 (1H, s), 8.81 (1H, d), 12.35 (1H, s). Example A26 (11 R)5,11,26-trimethyl-16-(morpholin-4-yl)-7-oxa-4,5,13,20,22, 26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. Preparation of 4-(3-chloro-4-nitrophenyl)morpholine (INT-A26-1). 2-Chloro-4-fluoro-1-nitrobenzene (3 g, 17.09 mmol, 1 equivalent), K ₂CO ₃A mixture of 1,4-dimethoxy- ...₂SO ₄Dry and concentrate under reduced pressure. The residue is purified on a silica gel column eluted with petroleum ether/ethyl acetate (5/1) to give 2.7 g of 4-(3-chloro-4-nitrophenyl)morpholine (INT-A26-1) (65%) as a yellow solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ 3.38-3.49 (4H, m), 3.63-3.75 (4H, m,), 7.00-7.04 (1H, m), 7.12 (1H, d,), 8.04 (1H, d,). Step 2. ( RPreparation of )-4-methyl-5-((5-morpholino-2-nitrophenyl)amino)pentan-1-ol (INT-A26-2). 4-(3-chloro-4-nitrophenyl)morpholine (1 g, 4.12 mmol, 1 equivalent), Cs ₂CO ₃(2.69 g, 8.24 mmol, 2 equiv.) and (4 RA mixture of 5-amino-4-methylpentan-1-ol (0.58 g, 4.94 mmol, 1.2 equiv.) in dimethylacetamide (15 mL) was stirred at 120 °C for 4 h under nitrogen atmosphere and cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by reverse phase flash chromatography using a C18 silica gel column with acetonitrile/water (0% to 100% gradient) as mobile phase to give 730 mg (4 R)-4-methyl-5-{[5-(oxo-4-yl)-2-nitrophenyl]amino}pentan-1-ol (INT-A26-2) (54%). LCMS: m/z (ESI), [M+H] ⁺=324.20. ¹HNMR (DMSO-d ₆, 400 MHz) δ 0.97 (3H, d), 1.21-1.29 (1H, m), 1.40-1.47 (3H, m), 1.78-1.87 (1H, m), 3.09-3.19 (1H, m), 3.21- 3.28 (1H, m), 3.45-3.50 (4H, m) 3.69-3.73 (6H, m), 4.40 (1H, s), 6.40-6.43 (1H, m), 7.00-7.10 (1H, m), 7.92 (1H, d), 8.02-8.12 (1H, m). Step 3. ( RPreparation of methyl 5-(1-methyl-5-((4-methyl-5-((5-oxolino-2-nitrophenyl)amino)pentyl)oxy)-1H-pyrazol-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (INT-A26-3). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 260 mg, 0.98 mmol, 1 eq) and triphenylphosphine (777 mg, 2.964 mmol, 3.0 eq) in tetrahydrofuran (3 mL) at 0°C were added diisopropyl azodicarboxylate (599 mg, 2.96 mmol, 3 eq) and (4 R)-4-methyl-5-{[5-(morpholin-4-yl)-2-nitrophenyl]amino}pentan-1-ol (638 mg, 1.97 mmol, 2 equiv.). The mixture was stirred at 0 °C for 2 h under nitrogen atmosphere, treated with water (100 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC and eluted with petroleum ether/ethyl acetate (1/1) to give 130 mg of 1-methyl-5-(1-methyl-5-{[(4 R)-4-methyl-5-{[5-(pyridine-4-yl)-2-nitrophenyl]amino}pentyl]oxy}pyrazol-4-yl)-6-oxopyridine-3-carboxylic acid methyl ester (INT-A26-3) (23%). LCMS: m/z (ESI), [M+H] ⁺=569.30. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.98 (3H, d), 1.31-1.45 (1H, m), 1.60 (1H, m), 1.74-1.92 (3H, m), 3.16 (1H, m), 3.23-3.30 (1H, m), 3.37-3.43 (4H, m), 3.57 (3H, s), 3.65-3.73 (7H, m), 3.77 (3H, s), 3.96 (2H, t), 6.01 (1H, d), 6.43-6.48 (1H, m), 7.92 (1H, d), 7.99 (1H, s), 8.14 (1H, d), 8.41-8.46 (2H, m). Step 4. ( RPreparation of methyl 5-(5-((5-((2-amino-5-oxolinophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (INT-A26-4). Raney nickel (40 mg, 0.47 mmol, 1 equivalent) and 1-methyl-5-(1-methyl-5-{[(4 R)-4-methyl-5-{[5-(pyridine-4-yl)-2-nitrophenyl]amino}pentyl]oxy}pyrazol-4-yl)-6-oxopyridine-3-carboxylic acid methyl ester (INT-A26-3, 270 mg, 0.47 mmol, 1 equivalent) was added to a stirring mixture in methanol (4 mL) with NH ₂NH ₂ ^.H ₂O (47 mg, 0.95 mmol, 2 eq.). The mixture was stirred at 0 °C for 1 h and filtered. The filter cake was washed with methanol (2×50 mL) and the resulting solution was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺=539.30. Step 5. Methyl-( RPreparation of 5-(5-((5-(2-amino-6-oxo-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A26-5). 5-(5-{[(4 RA mixture of methyl 5-{[2-amino-5-(morpholin-4-yl)phenyl]amino}-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (190 mg, 0.35 mmol, 1 eq.) and BrCN (41 mg, 0.38 mmol, 1.1 eq.) in ethanol (3 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was purified by Prep-TLC and eluted with dichloromethane/methanol (12/1) to give 100 mg of 5-(5-{[(4 R)-4-{[2-amino-6-(pyridine-4-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A26-5) (50%). ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.84 (d, 3H), 1.27-1.40 (1H, m), 1.44-1.60 (1H, m), 1.67-1.71 (1H, m), 1.80-1.94 (1H, m), 2.04 (1H, s), 2.94-3.03 (3H, m), 3.17 (1H, d), 3.55-3.61 (5H, m), 3.69-3.76 (4H, m), 3.78 (3H, s), 3.88-3.91 (2H, m), 6.21 (1H, s), 6.59-6.63 (1H, m), 6.76 (2H, d), 7.00 (1H, d), 7.99 (1H, s), 8.13 (1H, d), 8.45 (1H, d). Step 6 ( R)-5-(5-((5-(2-amino-6-oxolino-1H-benzo[d]imidazol-1-yl)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (INT-A26-6). 5-(5-{[(4 R)-4-{[2-amino-6-(pyridine-4-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (100 mg, 0.17 mmol, 1 equiv) and LiOH (8.5 mg, 0.35 mmol, 2 equiv) in tetrahydrofuran/H ₂O (4 mL/1 mL) was stirred at room temperature for 2 h under nitrogen atmosphere and concentrated under vacuum. The residue was purified by reverse phase flash chromatography using a C18 silica gel column and acetonitrile/water (0% to 100% gradient) as the mobile phase to obtain 85 mg of 5-(5-{[(4 R)-4-{[2-amino-6-(pyrrolidine-4-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A26-6) (87%). ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.78 (3H, d), 1.43 (1H, s), 1.54-1.75 (2H, m), 1.83 (1H, d), 2.03 (1H, s), 2.89-3.04 (4H, m) , 3.50 (3H, s), 3.60 (3H, s), 3.70-3.75 (4H, m), 3.79-3.82 (1H, m), 3.94 (3H, m), 6.56-6.62 (2H, m), 6.76 (1H, d), 6.96 (1H, d), 8.00 (2H, d), 8.01-8.03 (1H, s), 8.31 (1H, d). Step 7 (11 R)5,11,26-trimethyl-16-(morpholin-4-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A26). 5-(5-{[(4 R)-4-{[2-amino-6-(pyrrolidine-4-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (50 mg, 0.09 mmol, 1 equivalent), N,N-Diisopropylethylamine (35 mg, 0.27 mmol, 3 equivalents) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)urea hexafluorophosphate (51 mg, 0.13 mmol, 1.5 equiv) in 1,4-dioxane (3 mL) was stirred at 60 °C for 1 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by Prep-HPLC using an XBridge Prep OBD C18 column with 10 mmol/L NH₄HCO ₃of water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 16 mg (11 R)5,11,26-trimethyl-16-(morpholin-4-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (Example A26) (34%). LCMS: m/z (ESI), [M+H] ⁺=532.30. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.81 (3H, d), 1.43 (1H, q), 1.92 (2H, d), 2.19 (1H, br s), 2.80 (1H, br s), 3.14 (4H, t), 3.62 (3H, s), 3.72 (3H, s), 3.78 (4H, t), 3.89-3.97 (2H, m), 4.06-4.14 (1H, m), 4.31-4.41 (1H, m), 6.87 (1H, dd), 7.15 (1H, d), 7.38 (1H, d), 8.27 (1H, d), 8.35 (1H, s), 8.81 (1H, d), 12.37 (1H, s). Example A27 (11 R)-16-[3-(dimethylamino)pyrrolidin-1-yl]-5,11,26-trimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic[22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. (11 R)-16-[3-(dimethylamino)pyrrolidin-1-yl]-5,11,26-trimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A27). Under nitrogen atmosphere at room temperature, (11R)-16-bromo-5,11,26-trimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (M3, 40 mg, 0.07 mmol, 1 equivalent), N,N-dimethylpyrrolidin-3-amine (34 mg, 0.30 mmol, 4 equiv) and BrettPhos Pd G ₃To a stirred mixture of 2,4-dioxane (5 mL) and 1,4-dioxane (20 mg, 0.02 mmol, 0.3 eq.) was added LiHMDS (0.22 mL, 0.22 mmol, 3 eq.) dropwise. The reaction mixture was stirred at 60 °C for 30 min. After cooling to room temperature, the reaction was heated with saturated NH₄Cl solution (30 mL), and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (15/1) for elution, and the product was purified by Prep-HPLC using an XBridge Prep OBD C18 column with 10 mmol/L NH₄HCO ₃The product was further purified using water and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 5 mg (11 R)-16-[3-(dimethylamino)pyrrolidin-1-yl]-5,11,26-trimethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclic[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (Example A27) (13%). LCMS: m/z (ESI), [M+H] ⁺=559.50. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.81 (3H, d), 1.40-1.50 (1H, m), 1.88-1.95 (3H, m), 2.12-2.31 (8H, m), 2.79-2.84 (2H, m), 3.06-3.17 (1H, m), 3.23-3.49 (3H, m), 3.62 (3H, s), 3.72 (3H, s), 3.84-3.97 (2H, m), 4.06-4.15 (1H, m), 4.32-4.41 (1H, m), 6.47 (1H, d), 6.66 (1H, s), 7.33 (1H, d), 8.26 (1H, d), 8.36 (1H, s), 8.81 (1H, d), 12.28 (1H, s). Using similar conditions as described above for the synthesis of Example A27, the following Examples were prepared from M3: Example A28, Example A29, Example A30, Example A31, Example A32, Example A33, Example A34, Example A35, Example A36, Example A37, Example A38, Example A29, Example A40, Example A41, Example A42, Example A43, Example A44, Example A45, Example A46, Example A47, Example A48, Example A49, Example A50, Example A51, Example A52, Example A53, Example A54, Example A55, Example A56, Example A57, and Example A58. Structure and m/z and ¹The H NMR data are listed in Table 1. Example A59, Example A60A and Example A60B 6-Bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (Example A59), 15,21-Dimethyl-6-(4-methylpiperazin-1-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione, isomer 1 (Example A60A) and isomer 2 (Example A60B) Step 1. Preparation of 1-[(4-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (INT-A60-1). 1-Amino-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (2.0 g, 8.80 mmol, 1 equivalent), K ₂CO ₃A mixture of (2.44 g, 17.6 mmol, 2 equiv.) and 4-bromo-1-fluoro-2-nitrobenzene (3.88 g, 17.6 mmol, 2 equiv.) in DMSO (40 mL) was stirred at 120 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to dryness to give 800 mg of tert-butyl 1-[(4-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octane-3-carboxylate (INT-A60-1) (21%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=372.05. Step 2. N-Preparation of (4-bromo-2-nitrophenyl)-3-azabicyclo[3.2.1]octan-1-amine (INT-A60-2). A mixture of tert-butyl 1-[(4-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octane-3-carboxylate (550 mg, 1.29 mmol, 1 equivalent) and trifluoroacetic acid (2 mL) in dichloromethane (6 mL) was stirred at room temperature for 2 h under nitrogen atmosphere and saturated with NaHCO ₃(aqueous) solution (50 mL) and treated with CH ₂Cl ₂(3×50 mL) extraction. The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to give 435 mg of a yellow solid.N-(4-bromo-2-nitrophenyl)-3-azabicyclo[3.2.1]octan-1-amine (INT-A60-2) (100%). LCMS: m/z (ESI), [M+H] ⁺=328.00. Step 3. N-(4-bromo-2-nitrophenyl)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.1]octan-1-amine (INT-A60-3) preparation.N-(4-Bromo-2-nitrophenyl)-3-azabicyclo[3.2.1]octan-1-amine (435 mg, 1.34 mmol, 1 equivalent), (2-bromoethoxy)(tert-butyl)dimethylsilane (652 mg, 2.72 mmol, 2 equivalents), NaI (408 mg, 2.72 mmol, 2 equivalents) and K ₂CO ₃(377 mg, 2.72 mmol, 2 equiv) in DMF (5 mL) was stirred at 60 °C for 4 h under nitrogen atmosphere. The mixture was cooled to room temperature, treated with water (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 360 mg of N-(4-bromo-2-nitrophenyl)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.1]octan-1-amine (INT-A60-3) (54%). LCMS: m/z (ESI), [M+H] ⁺=485.90. Step 4. Preparation of 2-{1-[(4-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethanol (INT-A60-4). NA mixture of -(4-bromo-2-nitrophenyl)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.1]octan-1-amine (360 mg, 0.74 mmol, 1 eq) and tetrabutylammonium fluoride (388 mg, 1.48 mmol, 2 eq) in tetrahydrofuran (5 mL) was stirred at room temperature overnight under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (10/1) to give 260 mg of 2-{1-[(4-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethanol (INT-A60-4) (94%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=370.10. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.61-1.71 (3H, m), 1.79-1.83 (1H, m), 1.91-1.97 (1H, m), 2.11-2.17 (1H, m), 2.18-2.24 (1H, m), 2.30-2.49 (5H, m), 3.11-3.18 (1H, m), 3.45-3.55 (2H, m), 4.34 (1H, t), 7.17(1H, d), 7.57-7.67 (1H, m), 8.18 (1H, d), 8.29 (1H, s). Step 5. Preparation of methyl 5-[5-(2-{1-[(4-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A60-5). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 260 mg, 1.25 mmol, 1.97 equiv) and triphenylphosphine (782 mg, 2.98 mmol, 4.70 equiv) in tetrahydrofuran (5 mL) under nitrogen atmosphere at 0° C. was added 2-{1-[(4-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethanol (235 mg, 0.63 mmol, 1 equiv) and diisopropyl azodicarboxylate (451 mg, 2.23 mmol, 3.5 equiv). The mixture was stirred at 0° C. for 2 h, treated with water (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to give 260 mg of 5-[5-(2-{1-[(4-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A60-5) (66%) as an orange oil. LCMS: m/z (ESI), [M+H] ⁺=615.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.47-1.63 (2H, m), 1.66-1.70 (1H, m), 1.72-1.85 (1H, m), 1.88-1.94 (1H, m), 2.04-2.23 (4H, m), 2.66-2.76 (2H, m), 2.80 -2.89 (1H, m), 3.07-3.11 (1H, m), 3.58 (3H, s),3.73 (3H, s), 3.78 (3H, s), 4.10 (1H, s), 4.11 (1H, s), 6.94 (1H, d), 7.56-7.66 (1H, m), 8.02 (1H, s), 8.12 (1H, d), 8.17 (1H, d), 8.26 (1H, s), 8.43 (1H, d). Step 6. Preparation of 5-(5-(2-(1-((2-amino-4-bromophenyl)amino)-3-azabicyclo[3.2.1]oct-3-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A60-6). 5-[5-(2-{1-[(4-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (240 mg, 0.39 mmol, 1.00 equivalent), NH ₂NH ₂ ^.H ₂A mixture of O (39 mg, 0.78 mmol, 2 eq.) and Raney nickel (33 mg, 0.39 mmol, 1 eq.) in methanol (2 mL) was stirred at 0 °C for 2 h under nitrogen atmosphere. The mixture was filtered. The filter cake was washed with methanol (2×50 mL). The resulting solution was concentrated under reduced pressure. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (10/1) to give 200 mg of 5-(5-(2-(1-((2-amino-4-bromophenyl)amino)-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A60-6) (84%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=585.10. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.43-1.51 (4H, m), 1.63 -1.75 (1H, m), 1.77-1.81 (1H, m), 1.87-1.91 (1H, m), 1.95-1.99 (1H, m), 2.01-2.05 (1H, m), 2.09-2.13 (1H, m), 2.67-2.77 (3H, m), 3.03-3.09 (1H, m), 3.58 (3H, s), 3.71(3H, s), 3.79 (3H, s), 3.97-4.14 (2H, m), 4.87 (2H, s), 6.38 (1H, d), 6.46-6.56 (1H, m), 6.66 (1H, d), 8.00 (1H, s), 8.13 (1H, d), 8.45 (1H, d). Step 7. Preparation of 5-(5-{2-[1-(2-amino-5-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A60-7). A mixture of 5-(5-{2-[1-(2-amino-5-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (200 mg, 0.32 mmol, 1 eq.) and BrCN (38 mg, 0.36 mmol, 1.1 eq.) in ethanol (2 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature, treated with water (50 mL), and extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC eluting with (dichloromethane/methanol 12/1) to give 150 mg of 5-(5-{2-[1-(2-amino-5-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A60-7) (75%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=611.90. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.04-1.07 (1H, m), 1.22-1.26 (1H, m), 1.48-1.53 (1H, m), 1.71-1.84 (2H, m), 2.20-2.24 (2H, m), 2.27-2.33 (2H, m), 2.62 -2.76 (2H, m), 2.76 -2.84 (1H, m), 3.02 -3.08 (1H, m), 3.58 (3H, s), 3.73 (3H, s), 3.77 (3H, s), 4.09-4.13 (2H, m), 6.08 (2H, s), 6.93-6.97 (1H, m), 7.19 (1H, d), 7.25 (1H, d), 8.01 (1H, s), 8.11 (1H, d), 8.42 (1H, d). Step 8. Preparation of 5-(5-{2-[1-(2-amino-5-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A60-8). 5-(5-{2-[1-(2-amino-5-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (140 mg, 0.22 mmol, 1 equivalent) and LiOH ^.H ₂O (48 mg, 1.14 mmol, 5 equivalents) in tetrahydrofuran/H ₂O (2 mL/0.5 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated. The residue was purified by C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 100 mg of 5-(5-{2-[1-(2-amino-5-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A60-8) (73%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=595.95. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.54 (1H, m), 1.73-1.79 (2H, m), 2.15-2.21 (1H, m), 2.28-2.34 (2H, m), 2.63-2.69 (3H, m), 2.72-2.78 (1H, m), 2.85-2.91 (2H, m), 3.05-3.11 (1H, m), 3.49 (3H, s), 3.68 (3H, s), 4.01-4.19 (2H, m), 6.29 (2H, s), 6.90-6.99 (1H, m), 7.22 (1H, d), 7.27 (1H, d), 7.95 (2H, d), 8.24 (1H, d). Step 9. Preparation of 6-bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (Example A59). 5-(5-{2-[1-(2-amino-5-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (90 mg, 0.15 mmol, 1 equivalent), N,N-Diisopropylethylamine (58 mg, 0.45 mmol, 3 equivalents) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)urea hexafluorophosphate (114 mg, 0.30 mmol, 2 equiv.) and 1,4-dioxane (2 mL) was stirred at 60 °C for 30 min under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (30 mL), and the mixture was extracted with dichloromethane (2×30 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (12/1) to give 80 mg of 6-bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (Example A59) (91%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=580.20. ¹H NMR (DMSO-d ₆, 400 MHz) δ δ 1.53-1.77 (3H, m), 2.00 (1H, d), 2.39-2.63 (3H, m), 2.64-2.77 (2H, m), 3.16-3.28 (1H, m), 3.29-3.39 (2H, m), 3.62 (3H, s), 3.63-3.69 (1H, m), 3.72 (3H, s), 4.45-4.70 (2H, m), 7.28 (1H, d), 7.72 (1H, d), 8.02 (1H, s), 8.39-8.43 (2H, m), 8.78 (1H, s), 12.81 (1H, s). Step 10. Preparation of 15,21-dimethyl-6-(4-methylpiperazin-1-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (A60). 6-Bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriaconta-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (75 mg, 0.13 mmol, 1 eq.), 1-methylpiperazine (38 mg, 0.39 mmol, 3 eq.) and BrettPhos Pd G ₃To a stirred mixture of 1,4-dioxane (3 mL) and 2-nitropropene (35 mg, 0.03 mmol, 0.3 equiv.) was added LiHMDS (1.3 mL, 1.30 mmol, 10 equiv.). The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 2 h and cooled to room temperature. The reaction was heated with saturated NH₄Cl(aq) solution (50 mL) was quenched, and the mixture was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 22.3 mg of 15,21-dimethyl-6-(4-methylpiperazin-1-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione (A60) as a yellow solid (28%). LCMS: m/z (ESI), [M+H] ⁺=598.35. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.50-1.80 (3H, m), 1.97 (1H, d), 2.26-2.58 (10H, m), 2.55-2.80 (3H, m), 3.03-3.43 (6H, m), 3.63 (3H, s), 3.64-3.70 (1H, m), 3.72 (3H, s), 4.57 (1H, t), 4.69 (1H, d), 6.86 (1H, dd), 7.17 (1H, s), 7.57 (1H, d), 8.29 (1H, d), 8.42 (1H, s), 8.83 (1H, d), 12.56 (1H, s). Step 11. Preparation of 15,21-dimethyl-6-(4-methylpiperazin-1-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione, isomer 1 (Example A60A) and isomer 2 (Example A60B). A racemic mixture of 15,21-dimethyl-6-(4-methylpiperazin-1-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (16.9 mg, 0.02 mmol) was purified by Pre-SFC using a chiral ART cellulose-SB column (2*25 cm, 5 μm) with tert-butyl methyl ether containing 0.1% triethylamine as mobile phase A and ethanol/dichloromethane (1: 1) as mobile phase B to separate to obtain 1 mg of isomer 1 (5%) and 1 mg of isomer 2 (5%) as yellow solid. Isomer 1: LCMS: m/z (ESI), [M+H] ⁺=598.40. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.50-1.80 (3H, m), 1.97 (1H, d), 2.26-2.58 (10H, m), 2.55-2.80 (3H, m), 3.03-3.43 (6H, m), 3.63 (3H, s), 3.64-3.70 (1H, m), 3.72 (3H, s), 4.55 (1H, t), 4.69 (1H, d), 6.84 (1H, dd), 7.16 (1H, s), 7.55 (1H, d), 8.28 (1H, d), 8.41 (1H, s), 8.83 (1H, d), 12.54 (1H, s). Chiral-HPLC, Rt=3.374 minutes Isomer 2: LCMS: m/z (ESI), [M+H] ⁺=598.35. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.50-1.80 (3H, m), 1.97 (1H, d), 2.26-2.58 (10H, m), 2.55-2.80 (3H, m), 3.03-3.43 (6H, m), 3.63 (3H, s), 3.64-3.70 (1H, m), 3.72 (3H, s), 4.55 (1H, t), 4.69 (1H, d), 6.85 (1H, dd), 7.16 (1H, s), 7.56 (1H, d), 8.28 (1H, d), 8.41 (1H, s), 8.83 (1H, d), 12.55 (1H, s). Chiral-HPLC, Rt = 3.923 minutes Example A61A and Example A61B 15,21-Dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer 1 (Example A61A) and isomer 2 (Example A61B) Step 1. Preparation of tert-butyl 1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octane-3-carboxylate (INT-A61-1). tert-butyl 1-amino-3-azabicyclo[3.2.1]octane-3-carboxylate (500 mg, 2.21 mmol, 1 equivalent), o-fluoronitrobenzene (312 mg, 2.20 mmol, 1 equivalent) and K ₂CO ₃A mixture of (610.66 mg, 4.42 mmol, 2 equiv.) in dimethyl sulfoxide (10 mL) was stirred at 120 °C overnight under nitrogen atmosphere and cooled to room temperature. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (5/1) to give 600 mg of tert-butyl 1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octane-3-carboxylate (INT-A61-1) (78%) as an orange oil. LCMS: m/z (ESI), [M+H] ⁺= 291.95. Step 2. N-Preparation of (2-nitrophenyl)-3-azabicyclo[3.2.1]octan-1-amine (INT-A61-2). A mixture of tert-butyl 1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octane-3-carboxylate (550 mg, 1.58 mmol, 1 equiv) in trifluoroacetic acid (2 mL) and dichloromethane (6 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was treated with water (50 mL) and saturated NaHCO₃(aqueous solution). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to give 380 mg of orange oil.N-(2-Nitrophenyl)-3-azabicyclo[3.2.1]octan-1-amine (INT-A61-2). This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=248.00. Step 3. 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}- N-(2-nitrophenyl)-3-nitrobicyclo[3.2.1]octan-1-amine (INT-A61-3).N-(2-Nitrophenyl)-3-azabicyclo[3.2.1]octan-1-amine (380 mg, 1.54 mmol, 1 equivalent), (2-bromoethoxy)(tert-butyl)dimethylsilane (735 mg, 3.07 mmol, 2 equivalents) and K ₂CO ₃(425 mg, 3.07 mmol, 2 equivalents) in N,N-The mixture in dimethylformamide (5 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere and cooled to room temperature. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (5/1) to give 450 mg of 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}- N-(2-Nitrophenyl)-3-azabicyclo[3.2.1]octan-1-amine (INT-A61-3) (72%). LCMS: m/z (ESI), [M+H] ⁺=406.15. Step 4. Preparation of 2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethanol (INT-A61-4). 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}- NA mixture of -(2-nitrophenyl)-3-azabicyclo[3.2.1]octan-1-amine (400 mg, 1 mmol, 1 equiv) and tetrabutylammonium fluoride (516 mg, 2 mmol, 2 equiv) in tetrahydrofuran (10 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was heated with saturated NaHCO₃(aqueous solution) (100 mL) was quenched, and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to give 280 mg of 2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethanol (INT-A61-4) as an orange oil. This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=292.00. Step 5. Preparation of 1-methyl-5-[1-methyl-5-(2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)pyrazol-4-yl]-6-oxopyridine-3-carboxylic acid methyl ester (INT-A61-5). To a stirred mixture of 2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethanol (330 mg, 1.13 mmol, 1 eq), diisopropyl azodicarboxylate (687 mg, 3.40 mmol, 3 eq) and triphenylphosphine (891 mg, 3.40 mmol, 3 eq) in tetrahydrofuran (10 mL) under nitrogen atmosphere was added methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 298 mg, 1.13 mmol, 1 eq). After stirring at 0 °C under nitrogen atmosphere for 2 h, the reaction was quenched with water (100 mL) and the mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/1) to give 400 mg of 1-methyl-5-[1-methyl-5-(2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethoxy)pyrazol-4-yl]-6-oxopyridine-3-carboxylic acid methyl ester (INT-A61-5) (66%) as an orange solid. Step 6. Preparation of 5-[5-(2-{1-[(2-aminophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A61-6). To a stirred mixture of 1-methyl-5-[1-methyl-5-(2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)pyrazol-4-yl]-6-oxopyridine-3-carboxylic acid methyl ester (340 mg, 0.634 mmol, 1 eq.) and ranyl nickel (54.29 mg, 0.634 mmol, 1.0 eq.) in methanol (20 mL) at 0°C was added NH ₂NH ₂ ^.H ₂O (63.44 mg, 1.268 mmol, 2.0 equiv). The mixture was stirred at room temperature under nitrogen atmosphere for 1 h and filtered. The filter cake was washed with methanol (3×10 mL). The resulting solution was concentrated under reduced pressure. The residue was purified by Prep-TLC eluting with dichloromethane/methanol (12/1) to give 240 mg of 5-[5-(2-{1-[(2-aminophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A61-6) (63%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=507.25. Step 7. Preparation of 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A61-7). A mixture of methyl 5-[5-(2-{1-[(2-aminophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (300 mg, 0.59 mmol, 1 eq) and BrCN (94 mg, 0.89 mmol, 1.5 eq) in ethanol (5 mL) was stirred at room temperature overnight under nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was purified by Prep-TLC using dichloromethane/methanol (12/1) to give 200 mg of 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A61-7) (64%) as a brownish yellow solid. LCMS: m/z (ESI), [M+H] ⁺=532.25. Step 8. Preparation of 5-(5-(2-(-1-(2-amino-1H-benzo[d]imidazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester, isomer 1 (INT-A61-7A) and isomer 2 (INT-A61-7B). A racemic mixture of methyl 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (200 mg) was separated using an SFC DZ-CHIRALPAK IC-3 column (4.6*50 mm, 3.0 μm), tert-butyl methyl ether containing 0.2% diethylamine as mobile phase A and ethanol/dichloromethane (1/1) as mobile phase B to obtain 70 mg of isomer 1 (35%) and 70 mg of isomer 2 (35%) as yellow solids (35%). Step 9. Preparation of 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A61-8A). 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A61-7A, 70 mg, 0.13 mmol, 1 equivalent) and LiOH ^.H ₂A solution of O (22 mg, 0.53 mmol, 4 equiv.) in water (1 mL) and tetrahydrofuran (4 mL) was stirred at room temperature overnight under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC on an XBridge Shield RP18 OBD column using a column containing 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 45 mg of 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A61-8A) (70%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=518.10. Step 10. Preparation of 5,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer 1 (Example A61A). 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (45 mg, 0.087 mmol, 1 equivalent), N,N-Diisopropylethylamine (33.9, 0.261 mmol, 3 equivalents) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (66 mg, 0.17 mmol, 2 eq.) in dioxane (2 mL) was stirred at room temperature overnight under nitrogen atmosphere. After the mixture was concentrated under reduced pressure, the residue was purified by Prep-TLC using dichloromethane/methanol (12/1) to give 26.8 mg of 15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer 1 (Example A61A) as an off-white solid (61%). LCMS: m/z (ESI), [M+H] ⁺= 500.15. ¹H NMR (DMSO- d ₆, 400 MHz) δ 1.53-1.77 (3H, m), 2.00 (1H, d), 2.39-2.63 (3H, m), 2.64-2.77 (2H, m), 3.16-3.28 (1H, m), 3.29-3.39 (2H, m), 3.62 (3H, s), 3.63-3.69 (1H, m), 3.72 (3H, s), 4.55 (1H, t), 4.68 (1H, d), 7.12-7.23 (2H, m), 7.55-7.60 (1H, m), 7.69-7.75 (1H, m), 8.29 (1H, d), 8.41 (1H, d), 8.83 (1H, d), 12.76 (1H, s). Step 11. Preparation of 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A61-8B). 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A61-7B, 70 mg, 0.13 mmol, 1 equiv.) and LiOH ^.H ₂A mixture of O (22 mg, 0.53 mmol, 4 equiv.) in water (1 mL) and tetrahydrofuran (4 mL) was stirred at room temperature overnight under a nitrogen atmosphere. After the mixture was concentrated under reduced pressure, the residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 45 mg of 5-(5-{2-[-1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A61-8B) (70%) as an off-white solid. LCMS: m/z (ESI), [M+H] ⁺= 518.15. Step 12. Preparation of 15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (isomer 2 Example A61B). 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (45 mg, 0.087 mmol, 1 equivalent), N,N-Diisopropylethylamine (33.9, 0.261 mmol, 3 equivalents) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (66 mg, 0.17 mmol, 2 eq.) in dioxane (2 mL) was stirred at room temperature overnight under nitrogen atmosphere. After the mixture was concentrated under reduced pressure, the residue was purified by Prep-TLC using dichloromethane/methanol (12/1) to give 25.8 mg of 15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer 2 (Example A61B) as an off-white solid (57%). LCMS: m/z (ESI), [M+H] ⁺= 500.15. ¹H NMR (DMSO- d ₆, 400 MHz) δ 1.53-1.77 (3H, m), 2.00 (1H, d), 2.39-2.63 (3H, m), 2.64-2.77 (2H, m), 3.16-3.28 (1H, m), 3.29-3.39 (2H, m), 3.62 (3H, s), 3.63-3.69 (1H, m), 3.72 (3H, s), 4.55 (1H, t), 4.68 (1H, d), 7.12-7.23 (2H, m), 7.55-7.60 (1H, m), 7.69-7.75 (1H, m), 8.29 (1H, d), 8.41 (1H, d), 8.83 (1H, d), 12.76 (1H, s). Example A62A 15,21-Dimethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer 1 (Example A62A) Step 1. Preparation of 15,21-dimethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione, Isomer 1 (Example A62A). 5-Bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (M4A, 50 mg, 0.09 mmol, 1 eq.), morpholine (30 mg, 0.34 mmol, 4 eq.) and BrettPhos Pd G ₃To a stirred mixture of 2-nitropropene (23 mg, 0.03 mmol, 0.3 equiv) in dioxane (10 mL) was added LiHMDS (0.34 mL, 0.34 mmol, 4 equiv) dropwise. The reaction mixture was stirred at 60 °C for 30 min. After cooling to room temperature, the reaction was heated with saturated NH₄Cl solution (30 mL), and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄The residue was purified by Prep-TLC using dichloromethane/methanol (20/1) to give 22 mg of 15,21-dimethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione, Isomer 1 (Example A62A) as a white solid (43%). LCMS: m/z (ESI), [M+H] ⁺=585.35. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.53-1.82 (3H, m), 2.02 (1H, d), 2.39-2.61 (3H, m), 2.65-2.77 (3H, m), 3.10 (4H, q), 3.17-3.43 (2H, m), 3.62 (3H, s), 3.63-3.69 (1H, m), 3.72 (3H, s), 3.77 (4H, t), 4.54 (1H, t), 4.69 (1H, d), 6.91 (1H, dd), 7.20 (1H, s), 7.44 (1H, d), 8.28 (1H, d), 8.42 (1H, s), 8.83 (1H, d), 12.57 (1H, s). Using similar reaction conditions described above for the synthesis of Example A62A, the following examples were prepared from intermediate M4A: Example A63A, Example A64A, Example A65A, Example A66A, Example A66C, Example A67A, Example A68A, Example A69A, Example A70A, Example A71A, Example A72A, Example A73A, Example A76A, Example A77A, Example A78A, Example A79A, Example A81A, Example A82A, Example Example A83A, Example A85A, Example A86A, Example A87A, Example A88A, Example A89A, Example A90A, Example A91A, Example A92A, Example A95A, Example A97A, Example A98A, Example A99A, Example A104A, Example A105A, Example A106A, Example A107A, Example A108A. Example A109A. Structure and m/z and ¹The H NMR data are listed in Table 1. Example A62B 15,21-Dimethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer 2 (Example A62B) Step 1. Preparation of 15,21-dimethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione, isomer 2 (Example A62B). 5-Bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (M4B, 50 mg, 0.09 mmol, 1 eq.), morpholine (30 mg, 0.34 mmol, 4 eq.) and BrettPhos Pd G ₃To a stirred mixture of 2-nitropropene (23 mg, 0.03 mmol, 0.3 equiv) in dioxane (5 mL) was added LiHMDS (0.34 mL, 0.34 mmol, 4 equiv) dropwise. The reaction mixture was stirred at 60 °C for 30 min. After cooling to room temperature, the reaction was heated with saturated NH₄Cl solution (30 mL), and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄The residue was purified by Prep-TLC using dichloromethane/methanol (20/1) to give 6.4 mg of 15,21-dimethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione, Isomer 2 (Example A62B) as a white solid (12%). LCMS: m/z (ESI), [M+H] ⁺=585.35. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.53-1.82 (3H, m), 2.02 (1H, d), 2.39-2.61 (3H, m), 2.65-2.77 (3H, m), 3.10 (4H, q), 3.17-3.43 (2H, m), 3.62 (3H, s), 3.63-3.69 (1H, m), 3.72 (3H, s), 3.77 (4H, t), 4.54 (1H, t), 4.69 (1H, d), 6.91 (1H, dd), 7.20 (1H, s), 7.44 (1H, d), 8.28 (1H, d), 8.42 (1H, s), 8.83 (1H, d), 12.57 (1H, s). Using similar reaction conditions described above for the synthesis of Example A62B, the following examples were prepared from intermediate M4B: Example A63B, Example A64B, Example A65B, Example A66B, Example A66D, Example A67B, Example A68B, Example A69B, Example A70B, Example A71B, Example A72B, Example A73B, Example A76B, Example A77B, Example A78B, Example A79B, Example A81B, Example A82B, Example Example A83B, Example A85B, Example A86B, Example A87B, Example A88B, Example A89B, Example A90B, Example A91B, Example A92B, Example A95B, Example A97B, Example A98B, Example A99B, Example A104B, Example A105B, Example A106B, Example A107B, Example A108B. Example A109B. Structure and m/z and ¹The H NMR data are listed in Table 1. Example A74 15,21-Dimethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]triacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione Step 1. N-(5-bromo-2-nitrophenyl)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (INT-A74-1). 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (1 g, 3.35 mmol, 1 equivalent), 4-bromo-2-fluoro-1-nitrobenzene (1.84 g, 8.37 mmol, 2.5 equivalents) and K ₂CO ₃A mixture of (1.39 g, 10.05 mmol, 3 equiv.) in dimethyl sulfoxide (10 mL) was stirred at 120 °C for 4 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (5/1) to give 1.5 g of yellow oil.N-(5-bromo-2-nitrophenyl)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (INT-A74-1) (85%). LCMS: m/z (ESI), [M+H]+=498.15. Step 2. Preparation of 2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]nonan-3-yl}ethanol (INT-A74-2). NA solution of -(5-bromo-2-nitrophenyl)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (1.5 g, 3.00 mmol, 1 eq.) and tetrabutylammonium fluoride (1.57 g, 6.01 mmol, 2 eq.) in tetrahydrofuran (15 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was heated with saturated NaHCO₃(aqueous solution) (100 mL) was quenched, and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column eluting with dichloromethane/methanol (10/1) to give 1.2 g of 2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethanol (INT-A74-2) (93%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=384.00. Step 3. Preparation of 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A74-3). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 0.66 g, 2.49 mmol, 0.8 eq.) and triphenylphosphine (2.46 g, 9.369 mmol, 3 eq.) in tetrahydrofuran (10 mL) were added diisopropyl azodicarboxylate (1.89 g, 9.36 mmol, 3 eq.) and 2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethanol (1.20 g, 3.11 mmol, 1 eq.) at 0° C. The mixture was stirred at 0° C. for 2 h under nitrogen atmosphere. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC and eluted with petroleum ether/ethyl acetate (1/1) to give 1.2 g of 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A74-3) (57%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=629.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.58-1.76 (9H, m), 2.56-2.79 (2H, m), 2.90 (4H, q), 3.56 (3H, s), 3.72 (6H, d), 4.13 (2H, t), 6.70-6.85 (1H, m), 7.01 (1H, d), 7.95-8.12 (4H, m), 8.28 (1H, d). Step 4. Preparation of 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A74-4). To a stirred mixture of ranyl nickel (0.90 g) and methyl 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (1.1 g, 1.74 mmol, 1 equiv) in methanol (8 mL) at 0°C under nitrogen atmosphere was added NH₂NH ₂.H ₂O (47 mg, 0.95 mmol, 2 eq.). The mixture was stirred at 0 °C for 1 h. The mixture was filtered and the filter cake was washed with methanol (2×20 mL). The resulting solution was concentrated under reduced pressure. The residue was purified by Prep-TLC and eluted with dichloromethane/methanol (10/1) to give 910 mg of 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A74-4) (76%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺= 599.20. Step 5. Preparation of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A74-5). A mixture of methyl 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (900 mg, 1.50 mmol, 1 eq) and BrCN (174 mg, 1.65 mmol, 1.1 eq) in ethanol (10 mL) was stirred under nitrogen atmosphere at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC and eluted with dichloromethane/methanol (12/1) to give 640 mg of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A74-5) (68%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺=624.10. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.24 (1H, s), 1.78-1.95 (8H, m), 2.60-2.74 (2H, m), 2.85-2.95 (4H, m), 3.57 (3H, s), 3.71 (6H, d), 4.08-4.17 (2H, m), 5.95 (2H, s), 7.04 (2H, s), 7.47 (1H, s), 7.96 (1H, s), 8.12 (1H, ), 8.39 (1H, d). Step 6. 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A74-6). 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (620 mg, 0.99 mmol, 1 equiv) and LiOH (28 mg, 1.19 mmol, 1.2 equiv) were dissolved in tetrahydrofuran/H ₂O (4 mL/1 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under vacuum to give 550 mg of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A74-6) (90%) as a white solid. This material was used in the next reaction without purification. Step 7. Preparation of 5-bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21, 26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontriacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione (INT-A74-7). 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (550 mg, 0.90 mmol, 1 equivalent), N,N,N,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (1027 mg, 2.70 mmol, 3 equivalents) and N,N- A mixture of diisopropylethylamine (174 mg, 1.35 mmol, 1.5 equiv.) in dioxane (6 mL) was stirred at 60 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by prep-HPLC using an XBridge Prep OBD C18 column with 10 mmol/L NH₄HCO ₃of water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 500 mg of 5-bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontriacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione (INT-A74-7) (88%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=592.15. Step 8. Preparation of 15,21-dimethyl-5-(morpholin-4-yl)-23-oxo-2,9,11, 15,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontriacontria-3,5,7,9,13,17(34), 18(22),19-octaene-12,16-dione (Example A74). 5-Bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34), 18(22),19-octaene-12,16-dione (130 mg, 0.21 mmol, 1 equiv), morpholine (57 mg, 0.65 mmol, 3 equiv) and BrettPhos Pd G ₃To a stirred mixture of 1,4-dioxane (59 mg, 0.06 mmol, 0.3 eq.) and 1,4-dioxane (12 mL) was added LiHMDS (5.2 mL, 5.20 mmol, 6 eq.). The mixture was stirred at 60 °C for 1 h and cooled to room temperature. The reaction was heated with saturated NH₄Cl(aq) (15 mL) was quenched and the mixture was washed with CH ₂Cl ₂(3×30 mL) extraction. The combined organic layers were purified by anhydrous Na ₂SO ₄The residue was purified by Prep-TLC and eluted with methylene dichloride/methanol (12/1) to give 38.3 mg of 15,21-dimethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tetracontriacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione (Example A74) as a white solid (28%). LCMS: m/z (ESI), [M+H] ⁺= 599.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.82-2.02 (4H, m), 2.02-2.12 (3H, m), 2.80 (2H, d), 2.87 (2H, t), 3.08 (4H, t), 3.38-3.52 (4H, m), 3.62 (3H, s), 3.75 (3H, s), 3.77-3.85 (4H, m), 4.28 (2H, t), 6.93 (1H, dd), 7.34 (1H, d), 7.49 (1H, d), 8.31 (2H, d), 9.12 (1H, d), 13.20 (1H, s). Example A75 15,21-Dimethyl-5-(4-methylpiperazin-1-yl)-23-oxo-2,9,11,15, 20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione Step 1. Preparation of 15,21-dimethyl-5-(4-methylpiperazin-1-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34), 18(22),19-octaene-12,16-dione (Example A75). 5-Bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34), 18(22),19-octaene-12,16-dione (130 mg, 0.21 mmol, 1 equiv), 1-methylpiperazine (65.93 mg, 0.65 mmol, 3 equiv) and BrettPhos Pd G ₃To a stirred mixture of 2-nitropropene (59.67 mg, 0.06 mmol, 0.3 eq.) and 1,4-dioxane (13 mL) was added LiHMDS (5.2 mL, 5.2 mmol, 6 eq.). The mixture was stirred at 60 °C for 1 h and cooled to room temperature. The mixture was washed with saturated NH₄Cl(aqueous solution) (30 mL) was treated and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄The residue was purified by Prep-TLC and eluted with methylene dichloride/methanol (12/1) to give 31 mg of 15,21-dimethyl-5-(4-methylpiperazin-1-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tetracontriacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione (Example A75) as a light yellow solid (22%). LCMS: m/z (ESI), [M+H] ⁺=612.30. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.85-1.99 (4H, m), 2.05-2.09 (3H, m), 2.24 (3H, t), 2.46-2.50 (4H, m), 2.80 (2H, d), 2.87 (2H, t), 3.09 (4H, t), 3.52-3.59 (4H, m), 3.62 (3H, s), 3.75 (3H, s), 4.28 (2H, t), 6.92 (1H, dd), 7.33 (1H, d), 7.47 (1H, d), 8.31 (2H, d), 9.12 (1H, d), 13.19 (1H, s). Example A80A, Example A80A1, Example A80A2 15,21-Dimethyl-5-[3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic[24.4.1.1^{1,28}. 1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione, isomer A (Example A80A), isomer A1 (Example A80A1) and isomer A2 (Example A80A2) Step 1. Preparation of 15,21-dimethyl-5-[3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, Isomer A (Example A80A). 5-Bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriaconta-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (M4A, 90 mg, 0.15 mmol, 1 eq.), 1-methyl-4-(pyrrolidin-3-yl)piperazine (79.01 mg, 0.46 mmol, 3 eq.) and BrettPhos Pd G ₃To the stirred mixture of 4-nitropropene (42.31 mg, 0.04 mmol, 0.3 equiv) was added LiHMDS (3.6 mL, 3.6 mmol, 24 equiv) dropwise. The mixture was stirred at 60 °C for 1 h and then cooled to room temperature. The reaction was heated with saturated NH₄Cl solution (aqueous solution) (10 mL) was quenched, and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to Prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃.H ₂The mixture was purified by using water and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 2.6 mg of 15,21-dimethyl-5-[3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (Isomer A, Example A80A) as a yellow solid (2%). LCMS: m/z (ESI), [M+H]+= 667.40. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.57-1.87 (4H, m), 2.00 (1H, s), 2.16 (3H, s), 2.23-2.63 (12H, m), 2.66-2.76 (2H, m), 2.91 (1H, t), 3.07 (1H, q), 3.20-3.59 (6H, m), 3.62 (3H, s), 3.63-3.69 (1H, m), 3.72 (3H, s), 4.57 (1H, t), 4.69 (1H, d), 6.49 (1H, dd), 6.75 (1H, s), 7.38 (1H, d), 8.26 (1H, d), 8.41 (1H, s), 8.81 (1H, d), 12.51 (1H, s). SFC-HPLC, Rt=1.029 minutes. Step 2. Preparation of 15,21-dimethyl-5-[3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer A1 (Example A80A1) and isomer A2 (Example A80A2). A mixture of 15,21-dimethyl-5-[3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}. 1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione (Example A80A, 20 mg, 0.17 mmol) was chromatographed by Prep-chiral-HPLC using an XBridge Shield RP18 OBD column (30*150 mm, 5μm) containing 10 mmol/L NH₄HCO ₃and 0.1% NH ₃.H ₂O water and acetonitrile as the mobile phase to obtain 8.5 mg of isomer A1 (Example A80A1, 18%) and 3.2 mg of isomer A2 (Example A80A2, 6%) as yellow solids. Isomer A1: LCMS: m/z (ESI), [M+H] ⁺=667.45. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.57-1.87 (4H, m), 2.00 (1H, s), 2.16 (3H, s), 2.23-2.63 (12H, m), 2.66-2.76 (2H, m), 2.91 (1H, t), 3.07 (1H, q), 3.20-3.59 (6H, m), 3.62 (3H, s), 3.63-3.69 (1H, m), 3.72 (3H, s), 4.57 (1H, t), 4.69 (1H, d), 6.49 (1H, dd), 6.76 (1H, s), 7.38 (1H, d), 8.26 (1H, d), 8.42 (1H, s), 8.82 (1H, d), 12.53 (1H, s). Chiral-HPLC, Rt=5.235 min. Isomer A2: LCMS: m/z (ESI), [M+H]+=667.45. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.57-1.87 (4H, m), 2.00 (1H, s), 2.16 (3H, s), 2.23-2.63 (12H, m), 2.66-2.76 (2H, m), 2.91 (1H, t), 3.07 (1H, q), 3.20-3.59 (6H, m), 3.62 (3H, s), 3.63-3.69 (1H, m), 3.72 (3H, s), 4.57 (1H, t), 4.69 (1H, d), 6.47 (1H, dd), 6.76 (1H, s), 7.37 (1H, d), 8.26 (1H, d), 8.42 (1H, s), 8.82 (1H, d), 12.49 (1H, s). Chiral-HPLC, Rt=6.080 minutes Example A80B, Example A80B1, Example A80B2 15,21-Dimethyl-5-[3-(4-methylpiperazine-1-yl)pyrrolidin-1-yl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic[24.4.1.1^{1,28}. 1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tri-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione, isomer B (Example A80B), isomer B1 (Example A80B1) and isomer B2 (Example A80B2) Step 1. Preparation of 15,21-dimethyl-5-[3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, Isomer B (Example A80B). 5-Bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (M4B, 90 mg, 0.15 mmol, 1 eq.), 1-methyl-4-(pyrrolidin-3-yl)piperazine (79.01 mg, 0.46 mmol, 3 eq.) and BrettPhos Pd G ₃To the stirred mixture of 4-(42.31 mg, 0.04 mmol, 0.3 equiv) was added LiHMDS (3.6 mL, 3.60 mmol, 24 equiv) dropwise. The mixture was stirred at 60 °C for 1 h and then cooled to room temperature. The reaction was heated with saturated NH₄Cl solution (aqueous solution) (10 mL) was quenched, and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-HPLC using an XBridge Shield RP18 OBD column containing 10 mmol/L NH₄HCO ₃and 0.1% NH ₃.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 1.6 mg of 15,21-dimethyl-5-[3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione, isomer B (Example A80B) as a yellow solid (1%). LCMS: m/z (ESI), [M+H] ⁺=667.40 ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.57-1.87 (4H, m), 2.00 (1H, s), 2.16 (3H, s), 2.23-2.63 (12H, m), 2.66-2.76 (2H, m), 2.91 (1H, t), 3.07 (1H, q), 3.20-3.59 (6H, m), 3.62 (3H, s), 3.63-3.69 (1H, m), 3.72 (3H, s), 4.57 (1H, t), 4.69 (1H, d), 6.49 (1H, d), 6.75 (1H, s), 7.38 (1H, d), 8.26 (1H, d), 8.41 (1H, s), 8.81 (1H, d), 12.51 (1H, s). SFC-HPLC, Rt=0.869, Step 2. Preparation of 15,21-dimethyl-5-[3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer B1 (Example A80B1) and isomer B2 (Example A80B2). A mixture of 15,21-dimethyl-5-[3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione (Example A80B, 18 mg, 0.17 mmol) was purified by Prep-chiral-HPLC using an XBridge Prep OBD C18 column (30*150 mm, 5 μm) containing 10 mmol/L NH4HCO3 water and acetonitrile were used as mobile phases for separation to obtain 2.4 mg of isomer B1 (Example A80B1, 5%) and 1.2 mg of isomer B2 (Example A80B2, 2%) as yellow solids. Isomer B1: LCMS: m/z (ESI), [M+H] ⁺=667. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.57-1.87 (4H, m), 2.00 (1H, s), 2.16 (3H, s), 2.23-2.63 (12H, m), 2.66-2.76 (2H, m), 2.91 (1H, t), 3.07 (1H, q), 3.20-3.59 (6H, m), 3.62 (3H, s), 3.63-3.69 (1H, m), 3.72 (3H, s), 4.57 (1H, t), 4.69 (1H, d), 6.49 (1H, d), 6.75 (1H, s), 7.38 (1H, d), 8.26 (1H, d), 8.41 (1H, s), 8.81 (1H, d), 12.51 (1H, s). Chiral HPLC, Rt=3.906 min. Isomer B2: LCMS: m/z (ESI), [M+H] ⁺=667.45. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.57-1.87 (4H, m), 2.00 (1H, s), 2.16 (3H, s), 2.23-2.63 (12H, m), 2.66-2.76 (2H, m), 2.91 (1H, t), 3.07 (1H, q), 3.20-3.59 (6H, m), 3.62 (3H, s), 3.63-3.69 (1H, m), 3.72 (3H, s), 4.57 (1H, t), 4.69 (1H, d), 6.49 (1H, d), 6.75 (1H, s), 7.38 (1H, d), 8.26 (1H, d), 8.41 (1H, s), 8.81 (1H, d), 12.51 (1H, s). Chiral HPLC, Rt = 5.026 minutes. Example A84A and Example A84B 15,21-dimethyl-5-[4-fluoro-3-( N, N-dimethylamino)pyrrolidinyl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}. 1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione, isomer 1 (Example A84A) and isomer 2 (Example A84B) Step 1. Preparation of tert-butyl 3-(dimethylamino)-4-fluoropyrrolidine-1-carboxylate (INT-A84-1). tert-butyl 3-amino-4-fluoropyrrolidine-1-carboxylate (500 mg, 2.44 mmol, 1 eq.), polyoxymethylene (4410.29 mg, 48.96 mmol, 20 eq.) and NaBH(OAc) were added at 0 °C under nitrogen atmosphere.₃(2075.35 mg, 9.79 mmol, 4 equivalents) in Cl ₂Cl ₂Trimethylamine (990.90 mg, 9.79 mmol, 4 equiv.) was added dropwise to the stirred mixture in 4% paraformaldehyde (20 mL). The mixture was stirred at 0 °C for 2 h. The reaction was quenched with water (10 mL), and the mixture was washed with CH₂Cl ₂(3×20 mL) extraction. The combined organic layers were washed with brine (3×20 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. Apply the residue on a silica gel column using petroleum CH ₂Cl ₂/methanol (10/1) for purification to obtain 500 mg of tert-butyl 3-(dimethylamino)-4-fluoropyrrolidine-1-carboxylate (INT-A84-1) (79%) as a brown oil. ¹H NMR (DMSO- d ₆, 400 MHz) δ 1.40 (9H, s), 2.10-2.23 (5H, m), 2.85-2.95 (1H, m), 3.25 (1H, d), 3.47-3.64 (4H, m), 5.11-5.23 (1H, m). Step 2. 4-Fluoro- N, N- Preparation of dimethylpyrrolidin-3-amine (INT-A84-2). A mixture of tert-butyl 3-(dimethylamino)-4-fluoropyrrolidine-1-carboxylate (500 mg, 2.152 mmol, 1 eq.) and HCl in 1,4-dioxane (4 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. Solid K was added to the reaction solution.₂CO ₃After filtration, the filtrate was concentrated under reduced pressure, and 300 mg of 4-fluoro- N, N-Dimethylpyrrolidin-3-amine (INT-A84-2). This material was used in the next reaction without further purification. ¹H NMR (DMSO- d ₆, 400 MHz) δ 2.05-2.25 (6H, m), 2.40-2.65 (2H, m), 2.76-3.48 (4H, m), 4.94-5.08 (1H, m) Step 3. 15,21-dimethyl-5-[4-fluoro-3-( N, N-dimethylamino)pyrrolidinyl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triathrine-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, preparation of isomer 1 (Example A84A) and isomer 2 (Example A84B). 5-Bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (M4A, 150 mg, 0.25 mmol, 1.00 equivalent), BrettPhos Pd G ₃(70.52 mg, 0.07 mmol, 0.3 eq.) and 4-fluoro- N, NTo a stirred mixture of 2-dimethylpyrrolidin-3-amine (102.83 mg, 0.77 mmol, 3 equiv) in 1,4-dioxane (15 mL) was added LiHMDS (6 mL, 6.00 mmol, 24 equiv) dropwise. The mixture was stirred at 60 °C for 1 h and then cooled to room temperature. The reaction was heated with saturated NH₄Cl(aq) solution (15 mL) was quenched, and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was passed through Prep-HPLC using an XBridge Shield RP18 OBD column with 0.1% NH₃.H ₂O water and acetonitrile as the mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to obtain 9.8 mg of 15,21-dimethyl-5-[4-fluoro-3-( N, N-dimethylamino)pyrrolidinyl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}. 1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriaconta-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione, isomer 1 (Example A84A) (6%) and 10.0 mg of isomer 2 (Example A84B) (6%) as a yellow solid. Isomer 1: LCMS: m/z (ESI), [M+H] ⁺=630.40. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.48-1.68 (4H, m), 2.01-2.08 (1H, m), 2.30 (6H, s), 2.41-2.58 (3H, m), 2.55-2.79 (4H, m), 3.04-3.10 (2H, m), 3.22-3.32 (1H, m), 3.54-3.69 (3H, m), 3.62 (3H, s), 3.72 (3H, s), 4.55 (1H, t), 4.62-4.73 (1H, m), 5.25-5.35 (1H, m), 6.50 (1H, dd), 6.76 (1H, s), 7.40 (1H, d), 8.26 (1H, d), 8.42 (1H, s), 8.82 (1H, d), 12.52 (1H, s). SFC-HPLC, Rt=4.025 minutes. Isomer 2: LCMS: m/z (ESI), [M+H] ⁺=630.40. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.48-1.68 (4H, m), 2.01-2.08 (1H, m), 2.30 (6H, s), 2.41-2.58 (3H, m), 2.55-2.79 (4H, m), 3.04-3.10 (2H, m), 3.22-3.32 (1H, m), 3.54-3.69 (3H, m), 3.62 (3H, s), 3.72 (3H, s), 4.55 (1H, t), 4.62-4.73 (1H, m), 5.25-5.35 (1H, m), 6.59 (1H, dd), 6.86 (1H, s), 7.41 (1H, d), 8.27 (1H, d), 8.42 (1H, s), 8.82 (1H, d), 12.51 (1H, s). SFC-HPLC, Rt = 3.757 minutes. Example A84C and Example A84D 15,21-dimethyl-5-[4-fluoro-3-( N, N-dimethylamino)pyrrolidinyl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}. 1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione, isomer 3 (Example A84C) and isomer 4 (Example A84B) Step 1. 15,21-dimethyl-5-[4-fluoro-3-( N, N-dimethylamino)pyrrolidinyl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triathrine-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, preparation of isomer 3 (Example A84C) and isomer 4 (Example A84D). Under nitrogen atmosphere at 0 ° C, 5-bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (M4B, 150 mg, 0.25 mmol, 1 equivalent), 4-fluoro- N, N-dimethylpyrrolidin-3-amine (102.83 mg, 0.77 mmol, 3 equiv) and BrettPhos Pd G 3To the stirred mixture of 2-nitropropene (70.52 mg, 0.07 mmol, 0.3 equiv) was added LiHMDS (6 mL, 6.00 mmol, 24 equiv) dropwise. The mixture was stirred at 60 °C for 1 h and then cooled to room temperature. The reaction was heated with saturated NH₄Cl(aq) solution (10 mL) was quenched, and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was passed through Prep-HPLC using an XBridge Shield RP18 OBD column with 0.1% NH₃.H ₂O water and acetonitrile as the mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to obtain 11.8 mg of 15,21-dimethyl-5-[4-fluoro-3-( N, N-dimethylamino)pyrrolidinyl]-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriaconta-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer 3 (Example A84C) (7%) and 6.0 mg of isomer 4 (Example A84D) (3%) as a yellow solid. Isomer 3: LCMS: m/z (ESI), [M+H] ⁺=630.40. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.48-1.68 (4H, m), 2.01-2.08 (1H, m), 2.30 (6H, s), 2.41-2.58 (3H, m), 2.55-2.79 (4H, m), 3.04-3.10 (2H, m), 3.22-3.32 (1H, m), 3.54-3.69 (3H, m), 3.62 (3H, s), 3.72 (3H, s), 4.55 (1H, t), 4.62-4.73 (1H, m), 5.25-5.35 (1H, m), 6.50 (1H, dd), 6.76 (1H, s), 7.40 (1H, d), 8.26 (1H, d), 8.42 (1H, s), 8.82 (1H, d), 12.53 (1H, s). SFC-HPLC, Rt=3.983min Isomer 4: LCMS: m/z (ESI), [M+H] ⁺=630.40. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.48-1.68 (4H, m), 2.01-2.08 (1H, m), 2.30 (6H, s), 2.41-2.58 (3H, m), 2.55-2.79 (4H, m), 3.04-3.10 (2H, m), 3.22-3.32 (1H, m), 3.54-3.69 (3H, m), 3.62 (3H, s), 3.72 (3H, s), 4.55 (1H, t), 4.62-4.73 (1H, m), 5.25-5.35 (1H, m), 6.59 (1H, dd), 6.86 (1H, s), 7.41 (1H, d), 8.27 (1H, d), 8.42 (1H, s), 8.82 (1H, d), 12.55 (1H, s). SFC-HPLC, Rt = 3.724 minutes. Example A94A, Example 94A1 and Example A94A2 5-[3-(3-fluoroaziridocyclobutane-1-yl)pyrrolidin-1-yl]-15,21-dimethyl-23-oxadiazol-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}. 1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tri-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione, isomer A (Example A94A), isomer A1 (Example A94A1) and isomer A2 (Example A94A2) Step 1. Preparation of tert-butyl 3-(3-fluoroaziridocyclobutane-1-yl)pyrrolidine-1-carboxylate (INT-A94A-1). tert-butyl 3-oxopyrrolidine-1-carboxylate (1500 mg, 8.10 mmol, 1 equivalent) and 3-fluoroaziridocyclobutane hydrochloride (903 mg, 8.10 mmol, 1 equivalent) were mixed in CH₂Cl ₂The mixture in (50 mL) was stirred at room temperature under air atmosphere for 1 h. NaBH(OAc) was added to the above mixture in portions at 0°C within 2 minutes.₃(8582 mg, 40.49 mmol, 5 equiv.). The resulting mixture was stirred for another 2 h. The reaction was treated with saturated NH₄Cl(aq) (50 mL) was quenched and the mixture was washed with CH ₂Cl ₂(3×100 mL) extraction. The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using dichloromethane/methanol (12/1) to give 1.5 g of tert-butyl 3-(3-fluoroaziridocyclobutane-1-yl)pyrrolidine-1-carboxylate (INT-A94A-1) (75%) as a yellow oil. ¹H NMR (CDCl ₃, 400 MHz) δ 1.46 (9H, d), 1.68-1.83 (1H, m), 1.85-1.95 (1H, m), 3.05-3.15 (1H, m), 3.18-3.48 (6H, m), 3.72-3.87 (2H, m) Step 2. Preparation of 3-(3-fluoro-1-nitro-2-cyclobutane-1-yl)pyrrolidine (INT-A94A-2). 3-(3-fluoro-1-nitro-2-cyclobutane-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.05 mmol, 1 equivalent) and trifluoroacetic acid (3 mL) were mixed in CH ₂Cl ₂The solution in (9 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, treated with dichloromethane/methanol (10/1) (30 mL), and K ₂CO ₃Adjust to pH 7. The mixture was filtered and the filter cake was washed with methanol (2×10 mL). The resulting solution was concentrated under reduced pressure to give 150 mg of 3-(3-fluoroaziridocyclobutane-1-yl)pyrrolidine (INT-A94A-2) as a yellow oil. This material was used in the next reaction without further purification. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.75-1.84 (2H, m), 2.70-2.81 (2H, m), 2.82-2.95 (2H, m), 3.05-3.21 (3H, m), 3.59-3.62 (2H, m), 4.98-5.18 (2H, m) Step 3. Preparation of 5-[3-(3-fluoro-1-nitro-2-cyclobutane-1-yl)pyrrolidin-1-yl]-15,21-dimethyl-23-oxo-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (isomer A, Example A94A). 3-(3-fluoro-1-nitro-2-cyclobutane-1-yl)pyrrolidine (125 mg, 0.86 mmol, 5 equivalents), BrettPhos Pd G ₃To a stirred mixture of 5-bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (M4A, 100 mg, 0.173 mmol, 1 eq) in 1,4-dioxane (10 mL) was added LiHMDS (2.1 mL, 2.07 mmol, 12 eq). The resulting mixture was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was treated with saturated NH₄Cl(aq) (15 mL) was quenched and the mixture was washed with CH ₂Cl ₂(3×50 mL) extraction. The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10:1). The product was purified by Prep-HPLC using an XBridge Prep Phenyl OBD column with 0.1% NH₄HCO ₃The product was further purified by using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 13 mg of 5-[3-(3-fluoroazidocyclobutane-1-yl)pyrrolidin-1-yl]-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, Isomer A (Example A94A) as an off-white solid (12%). LCMS: m/z (ESI), [M+H] ⁺= 642.40. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.48-1.85 (4H, m), 1.89-2.05 (2H, m), 2.35-2.56 (4H, m), 2.68-2.76 (2H, m), 2.96 (1H, t), 3.07-3.20 (4H, m), 3.20-3.43 (4H, m), 3.45-3.70 (3H, m), 3.62 (3H, s), 3.72 (3H, s), 4.55 (1H, t), 4.63-4.73 (1H, m), 4.95-5.31 (1H, m), 6.44 (1H, d), 6.73 (1H, s), 7.37 (1H, d), 8.25 (1H, d), 8.42 (1H, s), 8.82 (1H, d), 12.50 (1H, s). Step 4. Preparation of 5-[3-(3-fluoroazidocyclobutane-1-yl)pyrrolidin-1-yl]-15,21-dimethyl-23-oxo-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer A1 (Example A94A1) and isomer A2 (Example A94A2). A mixture of 5-[3-(3-fluoroaziridocyclobutane-1-yl)pyrrolidin-1-yl]-15,21-dimethyl-23-oxadiazol-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}. 1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione (Example A94A, 10.5 mg) was chromatographed by Prep-chiral-HPLC using a CHIRALPAK IG column (2×25 cm, 5 μm) with 0.2% diethylamine and ethanol/CH₂Cl ₂The mixture was separated by using (1/1) hexane as the mobile phase to obtain 2.3 mg of 5-[3-(3-fluoroazidocyclobutane-1-yl)pyrrolidin-1-yl]-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriaconta-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione, isomer A1 (Example A94A1) as a yellow solid (21%) and 3.4 mg Isomer A2 (Example A94A2) (32%). Isomer A1: LCMS: m/z (ESI), [M+H] ⁺=642.35 ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.48-1.85 (4H, m), 1.89-2.05 (2H, m), 2.35-2.56 (4H, m), 2.68-2.76 (2H, m), 2.96 (1H, t), 3.07-3.20 (4H, m), 3.20-3.43 (4H, m), 3.45-3.70 (3H, m), 3.62 (3H, s), 3.72 (3H, s), 4.55 (1H, t), 4.63-4.73 (1H, m), 4.95-5.31 (1H, m), 6.44 (1H, d), 6.73 (1H, s), 7.37 (1H, d), 8.25 (1H, d), 8.42 (1H, s), 8.82 (1H, d), 12.50 (1H, s). Chiral HPLC, Rt=2.381 min. Isomer A2: LCMS: m/z (ESI), [M+H] ⁺=642.55. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.48-1.85 (4H, m), 1.89-2.05 (2H, m), 2.35-2.56 (4H, m), 2.68-2.76 (2H, m), 2.96 (1H, t), 3.07-3.20 (4H, m), 3.20-3.43 (4H, m), 3.45-3.70 (3H, m), 3.62 (3H, s), 3.72 (3H, s), 4.55 (1H, t), 4.63-4.73 (1H, m), 4.95-5.31 (1H, m), 6.44 (1H, d), 6.73 (1H, s), 7.37 (1H, d), 8.25 (1H, d), 8.42 (1H, s), 8.82 (1H, d), 12.50 (1H, s). Chiral HPLC, Rt=2.959 minutes. Example A94B, Example 94B1 and Example A94B2 5-[3-(3-fluoroazolocyclobutane-1-yl)pyrrolidin-1-yl]-15,21-dimethyl-23-oxo-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer B (Example A94B), isomer B1 (Example A94B1) and isomer B2 (Example A94B2) Step 1. Preparation of 5-[3-(3-fluoroazidocyclobutane-1-yl)pyrrolidin-1-yl]-15,21-dimethyl-23-oxo-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (isomer B, Example A94B). To 3-(3-fluoroaziridine cyclobutane-1-yl)pyrrolidine (INT-A94A-2, 125 mg, 0.86 mmol, 5 equivalents), BrettPhos Pd G ₃To a stirred mixture of 5-bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione (M4B, 100 mg, 0.173 mmol, 1 eq) in 1,4-dioxane (10 mL) was added LiHMDS (2.1 mL, 2.07 mmol, 12 eq). The resulting mixture was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was treated with saturated NH₄Cl(aq) (15 mL) was quenched and the mixture was washed with CH ₂Cl ₂(3×50 mL) extraction. The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1). The product was purified by Prep-HPLC using an XBridge Prep OBD C18 column with 0.1% NH₄HCO ₃The product was purified by using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 15.3 mg of 5-[3-(3-fluoroazidocyclobutane-1-yl)pyrrolidin-1-yl]-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, Isomer B (Example A94B) as an off-white solid (13%). LCMS: m/z (ESI), [M+H] ⁺= 642.40. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.48-1.85 (4H, m), 1.89-2.05 (2H, m), 2.35-2.56 (4H, m), 2.68-2.76 (2H, m), 2.96 (1H, t), 3.07-3.20 (4H, m), 3.20-3.43 (4H, m), 3.45-3.70 (3H, m), 3.62 (3H, s), 3.72 (3H, s), 4.55 (1H, t), 4.63-4.73 (1H, m), 4.95-5.31 (1H, m), 6.44 (1H, d), 6.73 (1H, s), 7.37 (1H, d), 8.25 (1H, d), 8.42 (1H, s), 8.82 (1H, d), 12.50 (1H, s). Step 2. Preparation of 5-[3-(3-fluoroazidocyclobutane-1-yl)pyrrolidin-1-yl]-15,21-dimethyl-23-oxo-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer B1 (Example A94B1) and isomer B2 (Example A94B2). A mixture of 5-[3-(3-fluoroaziridocyclobutane-1-yl)pyrrolidin-1-yl]-15,21-dimethyl-23-oxadiazol-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}. 1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione (Example A94B, 11 mg) was subjected to Prep-chiral-HPLC using a CHIRALPAK IG column (2×25 cm, 5 μm) with 0.2% diethylamine as mobile phase A and ethanol/CH₂Cl ₂(1/1) was separated using hexane as mobile phase B to give 3.7 mg of 5-[3-(3-fluoroazidocyclobutane-1-yl)pyrrolidin-1-yl]-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriaconta-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer B1 (Example A94B1) (28%) as a yellow solid and 4.5 mg Isomer B2 (Example A94B2) (34%). Isomer B1: LCMS: m/z (ESI), [M+H] ⁺=642.30. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.48-1.85 (4H, m), 1.89-2.05 (2H, m), 2.35-2.56 (4H, m), 2.68-2.76 (2H, m), 2.96 (1H, t), 3.07-3.20 (4H, m), 3.20-3.43 (4H, m), 3.45-3.70 (3H, m), 3.62 (3H, s), 3.72 (3H, s), 4.55 (1H, t), 4.63-4.73 (1H, m), 4.95-5.31 (1H, m), 6.44 (1H, d), 6.73 (1H, s), 7.37 (1H, d), 8.25 (1H, d), 8.42 (1H, s), 8.82 (1H, d), 12.50 (1H, s). Chiral HPLC, Rt=1.608 min. Isomer B2: LCMS: m/z (ESI), [M+H] ⁺=642.55. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.48-1.85 (4H, m), 1.89-2.05 (2H, m), 2.35-2.56 (4H, m), 2.68-2.76 (2H, m), 2.96 (1H, t), 3.07-3.20 (4H, m), 3.20-3.43 (4H, m), 3.45-3.70 (3H, m), 3.62 (3H, s), 3.72 (3H, s), 4.55 (1H, t), 4.63-4.73 (1H, m), 4.95-5.31 (1H, m), 6.48 (1H, d), 6.76 (1H, s), 7.38 (1H, d), 8.26 (1H, d), 8.42 (1H, s), 8.82 (1H, d), 12.52 (1H, s). Chiral HPLC, Rt = 2.068 minutes. Example A100 15,21-Dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione Step 1. Preparation of 2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.2]nonan-3-yl}ethanol (INT-A100-1). 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (250 mg, 0.83 mmol, 1 equivalent), K ₂CO ₃A mixture of 2-fluoro-1-nitro-2-nitro-1-yl (347 mg, 2.51 mmol, 3 equiv.) and o-fluoronitrobenzene (295 mg, 2.09 mmol, 2.5 equiv.) in acetonitrile (8 mL) was stirred at 100 °C for 8 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (20 mL), and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (5/1) to give 110 mg of 2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethanol (INT-A100-1) (38%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=306.15. Step 2. Preparation of 1-methyl-5-[1-methyl-5-(2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)pyrazol-4-yl]-6-oxopyridine-3-carboxylic acid methyl ester (INT-A100-2). To a stirred mixture of 2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethanol (100 mg, 0.32 mmol, 1 eq) and triphenylphosphine (257 mg, 0.98 mmol, 3 eq) in tetrahydrofuran (20 mL) was added diisopropyl azodicarboxylate (198 mg, 0.98 mmol, 3 eq) and methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 68 mg, 0.26 mmol, 0.8 eq) in tetrahydrofuran (5 mL) dropwise under nitrogen atmosphere at 0° C. The mixture was stirred at 0° C. for 2 h. The reaction was quenched with water (20 mL), and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column eluting with petroleum ether/ethyl acetate (1/1) to give 150 mg of 1-methyl-5-[1-methyl-5-(2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)pyrazol-4-yl]-6-oxopyridine-3-carboxylic acid methyl ester (INT-A100-2) (74%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=551.20. Step 3. Preparation of 5-[5-(2-{1-[(2-aminophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A100-3). To a stirred mixture of methyl 1-methyl-5-[1-methyl-5-(2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)pyrazol-4-yl]-6-oxopyridine-3-carboxylate (140 mg, 0.25 mmol, 1 eq) and ranyl nickel (69 mg) in methanol (5 mL) was added hydrazine hydrate (51 mg, 1.01 mmol, 4.00 eq) at 0 °C. The mixture was stirred at 0 °C under nitrogen atmosphere for 2 h. The resulting mixture was filtered, and the filter cake was washed with methanol (3 x 10 mL). The resulting solution was concentrated under reduced pressure to give 90 mg of 5-[5-(2-{1-[(2-aminophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A100-3) (58%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺=521.30. Step 4. Preparation of 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A100-4). A mixture of 5-[5-(2-{1-[(2-aminophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (90 mg, 0.17 mmol, 1 eq.) and BrCN (21 mg, 0.20 mmol, 1.20 eq.) in ethanol (5 mL) was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water (20 mL), and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/1) to give 60 mg of 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A100-4) (57%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=546.35. Step 5. Preparation of 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A100-5). 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (50 mg, 0.09 mmol, 1 equivalent) and LiOH.H ₂A mixture of O (7 mg, 0.27 mmol, 3 equiv.) in tetrahydrofuran (4 mL) and water (1 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was passed through C18FLASH using a 10 mmol/L NH₄HCO ₃and 0.1% NH ₃.H ₂O and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 25 mg of 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A100-5) (50%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=532.25. Step 6. Preparation of 15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]triacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione (Example A100). 5-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (30 mg, 0.05 mmol, 1 equivalent), N, N, N, N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (32 mg, 0.08 mmol, 1.5 equivalents) and N, N- A mixture of diisopropylethylamine (21 mg, 0.16 mmol, 3 equiv.) in 1,4-dioxane (5 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (10 mL), and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to Prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 26.8 mg of 15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione (Example A100) (92%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺= 514.20. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 1.85-1.98 (4H, m), 2.02-2.18 (3H, m), 2.78-2.88 (2H, m), 2.88-2.95 (2H, m), 3.40-3.52 (4H, m), 3.63 (3H, s), 3.75 (3H, s), 4.29 (2H, s), 7.12-7.21 (2H, m), 7.63 (1H, d), 7.89 (1H, d), 8.38-8.24 (2H, m), 9.12 (1H, d), 13.30 (1H, s). Example A101 (11R)-15-chloro-5,11,26-trimethyl-16-(4-methylpiperazin-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. (11 R)-15-chloro-5,11,26-trimethyl-16-(4-methylpiperazine-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]twenty-eight-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A101). In a nitrogen atmosphere at 0°C to (11 R)-15-chloro-5,11,26-trimethyl-16-(piperazin-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A23, 80 mg, 0.14 mmol, 1 equivalent), paraformaldehyde (38 mg, 0.42 mmol, 3 equivalents) and NaBH(OAc) ₃(60 mg, 0.28 mmol, 2 eq.) in CH ₂Cl ₂(20 mL) was added dropwise to the stirring mixture N, N-Diisopropylethylamine (36 mg, 0.28 mmol, 2 eq.). The mixture was stirred at 0 °C for 2 h. The reaction was quenched with water (10 mL), and the mixture was washed with CH₂Cl ₂(3×10 mL) extraction. The combined organic layers were washed with brine (3×10 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to Prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 32.4 mg (11 R)-15-chloro-5,11,26-trimethyl-16-(4-methylpiperazin-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (Example A101) (39%). LCMS: m/z (ESI), [M+H] ⁺=579.20. ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.86 (3H, d), 1.51-1.59 (1H, m), 1.86-2.08 (2H, m), 2.21-2.29 (5H, m), 2.51-2.64 (4H, m), 2.80-2.94 (4H, m), 3.62 (3H, s), 3.71 (3H, s), 3.91-4.03 (1H, m), 4.18 (1H, dd), 4.32-4.49 (1H, m), 4.75-4.97 (1H, m), 7.15 (1H, d), 7.58 (1H, d), 8.31-8.47 (2H, m), 8.85 (1H, d), 12.73 (1H, s). Example A102 and Example A103 (11 R)-5,11,30-trimethyl-7-oxa-4,5,13,18,24,26,30-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontidine-1(32),2(6),3,14,20,22,24,28-octaene-27,31-dione (Example A102) and (11 R)-5,11,18,30-tetramethyl-7-oxa-4,5,13,18,24,26, 30-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}. 0^{15,20}]triacontidine-1(32),2(6),3,14,20,22,24,28-octaene-27,31-dione (Example A103). Step 1. 2,2,2-Trifluoro- N- Preparation of (2-fluorophenylethyl) acetamide (INT-A102-1). A mixture of 2-(2-fluorophenyl) ethylamine (50 g, 359 mmol, 1 eq.), trimethylamine (73 g, 359 mmol, 2 eq.) and trifluoroacetic anhydride (75 g, 1.1 eq.) in dichloromethane (800 mL) was stirred at 0 °C for 3 h under a nitrogen atmosphere. The reaction was quenched with water (200 mL), and the mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by silica gel chromatography using petroleum ether/ethyl acetate (5/1) to give 76 g of 2,2,2-trifluoro- N-[2-(2-fluorophenyl)ethyl]acetamide (INT-A102-1) (90%). LCMS: m/z (ESI), [M+H] ⁺=236.05. Step 2. Preparation of 2,2,2-trifluoro-1-(5-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)ethan-1-one (INT-A102-2). 2,2,2-trifluoro- N-[2-(2-fluorophenyl)ethyl]acetamide (76 g, 323.15 mmol, 1 equivalent), (HCHO) _n(43 g, 969.5 mmol, 3 eq.) and H ₂SO ₄A mixture of (224 mL, 4201 mmol, 13 equiv) and AcOH (296 mL) was stirred at 0 °C for 3 h under nitrogen atmosphere. The reaction was quenched with water (800 mL) and neutralized to pH 7 with NaOH. The mixture was extracted with dichloromethane (3×500 mL). The combined organic layers were washed with brine (3×500 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (1/1) to give 10 g of 2,2,2-trifluoro-1-(5-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (INT-A102-2) (13%) as a brownish yellow oil. LCMS: m/z (ESI), [M+H] ⁺=248.10. Step 3. Preparation of 2,2,2-trifluoro-1-(5-fluoro-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (INT-A102-3). 2,2,2-trifluoro-1-(5-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (10 g, 40.45 mmol, 1 equivalent) and KNO ₃(4 g, 40.45 mmol, 1 eq.) in H ₂SO ₄The mixture in 4% paraformaldehyde (100 mL) was stirred at 0 °C overnight. The reaction was quenched with water (500 mL) and adjusted to pH 9 with NaOH. The mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine (3×200 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (3/1) to give 1.4 g of 2,2,2-trifluoro-1-(5-fluoro-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (INT-A102-3) (12%) as a yellow oil. ¹H NMR (DMSO, 400 MHz) δ 2.91-2.99 (2H, m), 3.85-3.92 (2H, m), 4.91 (2H, d), 7.45 (1H, d), 8.12 (1H, d). Step 4. 2,2,2-Trifluoro-1-(5-{[(2 RPreparation of 2,2,2-trifluoro-1-(5-fluoro-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (INT-A102-3, 15 g, 51.34 mmol, 1 equivalent), N,N-diisopropylethylamine (19.9 g, 154.01 mmol, 3 equivalents) and (4 RA mixture of 5-amino-4-methylpentan-1-ol (M3-6, 6016 mg, 51.34 mmol, 1 equivalent) in acetonitrile (150 mL) was stirred at 80 °C for 2 h. The mixture was cooled to room temperature. The reaction was quenched with water (500 mL), and the mixture was extracted with dichloromethane (3×500 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by eluting with petroleum ether/ethyl acetate (1/1) through a silica gel column to obtain 10 g of 2,2,2-trifluoro-1-(5-{[(2 R)-5-hydroxy-2-methylpentyl]amino}-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (INT-A102-3) (50%). LCMS: m/z (ESI), [M+H] ⁺=390.10. Step 5. (4 R)-4-methyl-5-[(6-nitro-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]pentan-1-ol (INT-A102-5). 2,2,2-trifluoro-1-(5-{[(2 R)-5-hydroxy-2-methylpentyl]amino}-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (10 g, 25.68 mmol, 1 equivalent) and K ₂CO ₃(10.6 g, 77.05 mmol, 3 equiv.) in methanol (80 mL) and H ₂O (40 mL) was stirred at room temperature for 5 h. The reaction was treated with water (500 mL), and the mixture was extracted with dichloromethane (3×500 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by passing through a silica gel column eluting with petroleum ether/ethyl acetate (1/1) to obtain 7 g (4 R)-4-methyl-5-[(6-nitro-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]pentan-1-ol (INT-A102-5) (93%). LCMS: m/z (ESI), [M+H] ⁺=294.15. ¹H NMR (DMSO-d ₆,400 MHz) δ 0.83-0.88 (3 H, m), 1.07-1.11 (1 H, m), 1.22-1.51 (3 H, m), 1.57-1.64 (1 H, m), 2.59 (2 H, t), 2.88-2.92 (3 H, m), 3.10-3.20 (1 H, m), 3.30-3.33 (2 H, m), 3.87 (2H, s), 4.37 (1 H, s), 6.56 (1 H, d), 6.69 (1 H, t), 7.26-7.37 (1 H, m), 7.70 (1 H, d). Step 6. 5-{[(2 RPreparation of tert-butyl 6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate (INT-A102-6). (4 RA mixture of )-4-methyl-5-[(6-nitro-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]pentan-1-ol (8 g, 27.27 mmol, 1 equiv), trimethylamine (5.5 g, 54.54 mmol, 2 equiv) and di-tert-butyl dicarbonate (7.1 g, 32.72 mmol, 1.2 equiv) in dichloromethane (100 mL) was stirred at room temperature for 2 h. The reaction was quenched with water (300 mL), and the mixture was extracted with dichloromethane (3×300 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by passing through a silica gel column eluting with petroleum ether/ethyl acetate (1/1) to obtain 6.5 g of 5-{[(2 R)-5-hydroxy-2-methylpentyl]amino}-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (INT-A102-6) (60%). LCMS: m/z (ESI), [M+H] ⁺=394.20. ¹H NMR (DMSO-d ₆400 MHz) δ 0.84 (3H, d), 1.03-1.17 (1H, m), 1.22-1.45 (2H, m), 1.45 (9H, s), 1.61 (1H, q), 2.75 (2H, t), 2.93-2.97 (1H, m), 3.08-3.12 (1H, m), 3.30-3.33 (2H, m), 3.51 (2H, t), 4.36 (1H, t), 4.52 (2H, s), 6.73 (1H, d), 6.83 (1H, s), 7.80 (1H, d) Step 7. 5-{[(2 RPreparation of tert-butyl 6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate (INT-A102-7). In a nitrogen atmosphere, 5-{[(2 RTo a stirred mixture of tert-butyl 5-(5-hydroxy-2-methylpentyl]amino}-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate (INT-A102-6, 800 mg, 2.03 mmol, 1 eq.) and methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 535 mg, 2.03 mmol, 1.0 eq.) in toluene (30 mL) was added 2-(tributyl-1^[5]-phosphinilidene)acetonitrile (2 g, 10.16 mmol, 5 eq.). The resulting mixture was stirred at 100 °C for 2 h and then cooled to room temperature. The reaction was quenched with water (100 mL) and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to give 700 mg 5-{[(2 R)-5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (INT-A102-7) (52%). LCMS: m/z (ESI), [M+H] ⁺= 639.30. ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.87 (3H, d), 0.92-0.96 (1H, m), 1.27 (1H, d), 1.44 (11H, s), 2.72-2.77 (2H, m), 2.94-3.03 (1H, m), 3.09-3.16 (1H, m), 3.18 (1H, d), 3.50 (2H, s), 3.58 (3H, s), 3.66 (3H, s), 3.78 (3H, s), 3.88-3.92 (2H, t), 4.50 (2H, s), 6.72 (1H, d), 6.83 (1H, s), 7.78 (1H, d), 8.00 (1H, s), 8.11 (1H, d), 8.45 (1H, d). Step 8. 6-amino-5-{[(2 RPreparation of 5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (INT-A102-8). To a mixture of 5-{[(2R)-5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (700 mg, 1.09 mmol, 1 equiv.) and ranyl nickel (187 mg, 2.19 mmol, 2 equiv.) in methanol (8 mL), NH ₂NH ₂ ^.H ₂O (109 mg, 2.19 mmol, 2 eq.). The mixture was stirred at 0 °C for 30 min under nitrogen atmosphere. The mixture was filtered and the filter cake was washed with methanol (3×40 mL). The resulting solution was concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 400 mg of 6-amino-5-{[(2 R)-5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (INT-A102-8) (59%). LCMS: m/z (ESI), [M+H] ⁺=609.30. Step 9. 5-(5-{[(4 RPreparation of methyl 6-oxopyridine-3-carboxylate (INT-A102-9). 6-amino-5-{[(2 RA mixture of tert-butyl 5-({4-[5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}-3,4-dihydro-1H-isoquinoline-2-carboxylate (400 mg, 0.65 mmol, 1 equiv) and BrCN (104 mg, 0.98 mmol, 1.5 equiv) in ethanol (5 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (50 mL), and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (12/1) to give 300 mg of 5-(5-{[(4 R)-4-{[2-amino-7-(tert-butoxycarbonyl)-6H,8H,9H-imidazo[4,5-f]isoquinolin-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A102-9) (72%). LCMS: m/z (ESI), [M+H] ⁺=634.30. Step 10. 5-(5-{[(4 RPreparation of 5-(5-{[(4 R)-4-{[2-amino-7-(tert-butoxycarbonyl)-6H,8H,9H-imidazo[4,5-f]isoquinolin-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (300 mg, 0.47 mmol, 1 equivalent) and LiOH ^.H ₂O (99 mg, 2.36 mmol, 5 equivalents) in tetrahydrofuran/H ₂O (2 mL/0.5 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 column using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 250 mg of 5-(5-{[(4R)-4-{[2-amino-7-(tert-butoxycarbonyl)-6H,8H,9H-imidazo[4,5-f]isoquinolin-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A102-10) (85%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=620.40. Step 11. (11 RPreparation of 5-(5-{[(4 )-(5-{[(4 )-(5-{[(4 )-(5-{[(4 )-(5-{[(4 )-(5-{[(4 )-(5-{[(4 )-(5-{[(4 )-(4 )-(5-{[(4 )-(4 )-(5-{[(4 )-(4 )-(5-{[(4 )-(4 )-(5-{[(4 )-(4 )-(5-{[(4 )-(4 )-(5-{[(4 )-(4 )-(5-{[(4 )-(4 )-(5-{[(4 )-(4 )-(5-{[(4 )-(4 )-(4 )-(5-{[(4 )-(4 )-(5-{[(4 )R)-4-{[2-amino-7-(tert-butoxycarbonyl)-6H,8H,9H-imidazo[4,5-f]isoquinolin-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (200 mg, 0.32 mmol, 1 equivalent), N,N,N,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (245 mg, 0.64 mmol, 2 equivalents) and N,N- A mixture of diisopropylethylamine (125 mg, 0.96 mmol, 3 equiv.) in 1,4-dioxane (5 mL) was stirred at 60 °C for 30 min under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (20 mL), and the mixture was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC eluting with (dichloromethane/methanol 12/1) to give 180 mg (11 R)-5,11,30-trimethyl-27,31-dioxo-7-oxa-4,5,13,18,24,26,30-heptaazahexacyclic [26.3.1.0^{2,6}.0^{13,25}. 0^{14,23}.0^{15,20}]triacontidine-1(32),2(6),3,14,20,22,24,28-octaene-18-carboxylic acid tert-butyl ester (INT-A102-11) (92%). LCMS: m/z (ESI), [M+H] ⁺=602.30. Step 12. (11 R)-5,11,30-trimethyl-7-oxa-4,5,13,18,24, 26,30-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(32),2(6),3,14,20,22,24,28-octaene-27,31-dione (Example A102). A mixture of (11R)-5,11,30-trimethyl-27,31-dioxo-7-oxa-4,5,13,18,24,26,30-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontria-1(32),2(6),3,14,20,22,24,28-octaene-18-carboxylic acid tert-butyl ester (200 mg, 0.33 mmol, 1 eq.) in dichloromethane/trifluoroacetic acid (3 mL/1 mL) was stirred at room temperature for 30 min under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was treated with saturated NaHCO₃(aqueous solution) (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 110 mg (11 R)-5,11,30-trimethyl-7-oxa-4,5,13,18,24,26,30-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontidine-1(32),2(6),3,14,20,22,24,28-octaene-27,31-dione (Example A102) (65%). LCMS: m/z (ESI), [M+H] ⁺=502.45. ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.81 (3H, d), 1.21-1.27 (1H, m), 1.41-1.45 (1H, m), 1.76-2.00 (4H, m), 2.35 (3H, s), 2.60-2.76 (2H, m), 3.52-3.58 (2H, m), 3.62 (3H, s), 3.71 (3H, s), 3.85-3.93 (1H, m), 4.11-4.27 (1H, m), 4.27-4.37 (1H, m), 6.91 (1H, d), 7.38 (1H, d), 8.28 (1H, d), 8.36 (1H, s), 8.77 (1H, d), 12.62 (1H, s). Step 13. Preparation of (11R)-5,11,18,30-tetramethyl-7-oxa-4,5,13,18, 24,26,30-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}. 0^{15,20}]triacontidine-1(32),2(6),3,14,20,22,24,28-octaene-27,31-dione (Example A103). In a nitrogen atmosphere, at room temperature, (11 R)-5,11,30-trimethyl-7-oxa-4,5,13,18,24,26,30-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontidine-1(32),2(6),3,14,20,22,24,28-octaene-27,31-dione (Example A102, 50 mg, 0.10 mmol, 1 equivalent), paraformaldehyde (26 mg, 0.30 mmol, 3 equivalents) and N, N-Diisopropylethylamine (25 mg, 0.20 mmol, 2 equiv.) was stirred in dichloromethane (2 mL) and NaBH(OAc) was added.₃(42 mg, 0.20 mmol, 2 equiv.). The reaction was quenched with water (50 mL), and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Prep OBD C18 column with 10 mmol/L NH₄HCO ₃of water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 26 mg (11 R)-5,11,18,30-tetramethyl-7-oxa-4,5,13,18,24,26,30-heptaazahexacyclo[26.3.1.0^{2,6}. 0^{13,25}.0^{14,23}.0^{15,20}]triacontidine-1(32),2(6),3,14,20, 22,24,28-octaene-27,31-dione (Example A103) (50%). LCMS: m/z (ESI), [M+H] ⁺=516.30 ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.81 (3H, d), 1.21-1.27 (1H, m), 1.41-1.45 (1H, m), 1.76-2.00 (3H, m), 2.35 (3H, s), 2.60-2.76 (2H, m), 3.21 (3H, s), 3.52-3.58 (2H, m), 3.62 (3H, s), 3.71 (3H, s), 3.85-3.93 (1H, m), 4.11-4.27 (1H, m), 4.27-4.37 (1H, m), 6.91 (1H, d), 7.38 (1H, d), 8.28 (1H, d), 8.36 (1H, s), 8.77 (1H, d), 12.62 (1H, s). Example A109 (12 R)-12,27-dimethyl-17-(4-methylpiperazine-1-yl)-8-oxo-14,21, 23,27-tetraazapentacyclic [23.3.1.0^{2,7}.0^{14,22}.0^{15,20}]twenty-nine-1(29),2(7),3,5,15,17,19,21,25-nonene-24,28-dione Step 1. Preparation of 5-(2-hydroxyphenyl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A109-1). 5-bromo-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (8 g, 32.51 mmol, 1 equivalent), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (7.87 g, 35.76 mmol, 1.1 equivalent), Pd(dppf)Cl ₂(1.43 g, 1.95 mmol, 0.06 eq.) and K ₂CO ₃(8.99 g, 65.02 mmol, 2 equivalents) in 1,4-dioxane (240 mL) and H ₂The mixture in 2% O (60 mL) was stirred at 80 °C under nitrogen atmosphere for 1.5 h. The mixture was cooled to room temperature. The reaction was quenched with water (500 mL), and the mixture was washed with CH₂Cl ₂(3×500 mL) extraction. The combined organic layers were washed with brine (3×500 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using petroleum ether/ethyl acetate (3/1) to give 5.6 g of methyl 5-(2-hydroxyphenyl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A109-1) (66%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=260.05. ¹H NMR (DMSO-d ₆, 400 MHz) δ 3.61 (3H, s), 3.82 (3H, s), 6.81-6.93 (2H, m), 7.18-7.22 (1H, m), 7.24-7.28 (1H, m), 7.86 (1H, d), 8.60 (1H, d), 9.39 (1H, s). Step 2. 5-(2-{[(4 RPreparation of methyl 5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A109-2). 5-(2-Hydroxyphenyl)-1-methyl-6-oxopyridine-3-carboxylate (1 g, 3.86 mmol, 1 equivalent), 2-(tributyl-1^[5]-phosphinilidene)acetonitrile (4.65 g, 19.29 mmol, 5 equivalents) and (4 RA mixture of 5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentan-1-ol (M3-7, 1.22 g, 3.86 mmol, 1 equiv.) in toluene (40 mL) was stirred at 130 °C for 1.5 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using petroleum ether/ethyl acetate (3/1) to give 1.7 g of 5-(2-{[(4 R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A109-2) (79%). LCMS: m/z (ESI), [M+H] ⁺=558.10. Step 3. 5-(2-{[(4 RPreparation of methyl 5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A109-3). At 0°C, 5-(2-{[(4RTo a stirred mixture of methyl 5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylate (800 mg, 1.43 mmol, 1 equiv) and ranyl nickel (80 mg, 0.93 mmol, 0.65 equiv) in methanol (35 mL) was added NH₂NH ₂ ^.H ₂O (143 mg, 2.87 mmol, 2 eq.). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine (3×80 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/5) to give 690 mg of 5-(2-{[(4 R)-5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A109-3) (91%). LCMS: m/z (ESI), [M+H] ⁺=528.00. Step 4. 5-(2-{[(4 RPreparation of methyl 4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A109-4). 5-(2-{[(4 RA mixture of methyl 5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylate (1.3 g, 2.46 mmol, 1 equiv) and BrCN (521 mg, 4.92 mmol, 2 equiv) in dichloromethane (30 mL) was stirred at room temperature for 4 h. The reaction was quenched with water (200 mL), and the mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (20/1) to give 1.32 g of 5-(2-{[(4 R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A109-4) (97%). LCMS: m/z (ESI), [M+H] ⁺=554.95. Step 5. 5-(2-{[(4 RPreparation of 5-(2-{[(4 )-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A109-5).RTo a stirred mixture of methyl 4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylate (1.3 g, 2.35 mmol, 1 eq.) in tetrahydrofuran (10 mL) were added LiOH (225.02 mg, 9.39 mmol, 4 eq.) and H ₂O (4 mL). The resulting mixture was stirred at room temperature for 1 h and concentrated under vacuum. The residue was purified by C18 FLASH chromatography using water and acetonitrile as mobile phases. The fractions containing the desired compound were evaporated to dryness to give 900 mg of 5-(2-{[(4 R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A109-5) (71%). LCMS: m/z (ESI), [M+H] ⁺=540.95. Step 6. (12 R)-17-bromo-12,27-dimethyl-8-oxa-14,21,23,27-tetraazapentacyclic [23.3.1.0^{2,7}.0^{14,22}.0^{15,20}]twenty-nine-1(29),2(7),3,5,15,17,19,21,25-nonene-24,28-dione (INT-A109-6). At room temperature, 5-(2-{[(4 R)-4-[(2-amino-6-bromo-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylic acid (450 mg, 0.83 mmol, 1 equivalent) was added to the stirred mixture in dioxane (10 mL) N,N-Diisopropylethylamine (323 mg, 2.50 mmol, 3 equiv.) and N,N,N,N-Tetramethyl- O-(7-Azabenzotriazole-1-yl)uronium hexafluorophosphate (476 mg, 1.25 mmol, 1.5 equiv). The resulting mixture was stirred at 60 °C for 1 h under a nitrogen atmosphere and cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC eluting with methylenedichloromethane/methanol (30/1) to give 350 mg (12 R)-17-bromo-12,27-dimethyl-8-oxa-14,21,23,27-tetraazapentacyclic [23.3.1.0^{2,7}.0^{14,22}. 0^{15,20}]twenty-nine-1(29),2(7),3,5,15,17,19,21,25-nonene-24,28-dione (INT-A109-6) (80%). LCMS: m/z (ESI), [M+H] ⁺=523.05. Step 7. (12 R)-12,27-dimethyl-17-(4-methylpiperazine-1-yl)-8-oxa-14,21,23,27-tetraazapentacyclic [23.3.1.0^{2,7}.0^{14,22}. 0^{15,20}]twenty-nine-1(29),2(7),3,5,15,17,19,21,25-nonene-24,28-dione (Example A109). In a nitrogen atmosphere at room temperature to (12 RTo a stirred mixture of )-17-bromo-12,27-dimethyl-8-oxa-14,21,23,27-tetraazapentacyclo[23.3.1.0^{2,7}.0^{14,22}.0^{15,20}]nonaconicotin-1(29),2(7), 3,5,15,17,19,21,25-nonene-24,28-dione (200 mg, 0.38 mmol, 1 eq), 1-methylpiperazine (127 mg, 1.27 mmol, 3.31 eq) and BrettPhos Pd G3 (90 mg, 0.10 mmol, 0.26 eq) in 1,4-dioxane (10 mL) was added LiHMDS (3.8 mL, 3.8 mmol, 10 eq) dropwise. The resulting mixture was stirred at 60 °C for 50 min and cooled to room temperature. The reaction was heated with saturated NH₄Cl(aqueous solution) (100 mL) was quenched, and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (30/1) for elution, and the product was purified by prep-HPLC using an XBridge Prep OBD C18 column with 10 mmol/L NH₄HCO ₃The product was further purified using water and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 13.7 mg (12 R)-12,27-dimethyl-17-(4-methylpiperazin-1-yl)-8-oxa-14,21,23,27-tetraazapentacyclic [23.3.1.0^{2,7}.0^{14,22}.0^{15,20}]twenty-nine-1(29),2(7),3,5,15,17,19,21,25-nonene-24,28-dione (Example A109) (7%). LCMS: m/z (ESI), [M+H] ⁺=541.35. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.92 (3H, d), 1.29-1.33 (1H, m), 1.60-1.66 (1H, m), 2.02-2.06 (2H, m), 2.24 (3H, s), 2.26-2.30 (1H, m), 2.49-2.51 (4H, m), 3.14 (4H, t), 3.60 (3H, s), 3.93-4.08 (3H, m), 4.20 (1H, t), 6.83-6.89 (1H, m), 6.86 (1H, dd), 6.92-6.96 (1H, m), 7.12 (1H, d), 7.25-7.29 (1H, m), 7.34 (1H, d), 7.69 (1H, dd), 8.33 (1H, d), 8.85 (1H, d), 12.27 (1H, s). Example A110 (12 R)-4-fluoro-12,27-dimethyl-17-(4-methylpiperazine-1-yl)-8-oxo-14,21,23,27-tetraazapentacyclic [23.3.1.0^{2,7}.0^{14,22}. 0^{15,20}]twenty-nine-1(29),2(7),3,5,15,17,19,21,25-nonene-24,28-dione Step 1. Preparation of 5-(5-fluoro-2-hydroxyphenyl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A110-1). 5-Bromo-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (2 g, 8.128 mmol, 1 equivalent), 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.32 g, 9.754 mmol, 1.2 equivalents), Pd(dppf)Cl ₂(0.48 g, 0.656 mmol, 0.08 eq.) and K ₂CO ₃(2.81 g, 20.320 mmol, 2.5 equiv.) in dioxane (40 mL) and H ₂The mixture in 2% O (10 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (150 mL), and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by silica gel chromatography eluting with dichloromethane/methanol (15/1) to give 1 g of methyl 5-(5-fluoro-2-hydroxyphenyl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A110-1) (44%) as a yellow solid. ¹H NMR (DMSO-d ₆, 400 MHz) 3.60 (3H, s), 3.81 (3H, s), 6.84-6.95 (1H,m), 6.96-7.08 (1H, m), 7.14 (1H, d), 7.94 (1H, d), 8.61 (1H, d), 9.41 (1H, s) Step 2. 5-(5-fluoro-2-{[(4R)-4-methyl-5-{[5-(4-methylpiperazin-1-yl)-2-nitrophenyl]amino}pentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A110-2). 5-(5-fluoro-2-hydroxyphenyl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (526 mg, 1.90 mmol, 1 equivalent), (4 RA mixture of )-4-methyl-5-{[5-(4-methylpiperazin-1-yl)-2-nitrophenyl]amino}pentan-1-ol (639.07 mg, 1.90 mmol, 1 equiv) and 2-(tributyl-1^[5]-phosphinilidene)acetonitrile (2.30 g, 9.50 mmol, 5 equiv) in toluene (5 mL) was stirred at 130 °C overnight under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/1) to give 500 mg of 5-(5-fluoro-2-{[(4R)-4-methyl-5-{[5-(4-methylpiperazin-1-yl)-2-nitrophenyl]amino}pentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A110-2) (44%) as a white solid. ¹H NMR (DMSO-d ₆ , 400 MHz) 0.90 (3H, s), 1.31-1.39 (4H, m), 2.20 (3H, s), 2.32-2.41 (4H, m), 2.44 (1H, t), 2.98-3.28 (2H, m), 3.40 (4H, t), 3.56 (3H, s), 3.76 (3H, s), 3.95 (2H, t), 5.77 (1H, s), 5.96 (1H, d), 6.43 (1H, d), 6.97-7.29 (4H, m), 7.83-7.95 (2H, m), 8.05 (1H, d), 8.39 (1H, t), 8.53 (1H, d). Step 3. 5-(2-{[(4 RPreparation of methyl 5-{[2-amino-5-(4-methylpiperazine-1-yl)phenyl]amino}-4-methylpentyl]oxy}-5-fluorophenyl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A110-3). At 0°C, 5-(5-fluoro-2-{[(4 RTo a stirred mixture of methyl 4-(4-methyl-5-{[5-(4-methylpiperazin-1-yl)-2-nitrophenyl]amino}pentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylate (500 mg, 0.83 mmol, 1 eq.) and ranyl nickel (3.60 mg, 0.042 mmol, 0.05 eq.) in methanol (20 mL) was added hydrazine (126.06 mg, 2.51 mmol, 3 eq.). The mixture was stirred at 0 °C for 30 min under nitrogen atmosphere. The obtained mixture was filtered, and the filter cake was washed with methanol (3×30 mL). The obtained solution was concentrated under reduced pressure. The residue was purified by C18 FLASH chromatography using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 400 mg of methyl 5-(2-{[(4R)-5-{[2-amino-5-(4-methylpiperazin-1-yl)phenyl]amino}-4-methylpentyl]oxy}-5-fluorophenyl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A110-3) (84%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺= 566.15. Step 4. 5-(2-{[(4 RPreparation of 5-(2-{[(4 RA mixture of methyl 5-{[2-amino-5-(4-methylpiperazin-1-yl)phenyl]amino}-4-methylpentyl]oxy}-5-fluorophenyl)-1-methyl-6-oxopyridine-3-carboxylate (240 mg, 0.42 mmol, 1 eq.) and BrCN (51 mg, 0.46 mmol, 1.1 eq.) in dichloromethane (5 mL) was stirred at room temperature for 4 h under a nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by Prep-TLC eluting with dichloromethane/methanol (1/1) to obtain 140 mg of 5-(2-{[(4 R)-4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-5-fluorophenyl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A110-4) (55%). LCMS: m/z (ESI), [M+H] ⁺=591.15. Step 5. 5-(2-{[(4 RPreparation of 5-(2-{[(4 R)-4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-5-fluorophenyl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (75 mg, 0.12 mmol, 1 equivalent) and LiOH ^.H ₂A mixture of 5-(2-[(4-(2-[(4-(2-[(4-(2-[(4-(2-[(4-(2-[(4-(2-[(4-(2-[(4-(2-[(4-(2-R)-4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-5-fluorophenyl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A110-5) (54%). LCMS: m/z (ESI), [M+H] ⁺=577.25. Step 6. (12 R)-4-fluoro-12,27-dimethyl-17-(4-methylpiperazine-1-yl)-8-oxa-14,21,23,27-tetraazapentacyclic [23.3.1.0^{2,7}. 0^{14,22}.0^{15,20}]twenty-nine-1(29),2(7),3,5,15,17,19,21, 25-nonene-24,28-dione (Example A110). 5-(2-{[(4 R)-4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-5-fluorophenyl)-1-methyl-6-oxopyridine-3-carboxylic acid (35 mg, 0.06 mmol, 1 equivalent), N,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (34 mg, 0.09 mmol, 1.5 equivalents) and N,N- A mixture of diisopropylethylamine (23 mg, 0.18 mmol, 3 equiv.) in 1,4-dioxane (2 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (50 mL), and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to obtain 3.6 mg (12 R)-4-fluoro-12,27-dimethyl-17-(4-methylpiperazine-1-yl)-8-oxa-14,21,23,27-tetraazapentacyclic [23.3.1.0^{2,7}. 0^{14,22}.0^{15,20}]twenty-nine-1(29),2(7),3,5,15,17,19,21, 25-nonene-24,28-dione (Example A110) (10%). LCMS: m/z (ESI), [M+H] ⁺=559.40. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 0.94 (3H, d), 1.31-1.40 (1H, m), 1.64-1.70 (1H, m), 2.01-2.14 (2H, m), 2.21-2.30 (1H, m), 2.41 (3H, s), 2.66-2.73 (4H, m), 3.22 (4H, t), 3.60 (3H, s), 3.76-3.85 (1H, m), 3.99-4.09 (2H, m), 4.13 (1H, s), 6.87-6.97 (2H, m), 6.98-7.09 (2H, m), 7.24 (1H, d), 7.47-7.55 (1H, m), 8.23 (1H, s), 8.91 (1H, s). Example A111 (12 R)-4,5-difluoro-12,27-dimethyl-17-(4-methylpiperazine-1-yl)-8-oxo-14,21,23,27-tetraazapentacyclic [23.3.1.0^{2,7}.0^{14,22}. 0^{15,20}]twenty-nine-1(29),2(7),3,5,15,17,19,21,25-nonene-24,28-dione Step 1. Preparation of methyl 5-(4,5-difluoro-2-hydroxyphenyl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A111-1). To a stirred mixture of methyl 5-bromo-1-methyl-6-oxopyridine-3-carboxylate (2.00 g, 8.12 mmol, 1 eq.) and 4,5-difluoro-2-hydroxyphenylboronic acid (2.12 g, 12.19 mmol, 1.5 eq.) in 1,4-dioxane (32 mL) and water (8 mL) were added portionwise 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) (1.19 g, 1.62 mmol, 0.2 eq.) and K ₂CO ₃(2.81 g, 20.32 mmol, 2.5 equiv.). The resulting mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×80 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to C18 FLASH chromatography using a 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂Purification was performed using water with 0.04% 2-nitropropane and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 1.38 g of methyl 5-(4,5-difluoro-2-hydroxyphenyl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A111-1) (57%) as a white solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ 3.59 (3H, s), 3.81 (3H, s), 6.81-6.91 (1H, m), 7.33-7.41 (1H, d), 7.92 (1H, d), 8.61 (1H, d), 9.90 (1H, s). Step 2. 5-(4,5-difluoro-2-{[(4 RPreparation of methyl 5-(4,5-difluoro-2-hydroxyphenyl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A111-2). Methyl 5-(4,5-difluoro-2-hydroxyphenyl)-1-methyl-6-oxopyridine-3-carboxylate (500 mg, 1.69 mmol, 1 equivalent) and (4 R)-4-methyl-5-{[5-(4-methylpiperazin-1-yl)-2-nitrophenyl]amino}pentan-1-ol (INT-A25-3, 569 mg, 1.69 mmol, 1 equiv) was added in portions to a stirred mixture of toluene (7 mL) with 2-(tributyl-λ5-phosphinidylidene)acetonitrile (2.04 g, 8.47 mmol, 5 equiv). The resulting mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature. The reaction was quenched with water (200 mL), and the mixture was extracted with dichloromethane (3×300 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. Pass the residue through C18 FLASH using 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 620 mg of 5-(4,5-difluoro-2-{[(4R)-4-methyl-5-{[5-(4-methylpiperazin-1-yl)-2-nitrophenyl]amino}pentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A111-2) (59%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺= 614.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.91 (4H, d), 1.20-1.32 (1H, m), 1.59-1.72 (3H, m), 1.75-1.87 (1H, m), 2.32 (3H, d), 3.04-3.13 (1H, m), 3.19-3.25 (1H, m), 3.320-3.36 (8H, m), 3.56 (3H, s), 3.76 (3H, s), 3.97 (3H, t), 5.76 (1H, s), 5.98 (1H, s), 6.40-6.46 (1H, m), 7.18-7.28 (1H, m), 7.40-7.50 (1H, m), 7.84-7.95 (2H, m), 8.37 (1H, t), 8.53 (1H, d). Step 3. 5-(2-{[(4 RPreparation of methyl 5-{[2-amino-5-(4-methylpiperazine-1-yl)phenyl]amino}-4-methylpentyl]oxy}-4,5-difluorophenyl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A111-3). In a nitrogen atmosphere, 5-(4,5-difluoro-2-{[(4 RTo a stirred mixture of methyl 4-(2-(4-methylpiperazin-1-yl)-2-nitrophenyl]amino}pentyl]oxy}phenyl)-1-methyl-6-oxopyridine-3-carboxylate (600 mg, 0.97 mmol, 1 eq.) and ranyl nickel (251 mg, 2.93 mmol, 3 eq.) in methanol (5 mL) was added hydrazine hydrate (98%) (2.45 mg, 0.04 mmol, 3 eq.). The resulting mixture was stirred at 0 °C for 30 min under a nitrogen atmosphere. The mixture was filtered, and the filter cake was washed with methanol (3×10 mL). The resulting solution was concentrated under reduced pressure to give 310 mg of 5-(2-{[(4 R)-5-{[2-amino-5-(4-methylpiperazin-1-yl)phenyl]amino}-4-methylpentyl]oxy}-4,5-difluorophenyl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A111-3). This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=582.25. Step 4. 5-(2-{[(4 RPreparation of methyl 4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-4,5-difluorophenyl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A111-4). 5-(2-{[(4 RA mixture of methyl 5-{[2-amino-5-(4-methylpiperazin-1-yl)phenyl]amino}-4-methylpentyl]oxy}-4,5-difluorophenyl)-1-methyl-6-oxopyridine-3-carboxylate (700 mg, 1.20 mmol, 1 equiv) and cyanogen bromide (190 mg, 1.80 mmol, 1.5 equiv) in dichloromethane (10 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (10 mL), and the mixture was extracted with dichloromethane (3×60 mL). The combined organic layers were washed with brine (3×20 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. Pass the residue through C18FLASH using 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O and acetonitrile water as the mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 120 mg of 5-(2-{[(4 R)-4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-4,5-difluorophenyl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A111-4) (16%). LCMS: m/z (ESI), [M+H] ⁺=609.15. Step 5. Preparation of 5-(2-{[(4R)-4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-4,5-difluorophenyl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A111-5). 5-(2-{[(4 RA mixture of methyl 4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-4,5-difluorophenyl)-1-methyl-6-oxopyridine-3-carboxylate (100 mg, 0.16 mmol, 1 equiv) and lithium hydroxide monohydrate (10 mg, 0.24 mmol, 1.5 equiv) in tetrahydrofuran (2 mL) and water (0.5 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (5 mL), and the mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (3×5 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 50 mg of 5-(2-{[(4 R)-4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-4,5-difluorophenyl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A111-5) (51%). LCMS: m/z (ESI), [M+H] ⁺=595.20. Step 6. (12 R)-4,5-difluoro-12,27-dimethyl-17-(4-methylpiperazine-1-yl)-8-oxa-14,21,23,27-tetraazapentacyclic [23.3.1.0^{2,7}. 0^{14,22}.0^{15,20}]twenty-nine-1(29),2(7),3,5,15,17,19,21, 25-nonene-24,28-dione (Example A111). 5-(2-{[(4 R)-4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-4,5-difluorophenyl)-1-methyl-6-oxopyridine-3-carboxylic acid (40 mg, 0.06 mmol, 1 equivalent), N,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (38 mg, 0.10 mmol, 1.5 equivalents) and N,N- A mixture of diisopropylethylamine (26 mg, 0.20 mmol, 3 equiv.) in 1,4-dioxane (4 mL) was stirred at room temperature under nitrogen atmosphere for 3 h. The reaction was quenched with water (10 mL), and the mixture was extracted with dichloromethane (3×15 mL). The combined organic layers were washed with brine (3×10 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (5/1) to give 9 mg (12 R)-4,5-difluoro-12,27-dimethyl-17-(4-methylpiperazine-1-yl)-8-oxa-14,21,23,27-tetraazapentacyclic [23.3.1.0^{2,7}.0^{14,22}. 0^{15,20}]twenty-nine-1(29),2(7),3,5,15,17,19,21,25-nonene-24,28-dione (Example A111) (22%). LCMS: m/z (ESI), [M+H] ⁺=577.30. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.92 (3H, d), 1.15-1.65 (3H, m), 2.00-2.10 (2H, m), 2.35-2.45 (4H, m), 2.50 (3H, s), 3.10-3.30 (4H, m), 3.32 (3H, s), 3.91-3.97 (2H, m), 4.05 (1H, d), 4.19 (1H, t), 6.88 (1H, dd), 7.11 (1H, s), 7.26 (1H, dd), 7.35 (1H, d), 7.76 (1H, dd), 8.38 (1H, d), 8.89 (1H, d), 12.31 (1H, s) Example A112 5,12,12,26-Tetramethyl-16-(4-methylpiperazin-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione Step 1. NPreparation of tert-butyl-[(3E)-6-(benzyloxy)-2-methylhex-3-en-2-yl]carbamate (INT-A112-1). To a stirred mixture of (3-benzyloxypropyl)triphenylphosphonium bromide (14.5 g, 30 mmol, 1.1 equiv) in tetrahydrofuran (100 mL) at 0°C was added KHMDS (5.9 g, 30 mmol, 1.1 equiv) dropwise under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 1 h under nitrogen atmosphere. To the above mixture was added N-tert-Butyl (2-methyl-1-oxopropan-2-yl)carbamate (5 g, 26.7 mmol, 1 equiv). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (5/1) to give 6 g of colorless oil.N-[(3E)-6-(Benzyloxy)-2-methylhex-3-en-2-yl]carbamic acid tert-butyl ester (INT-A112-1) (70%).¹H NMR (CDCl ₃, 400 MHz) δ 1.44 (9H, s), 1.46 (6H, s), 2.50-2.62 (2H, m), 3.45-3.52 (2H, m), 4.56 (2H, s), 5.32-5.42 (1H, m), 5.56-6.02 (1H, m), 7.29-7.39 (5H, m). Step 2. NPreparation of tert-butyl-(6-hydroxy-2-methylhexan-2-yl)carbamate (INT-A112-2).NA mixture of tert-butyl-[(3E)-6-(benzyloxy)-2-methylhex-3-en-2-yl]carbamate (2 g, 6.26 mmol, 1 equiv) and Pd/C (3.3 g, 31 mmol, 5 equiv) in methanol (40 mL) was stirred at room temperature under a hydrogen atmosphere for 16 h. The mixture was filtered and the filter cake was washed with methanol (3×40 mL). The resulting solution was concentrated under reduced pressure to give 1.4 g of N-tert-Butyl (6-hydroxy-2-methylhexan-2-yl)carbamate (INT-A112-2) (97%). ¹H NMR (CDCl ₃, 400 MHz) δ1.26 (6H, s), 1.32-1.41 (2H, m), 1.45 (9H, s), 1.60 (2H, d), 1.65-1.72 (2H, m), 3.62-3.73 (2H, m). Step 3. Preparation of 5-amino-5-methylhexan-1-ol (INT-A112-3). NA solution of tert-butyl-(6-hydroxy-2-methylhexan-2-yl)carbamate (1.3 g, 5.6 mmol, 1 equiv) in trifluoroacetic acid (4 mL) and dichloromethane (16 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was treated with saturated NaHCO₃(aqueous solution) (30 mL) and extracted with dichloromethane (3×30 mL). The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC eluting with dichloromethane/methanol (10/1) to give 680 mg of 5-amino-5-methylhexan-1-ol (INT-A112-3) (92%) as a colorless oil. ¹H NMR (CD ₃OD, 400 MHz) δ 1.35 (6H, d), 1.48-1.55 (2H, m), 1.65-1.72 (2H, m), 1.80-1.86 (2H, m), 4.40-4.49 (2H, m). Step 4. Preparation of 5-((5-bromo-2-nitrophenyl)amino)-5-methylhexan-1-ol (INT-A112-4). 5-Amino-5-methylhexan-1-ol (680 mg, 5.18 mmol, 1 equivalent), K ₂CO ₃A mixture of (2150 mg, 15.52 mmol, 3 eq.) and 4-bromo-2-fluoro-1-nitrobenzene (1140 mg, 5.18 mmol, 1 eq.) in acetonitrile was stirred at 60 °C for 16 h and cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with dichloromethane (3×20 mL). The resulting solution was concentrated under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/1) to give 1.3 g of 5-((5-bromo-2-nitrophenyl)amino)-5-methylhexan-1-ol (INT-A112-4) (76%) as a yellow oil. LCMS: m/z (ES+), [M+H ] ⁺=331.00. Step 5. Preparation of 5-(5-((5-((5-bromo-2-nitrophenyl)amino)-5-methylhexyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (INT-A112-5). Methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 509 mg, 1.93 mmol, 1 equivalent) and PPh were added to the mixture at 0 °C under a nitrogen atmosphere.₃To a stirred mixture of 5-((5-bromo-2-nitrophenyl)amino)-5-methylhexan-1-ol (638 mg, 1.93 mmol, 1 eq.) and diisopropyl azodicarboxylate (1172 mg, 5.80 mmol, 3 eq.) (1520 mg, 5.80 mmol, 3 eq.) in tetrahydrofuran (20 mL) were added. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×60 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (20/1) to give 610 mg of 5-[5-({5-[(5-bromo-2-nitrophenyl)amino]-5-methylhexyl}oxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A112-5) (55%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=578.30. Step 6. Preparation of 5-(5-((5-((2-amino-5-bromophenyl)amino)-5-methylhexyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A112-6). 5-[5-({5-[(5-bromo-2-nitrophenyl)amino]-5-methylhexyl}oxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (600 mg, 1.04 mmol, 1 equivalent) and NH ₂NH ₂ ^.H ₂To a stirred mixture of 2-nitropropene (104 mg, 2.08 mmol, 2 eq.) in methanol (20 mL) was added Raney nickel (445.88 mg, 5.21 mmol, 5 eq.). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was filtered, and the filter cake was washed with methanol (3×20 mL). The resulting solution was concentrated under reduced pressure to give 450 mg of methyl 5-(5-((5-((2-amino-5-bromophenyl)amino)-5-methylhexyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (INT-A112-6) as a yellow solid. This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=546.05. Step 7. Preparation of 5-(5-((5-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-5-methylhexyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A112-7). A mixture of 5-[5-({5-[(2-amino-5-bromophenyl)amino]-5-methylhexyl}oxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (450 mg, 0.82 mmol, 1 eq.) and BrCN (174 mg, 1.65 mmol, 2 eq.) in ethanol (15 mL) was stirred at room temperature for 2 h. The reaction was quenched with water (20 mL), and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×20 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 300 mg of 5-(5-{[5-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-5-methylhexyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A112-7) (64%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=573.25. ¹H NMR (DMSO, 400 MHz) δ 1.24 (2H, s), 1.66-1.72 (2H, m), 1.77 (6H, s), 1.99-2.07 (2H, m), 3.58 (6H, s), 3.80 (3H, s), 3.85-3.90 (2H, m), 6.31 (2H, s), 7.10 (2H, d), 7.61 (1H, s), 7.97 (1H, s), 8.09 (1H, d), 8.45 (1H, d). Step 8. Preparation of 5-(5-((5-(2-amino-6-bromo-1,3-benzo[d]imidazol-1-yl)-5-methylhexyl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (INT-A112-8). 5-[5-({5-[(aminomethyl)(3-bromophenyl)amino]-5-methylhexyl}oxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (280 mg, 0.5 mmol, 1 eq.) was added to THF (6 mL) and H ₂Add LiOH to the stirred mixture in O (1.5 mL)^.H ₂O (63 mg, 1.5 mmol, 3 equiv.). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h and concentrated under reduced pressure. The residue was passed through a C18 FLASH column using a 5% HPLC-MS/MS column containing 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 150 mg of 5-(5-{[5-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-5-methylhexyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A112-8) (54%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=557.25. Step 9. Preparation of 16-bromo-5,12,12,26-tetramethyl-7-oxa-4,5,13,20,22, 26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A112-9). 5-(5-{[5-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-5-methylhexyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (150 mg, 0.27 mmol, 1 equivalent), N,N-Diisopropylethylamine (104 mg, 0.81 mmol, 3 equivalents) and N,N,N,NA mixture of 2-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (205 mg, 0.54 mmol, 2 equiv.) in dioxane (5 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (20 mL), and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×20 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane/methanol (10/1) to give 140 mg of 16-bromo-5,12,12,26-tetramethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (INT-A112-9) (96%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=539.20 Step 10. Preparation of 5,12,12,26-tetramethyl-16-(4-methylpiperazin-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadeca-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A112). To a stirred mixture of 16-bromo-5,12,12,26-tetramethyl-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (70 mg, 0.13 mmol, 1 eq), BrettPhos (7 mg, 0.013 mmol, 0.1 eq) and 1-methyl-piperazine (65 mg, 0.65 mmol, 5 eq) in dioxane (5 mL) was added LiHMDS (1.3 mL, 1.3 mmol, 10 eq) dropwise at room temperature under nitrogen atmosphere. The mixture was stirred at 60 °C for 2 h under nitrogen atmosphere and cooled to room temperature. The reaction was heated with saturated NH₄Cl(aqueous solution) (10 mL) was quenched, and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane/methanol (12/1) to give 24.7 mg of 5,12,12,26-tetramethyl-16-(4-methylpiperazin-1-yl)-7-oxa-4,5,13,20,22,26-hexaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3, 14,16,18,20,24-octaene-23,27-dione (Example 112) as an off-white solid (33%). LCMS: m/z (ESI), [M+H] ⁺=559.30. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.20-1.26 (2H, m), 1.68-1.76 (4H, m), 1.92 (6H, s), 2.28 (3H, s), 2.40-2.60 (4H, m), 3.11 (4H, br s), 3.63 (3H, s), 3.70 (3H, s), 4.08 (2H, t), 6.92 (1H, dd), 7.27 (1H, d), 7.44 (1H, d), 8.27 (1H, d), 8.32 (1H, s), 8.81 (1H, d), 12.71 (1H, s). Example A113 6-Fluoro-15,21-dimethyl-5-(morpholin-4-yl)-23-oxo-2,9,11,15,20,21, 26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione Step 1. Preparation of 2-{1-[(5-bromo-4-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]nonan-3-yl}ethanol (INT-A113-1). To a stirred mixture of 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (M5-9, 700 mg, 2.35 mmol, 1 eq) in DMSO (10 mL) at room temperature were added trimethylamine (712 mg, 7.04 mmol, 3 eq) and 1-bromo-2,5-difluoro-4-nitrobenzene (1.12 g, 4.69 mmol, 2 eq). The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere and cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by C18 FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to dryness to give 800 mg of 2-{1-[(5-bromo-4-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethanol (INT-A113-1) (85%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=404.00. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.49-1.61 (2H, m), 1.74-1.83 (4H, m), 1.90 (1H, s), 2.35-2.46 (2H, m), 2.55 (2H, t), 2.64 (2H, d), 2.86 (2H, s), 3.58 (2H, q), 4.43 (1H, t), 7.25 (1H, d), 7.99 (1H, s), 8.07 (1H, d). Step 2. Preparation of methyl 5-[5-(2-{1-[(5-bromo-4-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A113-2). To a stirred mixture of 2-{1-[(5-bromo-4-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethanol (785 mg, 1.95 mmol, 1 eq) and methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 667 mg, 2.54 mmol, 1.3 eq) in toluene (20 mL) was added 2-(tributyl-λ5-phosphinidylidene)acetonitrile (2826 mg, 11.71 mmol, 6 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 3 h. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL) and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC and eluted with petroleum ether/ethyl acetate (1/2) to give 670 mg of 5-[5-(2-{1-[(5-bromo-4-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A113-2) (53%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=647.15. Step 3. Preparation of 5-[5-(2-{1-[(2-amino-5-bromo-4-fluorophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A113-3). To a stirred mixture of 5-[5-(2-{1-[(5-bromo-4-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (660 mg, 1.02 mmol, 1 eq) and ranyl nickel (175 mg, 2.04 mmol, 2 eq) in methanol (10 mL) was added NH ₂NH ₂.H ₂O (153 mg, 3.06 mmol, 3 equiv.). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (80 mL), and the mixture was extracted with dichloromethane (3×80 mL). The combined organic layers were washed with brine (3×80 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC and eluted with petroleum ether/ethyl acetate (1/32) to give 490 mg of 5-[5-(2-{1-[(2-amino-5-bromo-4-fluorophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A113-3) (78%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺= 617.10. Step 4. Preparation of 5-(5-{2-[1-(2-amino-6-bromo-5-fluoro-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A113-4). To a stirred mixture of 5-[5-(2-{1-[(2-amino-5-bromo-4-fluorophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (480 mg, 0.78 mmol, 1 eq) in ethanol (5 mL) at room temperature was added BrCN (165 mg, 1.55 mmol, 2 eq). The resulting mixture was stirred at 60 °C for 1 h and cooled to room temperature. The reaction was quenched with saturated sodium thiosulfate (aq.) (60 mL) and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC and eluted with dichloromethane/methanol (20/1) to give 250 mg of 5-(5-{2-[1-(2-amino-6-bromo-5-fluoro-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A113-4) (50%) as a reddish brown solid. LCMS: m/z (ESI), [M+H] ⁺=642.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.04-1.30 (2H, m), 1.81 (1H, s), 1.80-1.98 (5H, m), 2.69 (2H, s), 2.81-2.94 (4H, m), 3.56 (3H, s), 3.65-3.77 (6H, m), 4.12 (2H, t), 6.11 (2H, s), 7.05 (1H, d), 7.48 (1H, d), 7.97 (1H, s), 8.10 (1H, d), 8.38 (1H, d). Step 5. Preparation of 5-(5-{2-[1-(2-amino-6-bromo-5-fluoro-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A113-5). To a stirred solution of 5-(5-{2-[1-(2-amino-6-bromo-5-fluoro-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (220 mg, 0.34 mmol, 1 eq.) in tetrahydrofuran (4 mL) at room temperature was added LiOH (21 mg, 0.86 mmol, 2.5 eq.) in H ₂O (1 mL). The resulting mixture was stirred at 60 ° C for 1 h and cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by C18 FLASH chromatography using water and acetonitrile as mobile phases. The fractions containing the desired compound were evaporated to dryness to give 190 mg of 5-(5-{2-[1-(2-amino-6-bromo-5-fluoro-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A113-5) (88%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=630.10. Step 6. Preparation of 5-bromo-6-fluoro-15,21-dimethyl-23-oxa-2,9,11,15,20, 21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]triacontriacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione (INT-A113-6). To a stirred solution of 5-(5-{2-[1-(2-amino-6-bromo-5-fluoro-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (190 mg, 0.30 mmol, 1 equiv.) in 1,4-dioxane (5 mL) was added at room temperature.N,N-Diisopropylethylamine (117 mg, 0.91 mmol, 3 equiv.) and N,N,N,N-Tetramethyl- O-(7-Azabenzotriazole-1-yl)uronium hexafluorophosphate (230 mg, 0.60 mmol, 2 equiv). The resulting mixture was stirred at 60 °C for 1 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (30 mL), and the mixture was extracted with dichloromethane (3×30 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄The residue was purified by Prep-TLC and eluted with dichloromethane/methanol (22/1) to give 150 mg of 5-bromo-6-fluoro-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tetracontriacontria-3,5,7,9,13,17(34), 18(22),19-octaene-12,16-dione (INT-A113-6) (81%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺=610.30. Step 7. Preparation of 6-fluoro-15,21-dimethyl-5-(morpholin-4-yl)-23-oxo-2,9, 11,15,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34), 18(22),19-octaene-12,16-dione (Example A113). 5-Bromo-6-fluoro-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34), 18(22),19-octaene-12,16-dione (50 mg, 0.08 mmol, 1 equivalent), BrettPhos Pd G ₃To a stirred mixture of 1,4-dioxane (4 mL) and 2-nitropropene (23 mg, 0.03 mmol, 0.3 equiv) and morpholine (22 mg, 0.25 mmol, 3 equiv) was added LiHMDS (0.82 mL, 0.82 mmol, 10 equiv). The resulting mixture was stirred at 60 °C for 30 min under nitrogen atmosphere and cooled to room temperature. The reaction was heated with saturated NH₄Cl(aqueous solution) (80 mL) was quenched, and the mixture was extracted with dichloromethane (3×80 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC and eluted with dichloromethane/methanol (25/1). The product was purified by prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃The mixture was further purified by using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 1.2 mg of 6-fluoro-15,21-dimethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione (Example A113) as a white solid (2%). LCMS: m/z (ESI), [M+H] ⁺=617.35. ¹H NMR (CDCl ₃, 400 MHz) δ 2.00-2.20 (9H, m), 2.84 (2H, d), 2.95 (2H, t), 3.06 (4H, t), 3.40-3.50 (2H, m), 3.71 (3H, s), 3.80 (3H, s), 3.91 (4H, t), 4.23 (2H, t), 7.01 (1H, d), 7.39 (1H, d), 8.23 (1H, d), 8.50 (1H, s), 9.19 (1H, d), 13.50 (1H, s). Example A115 6-Fluoro-15,21-dimethyl-5-(4-methylpiperazin-1-yl)-23-oxo-2,9, 11,15,20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34), 18(22),19-octaene-12,16-dione 5-Bromo-6-fluoro-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}. 1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13, 17(34),18(22),19-octaene-12,16-dione (INT-A113-6, 50 mg, 0.08 mmol, 1 equivalent), BrettPhos Pd G ₃To a stirred mixture of 1,4-dioxane (4 mL) and 1-methylpiperazine (23 mg, 0.03 mmol, 0.3 equiv) was slowly added LiHMDS (0.82 mL, 0.82 mmol, 10 equiv). The resulting mixture was stirred at 60 °C for 30 min and then cooled to room temperature. The reaction was heated with saturated NH₄Cl(aqueous solution) (80 mL) was quenched, and the mixture was extracted with dichloromethane (3×80 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC and eluted with dichloromethane/methanol (12/1). The product was purified by prep-HPLC using an XBridge Prep OBD C18 column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃.H ₂The mixture was further purified by using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 0.8 mg of 6-fluoro-15,21-dimethyl-5-(4-methylpiperazin-1-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34), 18(22),19-octaene-12,16-dione (Example A115) as a white solid (2%). LCMS: m/z (ESI), [M+H] ⁺=630.40. ¹H NMR (CD ₃OD, 400 MHz) δ 2.02-2.07 (4H, m), 2.08-2.19 (4H, m), 2.40 (3H, s), 2.62-2.78 (4H, m), 2.85-2.97 (4H, m), 3.03-3.13 (3H, m), 3.43-3.55 (4H, m), 3.69 (3H, s), 3.79 (3H, s), 4.31 (2H, t), 7.23 (1H, s), 7.51 (1H, d), 8.33 (1H, s), 8.34 (1H, s), 9.27 (1H, s). Example A116 6-Fluoro-15,21-dimethyl-23-oxo-2,9,11,15,20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione 5-Bromo-6-fluoro-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}. 1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13, 17(34),18(22),19-octaene-12,16-dione (INT-A113-6, 20 mg, 0.03 mmol, 1 equivalent) and BrettPhos Pd G ₃To a stirred mixture of (9 mg, 0.01 mmol, 0.3 equiv) and 1,4-dioxane (2 mL) was slowly added LiHMDS (0.33 mL, 0.33 mmol, 10 equiv). The resulting mixture was stirred at 60 °C for 30 min and cooled to room temperature. The reaction was heated with saturated NH₄Cl(aqueous solution) (50 mL) was quenched. The mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (3×20 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC and eluted with dichloromethane/methanol (22/1). The product was purified by prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃The mixture was further purified by using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 0.9 mg of 6-fluoro-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18, 22}]triacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione (Example A116) as a white solid (5%). LCMS: m/z (ESI), [M+H] ⁺=532.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.88-1.94 (4H, m), 1.96-2.13 (3H, m), 2.79 (2H, d), 2.86 (2H, t), 3.39-3.42 (4H, m), 3.62 (3H, s), 3.74 (3H, s), 4.28 (2H, t), 6.91-7.01 (1H, m), 7.45 (1H, dd), 7.87 (1H, dd), 8.27-8.35 (2H, m), 9.10 (1H, d), 13.34 (1H, s). Example A117A, Example A117B, Example A118A and Example A118B 6-Fluoro-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer 1 (Example A117A) and isomer 2 (Example A117B); 6-Fluoro-15,21-dimethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21, 26-Heptazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]tris-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione, isomer 1 (Example A118A) and isomer 2 (Example A118B). Step 1. Preparation of 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-azabicyclo[3.2.1]octan-1-amine (INT-A117-1).NA mixture of tert-butyl-(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.1]octan-1-yl)carbamate (M4-9, 10 g, 26 mmol, 1 equivalent) in trifluoroacetic acid (35 mL) and dichloromethane (100 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with saturated NaHCO₃(aqueous solution) (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×200 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to give 7.3 g of 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-azabicyclo[3.2.1]octan-1-amine (INT-A117-1) (98%) as a yellow solid. Use the crude product without purification. LCMS: m/z (ESI), [M+H] ⁺=285.15. Step 2. Preparation of 2-{1-[(5-bromo-4-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethanol (INT-A117-2). A mixture of 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.1]octan-1-amine (2 g, 7.03 mmol, 1 eq.), triethylamine (2.84 g, 28.11 mmol, 4 eq.) and 1-bromo-2,5-difluoro-4-nitrobenzene (5.01 g, 21.08 mmol, 3 eq.) in DMSO (30 mL) was stirred at 100 °C for 3 h. The mixture was cooled to room temperature. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column and eluted with ethyl acetate/petroleum ether (1/1) to give 1.5 g of 2-{1-[(5-bromo-4-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethanol (INT-A117-2) (55%) as an orange oil. LCMS: m/z (ESI), [M+H] ⁺=387.95. Step 3. Preparation of 5-[5-(2-{1-[(5-bromo-4-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A117-3). A mixture of 2-{1-[(5-bromo-4-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethanol (700 mg, 1.80 mmol, 1 eq.), 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M2, 712 mg, 2.70 mmol, 1.5 eq.) and 2-(tributylphosphino)acetonitrile (2.61 g, 10.82 mmol, 6 eq.) in toluene (20 mL) was stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with water (50 mL), and the mixture was washed with CH ₂Cl ₂(3×50 mL) extraction. The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-TLC using CH ₂Cl ₂/methanol (25/1) for purification to obtain 700 mg of 5-[5-(2-{1-[(5-bromo-4-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A117-3) (61%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=633.35. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.53-1.74 (4H, m), 1.75-1.87 (1H, m), 1.93 (1H, s), 2.16 (1H, d), 2.21 (2H, d), 2.70 (1H, d), 2.76-2.86 (2H, m), 3.16 (1H, d), 3.57 (3H, s), 3.76 (6H, d), 4.09 (2H, t), 7.26 (1H, d), 7.97 (1H, s), 8.04-8.11 (2H, m), 8.17 (1H, s), 8.41 (1H, d). Step 4. Preparation of methyl 5-[5-(2-{1-[(2-amino-5-bromo-4-fluorophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A117-4). To a stirred mixture of methyl 5-[5-(2-{1-[(5-bromo-4-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (680 mg, 1.07 mmol, 1 eq) and ranyl nickel (184 mg, 2.15 mmol, 2 eq) in methanol (10 mL) was added hydrazine hydrate (107 mg, 2.15 mmol, 2 eq) at room temperature. The resulting mixture was stirred at room temperature for 1 h and filtered. The filter cake was washed with methanol (3×10 mL). The filtrate was concentrated under reduced pressure to obtain 600 mg of 5-[5-(2-{1-[(2-amino-5-bromo-4-fluorophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A117-4) (99%) as a white solid. The crude product was used in the next reaction without purification. LCMS: m/z (ESI), [M+H] ⁺= 603.10. Step 5. Preparation of 5-(5-{2-[1-(2-amino-6-bromo-5-fluoro-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A117-5). A mixture of 5-[5-(2-{1-[(2-amino-5-bromo-4-fluorophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (550 mg, 0.91 mmol, 1 eq) and BrCN (193 mg, 1.82 mmol, 2 eq) in ethanol (10 mL) was stirred at room temperature overnight under nitrogen atmosphere. The reaction mixture was concentrated under vacuum. The residue was purified by filtration with N, N-dimethylformamide (10 mL) for purification to obtain 280 mg of 5-(5-{2-[1-(2-amino-6-bromo-5-fluoro-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A117-5) (48%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=628.10. Step 6. Preparation of 5-(5-{2-[1-(2-amino-6-bromo-5-fluoro-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (isomer 1, INT-A117A-6 and isomer 2, INT-A117B-6). A racemic mixture of 5-(5-{2-[1-(2-amino-6-bromo-5-fluoro-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (200 mg) was purified by prep-chiral-HPLC using a CHIRALPAK IG column (2×25 cm, 5 μm) with a mobile phase of hexane (containing 0.1% diethylamine) and ethanol/CH₂Cl ₂(1/1) of mobile phase B to obtain 5-(5-{2-[1-(2-amino-6-bromo-5-fluoro-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester, 90 mg of isomer 1 (INT-A117A-6, 45%) and 90 mg of isomer 2 (INT-A117B-6, 45%) as an off-white solid. INT-A117A-6: chiral-HPLC, Rt=3.619 minutes. INT-A117B-6: chiral-HPLC, Rt=4.508 minutes. Step 7. Preparation of 5-(5-{2-[1-(2-amino-6-bromo-5-fluoro-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A117A-7). 5-(5-{2-[1-(2-amino-6-bromo-5-fluoro-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A117A-6, 80 mg, 0.13 mmol, 1 eq.) and LiOH (6 mg, 0.25 mmol, 2 eq.) were dissolved in THF (2 mL) and H ₂O (0.5 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure to give 65 mg of 5-(5-{2-[1-(2-amino-6-bromo-5-fluoro-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A117A-7) (83%) as a yellow solid. This material was used in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺=614.20. Step 8. Preparation of 5-bromo-6-fluoro-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (INT-A117A-8). 5-(5-{2-[1-(2-amino-6-bromo-5-fluoro-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A117A-7, 60 mg, 0.10 mmol, 1 equivalent), N, N, N, N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (74 mg, 0.20 mmol, 2 equivalents) and N,N- A mixture of diisopropylethylamine (38 mg, 0.30 mmol, 3 equiv.) in 1,4-dioxane (6 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (20 mL), and the mixture was washed with CH₂Cl ₂(3×30 mL) extraction. The combined organic layers were purified by anhydrous Na ₂SO ₄The residue was purified by prep-TLC and eluted with dichloromethane/methanol (12/1) to give 50 mg of 5-bromo-6-fluoro-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (INT-A117A-8) (85%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺=594.05. Step 9. 6-Fluoro-15,21-dimethyl-23-oxo-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (isomer 1, Example A117A) and 6-fluoro-15,21-dimethyl-5-(morpholin-4-yl)-23-oxo-2,9,11,15,20,21, Preparation of 26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (isomer 1, Example A118A). 5-Bromo-6-fluoro-15,21-dimethyl-23-oxa-2,9,11,15,20,21, 26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (INT-A117A-8, 50 mg, 0.08 mmol, 1 equivalent), morpholine (146 mg, 1.68 mmol, 20 equivalents), BrettPhos Pd G ₃A mixture of (22 mg, 0.03 mmol, 0.3 equiv) and t-BuOK (113 mg, 1.01 mmol, 12 equiv) in 1,4-dioxane (4 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (20 mL), and the mixture was washed with CH₂Cl ₂(3×30 mL) extraction. The combined organic layers were purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC and eluted with dichloromethane/methanol (12/1). The product was purified by Prep-HPLC using an XBridge Shield RP18 OBD column with 0.1% NH₄HCO ₃The mixture was further purified by using water and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 5.5 mg of 6-fluoro-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (isomer 1, Example A117A, 8%) and 8.1 mg of 6-Fluoro-15,21-dimethyl-5-(morpholin-4-yl)-23-oxo-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (isomer 1, Example A118A, 11%). Example 117A: LCMS: m/z (ESI), [M+H] ⁺=518.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.52-1.83 (3H, m), 2.02 (1H, d), 2.38-2.43 (2H, m), 2.51-2.65 (2H, m), 2.72-2.78 (1H, m), 3.21-3.27 (2H, m), 3.37-3.46 (1H, m), 3.63 (3H, s), 3.64-3.70 (1H, m), 3.72 (3H, s), 4.57 (1H, t), 4.71 (1H, d), 6.98-7.03 (1H, m), 7.37 (1H, dd), 7.72 (1H, dd), 8.29 (1H, d), 8.41 (1H, d), 8.83 (1H, s), 12.82 (1H, s). Example 118A: LCMS: m/z (ESI), [M+H] ⁺=603.20. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.48-1.82 (3H, m), 2.02 (1H, d), 2.38-2.49 (2H, m), 2.51-2.56 (2H, m), 2.62-2.77 (2H, m), 2.85-3.07 (4H, m), 3.21-3.27 (1H, m), 3.37-3.46 (1H, m), 3.62 (3H, s), 3.63-3.70 (1H, m), 3.72 (3H, s), 3.77 (4H, t), 4.57 (1H, t), 4.71 (1H, d), 7.21-7.43 (2H, m), 8.28 (1H, d), 8.41 (1H, d), 8.81 (1H, s), 12.71 (1H, s). Example A117B, 6-fluoro-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (isomer 2) was prepared from INT-A117B-6 as a light yellow solid using the same reaction sequence as described in the synthesis of Example A117A. LCMS: m/z (ESI), [M+H] ⁺=518.30. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.56-1.82 (3H, m), 2.02 (1H, d), 2.38-2.45 (2H, m), 2.51-2.55 (1H, m), 2.62-2.78 (2H, m), 3.15-3.25 (2H, m), 3.37-3.46 (1H, m), 3.63 (3H, s), 3.64-3.70 (1H, m), 3.72 (3H, s), 4.53 (1H, t), 4.65 (1H, d), 6.98-7.04 (1H, m), 7.37 (1H, dd), 7.72 (1H, dd), 8.29 (1H, d), 8.41 (1H, d), 8.83 (1H, s), 12.82 (1H, s). Example A118B, 6-fluoro-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (isomer 2) was prepared from INT-A117B-6 as a light yellow solid using the same reaction sequence as described in the synthesis of Example A118A. LCMS: m/z (ESI), [M+H] ⁺=603.30. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.52-1.82 (3H, m), 2.03 (1H, d), 2.38-2.45 (2H, m), 2.51-2.62 (3H, m), 2.65-3.12 (6H, m), 3.21-3.27 (1H, m), 3.37-3.46 (1H, m), 3.62 (3H, s), 3.63-3.70 (1H, m), 3.72 (3H, s), 3.77 (4H, t), 4.55 (1H, t), 4.67 (1H, d), 7.29 (1H, d), 7.37 (1H, d), 8.27 (1H, s), 8.41 (1H, s), 8.81 (1H, s), 12.71 (1H, s). Example A119 5-[4-(Dimethylamino)piperidin-1-yl]-15,21-dimethyl-23-oxo-2,9,11,15,20,21,26-heptaazaheptacyclic[26.2.2.1^{1,26}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34), 18(22),19-octaene-12,16-dione Under nitrogen atmosphere at room temperature, 5-bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34), 18(22),19-octaene-12,16-dione (M5, 100 mg, 0.16 mmol, 1 equivalent) was added.N,N-dimethylpiperidin-4-amine (64.92 mg, 0.50 mmol, 3 equiv) and BrettPhos Pd G ₃To a stirred mixture of 4-(45.90 mg, 0.05 mmol, 0.3 eq.) and 1,4-dioxane (10 mL) was added LiHMDS (1 mL, 1.014 mmol, 6 eq.) dropwise. The mixture was stirred at 60 °C for 1 h and then cooled to room temperature. The reaction was heated with saturated NH₄Cl(aqueous solution) (15 mL) was quenched, and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 50.1 mg of 5-[4-(dimethylamino)piperidin-1-yl]-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,17(34), 18(22),19-octaene-12,16-dione (Example A119) (46%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺=640.40. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.47-1.59 (2H, m), 1.81-1.99 (6H, m), 2.00-2.13 (3H, m), 2.22 (6H, s), 2.57-2.70 (2H, m), 2.75-2.82 (2H, m), 2.86 (2H, t), 3.38-3.50 (4H, m), 3.50-3.59 (3H, m), 3.62 (3H, s), 3.74 (3H, s), 4.27 (2H, t), 6.91 (1H, d), 7.34 (1H, s), 7.45 (1H, d), 8.30 (2H, d), 9.11 (1H, d), 13.18 (1H, s). Examples A120-A128 (Table 2) were prepared using the same reaction sequence described above for the synthesis of Example A119 from M5. Example A129B 21-Methyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18, 22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer 2 (Example A129B) Step 1. Preparation of 1-benzyl-2-methylpyrazol-3-one (INT-A129-1). 2-Methyl-1H-pyrazol-3-one (10 g, 101.93 mmol, 1 equivalent), K ₂CO ₃A mixture of (42.26 g, 305.79 mmol, 3 equiv) and BnBr (18.31 g, 107.02 mmol, 1.05 equiv) in acetonitrile (100 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (300 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by C18 FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to dryness to give 5.5 g of 1-benzyl-2-methylpyrazol-3-one (INT-A129-1) (28%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=189.10. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 3.14 (3H, s), 4.97 (2H, s), 5.23 (1H, d), 7.14-7.22 (2H, m), 7.26-7.38 (3H, m), 7.92 (1H, d). Step 2. Preparation of 1-benzyl-4-iodo-2-methylpyrazol-3-one (INT-A129-2). To a stirred mixture of 1-benzyl-2-methylpyrazol-3-one (6.35 g, 33.73 mmol, 1 eq.) in acetonitrile (200 mL) was added NIS (8.35 g, 37.10 mmol, 1.1 eq.) in portions and stirred at 0 °C for 2 h under nitrogen atmosphere. The reaction was quenched with saturated sodium thiosulfate solution (200 mL), and the mixture was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by C18 FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to dryness to give 9.5 g of 1-benzyl-4-iodo-2-methylpyrazol-3-one (INT-A129-2) (89%) as a reddish-brown semisolid. LCMS: m/z (ESI), [M+H] ⁺=315.05. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 3.22 (3H, s), 5.00 (2H, s), 7.16-7.41 (5H, m), 8.18 (1H, s). Step 3. Preparation of 5-bromo-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylic acid methyl ester (INT-A129-3). Under nitrogen atmosphere at 0 °C, 5-bromo-6-hydroxypyridine-3-carboxylic acid methyl ester (10 g, 43.09 mmol, 1 equivalent) and K ₂CO ₃To a stirred mixture of 2-(trimethylsilyl)ethoxymethyl chloride (10.78 g, 64.64 mmol, 1.5 equiv.) (11.91 g, 86.194 mmol, 2 equiv.) in acetonitrile (200 mL) was added dropwise 2-(trimethylsilyl)ethoxymethyl chloride (10.78 g, 64.64 mmol, 1.5 equiv.). The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is recrystallized from petroleum ether/ethyl acetate (20/1) to give 8 g of methyl 5-bromo-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylate (INT-A129-3) (51%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=364.10. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 0.00 (9H, s), 0.89-0.94 (2H, m), 3.60-3.68 (2H, m), 3.84 (3H, s), 5.44 (2H, s), 8.24 (1H, d), 8.58 (1H, d). Step 4. Preparation of methyl 6-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carboxylate (INT-A129-4). 5-Bromo-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylic acid methyl ester (6.89 g, 19.01 mmol, 1 equivalent), KOAc (5.60 g, 57.054 mmol, 3 equivalents), Pd(dppf)Cl ₂CH ₂Cl ₂A mixture of (1.55 g, 1.90 mmol, 0.1 eq.) and bis(pinacol)diboron (7.24 g, 28.52 mmol, 1.5 eq.) in 1,4-dioxane (100 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere and then cooled to room temperature. The mixture was used directly in the next step without further work-up. LCMS: m/z (ESI), [M+H] ⁺=328.05. Step 5. Preparation of 5-(1-benzyl-2-methyl-3-oxopyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylic acid methyl ester (INT-A129-5). Freshly prepared 6-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carboxylic acid methyl ester (INT-A129-4), K ₂CO ₃(5.28 g, 38.20 mmol, 3 equivalents), Pd(dppf)Cl ₂CH ₂Cl ₂A mixture of (1.04 g, 1.27 mmol, 0.1 equiv) and 1-benzyl-4-iodo-2-methylpyrazol-3-one (4 g, 12.73 mmol, 1.00 equiv) in dioxane (100 mL) and water (25 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, treated with water (100 mL), and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by reverse C18 FLASH chromatography using acetonitrile and water (0% to 100% gradient) as mobile phase to give 2.5 g of 5-(1-benzyl-2-methyl-3-oxopyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylic acid methyl ester (INT-A129-5) (41%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=470.30. Step 6. Preparation of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylate (INT-A129-6). A mixture of methyl 5-(1-benzyl-2-methyl-3-oxopyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylate (2.5 g, 5.32 mmol, 1.00 equiv) and Pd/C (2.83 g, 26.62 mmol, 5 equiv) in methanol (50 mL) was stirred at room temperature overnight under a hydrogen atmosphere. The resulting mixture was filtered. The filter cake was washed with methanol (3×100 mL). The filtrate was concentrated under reduced pressure to obtain 1.5 g of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylate (INT-A129-6) (74%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=380.00. Step 7. Preparation of 2-{1-[(5-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethanol (INT-A129-7). A mixture of 2-{1-amino-3-azabicyclo[3.2.1]octan-3-yl}ethanol dihydrochloride (4.8 g, 19.75 mmol, 1 eq.), trimethylamine (9.99 g, 98.77 mmol, 5 eq.) and 2,4-difluoro-1-nitrobenzene (4.71 g, 29.63 mmol, 1.5 eq.) in acetonitrile (100 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere and cooled to room temperature. The reaction was quenched with water (300 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (2/1) to give 5.5 g of 2-{1-[(5-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethanol (INT-A129-7) (90 %) as an orange oil. LCMS: m/z (ESI), [M+H] ⁺=310.10. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 1.58-1.73 (3H, m), 1.76-1.98 (2H, m), 2.08-2.25 (4H, m), 2.36-2.51 (2H, m), 2.68 (1H, dd), 3.12-3.20 (1H, m), 3.44-3.58 (2H, m), 4.35 (1H, t), 6.53-6.62 (1H, m), 6.83 (1H, dd), 8.19 (1H, dd), 8.43-8.48 (1H, m). Step 8. Preparation of 2-{1-[(5-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethanol (isomer 2, INT-A129-7B). A racemic mixture of 2-{1-[(5-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethanol (15 g) was subjected to Prep_SFC (CHIRALPAK IG, 3*25 cm, 5 μm) with CO ₂The mixture was separated by eluting with a mobile phase A of 1% and a mobile phase B of methanol to obtain 6.2 g (41%) of isomer 1 (INT-A129-7A) as an orange oil and 6.5 g of isomer 2 (INT-A129-7B) (43%) as a light yellow oil. Isomer 1: LCMS: m/z (ESI), [M+H] ⁺=310.20. Rt= 1.429 min. Isomer 2: LCMS: m/z (ESI), [M+H] ⁺=310.20. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 1.59-1.73 (3H, m), 1.82 (1H, d), 1.94 (1H, s), 2.17 (2H, dd), 2.44 (2H, d), 2.68 (1H, d), 3.17 (2H, d), 3.51 (2H, s), 4.11 (1H, q), 4.35 (1H, d), 6.58 (1H, t), 6.83 (1H, d), 8.19 (1H, dd), 8.45 ( 1H, s). Rt=1.987 minutes. Step 9. 2-(1-{[5-(morpholin-4-yl)-2-nitrophenyl]amino}-3-azabicyclo[3.2.1]octan-3-yl)ethanol (INT -A129-9B). 2-{1-[(5-fluoro-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethanol (INT- A129-7B, 6.5 g, 21.01 mmol, 1 eq.), morpholine (6.4 g, 73.54 mmol, 3.5 eq.) and trimethylamine (6.38 g, 63.03 mmol, 3 eq.) in dimethyl sulfoxide (100 mL) The mixture was stirred at 120 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (800 mL), and the mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (3×500 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to obtain 7.4 g of 2-(1-{[5-(morpholin-4-yl)-2-nitrophenyl]amino}-3-azabicyclo[3.2.1]octan-3-yl)ethanol (INT-A129-9B) (93%) as an orange solid. LCMS: m/z (ESI), [M+H] ⁺=377.25. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 1.63-1.71 (3H, m), 1.83-1.87 (1H, m), 1.92-1.96 (1H, m), 2.05 (1H, d), 2.14-2.22 (2H, m), 2.32-2.51 (3H, m), 2.51-2.57 (1H, m), 2.65 (1H, dd), 3.31-3.37 (4H, m), 3.45-3.56 (2H, m), 3.73 (4H, t), 4.35 (1H, t), 6.09 (1H, d), 6.46 (1H, dd), 7.93 (1H, d), 8.67 (1H, s). Step 10. Preparation of methyl 5-(1-methyl-5-{2-[1-{[5-(oxolin-4-yl)-2-nitrophenyl]amino}-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}pyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylate (INT-A129-10B). To a stirred mixture of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylate (INT-A129-6, 756 mg, 1.99 mmol, 1.5 equiv), 2-[1-{[5-(morpholin-4-yl)-2-nitrophenyl]amino}-3-azabicyclo[3.2.1]octan-3-yl]ethanol (INT-A129-9B, 500 mg, 1.32 mmol, 1.00 equiv) and triphenylphosphine (1045 mg, 3.98 mmol, 3 equiv) in tetrahydrofuran (10 mL) was added diisopropyl azodicarboxylate (805 mg, 3.98 mmol, 3 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 h under nitrogen atmosphere. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on Prep-TLC using petroleum ether/ethyl acetate (1/3) to give 400 mg of 5-(1-methyl-5-{2-[1-{[5-(oxolin-4-yl)-2-nitrophenyl]amino}-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}pyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylic acid methyl ester (INT-A129-10B) (40%) as an orange solid. LCMS: m/z (ESI), [M+H] ⁺= 738.60. Step 11. Preparation of 5-(5-{2-[1-{[2-amino-5-(oxolin-4-yl)phenyl]amino}-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylic acid methyl ester (INT-A129-11B). To a stirred mixture of methyl 5-(1-methyl-5-{2-[1-{[5-(morpholin-4-yl)-2-nitrophenyl]amino}-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}pyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylate (INT-A129-10B, 380 mg, 0.51 mmol, 1 eq) and ranyl nickel (220.59 mg, 2.57 mmol, 5 eq) in methanol (10 mL) was added hydrazine hydrate (98%) (38.67 mg, 0.77 mmol, 1.5 eq) dropwise and stirred at 0 °C for 2 h under nitrogen atmosphere. The resulting mixture was filtered. The filter cake was washed with methanol (3×50 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺=708.70. Step 12. Preparation of 5-(5-{2-[1-[2-amino-6-(oxo-4-yl)-1,3-benzodiazol-1-yl]-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylic acid methyl ester (INT-A129-12B). A mixture of 5-(5-{2-[1-{[2-amino-5-(morpholin-4-yl)phenyl]amino}-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylic acid methyl ester (INT-A129-11B) and BrCN (62.54 mg, 0.59 mmol, 1.1 equiv) in ethanol (10 mL) was stirred at room temperature overnight under nitrogen atmosphere. The reaction was heated with saturated NaHCO₃The solution (50 mL) was quenched, and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC eluting with dichloromethane/methanol (15/1) to give 250 mg of 5-(5-{2-[1-[2-amino-6-(oxolin-4-yl)-1,3-benzodiazol-1-yl]-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylic acid methyl ester (INT-A129-12B) (63%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=733.65. Step 13. Preparation of 5-(5-{2-[1-[2-amino-6-(oxo-4-yl)-1,3-benzodiazol-1-yl]-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylic acid (INT-A129-13B). A mixture of methyl 5-(5-{2-[1-[2-amino-6-(morpholin-4-yl)-1,3-benzodiazol-1-yl]-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylate (INT-A129-12B, 80 mg, 0.10 mmol, 1 eq) and LiOH (4 mg, 0.17 mmol, 1.5 eq) in tetrahydrofuran (2 mL) and water (0.5 mL) was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺=719.55. Step 14. Preparation of 21-methyl-5-(morpholin-4-yl)-15-{[2-(trimethylsilyl)ethoxy]methyl}-23-oxo-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (INT-A129-14B). 5-(5-{2-[1-[2-amino-6-(morpholin-4-yl)-1,3-benzodiazol-1-yl]-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-3-carboxylic acid (INT-A129-13B, 80 mg, 0.10 mmol, 1 equivalent), N,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (63 mg, 0.16 mmol, 1.5 equiv.) and N,N- A mixture of diisopropylethylamine (43 mg, 0.33 mmol, 3 equiv.) in dioxane (5 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC eluting with dichloromethane/methanol (20/1) to give 50 mg of 21-methyl-5-(morpholin-4-yl)-15-{[2-(trimethylsilyl)ethoxy]methyl}-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (INT-A129-14B) (64%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=701.60. Step 15. Preparation of 21-methyl-5-(morpholin-4-yl)-23-oxo-2,9,11,15,20, 21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (Example A129B). A mixture of 21-methyl-5-(morpholin-4-yl)-15-{[2-(trimethylsilyl)ethoxy]methyl}-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (INT-A129-14B, 45 mg, 0.06 mmol, 1 equiv) in 1,4-dioxane (2 mL) in HCl was stirred at room temperature for 2 h under nitrogen atmosphere. The mixture was treated with saturated NaHCO ₃The solution was neutralized to pH 7. The mixture was extracted with dichloromethane (3×20 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-HPLC (XBridge Prep OBD C18 column, 30*150 mm, 5μm) using water (containing 10 mmol/L NH₄HCO ₃and 0.05% NH ₃H ₂O) and mobile phase B of CAN to obtain 14.3 mg of 21-methyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18, 22}]tritriacontac-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (39%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=571.45. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 1.50-1.83 (4H, m), 2.00 (1H, d), 2.71 (2H, s), 3.05-3.15 (5H, m), 3.17-3.23 (3H, m), 3.62-3.92 (9H, m), 4.56 (1H, t), 4.65-4.72 (1H, m), 6.90 (1H, d), 7.19 (1H, s), 7.41 (1H, d), 7.87 (1H, s), 8.40 (1H, s), 8.82 (1H, d), 11.96 (1H, s), 12.62 (1H, s). Example A130B 15-Methyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18, 22}]tris-3,5,7,9,13,17(33),18,21-octaene-12,16-dione, isomer 2 (Example A130B) Step 1. Preparation of tert-butyl 3-hydroxy-4-iodopyrazole-1-carboxylate (INT-A130-1). To a stirred mixture of tert-butyl 3-hydroxypyrazole-1-carboxylate (4 g, 21.71 mmol, 1 eq.) in acetonitrile (80 mL) was added NIS (5.86 g, 26.05 mmol, 1.2 eq.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C under nitrogen atmosphere for 2 h. The reaction was quenched with saturated sodium thiosulfate solution, and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by C18 FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to dryness to give 2.5 g of tert-butyl 3-hydroxy-4-iodopyrazole-1-carboxylate (40%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺= 311.00. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 1.53 (9H, s), 8.18 (1H, s), 11.63 (1H, s). Step 2. Preparation of tert-butyl 4-iodo-3-{2-[1-{[5-(oxo-4-yl)-2-nitrophenyl]amino}-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}pyrazole-1-carboxylate (INT-A130-2B). To a stirred mixture of 2-[1-{[5-(morpholin-4-yl)-2-nitrophenyl]amino}-3-azabicyclo[3.2.1]octan-3-yl]ethanol (INT-A129-9B, 500 mg, 1.32 mmol, 1.00 equiv) and triphenylphosphine (1045 mg, 3.98 mmol, 3 equiv) in tetrahydrofuran (10 mL) under nitrogen atmosphere at 0° C. was added diisopropyl azodicarboxylate (805 mg, 3.98 mmol, 3 equiv) and tert-butyl 3-hydroxy-4-iodopyrazole-1-carboxylate (617 mg, 1.99 mmol, 1.5 equiv). The resulting mixture was stirred at 0° C. for 2 h under nitrogen atmosphere. The reaction mixture was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/1) to give 550 mg of tert-butyl 4-iodo-3-{2-[1-{[5-(oxolin-4-yl)-2-nitrophenyl]amino}-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}pyrazole-1-carboxylate (61%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺= 669.40. Step 3. Preparation of 5-[1-(tert-butoxycarbonyl)-3-{2-[1-{[5-(oxoline-4-yl)-2-nitrophenyl]amino}-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}pyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A130-3B). 4-iodo-3-{2-[1-{[5-(oxoline-4-yl)-2-nitrophenyl]amino}-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}pyrazole-1-carboxylic acid tert-butyl ester (INT-A130-3B, 550 mg, 0.823 mmol, 1 equivalent), K ₂CO ₃(341 mg, 2.46 mmol, 3 equivalents), Pd(dppf)Cl ₂CH ₂Cl ₂A mixture of methyl 1-methyl-6-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (67 mg, 0.08 mmol, 0.1 equiv) and methyl 1-methyl-6-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (361 mg, 1.23 mmol, 1.5 equiv) in dioxane (20 mL) and water (5 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature, treated with water (100 mL), and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. Pass the residue through C18 FLASH using 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 130 mg of 5-[1-(tert-butoxycarbonyl)-3-{2-[1-{[5-(oxolin-4-yl)-2-nitrophenyl]amino}-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}pyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (22%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=708.55. Step 4. Preparation of 5-(3-{2-[1-[2-amino-6-(oxo-4-yl)-1,3-benzodiazol-1-yl]-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1H-pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A130-4B). To a stirred mixture of ranyl nickel (6.05 mg, 0.07 mmol, 1 eq.) and methyl 5-[1-(tert-butoxycarbonyl)-3-{2-[1-{[5-(morpholin-4-yl)-2-nitrophenyl]amino}-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}pyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (50 mg, 0.07 mmol, 1 eq.) in methanol (1 mL) at 0 °C under nitrogen atmosphere was added hydrazine hydrate (10.61 mg, 0.21 mmol, 3 eq.). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was filtered, and the filter cake was washed with methanol (3×5 mL). The filtrate was concentrated under reduced pressure. To this residue, ethanol (1 mL) and BrCN (8.23 mg, 0.07 mmol, 1.1 equiv) were added. The resulting mixture was stirred at room temperature for another 2 h and treated with LiOH.H ₂O (5.93 mg, 0.14 mmol, 2 equivalents) in H ₂O (0.2 mL). The resulting mixture was stirred at 40 °C for 2 h and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using 10% to 50% acetonitrile/water elution to give 15 mg of 5-(3-{2-[(1S,5S)-1-[2-amino-6-(oxolin-4-yl)-1,3-benzodiazol-1-yl]-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}-1H-pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (36%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=589.40. Step 5. Preparation of 15-methyl-5-(morpholin-4-yl)-23-oxo-2,9,11,15,20, 21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33),18,21-octaene-12,16-dione (Example A130B). 5-(3-{2-[1-[2-amino-6-(morpholin-4-yl)-1,3-benzodiazol-1-yl]-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1H-pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A130-4B, 20 mg, 0.03 mmol, 1 equivalent), N,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (19.38 mg, 0.05 mmol, 1.5 equivalents) and N,N- A mixture of diisopropylethylamine (13.17 mg, 0.10 mmol, 3 equiv.) in 1,4-dioxane (2 mL) was stirred at 40 °C for 2 h under nitrogen atmosphere. The reaction was quenched with water (30 mL), and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column eluting with dichloromethane/methanol (25/1) to give 4.9 mg of 15-methyl-5-(morpholin-4-yl)-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}. 1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontac-3,5,7,9,13, 17(33),18,21-octaene-12,16-dione (25%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=571.20. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.51-1.61 (2H, m), 1.68 (1H, d), 2.45-2.67 (6H, m), 3.09 (4H, q), 3.37-3.55 (3H, m), 3.62 (3H, s), 3.76 (4H, t), 4.14 (2H, d), 4.32 (1H, d), 6.87-6.93 (1H, m), 7.18 (1H, d), 7.42 (1H, d), 8.20 (1H, d), 8.44 (1H, d), 9.19 (1H, d), 11.95 (1H, s), 12.53 (1H, s). Example A132B 5-Hydroxy-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18, 22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer 2 (Example A132B) 5-Bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (M4B, 150 mg, 0.26 mmol, 1 equivalent), Pd ₂(dba) ₃(47.49 mg, 0.05 mmol, 0.2 eq.), t-BuXPhos (22.02 mg, 0.052 mmol, 0.2 eq.), KOH (58.19 mg, 1.036 mmol, 4 eq.) in 1,4-dioxane (3 mL) and H ₂The mixture in 2% O (2 mL) was stirred at 100 °C for 2 h under nitrogen atmosphere. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by C18 FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 4.8 mg of 5-hydroxy-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (isomer 2) (3%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=516.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.52-1.63 (1H, m), 1.63-1.79 (2H, m), 1.99 (1H, d), 2.42-2.72 (8H, m), 3.62 (3H, s), 3.63-3.69 (1H, m), 3.71 (3H, s), 4.54 (1H, t), 4.67 (1H, d), 6.63 (1H, dd), 7.16 (1H, d), 7.35 (1H, d), 8.26 (1H, d), 8.41 (1H, s), 8.81 (1H, d), 9.32 (1H, s), 12.55 (1H, s). Example A133B 5-[(2-Hydroxyethyl)amino]-15,21-dimethyl-23-oxo-2,9,11,15,20, 21,26-heptaazaheptacyclic[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione, isomer 2 Step 1. 5-({2-[(tert-butyldimethylsilyl)oxy]ethyl}amino)-15,21-dimethyl-23-oxo-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}] -3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (INT-A133-1B). 5-Bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}. A mixture of 0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (120 mg, 0.20 mmol, 1 eq.), (2-aminoethoxy)(tert-butyl)dimethylsilane (M4B, 109.12 mg, 0.62 mmol, 3 eq.), BrettPhos Pd G3 (56.41 mg, 0.06 mmol, 0.3 eq.) and LiHMDS (347.12 mg, 2.07 mmol, 10 eq.) in dioxane (5 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The reaction was heated with NH ₄Cl(aqueous solution) (50 mL) was quenched, and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄The residue was purified by silica gel column chromatography using dichloromethane/methanol (20:1) to give 65 mg of 5-({2-[(tert-butyldimethylsilyl)oxy]ethyl}amino)-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione as a yellow solid (46%). LCMS: m/z (ESI), [M+H] ⁺=673.30. Step 2. 5-[(2-Hydroxyethyl)amino]-15,21-dimethyl-23-oxo-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tri-3,5,7,9,13,17(33), 18(22),19-octaene-12,16-dione (Example A133B). 5-({2-[(tert-butyldimethylsilyl)oxy]ethyl}amino)-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13, 17(33),18(22),19-octaene-12,16-dione (INT-A133-1B, 60 mg, 0.09 mmol, 1 equivalent) was dissolved in HCl in 1,4-dioxane (2 The solution in 10% ethanol (20% ethanol) was stirred at 15 °C for 2 h under nitrogen atmosphere. The reaction was treated with NaHCO₃The solution (50 mL) was quenched and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by C18 FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 32.3 mg of 5-[(2-hydroxyethyl)amino]-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18, 22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (60%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=559.20. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.48-1.82 (3H, m), 1.98 (1H, d), 2.42 (3H, d), 2.56 (1H, s), 2.73 (1H, d), 3.10 (2H, s), 3.18-3.25 (1H, m), 3.31 (1H, s), 3.55-3.63 (6H, m), 3.66 (1H, d), 3.72 (3H, s), 4.55 (1H, t), 4.64-4.74 (2H, m), 5.47 (1H, s), 6.51 (1H, dd), 6.96 (1H, s), 7.28 (1H, d), 8.25 (1H, d), 8.41 (1H, s), 8.82 (1H, d), 12.47 (1H, s). Example B1 15,21-Dimethyl-23-oxo-2,9,11,16,20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontetrazol-3,5,7,9,13,15,17(34),18(22), 19-nonan-12-one Step 1. Preparation of methyl 2-methyl-6-[1-methyl-5-(2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)pyrazol-4-yl]pyridine-4-carboxylate (INT-B1-1). To a stirred mixture of 2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethanol (250 mg, 0.81 mmol, 1 eq) and methyl 2-(5-hydroxy-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (M1, 202 mg, 0.81 mmol, 1 eq) in toluene (100 mL) was added 2-(tributyl-λ5-phosphinilidene)acetonitrile (1580 mg, 6.55 mmol, 8 eq) under nitrogen atmosphere. The mixture was stirred at 100 °C for 4 h, cooled to room temperature, and concentrated under reduced pressure. The reaction was quenched with water (80 mL), and the mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine (3×150 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (10/1) to give 420 mg of methyl 2-methyl-6-[1-methyl-5-(2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)pyrazol-4-yl]pyridine-4-carboxylate (INT-B1-1) (95%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=535.30. Step 2. Preparation of methyl 2-[5-(2-{1-[(2-aminophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (INT-B1-2). To a stirred mixture of methyl 2-methyl-6-[1-methyl-5-(2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)pyrazol-4-yl]pyridine-4-carboxylate (400 mg, 0.75 mmol, 1 eq.) and ranyl nickel (512 mg, 5.98 mmol, 8 eq.) in MeOH (30 mL) was added NH ₂NH ₂.H ₂O (74 mg, 1.50 mmol, 2 eq.). The resulting mixture was stirred at room temperature for 2 h and filtered. The filter cake was washed with methanol (3×20 mL). The resulting solution was concentrated under reduced pressure to give 360 mg of 2-[5-(2-{1-[(2-aminophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid methyl ester (INT-B1-2) as a yellow solid. This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=505.30. Step 3. Preparation of methyl 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B26-3). To a stirred mixture of methyl 2-[5-(2-{1-[(2-aminophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (360 mg, 0.71 mmol, 1 eq.) and BrCN (113 mg, 1.06 mmol, 1.5 eq.) in ethanol (30 mL) was added under nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for 1 h and concentrated under vacuum. The residue was purified by Prep-TLC using dichloromethane/methanol (15/1) to give 256 mg of methyl 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B26-3) (67%) as a pink solid. LCMS: m/z (ESI), [M+H]+=530.35. Step 4. Preparation of 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B1-4). 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid methyl ester (250 mg, 0.47 mmol, 1 equivalent) and LiOH.H ₂O (39 mg, 0.94 mmol, 2 equivalents) in tetrahydrofuran (20 mL) and H ₂The mixture in 4 mL of O was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by C18 FLASH chromatography using 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂Purification was performed using water with 0.05% ethanol and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 170 mg of 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B1-4) (69%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=516.15. ¹H NMR (CD ₃OD, 400 MHz) δ 1.78-1.98 (7H, m), 2.43 (3H, s), 2.64 (2H, d), 2.82 (2H, t), 2.90 (2H, t), 3.16 (2H, s), 3.68 (3H, s), 4.26 (2H, t), 3.74-6.79 (1H, m), 6.89 (1H, t), 7.07-7.10 (1H, m), 7.35 (1H, d), 7.38 (1H, d), 7.73 (1H, s), 7.76 (1H, s). Step 5. Preparation of 15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,15,17(34),18(22), 19-nonan-12-one (Example B1). Under nitrogen atmosphere at room temperature, 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (160 mg, 0.31 mmol, 1 equivalent) andN, N, N, N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (353 mg, 0.93 mmol, 3 equivalents) was added to a stirred mixture of 1,4-dioxane (10 mL) N, N-Diisopropylethylamine (160 mg, 1.24 mmol, 4 equiv.). The mixture was stirred at 60 °C for 3 h under air atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine (3×150 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to Prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 63.1 mg of 15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,15,17(34),18(22), 19-nonan-12-one (Example B1) as a white solid (40%). LCMS: m/z (ESI), [M+H] ⁺=498.20. ¹H NMR (DMSO-d ₆ ,400 MHz) δ 1.82-2.04 (4H, m), 2.04-2.15 (3H, m), 2.55 (3H, s), 2.82 (2H, s), 2.87 (2H, t), 3.42-3.55 (4H, m), 3.77 (3H, s), 4.38 (2H, t), 7.18 (2H, dt), 7.62 (1H, d), 7.65 (1H, d), 7.89 (1H, s), 7.91 (1H, d), 8.77 (1H, s), 13.32 (1H, s). Example B2 15,21-Dimethyl-5-(morpholin-4-yl)-23-oxo-2,9,11,16,20,21,26-heptaazaheptacyclic[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]triacontria-3,5,7,9,13,15,17(34),18(22), 19-nonan-12-one Step 1. Preparation of methyl 2-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (INT-B2-1). A mixture of 2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethanol (380 mg, 0.98 mmol, 1 eq), 2-(tributyl-λ5-phosphinilidene)acetonitrile (1193 mg, 4.94 mmol, 5 eq) and methyl 2-(5-hydroxy-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (M1, 366 mg, 1.48 mmol, 1.5 eq) in toluene (5 mL) was stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on Prep-TLC using petroleum ether/ethyl acetate (3/1) to give 500 mg of methyl 2-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (INT-B2-1) (82%) as an orange oil. LCMS: m/z (ESI), [M+H] ⁺=613.15. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 1.44-1.47 (2H, m), 1.74-1.81 (6H, m), 1.89-1.96 (1H, m), 2.48 (3H, s), 2.66-2.72 (2H, m), 2.89-2.97 (4H, m), 3.74 (3H, s), 3.84 (3H, s), 4.39 (2H, t), 6.72-6.77 (1H, m), 7.01 (1H, d), 7.33 (1H, d), 7.77 (1H, d), 7.86 (1H, s), 7.95 (1H, d), 8.06 (1H, s). Step 2. Preparation of methyl 2-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (INT-B2-2). To a stirred mixture of methyl 2-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (480 mg, 0.78 mmol, 1 eq) and ranyl nickel (335 mg, 3.91 mmol, 5 eq) in methanol (5 mL) was added hydrazine hydrate (98%) (61 mg, 1.22 mmol, 1.5 eq) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C under nitrogen atmosphere for 2 h. The reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/1) to give 370 mg of 2-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid methyl ester (INT-B2-2) (81 %) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=583.20. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 1.38-1.49 (2H, m), 1.69-1.76 (4H, m), 1.85-1.88 (1H, m), 2.25-2.32 (2H, m), 2.52 (3H, s), 2.63-2.68 (2H, m), 2.78-2.83 (2H, m), 2.84-2.91 (2H, m), 3.72 (3H, s), 3.86 (3H, s), 4.03 (1H, s), 4.27-4.37(2H, m), 4.68 (2H, s), 6.46 (2H, d), 6.58 (1H, d), 7.43 (1H, d), 7.83 (1H, d), 7.89 (1H, s). Step 3. Preparation of methyl 2-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B2-3). A mixture of methyl 2-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (350 mg, 0.60 mmol, 1 eq) and BrCN (95 mg, 0.90 mmol, 1.5 eq) in ethanol (2 mL) was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/3) to give 360 mg of methyl 2-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B2-3) (98%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=610.15. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 1.79-1.97 (7H, m), 2.51 (3H, s), 2.70-2.74 (2H, m), 2.79-2.87 (2H, m), 2.92-2.99 (2H, m), 3.18 (2H, s), 3.74 (3H, s), 3.84 (3H, s), 4.37 (2H, t), 6.05 (2H, s), 6.99-7.08 (2H, m), 7.41 (1H, d), 7.46 (1H, d), 7.81 (1H, d), 7.89 (1H, s). Step 4. Preparation of lithium 2-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpicolinate (INT-B2-4). A mixture of methyl 2-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (340 mg, 0.55 mmol, 1 eq) and LiOH (16 mg, 0.67 mmol, 1.2 eq) in ethanol (2 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure to give 2-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B2-4) as a white solid. The crude product was used directly in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=594.45. Step 5. Preparation of 5-bromo-15,21-dimethyl-23-oxa-2,9,11,16,20,21, 26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3, 8}.0^{18,22}]triacontriacontria-3,5,7,9,13,15,17(34), 18(22),19-nonan-12-one (INT-B2-5). 2-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (330 mg crude, about 0.5 mmol, about 1 equivalent), N,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (417 mg, 1.10 mmol, 2 equivalents) and N,N- A mixture of diisopropylethylamine (213 mg, 1.65 mmol, 3 equiv.) in 1,4-dioxane (5 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×150 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by trituration with petroleum ether (10 mL) to give 280 mg of 5-bromo-15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]triacontriacontria-3,5,7,9,13,15,17(34), 18(22),19-nonan-12-one (INT-B2-5) (88%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=578.05. Step 6. Preparation of 15,21-dimethyl-5-(morpholin-4-yl)-23-oxo-2,9,11, 16,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2, 10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,15,17(34), 18(22),19-nonan-12-one (Example B2). 5-Bromo-15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]triacontria-3,5,7,9,13,15,17(34),18(22),19-nonan-12-one (100 mg, 0.17 mmol, 1 equivalent), Brettphos Pd G ₃To a stirred mixture of 1,4-dioxane (10 mL) and morpholine (47 mg, 0.05 mmol, 0.3 equiv) was added LiHMDS (2 mL, 2.00 mmol, 11.53 equiv) dropwise. The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 1 h and cooled to room temperature. The reaction was heated with saturated NH₄Cl(aq) (50 mL) was quenched and the mixture was washed with CH₂Cl ₂(3×50 mL) extraction. The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Prep OBD C18 column with 10 mmol/L NH₄HCO ₃of water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 14.4 mg of 15,21-dimethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,16,20, 21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,15,17(34),18(22),19-nonan-12-one (Example B2) as a yellow solid (14%). LCMS: m/z (ESI), [M+H] ⁺= 583.40. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 1.88-1.99 (4H, m), 2.03-2.11 (3H, m), 2.54 (3H, s), 2.78-2.90 (4H, m), 3.04-3.10 (4H, m), 3.42-3.50 (4H, m), 3.75-3.80 (7H, m), 4.36-4.40 (2H, m), 6.95 (1H, dd), 7.35 (1H, s), 7.51 (1H, d), 7.61 (1H, d), 7.89 (1H, s), 8.76 (1H, s), 13.21 (1H, s). Example B3 15,21-Dimethyl-5-(4-methylpiperazine-1-yl)-23-oxo-2,9,11,16, 20,21,26-heptaazaheptacyclic[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]triacontetrazol-3,5,7,9,13,15,17(34),18(22), 19-nonan-12-one Step 1. Preparation of 15,21-dimethyl-5-(4-methylpiperazin-1-yl)-23-oxa-2, 9,11,16,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,15,17(34), 18(22),19-nonan-12-one (Example B3). 5-Bromo-15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]triacontria-3,5,7,9,13,15,17(34),18(22),19-nonan-12-one (100 mg, 0.17 mmol, 1 equivalent), BrettPhos Pd G ₃To a stirred mixture of 1,4-dioxane (10 mL) and 1-methylpiperazine (550 mg, 0.60 mmol, 3.5 equiv) was added LiHMDS (2 mL, 2.000 mmol, 11.53 equiv) dropwise. The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 1 h and cooled to room temperature. The reaction was heated with saturated NH₄Cl(aq) (50 mL) was quenched and the mixture was washed with CH₂Cl ₂(3×50 mL) extraction. The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃of water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to obtain 13.7 mg of 15,21-dimethyl-5-(4-methylpiperazin-1-yl)-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,15,17(34), 18(22),19-nonan-12-one (Example B3) (13%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=596.40. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 1.84-2.01 (4H, m), 2.03-2.10 (3H, m), 2.24 (3H, s), 2.54 (4H, s), 2.79-2.84 (2H, m), 2.85-2.90 (2H, m), 3.10 (4H, t), 3.28-3.36 (3H, m), 3.42-3.50 (4H, m), 3.76 (3H, s), 4.37 (2H, d), 6.94 (1H, dd), 7.34 (1H, s), 7.49 (1H, d), 7.61 (1H, d), 7.89 (1H, s), 8.76 (1H, s), 13.20 (1H, s). Example B4 15,21-Dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazahexacyclo[24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontahedral-3,5,7,9,13(32),14,16,18(22),19-nonan-12-one Step 1. Preparation of tert-butyl 3-[(2-nitrophenyl)amino]azoloheptan-1-carboxylate (INT-B4-1). Add o-fluoronitrobenzene (5.00 g, 35.44 mmol, 1 equivalent), K ₂CO ₃A mixture of (9.79 g, 70.87 mmol, 2 eq.) and tert-butyl 3-aminoazacycloheptane-1-carboxylate (7.59 g, 35.44 mmol, 1 eq.) in acetonitrile (80 mL) was stirred at 80 °C for 3 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (21/1) to give 9 g of tert-butyl 3-[(2-nitrophenyl)amino]azanacycloheptane-1-carboxylate (INT-B4-1) (75%) as a reddish brown oil. LCMS: m/z (ESI), [M+H] ⁺=336.15. ¹H NMR (400 MHz, DMSO-d ₆) δ 1.38 (9H, s), 1.49-1.65 (1H, m), 1.62-1.75 (3H, m), 1.75-1.82 (1H, m), 1.96-2.01 (1H, m), 3.37-3.50 (2H , m), 3.61-3.69 (1H, m), 3.83-4.03 (2H, m), 6.66-6.76 (1H, m), 7.21-7.25 (1H, m), 7.51-7.61 (1H, m), 8.01 -8.13 (1H, m), 8.20 (1H, d). Step 2. N- Preparation of (2-nitrophenyl) azacycloheptane-3-amine (INT-B4-2). To a stirred mixture of tert-butyl 3-[(2-nitrophenyl) amino] azacycloheptane-1-carboxylate (4.00 g, 11.93 mmol, 1 equiv.) in dichloromethane (12 mL) was slowly added 1,4-dioxane (60 mL) containing HCl at room temperature. The resulting mixture was stirred at room temperature for 1.5 h. The mixture was concentrated under reduced pressure. The residue was treated with saturated NaHCO ₃(aqueous solution) (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to obtain 2.8 g of yellow oil.N-(2-Nitrophenyl)azacycloheptane-3-amine (INT-B4-2). This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=236.10. Step 3. 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}- NPreparation of -(2-nitrophenyl) azacycloheptyl-3-amine (INT-B4-3). Freshly prepared N-(2-nitrophenyl) azacycloheptane-3-amine (2.8 g, about 1 equivalent), (2-bromoethoxy)(tert-butyl)dimethylsilane (6.39 g, 26.69 mmol, 2 equivalents), K ₂CO ₃A mixture of (3.69 g, 26.69 mmol, 2 equiv.) and KI (4.43 g, 26.69 mmol, 2 equiv.) in DMF (80 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using petroleum ether/ethyl acetate (19/1) to give 5.2 g of 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}- N-(2-Nitrophenyl) azacycloheptane-3-amine (INT-B4-3) (99%). LCMS: m/z (ESI), [M+H] ⁺=394.20. ¹H NMR (400 MHz, DMSO-d ₆) δ 0.03 (6H, s), 0.81 (9H, s), 1.45-1.63 (3H, m), 1.74-1.81 (3H, m), 2.57-2.77 (3H, m), 2.78-2.95 (3H, m), 3.29 (1H, t), 3.63-3.84 (3H, m), 6.65-6.71 (1H, m), 7.05 (1H, d), 7.51-7.58 (1H, m), 8.07-8.13 (1H, m), 8.74 (1H, d). Step 4. Preparation of 2-{3-[(2-nitrophenyl)amino]azanacycloheptan-1-yl}ethanol (INT-B4-4). To a stirred mixture of 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-N-(2-nitrophenyl)azanacycloheptyl-3-amine (3 g, 7.62 mmol, 1 equiv) in tetrahydrofuran (50 mL) was added tetrahydrofuran (12 mL) containing tetrabutylammonium fluoride at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/1) to give 1.5 g of 2-{3-[(2-nitrophenyl)amino]azanacycloheptan-1-yl}ethanol (INT-B4-4) (70%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=280.10. Step 5. Preparation of 2-methyl-6-[1-methyl-5-(2-{3-[(2-nitrophenyl)amino]azanacyclohept-1-yl}ethoxy)pyrazol-4-yl]pyridine-4-carboxylic acid methyl ester (INT-B4-5). To a stirred mixture of 2-{3-[(2-nitrophenyl)amino]azanacycloheptan-1-yl}ethanol (1.5 g, 5.370 mmol, 1 eq) and triphenylphosphine (4.30 g, 16.38 mmol, 3.05 eq) in tetrahydrofuran (30 mL) was added methyl 2-(5-hydroxy-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (M1, 1.46 g, 5.91 mmol, 1.1 eq) and diisopropyl azodicarboxylate (2.71 g, 13.43 mmol, 2.5 eq) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (300 mL) and the mixture was extracted with dichloromethane (3×300 mL). The combined organic layers were washed with brine (3×300 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by reverse phase flash chromatography using 10% to 50% acetonitrile/water elution to give 1.6 g of methyl 2-methyl-6-[1-methyl-5-(2-{3-[(2-nitrophenyl)amino]azanacyclohept-1-yl}ethoxy)pyrazol-4-yl]pyridine-4-carboxylate (INT-B4-5) (59%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=509.25. ¹H NMR (400 MHz, DMSO-d ₆) δ 1.44-1.80 (6H, m), 2.48-2.54 (2H, m), 2.71-2.81 (1H, m), 2.85-2.92 (2H, m), 2.94-3.14 (3H, m), 3.70 (3H, s), 3.86 (3H, s), 3.92 (1H, s), 4.28-4.35 (2H, m), 6.63-6.68 (1H, m), 6.96-7.03 (1H, m), 7.38 (1H, d), 7.46-7.51 (1H, m), 7.80-7.83 (1H, m), 7.88 (1H, s), 8.00-8.05 (1H, m), 8.62 (1H, d). Step 6. Preparation of methyl 2-[5-(2-{3-[(2-aminophenyl)amino]azacyclohept-1-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (INT-B4-6). To a stirred mixture of methyl 2-methyl-6-[1-methyl-5-(2-{3-[(2-nitrophenyl)amino]azacyclohept-1-yl}ethoxy)pyrazol-4-yl]pyridine-4-carboxylate (1.00 g, 1.97 mmol, 1 eq.) and ranyl nickel (340 mg, 3.93 mmol, 2 eq.) in MeOH (30 mL) was added NH ₂NH ₂.H ₂O (295 mg, 5.90 mmol, 3 eq.). The resulting mixture was stirred at room temperature for 1 h. The mixture was filtered and the filter cake was washed with dichloromethane (3×30 mL). The resulting solution was concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (30/1) to give 500 mg of 2-[5-(2-{3-[(2-aminophenyl)amino]azanacyclohept-1-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid methyl ester (INT-B4-6) (53%) as a reddish brown oil. LCMS: m/z (ESI), [M+H] ⁺=479.25. Step 7. Preparation of methyl 2-(5-{2-[3-(2-amino-1,3-benzodiazol-1-yl)azepine-1-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B4-7). A mixture of methyl 2-[5-(2-{3-[(2-aminophenyl)amino]azepine-1-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (490 mg, 1.02 mmol, 1 eq.) and cyanogen bromide (108 mg, 1.02 mmol, 1 eq.) in dichloromethane (5 mL) was stirred at room temperature for 2 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was purified by Prep-TLC using dichloromethane/methanol (30/1) to give 490 mg of methyl 2-(5-{2-[3-(2-amino-1,3-benzodiazol-1-yl)azinecyclohept-1-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B4-7) (95%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=504.25. ¹H NMR (400 MHz, DMSO-d ₆) δ 1.50-1.56 (1H, m), 1.61-1.70 (1H, m), 1.73-1.99 (2H, m), 2.52 (5H, s), 2.93-3.03 (1H, m), 3.17 (1H, s), 3.26-3.32 (3H, m), 3.70 (3H, s), 3.84 (3H, s), 4.28 (2H, s), 4.62 (1H, s), 6.96 (1H, s), 7.00 (1H, d), 7.20 (1H, d), 7.39 (1H, s), 7.44 (1H, d), 7.83-7.88 (1H, m), 7.91 (1H, s). Step 8. Preparation of 2-(5-{2-[3-(2-amino-1,3-benzodiazol-1-yl)azacyclohept-1-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B4-8). 2-(5-{2-[3-(2-amino-1,3-benzodiazol-1-yl)azacyclohept-1-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid methyl ester (480 mg, 0.95 mmol, 1 eq.) and LiOH (45 mg, 1.91 mmol, 2 eq.) were dissolved in tetrahydrofuran (6 mL) and H ₂O (1.5 mL) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography using 10% to 30% acetonitrile/water elution to give 125 mg of 2-(5-{2-[3-(2-amino-1,3-benzodiazol-1-yl)azinecyclohept-1-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B4-8) (27%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=490.15. Step 9. Preparation of 15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazahexacyclo[24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13(32),14,16,18(22),19-nonan-12-one (Example B4). 2-(5-{2-[3-(2-amino-1,3-benzodiazol-1-yl)azacyclohept-1-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (120 mg, 0.25 mmol, 1 equivalent), N,N-Diisopropylethylamine (95 mg, 0.74 mmol, 3 equiv.) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (140 mg, 0.37 mmol, 1.5 equiv.) in 1,4-dioxane (6 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using a HPLC-HPLC column containing 10 mmol/L NH₄HCO ₃The product was purified by using water and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to give 60.9 mg of 15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazahexacyclo[24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontac-3,5,7,9,13(32),14,16,18(22),19-nonan-12-one (Example B4) as a white solid (52%). LCMS: m/z (ESI), [M+H] ⁺=472.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.63-2.02 (6H, m), 2.57 (3H, s), 2.62-2.76 (1H, m), 2.79-2.85 (1H, m), 2.88-3.01 (3H, m), 3.10-3.17 (1H, m), 3.76 (3H, s), 4.04 (1H, br s), 4.38 (1H, br s), 5.15 (1H, br s), 7.19-7.30 (2H, m), 7.52-7.59 (2H, m), 7.68 (1H, d), 7.91 (1H, s), 8.62 (1H, s), 12.72 (1H, s). Example B6 11-Cyclopropyl-26-methyl-8-(2,2,2-trifluoroethyl)-11H,51H-11-oxa-4,8-diazo-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one Step 1. Preparation of methyl 2-chloro-6-(2-cyclopropyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)isonicotinate (INT-B6-1). To a stirred mixture of 2-cyclopropyl-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (2.3 g, 6.04 mmol, 1 eq.) and freshly prepared (6-chloro-4-(methoxycarbonyl)pyridin-2-yl)boronic acid (M1-3, 9.0 g crude material, about 30 mmol, about 5 eq.) in toluene (20 mL) and water (5 mL) was added Pd at room temperature under nitrogen atmosphere.₂(dba) ₃(1.1 g, 1.21 mmol, 0.2 equiv.), di(1-adamantyl)-n-butylphosphine (0.1 g, 1.21 mmol, 0.2 equiv.) and Cs ₂CO ₃(4.9 g, 15.12 mmol, 2.5 equiv.). The resulting mixture was stirred at 80 °C for 2 h and cooled to room temperature. The reaction was quenched with water (300 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (1/1) to give 1.8 g of methyl 2-chloro-6-(2-cyclopropyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)pyridine-4-carboxylate (INT-B6-1) (70%) as a yellow oil. ¹H NMR (DMSO-d ₆, 400 MHz) δ -0.05 (9H, s), 0.78-0.83 (2H, m), 0.87-0.90 (4H, m), 3.30 (2H, d), 3.94-3.98 (3H, m), 2.05-2.10 (1H, m), 5.41 (2H, s), 7.55-7.51 (1H, m), 8.66-8.70 (2H, m). Step 2. Preparation of 2-(2-cyclopropyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)-6-methylisonicotinate (INT-B6-2). PCy was added to a stirred mixture of methyl 2-chloro-6-(2-cyclopropyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)pyridine-4-carboxylate (1.8 g, 4.24 mmol, 1 eq.) and trimethyl-1,3,5,2,4,6-trioxatriborinane (3.2 g, 25.47 mmol, 6.0 eq.) in 1,4-dioxane (25 mL) at room temperature under nitrogen atmosphere.₃.HBF ₄(0.5 g, 1.27 mmol, 0.3 eq), Pd(dppf)Cl ₂CH ₂Cl ₂(0.6 g, 0.84 mmol, 0.2 eq.) and K ₂CO ₃(1.1 g, 8.49 mmol, 2.0 equiv.). The resulting mixture was stirred at 100 °C overnight and cooled to room temperature. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/1) to give 1.3 g of methyl 2-(2-cyclopropyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)-6-methylisonicotinate (INT-B6-2) (75%) as a brown solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ -0.05 (9H, s), 0.80-0.84 (2H, m), 1.00-1.05 (4H, m), 2.53 (3H, s), 2.74-2.80 (1H, m), 3.45-3.50 (2H, m), 3.89 (3H, s), 5.38 (2H, s), 7.45 (1H, d), 8.55 (1H, d), 8.59 (1H, s). Step 3. Preparation of methyl 2-(1-cyclopropyl-5-hydroxypyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B6-3). A mixture of methyl 2-(2-cyclopropyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-6-methylpyridine-4-carboxylate (1.3 g, 3.22 mmol, 1 eq.) and HCl in 1,4-dioxane (10 mL) was stirred at room temperature for 2 h under nitrogen atmosphere and concentrated under vacuum. The residue was washed with CH₂Cl ₂(20 mL) and saturated NaHCO ₃(aqueous solution) (50 mL). The resulting mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was loaded on a silica gel column and eluted with dichloromethane/methanol (10/1) to give 844 mg of methyl 2-(1-cyclopropyl-5-hydroxypyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B6-3) (95%) as a brown solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.88-1.00 (4H, m), 1.24 (1H, s), 2.57 (3H, s), 3.91 (3H, s), 7.33 (1H, s), 7.91 (2H, s). Step 4. Preparation of 2-(1-cyclopropyl-5-(2-((2-((2-nitrophenyl)amino)ethyl)(2,2,2-trifluoroethyl)amino)ethoxy)-1H-pyrazol-4-yl)-6-methylisonicotinate (INT-B6-4). To a stirred mixture of methyl 2-(1-cyclopropyl-5-hydroxypyrazol-4-yl)-6-methylpyridine-4-carboxylate (142 mg, 0.52 mmol, 1.0 equiv) and triphenylphosphine (409 mg, 1.56 mmol, 3.0 equiv) in tetrahydrofuran (10 mL) was added diisopropyl azodicarboxylate (315 mg, 1.56 mmol, 3.0 equiv) and 2-({2-[(2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethanol (INT-A1-2, 400 mg, 1.30 mmol, 2.5 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h. The reaction was quenched with water (50 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. Pass the residue through a silica gel column using CH ₂Cl ₂/methanol (10/1) for purification to obtain 540 mg of 2-(1-cyclopropyl-5-(2-((2-((2-nitrophenyl)amino)ethyl)(2,2,2-trifluoroethyl)amino)ethoxy)-1H-pyrazol-4-yl)-6-methylisonicotinate (INT-B6-4) (57%) as a yellow oil. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.91-0.99 (2H, m), 1.02-1.11 (2H, m), 2.53 (3H, s), 3.01-3.07 (2H, m), 3.39-3.43 (4H, m), 3.51-3.67 (3H, m), 3.88 (3H, s), 4.32 (2H, t), 6.61-6.66 (1H, m), 7.02-7.08 (1H. m), 7.38-7.54 (2H, m), 7.83-7.78 (2H, m), 8.03-8.07 (1H, m), 8.22 (1H, t). Step 5. Preparation of methyl 2-{5-[2-({2-[(2-aminophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-cyclopropylpyrazol-4-yl}-6-methylpyridine-4-carboxylate (INT-B6-5). Methyl 2-{1-cyclopropyl-5-[2-({2-[(2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]pyrazol-4-yl}-6-methylpyridine-4-carboxylate (500 mg, 0.88 mmol, 1 eq.) and Zn (464 mg, 7.11 mmol, 8 eq.) were added to tetrahydrofuran (10 mL) and H ₂Add NH O (2.5 mL) to the stirring mixture₄Cl (475 mg, 8.89 mmol, 10 equiv). The mixture was stirred at the temperature for 2 h. The reaction was quenched with water (50 mL), and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. Pass the residue through a silica gel column using CH ₂Cl ₂/methanol (5/1) for purification to obtain 190 mg of 2-{5-[2-({2-[(2-aminophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-cyclopropylpyrazol-4-yl}-6-methylpyridine-4-carboxylic acid methyl ester (INT-B6-5) (40%) as a yellow oil. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.92-1.01 (2H, m), 1.03-1.07 (2H, m), 2.55 (3H, s), 3.00 (2H, t), 3.14 (2H, s), 3.48-3.52 (2H, m), 3.58-3.63 (1H, m), 3.89 (3H, s), 3.98-4.04 (1H, m), 4.29-4.31 (2H, m), 4.40 (2H, s), 6.37-6.49 (3H, m), 6.48-6.54 (1H, m), 7.49 (1H, d), 7.81-7.91 (2H, m). Step 6. Preparation of methyl 2-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-cyclopropylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (INT-B6-6). A mixture of methyl 2-{5-[2-({2-[(2-aminophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-cyclopropylpyrazol-4-yl}-6-methylpyridine-4-carboxylate (170 mg, 0.31 mmol, 1 eq) and BrCN (37 mg, 0.35 mmol, 1.1 eq) in ethanol (5 mL) was stirred under nitrogen atmosphere at room temperature for 4 h. The mixture was concentrated in vacuo. The residue was subjected to Prep-TLC using CH ₂Cl ₂/methanol (10/1) for purification to obtain 125 mg of 2-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-cyclopropylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid methyl ester (INT-B6-6) (70%) as a brown oil. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.92-0.98 (2H, m), 1.03-1.07 (2H, m), 2.54 (3H, s), 2.97-3.07 (2H, m), 3.14-3.24 (2H, m), 3.50-3.64 (3H, m), 3.86 (3H, s), 4.08 (2H, t), 4.25 (2H, t), 6.47 (2H, s), 6.78-6.80 (1H, m), 6.87-6.91 (1H, m), 7.03-7.17 (2H, m), 7.47 (1H, d), 7.85 (2H, d). Step 7. Preparation of 2-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-cyclopropylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid (INT-B6-7). 2-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-cyclopropylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid methyl ester (120 mg, 0.22 mmol, 1 eq) and LiOH (10 mg, 0.43 mmol, 2 eq) were dissolved in tetrahydrofuran (4 mL) and H ₂The mixture in 4% ethyl acetate (1 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 90 mg of 2-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-cyclopropylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid (INT-B6-7) (76%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺= 544.30. Step 8. Preparation of 5-cyclopropyl-26-methyl-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,27-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(27),2(6),3,14,16,18,20,24(28),25-nonan-23-one (Example B6). 2-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-cyclopropylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid (80 mg, 0.14 mmol, 1 equivalent) and N,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (83 mg, 0.22 mmol, 1.5 equivalents) and 1,4-dioxane (3 mL) were added to the stirred mixture.N,N-Diisopropylethylamine (57 mg, 0.44 mmol, 3.0 equiv.). The reaction mixture was stirred at the temperature for 2 h and concentrated under vacuum. The residue was purified by Prep-HPLC using a HPLC-HPLC system containing 10 mmol/L NH₄HCO ₃and 0.1% NH ₄OH water and acetonitrile as mobile phase for purification to obtain 40 mg of 5-cyclopropyl-26-methyl-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20, 22,27-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(27),2(6),3,14,16,18,20,24(28),25-nonan-23-one (Example B6) (52%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=526.20. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.98-1.08 (2H, m), 1.04-1.15 (2H, m), 2.48-2.54 (1H, m), 2.57 (3H, s), 3.14-3.23 (2H, m), 3.33-3.38 (1H, m), 3.56-3.73 (3H, m), 4.31 (2H, t), 4.34-4.42 (2H, m), 7.20-7.35 (2H, m), 7.51-7.59 (2H, m), 7.72-7.79 (1H, m), 7.85 (1H, s), 8.55 (1H, d), 12.73 (1H, s). Example B7A and Example B7B 15,21-Dimethyl-23,29-dioxa-2,9,11,16,20,21,26-heptaazahexacyclo[24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontidine-3,5,7,9,13(32),14,16,18(22),19-nonan-12-one, isomer 1 (Example B7A) and isomer 2 (Example B7B) Step 1. Preparation of tert-butyl 6-[(2-nitrophenyl)amino]-1,4-oxazinecycloheptane-4-carboxylate (INT-B7-1). Add o-fluoronitrobenzene (1 g, 7.09 mmol, 1 equivalent), K ₂CO ₃A mixture of tert-butyl 6-amino-1,4-oxazinecycloheptane-4-carboxylate (1.69 g, 7.79 mmol, 1.1 equiv.) in acetonitrile (20 mL) was stirred at 100 °C for 12 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (3/1) to give 1.9 g of tert-butyl 6-[(2-nitrophenyl)amino]-1,4-oxazolidinone-4-carboxylate (INT-B7-1) (79%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=338.10. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.03 (6H, s), 1.33 (3H, s), 3.29 (2H, d), 3.58-3.79 (2H, m), 3.81-3.96 (2H, m), 4.02-4.13 (2H, m), 6.72 (1H, q), 7.17 (1H, d), 7.55 (1H, q), 8.05-8.13 (1H, m), 8.36-8.46 (1H, m). Step 2. N- Preparation of (2-nitrophenyl)-1,4-oxazacycloheptane-6-amine (INT-B7-2). A mixture of tert-butyl 6-[(2-nitrophenyl)amino]-1,4-oxazacycloheptane-4-carboxylate (2 g, 5.928 mmol, 1 eq.) in trifluoroacetic acid (10 mL) and dichloromethane (40 mL) was stirred at room temperature overnight under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was treated with saturated NaHCO ₃(aqueous solution) (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×200 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to obtain 1.4 g of yellow oil.N-(2-Nitrophenyl)-1,4-oxazolidinone-6-heptylamine (INT-B7-2) (99%). This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=238.10. Step 3. 4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}- N-(2-nitrophenyl)-1,4-oxazolidinone-6-heptylamine (INT-B7-3).N-(2-nitrophenyl)-1,4-oxazinecycloheptyl-6-amine (1.4 g, 5.90 mmol, 1 equivalent), (2-bromoethoxy)(tert-butyl)dimethylsilane (2.12 g, 8.85 mmol, 1.5 equivalent) and K ₂CO ₃(2.45 g, 17.70 mmol, 3 equiv.) in acetonitrile (20 mL) was stirred at 60 °C overnight under nitrogen atmosphere and cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/1) to give 1.8 g of 4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}- N-(2-Nitrophenyl)-1,4-oxazolidinone-6-heptylamine (INT-B7-3) (77%). LCMS: m/z (ESI), [M+H] ⁺=396.15. Step 4. Preparation of 2-{6-[(2-nitrophenyl)amino]-1,4-oxazolidinylcyclohept-4-yl}ethanol (INT-B7-4). 4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}- NA mixture of -(2-nitrophenyl)-1,4-oxazolidinone cycloheptyl-6-amine (1.7 g, 4.29 mmol, 1 equiv) and tetrabutylammonium fluoride (2.25 g, 8.59 mmol, 2 equiv) in tetrahydrofuran (20 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. Pass the residue through C18 FLASH using 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂Purification was performed using water with 0.05% iodine and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 1 g of 2-{6-[(2-nitrophenyl)amino]-1,4-oxazolidinylcyclohept-4-yl}ethanol (INT-B7-4) (82%) as an orange oil. LCMS: m/z (ESI), [M+H] ⁺=282.10. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.64-2.71 (3H, m), 2.81-2.94 (2H, m), 3.03-3.18 (1H, m), 3.45-3.59 (2H, m), 3.59-3.75 (3H, m), 3.95-3.99 (1H, m), 4.04-4.13 (1H, m), 4.41 (1H, t), 6.66-7.00 (1H, m), 7.01-7.02 (1H, m), 7.49-7.53 (1H, m), 8.07-8.10 (1H, m), 8.79 (1H, d) Step 5. Preparation of methyl 2-methyl-6-[1-methyl-5-(2-{6-[(2-nitrophenyl)amino]-1,4-oxazolidin-4-yl}ethoxy)pyrazol-4-yl]pyridine-4-carboxylate (INT-B7-5). To a stirred mixture of 2-{6-[(2-nitrophenyl)amino]-1,4-oxazolidinecycloheptan-4-yl}ethanol (1.00 g, 3.55 mmol, 1.2 equiv) and triphenylphosphine (2.33 g, 8.89 mmol, 3 equiv) in tetrahydrofuran (20 mL) was added diisopropyl azodicarboxylate (1.80 g, 8.89 mmol, 3 equiv) and methyl 2-(5-hydroxy-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (0.73 g, 2.96 mmol, 1.00 equiv) in THF (10 mL) at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 2 h. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×200 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/1) to give 0.9 g of 2-methyl-6-[1-methyl-5-(2-{6-[(2-nitrophenyl)amino]-1,4-oxazolidin-4-yl}ethoxy)pyrazol-4-yl]pyridine-4-carboxylic acid methyl ester (INT-B7-5) (59%) as an orange oil. LCMS: m/z (ESI), [M+H] ⁺=511.20. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.52 (3H, s), 2.91-2.95 (2H, m), 3.05 (1H, d), 3.10 (1H, q), 3.17 (2H, d), 3.67 (2H, d), 3.70 (3H, s), 3.87 (3H, s), 3.90-3.95 (1H, m), 4.05-4.12 (2H, m), 4.20-4.34 (2H, m), 6.64-6.68 (1H, m), 6.97 (1H, d), 7.42 (1H, d), 7.45-7.50 (1H, m), 7.81 (1H, d), 7.88 (1H, s), 8.02-8.05 (1H, m), 8.67 (1H, d). Step 6. Preparation of methyl 2-[5-(2-{6-[(2-aminophenyl)amino]-1,4-oxazacycloheptan-4-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (INT-B7-6). To a stirred mixture of methyl 2-methyl-6-[1-methyl-5-(2-{6-[(2-nitrophenyl)amino]-1,4-oxazacycloheptan-4-yl}ethoxy)pyrazol-4-yl]pyridine-4-carboxylate (540 mg, 1.06 mmol, 1 eq.) and ranyl nickel (725 mg, 8.46 mmol, 8 eq.) in methanol (5 mL) at 0 °C was added hydrazine hydrate (79 mg, 1.59 mmol, 1.5 eq.). The mixture was stirred at 0 °C for 2 h under nitrogen atmosphere. The resulting mixture was filtered. The filter cake was washed with methanol (3×50 mL), and the resulting solution was concentrated under reduced pressure to give 480 mg of methyl 2-[5-(2-{6-[(2-aminophenyl)amino]-1,4-oxazolidin-4-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (INT-B7-6) as a brown solid. This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺= 481.25. Step 7. Preparation of methyl 2-(5-{2-[6-(2-amino-1,3-benzodiazol-1-yl)-1,4-oxazacyclohept-4-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B7-7). A mixture of methyl 2-[5-(2-{6-[(2-aminophenyl)amino]-1,4-oxazacyclohept-4-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (500 mg, 1.04 mmol, 1 eq.) and BrCN (132 mg, 1.25 mmol, 1.2 eq.) in dichloromethane (5 mL) was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water (80 mL), and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using petroleum ether/ethyl acetate (1/1) to give 400 mg of methyl 2-(5-{2-[6-(2-amino-1,3-benzodiazol-1-yl)-1,4-oxazolidin-4-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B7-7) (76%) as an orange oil. LCMS: m/z (ESI), [M+H] ⁺=506.30. Step 8. Preparation of 2-(5-{2-[6-(2-amino-1,3-benzodiazol-1-yl)-1,4-oxazacyclohept-4-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B7-8). 2-(5-{2-[6-(2-amino-1,3-benzodiazol-1-yl)-1,4-oxazacyclohept-4-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid methyl ester (200 mg, 0.39 mmol, 1 equivalent) and LiOH.H ₂A mixture of O (25 mg, 0.59 mmol, 1.5 equiv.) in tetrahydrofuran (4 mL) and water (1 mL) was stirred at room temperature for 2 h under a nitrogen atmosphere and concentrated under reduced pressure. The residue was passed through a C18 FLASH using a 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂Purification was performed using water with 0.04% iodine and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 180 mg of 2-(5-{2-[6-(2-amino-1,3-benzodiazol-1-yl)-1,4-oxazol-4-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B7-8) (92%) as a pink solid. LCMS: m/z (ESI), [M+H] ⁺=492.30. Step 9. 15,21-Dimethyl-23,29-dioxa-2,9,11,16,20,21, 26-heptaazahexacyclic [24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18, 22}]32-3,5,7,9,13(3 2),14,1Preparation of 6,18(22),19-nonan-12-one (Example B7). 2-(5-{2-[6-(2-amino-1,3-benzodiazol-1-yl)-1,4-oxazolidinone-4-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (160 mg, 0.33 mmol, 1 equivalent), HATU (186 mg, 0.49 mmol, 1.5 equivalents) and N,N- A mixture of diisopropylethylamine (126 mg, 0.98 mmol, 3 equiv.) in 1,4-dioxane (5 mL) was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water (30 mL), and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by trituration with methanol (50 mL) to give 8.3 mg of 15,21-dimethyl-23,29-dioxa-2,9,11,16,20,21,26-heptaazahexacyclo[24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontac-3,5,7,9,13(32),14,16,18(22),19-nonan-12-one (Example B7) as a white solid (5%). LCMS: m/z (ESI), [M+H] ⁺= 474.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.57 (3H, s), 2.82-2.91 (3H, m), 2.93-3.01 (1H, m), 3.24-3.44 (2H, m), 3.75 (3H, s), 3.72-3.78 (1H, m), 3.96 (1H, br s), 4.03-4.26 (2H, m), 4.59 (2H, d), 5.45 (1H, br s), 7.20-7.33 (2H, m), 7.52-7.58 (2H, m), 7.69 (1H, d), 7.92 (1H, s), 8.61 (1H, s), 12.67 (1H, s). Step 10. Preparation of 15,21-dimethyl-23,29-dioxa-2,9,11,16,20,21, 26-heptaazahexacyclo[24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18, 22}]triacontria-3,5,7,9,13(32),14,16,18(22),19-nonan-12-one, Isomer 1 (Example B7A) and Isomer 2 (Example B7B). A mixture of 15,21-dimethyl-23,29-dioxa-2,9,11,16,20,21,26-heptaazahexacyclo[24.4.1.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontac-3,5,7,9,13(32),14,16,18(22),19-nonan-12-one (Example B7, 80 mg) was chromatographed by Prep-chiral-HPLC using a CHIRALPAK IG column (2*25 cm, 5 μm) with hexane and EtOH/CH containing 0.2% DEA.₂Cl ₂(1/1) was used as the mobile phase to separate 32 mg of isomer 1 (Example B7A, 40%) and 34 mg of isomer 2 (Example B7B, 42%) as white solids. Isomer 1: LCMS: m/z (ESI), [M+H] ⁺=474.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.57 (3H, s), 2.82-2.91 (3H, m), 2.93-3.01 (1H, m), 3.24-3.44 (2H, m), 3.75 (3H, s), 3.72-3.78 (1H, m), 3.96 (1H, br s), 4.03-4.26 (2H, m), 4.59 (2H, d), 5.45 (1H, br s), 7.20-7.33 (2H, m), 7.52-7.58 (2H, m), 7.69 (1H, d), 7.92 (1H, s), 8.61 (1H, s), 12.67 (1H, s). Chiral-HPLC, Rt=2.016 min. Isomer 2: LCMS: m/z (ESI), [M+H] ⁺=474.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.57 (3H, s), 2.82-2.91 (3H, m), 2.93-3.01 (1H, m), 3.24-3.44 (2H, m), 3.75 (3H, s), 3.72-3.78 (1H, m), 3.96 (1H, br s), 4.03-4.26 (2H, m), 4.59 (2H, d), 5.45 (1H, br s), 7.20-7.33 (2H, m), 7.52-7.58 (2H, m), 7.69 (1H, d), 7.92 (1H, s), 8.61 (1H, s), 12.67 (1H, s). Chiral-HPLC, Rt = 2.626 minutes. Example B8A and Example B8B 15,21-Dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,15,17(33),18(22), 19-nonan-12-one, isomer 1 (Example B8A) and isomer 2 (Example B8B) Step 1. Preparation of methyl 2-methyl-6-[1-methyl-5-(2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)pyrazol-4-yl]pyridine-4-carboxylate (INT-B8-1). To a stirred mixture of 2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethanol (INT-A61-4, 380 mg, 1.30 mmol, 1 eq.) and triphenylphosphine (685 mg, 2.61 mmol, 2 eq.) in tetrahydrofuran (10 mL) at 0 °C under nitrogen atmosphere was added methyl 2-(5-hydroxy-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (M1, 323 mg, 1.30 mmol, 1 eq.) and diisopropyl azodicarboxylate (528 mg, 2.61 mmol, 2 eq.). The resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched with water (30 mL), and the mixture was washed with CH₂Cl ₂(3×50 mL) extraction. The combined organic layers were washed with brine (3×75 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using petroleum ether/ethyl acetate (1/1) to give 460 mg of methyl 2-methyl-6-[1-methyl-5-(2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethoxy)pyrazol-4-yl]pyridine-4-carboxylate (INT-B8-1) (67%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=521.15. Step 2. Preparation of methyl 2-[5-(2-{1-[(2-aminophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (INT-B8-2). To a stirred mixture of methyl 2-methyl-6-[1-methyl-5-(2-{1-[(2-nitrophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)pyrazol-4-yl]pyridine-4-carboxylate (500 mg, 0.96 mmol, 1 eq.) and ranyl nickel (80 mg) in methanol (10 mL) was added hydrazine hydrate (92 mg, 2.88 mmol, 3 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was filtered and the filter cake was washed with methanol (3×20 mL). The resulting solution was concentrated under reduced pressure. The mixture was purified by prep-TLC using dichloromethane/methanol (20/1) to give 400 mg of 2-[5-(2-{1-[(2-aminophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid methyl ester (INT-B8-2) (85%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=491.15. Step 3. Preparation of methyl 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B8-3). To a stirred mixture of methyl 2-[5-(2-{1-[(2-aminophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (455 mg, 0.93 mmol, 1 eq.) in ethanol (20 mL) was added BrCN (334 mg, 3.15 mmol, 3.4 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (20/1) to give 350 mg of methyl 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B8-3) (73%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=516.15. Step 4. Preparation of methyl 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate, isomer 1 (INT-B8-3A) and isomer 2 (INT-B8-3B). A racemic mixture of methyl 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (350 mg) was purified by Prep-chiral-HPLC using a CHIRALPAK IG chiral column (2×25 cm, 5 μm) using methyl tert-butyl ether and ethanol/CH ₂Cl ₂(1/1) was used as the mobile phase to separate 90 mg of isomer 1 (INT-B8-3A, 25%) and 80 mg of isomer 2 (INT-B8-3B, 22%) as white solids. Chiral-HPLC: Rt (isomer 1) = 1.312 min, Rt (isomer 2) = 2.047 min. Step 5. Preparation of 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B8-4A). To a stirred mixture of methyl 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B8-3A, 85 mg, 0.16 mmol, 1 equiv.) in tetrahydrofuran (8 mL) at room temperature under nitrogen atmosphere was added LiOH ^.H ₂O (16 mg, 0.66 mmol, 4 equiv) of H ₂O (2 mL). The resulting mixture was stirred at 60 °C for 30 minutes, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by reverse flash chromatography using a C18 silica gel column using water and acetonitrile as mobile phases. The fractions containing the desired compound were evaporated to dryness to give 80 mg of 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B8-4A) (96%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=502.20. Step 6. Preparation of 15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]tritriaconta-3,5,7,9,13,15,17(33),18(22), 19-nonan-12-one, isomer 1 (Example B8A). N, N-diisopropylethylamine (58 mg, 0.45 mmol, 3 equivalents), 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B8-4A, 75 mg, 0.15 mmol, 1 equivalent) and N, N, N, N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)urea hexafluorophosphate (85 mg, 0.22 mmol, 1.5 equiv.) in 1,4-dioxane (7 mL) was stirred at 60 °C for 1 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (20 mL), and the mixture was washed with CH₂Cl ₂(3×30 mL) extraction. The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC and eluted with dichloromethane/methanol (25/1) to give 57.4 mg of 15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontac-3,5,7,9,13,15,17(33), 18(22),19-nonan-12-one (isomer 1, Example B8A) (79%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=484.30. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.59-1.80 (3H, m), 2.02 (1H, d), 2.38-2.50 (3H, m), 2.56 (3H, s), 2.63-2.82 (3H, m), 3.22-3.45 (2H, m), 3.74 (3H, s), 3.77-3.83 (1H, m), 4.56 (1H, t), 4.71 (1H, d), 7.16-7.25 (2H, m), 7.55-7.63 (2H, m), 7.73-7.84 (1H, m), 7.94 (1H, s), 8.44 (1H, s), 12.87 (1H, s). SFC-HPLC, Rt = 1.282 min. Step 7. Preparation of 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B8-4B). To a stirred mixture of methyl 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B8-3B, 75 mg, 0.15 mmol, 1 equiv.) in tetrahydrofuran (8 mL) at room temperature under nitrogen atmosphere was added LiOH ^.H ₂O (14 mg, 0.58 mmol, 4 equiv) of H ₂O (2 mL). The resulting mixture was stirred at 60 °C for 30 min. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse flash chromatography using a C18 silica gel column using water and acetonitrile as mobile phases. The fractions containing the desired compound were evaporated to dryness to give 70 mg of 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B8-4B) (96%) as an off-white solid. LCMS: m/z (ESI), [M+H] ⁺=502.20. Step 8. Preparation of 15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]tritriaconta-3,5,7,9,13,15,17(33),18(22), 19-nonan-12-one, isomer 2 (Example B8B). N, N-diisopropylethylamine (50 mg, 0.39 mmol, 3 equivalents), 2-(5-{2-[1-(2-amino-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B8-4B, 65 mg, 0.13 mmol, 1 equivalent) and N, N, N, N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)urea hexafluorophosphate (74 mg, 0.20 mmol, 1.5 equiv) in 1,4-dioxane (6 mL) was stirred at 60 °C for 1 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (20 mL), and the mixture was washed with CH₂Cl ₂(3×30 mL) extraction. The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC and eluted with dichloromethane/methanol (25/1) to give 46.5 mg of 15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontac-3,5,7,9,13,15,17(33), 18(22),19-nonan-12-one, isomer 2 (Example B8B) (74%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=484.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.59-1.80 (3H, m), 2.02 (1H, d), 2.38-2.50 (3H, m), 2.56 (3H, s), 2.63-2.82 (3H, m), 3.22-3.45 (2H, m), 3.74 (3H, s), 3.77-3.83 (1H, m), 4.56 (1H, t), 4.71 (1H, d), 7.16-7.25 (2H, m), 7.55-7.63 (2H, m), 7.73-7.84 (1H, m), 7.94 (1H, s), 8.44 (1H, s), 12.87 (1H, s). SFC-HPLC, Rt = 1.060 minutes. Example B9A and Example B9B 15,21-Dimethyl-5-(4-methylpiperazin-1-yl)-23-oxa-2,9,11,16, 20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,15,17(33),18(22), 19-nonan-12-one, isomer 1 (Example B9A) and isomer 2 (Example B9B). Step 1. Preparation of methyl 2-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (INT-B9-1). To a stirred mixture of methyl 2-(5-hydroxy-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (M1, 1.40 g, 5.67 mmol, 1.05 equiv) and triphenylphosphine (3.97 g, 15.12 mmol, 2.8 equiv) in tetrahydrofuran (30 mL) at 0 °C under nitrogen atmosphere was added diisopropyl azodicarboxylate (2.73 g, 13.50 mmol, 2.5 equiv) followed by 2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethanol (M4-11, 2 g, 5.40 mmol, 1 equiv). After stirring at 0 °C for 3 h, the reaction was quenched with water (400 mL), and the mixture was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine (3×300 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel column eluting with dichloromethane/methanol (30/1) to give 2 g of 2-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid methyl ester (INT-B9-1) (61%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=601.00. Step 2. Preparation of methyl 2-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (INT-B9-2). To a stirred mixture of methyl 2-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (2 g, 3.33 mmol, 1 eq.) in methanol (60 mL) at room temperature, add ranyl nickel (457 mg, 5.33 mmol, 1.6 eq.) and NH ₂NH ₂ ^.H ₂O (835 mg, 16.68 mmol, 5 equiv.). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (300 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane/methanol (20/1) to give 1.34 g of methyl 2-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (INT-B9-2) (70%) as a reddish brown solid. LCMS: m/z (ESI), [M+H] ⁺= 571.05. Step 3. Preparation of methyl 2-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B9-3). To a stirred mixture of methyl 2-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (500 mg, 0.87 mmol, 1 eq.) in ethanol (8 mL) was added BrCN (139 mg, 1.31 mmol, 1.5 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was treated with saturated NaHCO₃(100 mL) and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane/methanol (15/1) to give 400 mg of methyl 2-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B9-3) (76.63%) as a reddish brown oil. LCMS: m/z (ESI), [M+H] ⁺=596.10. Step 4. Preparation of methyl 2-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate, isomer 1 (INT-B9-3A) and isomer 2 (INT-B9-3B). The racemic mixture of methyl 2-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (400 mg) was subjected to Prep-chiral-HPLC using a CHIRAL ART cellulose-SB column (5*25 cm, 5 μm) using CO ₂and CH ₃OH/CH ₂Cl ₂(2/1) was used as the mobile phase to separate to obtain 150 mg of isomer 1 (INT-B9-3A, 42%) and 150 mg of isomer 2 (INT-B9-3B, 42%) as white solids. SFC-HPLC, Rt (isomer 1) = 1.760 min, Rt (isomer 2) = 1.889 min. Step 5. Preparation of 2-(5-{2-1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (isomer 1, INT-B9-4A). To a stirred solution of methyl 2-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (490 mg, 0.82 mmol, 1 eq.) in THF (8 mL) at room temperature was added LiOH (78 mg, 3.29 mmol, 4 eq.) in H ₂O (2 mL). The resulting mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by reverse flash chromatography using water and acetonitrile as mobile phases to give 410 mg of 2-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (isomer 1, INT-B9-4A) (85%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=580.05. Step 6. Preparation of 5-bromo-15,21-dimethyl-23-oxa-2,9,11,16,20,21, 26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3, 8}.0^{18,22}]triacontria-3,5,7,9,13,15,17(33),18(22), 19-nonan-12-one (isomer 1, INT-B9-5A). To a stirred solution of 2-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (390 mg, 0.67 mmol, 1 eq.) in dioxane (10 mL) was added at room temperature N,N-Diisopropylethylamine (260 mg, 2.01 mmol, 3 equiv.) and N,N,N,N-Tetramethyl- O-(7-Azabenzotriazole-1-yl)uronium hexafluorophosphate (383 mg, 1.01 mmol, 1.5 equiv). The reaction mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The crude product was purified by prep-TLC using dichloromethane/methanol (25/1) to give 350 mg of 5-bromo-15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontac-3,5,7,9,13,15,17(33),18(22), 19-nonan-12-one (isomer 1, INT-B9-5A) (92%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺=564.05. Step 7. Preparation of 15,21-dimethyl-5-(4-methylpiperazin-1-yl)-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,15,17(33), 18(22), 19-nonan-12-one (isomer 1, Example B9A). 5-Bromo-15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,15,17(33), 18(22),19-nonan-12-one (130 mg, 0.23 mmol, 1 eq.), 1-methylpiperazine (34.7 mg, 0.35 mmol, 1.5 eq.) and BrettPhos Pd G ₃To a stirred mixture of 2-nitropropene (62.8 mg, 0.07 mmol, 0.3 equiv) in dioxane (5 mL) was added LiHMDS (2.3 mL, 2.31 mmol, 10 equiv) dropwise. The reaction mixture was stirred at 60 °C under nitrogen atmosphere for 1 h. After cooling to room temperature, the reaction was heated with saturated NH₄Cl (30 mL) was quenched, and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×30 mL) and purified by anhydrous Na ₂SO ₄The residue was purified by prep-TLC eluting with dichloromethane/methanol (18/1) to give 41.6 mg of 15,21-dimethyl-5-(4-methylpiperazin-1-yl)-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,15,17(33),18(22),19-nonan-12-one, Isomer 1 (Example B9A) as a white solid (30%). LCMS: m/z (ESI), [M+H] ⁺=582.40. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.52-1.82 (3H, m), 2.03 (1H, d), 2.24 (3H, s), 2.40-2.60 (8H, m), 2.55 (3H, s), 2.64-2.79 (2H, m), 3.12 (4H, q), 3.20-3.30 (1H, m), 3.37-3.45 (1H, m), 3.74 (3H, s), 3.77 (1H, br s), 4.56 (1H, t), 4.70 (1H, d), 6.93 (1H, dd), 7.19 (1H, d), 7.42 (1H, d), 7.57 (1H, d), 7.94 (1H, s), 8.42 (1H, s), 12.69 (1H, s). SFC-HPLC, Rt=3.968 minutes. Using INT-B9-3B as the starting material, the same reaction sequence described above for the synthesis of Example B9A gave 48.4 mg of 15,21-dimethyl-5-(4-methylpiperazin-1-yl)-23-oxa-2,9,11,16,20, 21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}. 0^{3,8}.0^{18,22}]tritriacontac-3,5,7,9,13,15,17(33), 18(22),19-nonan-12-one, isomer 2 (Example B9B) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=582.40. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.52-1.82 (3H, m), 2.03 (1H, d), 2.24 (3H, s), 2.40-2.60 (8H, m), 2.55 (3H, s), 2.64-2.79 (2H, m), 3.12 (4H, q), 3.20-3.30 (1H, m), 3.37-3.45 (1H, m), 3.74 (3H, s), 3.77 (1H, br s), 4.56 (1H, t), 4.70 (1H, d), 6.93 (1H, dd), 7.19 (1H, d), 7.42 (1H, d), 7.57 (1H, d), 7.94 (1H, s), 8.42 (1H, s), 12.69 (1H, s). SFC-HPLC, Rt = 3.745 minutes. Example B10A and Example B10B 15,21-Dimethyl-5-(morpholin-4-yl)-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}. 0^{18,22}]tritriacontahedral-3,5,7,9,13,15,17(33),18(22),19-nonan-12-one, isomer 1 (Example B10A) and isomer 2 (Example B10B) The title compound was prepared using the same reaction sequence described for the preparation of Examples B9A and B9B. Example B10A: LCMS: m/z (ESI), [M+H]+=569.40. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.56-1.81 (3H, m), 2.03 (1H, d), 2.37-2.48 (3H, m), 2.55 (3H, s), 2.57-2.79 (3H, m), 3.04-3.18 (4H, m), 3.19-3.29 (2H, m), 3.37-3.47 (1H, m), 3.74 (3H, s), 3.75-3.83 (4H, m), 4.56 (1H, t), 4.71 (1H, d), 6.94 (1H, dd), 7.21 (1H, d), 7.45 (1H, d), 7.57 (1H, d), 7.94 (1H, s), 8.43 (1H, s), 12.71 (1H, s). SFC-HPLC, Rt=1.549 min Example B10B: LCMS: m/z (ESI), [M+H]+=569.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.56-1.81 (3H, m), 2.03 (1H, d), 2.37-2.48 (3H, m), 2.55 (3H, s), 2.57-2.79 (3H, m), 3.04-3.18 (4H, m), 3.19-3.29 (2H, m), 3.37-3.47 (1H, m), 3.74 (3H, s), 3.75-3.83 (4H, m), 4.56 (1H, t), 4.71 (1H, d), 6.94 (1H, dd), 7.21 (1H, d), 7.45 (1H, d), 7.57 (1H, d), 7.94 (1H, s), 8.43 (1H, s), 12.71 (1H, s). SFC-HPLC, Rt=1.639 min Example B11 (12 R)-5,12,27-trimethyl-8-oxa-5,14,21,23,28-pentazapentacyclic [23.3.1.0^{2,7}.0^{14,22}.0^{15,20}]twenty-nine-1(29),2,6,15, 17,19,21,25,27-nonene-4,24-dione Step 1. (4 RPreparation of )-4-methyl-5-[(2-nitrophenyl)amino]pentan-1-ol (INT-B11-1). o-Fluoronitrobenzene (1.32 g, 9.386 mmol, 1.1 equivalents), (4 R)-5-amino-4-methylpentan-1-ol (1 g, 8.533 mmol, 1.00 equiv) and K ₂CO ₃(3.54 g, 25.599 mmol, 3 equiv.) in acetonitrile (20 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (800 mL), and the mixture was extracted with dichloromethane (3×600 mL). The combined organic layers were washed with brine (3×500 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by silica gel chromatography using petroleum ether/ethyl acetate (1/1) to give 1.6 g (4 R)-4-methyl-5-[(2-nitrophenyl)amino]pentan-1-ol (INT-B11-1) (78%). LCMS: m/z (ESI), [M+H] ⁺=239.05. Step 2. Preparation of 2-(benzyloxy)-5-[(2-methoxyethoxy)methoxy]pyridine (INT-B11-2). 6-(benzyloxy)pyridine-3-ol (5 g, 24.84 mmol, 1 equivalent) was added to N,N- To the stirred mixture in dimethylformamide was added sodium hydroxide (60% in oil, 4 g, 12.42 mmol, 2 eq). The mixture was stirred for 15 min before the addition of 1-(chloromethoxy)-2-methoxyethane (3.1 g, 24.84 mmol, 1 eq). The mixture was stirred at 0 °C for 2 h. The reaction was quenched with water (50 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column eluted with petroleum ether/ethyl acetate (3/1) to give 6 g of 2-(benzyloxy)-5-[(2-methoxyethoxy)methoxy]pyridine (INT-B11-2) (75%) as a light yellow oil. LCMS: m/z (ESI), [M+H] ⁺=290.10. ¹H NMR (DMSO- d ₆, 400 MHz) δ 3.22 (3H, s), 3.36-3.51 (2H, m), 3.65-3.80 (2H, m), 5.21 (2H, s), 5.29 (2H, s), 6.85 (1H, d), 7.28-7.42 (3H, m), 7.35-7.50 (2H, m), 7.50 (1H, d), 7.93 (1H, d). Step 3. Preparation of 2-(benzyloxy)-4-iodo-5-[(2-methoxyethoxy)methoxy]pyridine (INT-B11-3). To a stirred mixture of 2-(benzyloxy)-5-[(2-methoxyethoxy)methoxy]pyridine (5.8 g, 20.04 mmol, 1 equiv) in tetrahydrofuran (5 mL) at -78 °C under nitrogen atmosphere was added n-butyl lithium solution (2.5 M in tetrahydrofuran, 17 mL, 2 mmol). The mixture was stirred at -78 °C for 30 minutes. I was then added dropwise.₂(8.1 g, 32.07 mmol, 1.60 equiv) in 10 mL tetrahydrofuran, and the mixture was stirred at -78 °C under nitrogen atmosphere for 1 h. The reaction was treated with saturated NH₄Cl (100 mL) was quenched, and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column eluted with petroleum ether/ethyl acetate (3/1) to give 5.5 g of 2-(benzyloxy)-4-iodo-5-[(2-methoxyethoxy)methoxy]pyridine (INT-B11-3) (59%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=415.95. ¹H NMR (CDCl ₃, 400 MHz) δ 3.42 (3H, s), 3.52-3.70 (2H, m), 3.85-4.02 (2H, m), 5.27 (2H, s), 5.33 (2H, s), 7.35-7.46 (6H, m), 7.94 (1H, s) Step 4. Preparation of 2'-(benzyloxy)-6-chloro-5'-[(2-methoxyethoxy)methoxy]-[2,4'-bipyridine]-4-carboxylic acid methyl ester (INT-B11-4). 2-Chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-4-carboxylic acid methyl ester (M1-1, 4 g crude product), 2-(benzyloxy)-4-iodo-5-[(2-methoxyethoxy)methoxy]pyridine (4.1 g, 10.08 mmol, 1 equivalent), Pd ₂(dba) ₃(0.92 g, 1.00 mmol, 0.1 eq.), bis(adamantan-1-yl)(butyl)phosphine (0.36 g, 1.00 mmol, 0.1 eq.) and Cs ₂CO ₃(9.8 g, 30.24 mmol, 3.00 equiv.) in toluene/H ₂O (40 mL/10 mL) was stirred at 80 °C for 16 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/1) to give 4.8 g of methyl 2'-(benzyloxy)-6-chloro-5'-[(2-methoxyethoxy)methoxy]-[2,4'-bipyridine]-4-carboxylate (INT-B11-4) (93%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=459.05. Step 5. Preparation of 2'-(benzyloxy)-5'-[(2-methoxyethoxy)methoxy]-6-methyl-[2,4'-bipyridine]-4-carboxylic acid methyl ester (INT-B11-5). 2'-(benzyloxy)-6-chloro-5'-[(2-methoxyethoxy)methoxy]-[2,4'-bipyridine]-4-carboxylic acid methyl ester (2.8 g, 6.10 mmol, 1 equivalent), Pd(dppf)Cl ₂(0.89 g, 1.22 mmol, 0.2 equivalent), K ₂CO ₃(1.6 g, 12.20 mmol, 2 equivalents), PCy ₃.HBF ₄A mixture of (0.67 g, 1.83 mmol, 0.3 equiv) and trimethyl-1,3,5,2,4,6-trioxatriborinane (2.07 g, 16.47 mmol, 2.7 equiv) in 1,4-dioxane (28 mL) was stirred at 100 °C for 3 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/1) to give 1.8 g of 2'-(benzyloxy)-5'-[(2-methoxyethoxy)methoxy]-6-methyl-[2,4'-bipyridine]-4-carboxylic acid methyl ester (INT-B11-5) (60%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺= 439.15. Step 6. Preparation of methyl 2'-hydroxy-5'-[(2-methoxyethoxy)methoxy]-6-methyl-[2,4'-bipyridine]-4-carboxylate (INT-B11-6). A mixture of methyl 2'-(benzyloxy)-5'-[(2-methoxyethoxy)methoxy]-6-methyl-[2,4'-bipyridine]-4-carboxylate (1.8 g, 4.105 mmol, 1 eq.) and Pd/C (10%, 500 mg) in methanol (10 mL) was stirred under a hydrogen atmosphere for 1 h. The resulting mixture was filtered, and the filter cake was washed with methanol (150 mL). The solution was concentrated under reduced pressure. The residue was purified on a silica gel column using dichloromethane/methanol (10/1) to give 1.3 g of 2'-hydroxy-5'-[(2-methoxyethoxy)methoxy]-6-methyl-[2,4'-bipyridine]-4-carboxylic acid methyl ester (INT-B11-6) (82%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺= 349.05. Step 7. Preparation of 5'-[(2-methoxyethoxy)methoxy]-1',6-dimethyl-2'-oxo-[2,4'-bipyridine]-4-carboxylic acid methyl ester (INT-B11-7) Methyl 2'-hydroxy-5'-[(2-methoxyethoxy)methoxy]-6-methyl-[2,4'-bipyridine]-4-carboxylic acid methyl ester (1.1 g, 3.15 mmol, 1 equivalent), K ₂CO ₃(1.3 g, 9.47 mmol, 3 equiv.) and CH ₃A mixture of I (672 mg, 4.73 mmol, 1.5 equiv.) in acetone (10 mL) was stirred at 60 °C for 12 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. Pass the residue through C18 FLASH using 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O and acetonitrile as the mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 1 g of 5'-[(2-methoxyethoxy)methoxy]-1',6-dimethyl-2'-oxo-[2,4'-bipyridine]-4-carboxylic acid methyl ester (INT-B11-7) (83%) as a light yellow oil. LCMS: m/z (ESI), [M+H] ⁺=363.10. ¹H NMR (CDCl ₃, 400 MHz) δ 2.66 (3H, s), 3.41 (3H, s), 3.58 (5H, d), 3.71-3.96 (2H, m), 3.96 (3H, s), 5.02 (2H, s), 6.92 (1H, s), 7.45 (1H, s), 7.73 (1H, d), 7.99 (1H, d) Step 8. Preparation of 5'-hydroxy-1',6-dimethyl-2'-oxo-[2,4'-bipyridine]-4-carboxylic acid methyl ester (INT-B11-8). A solution of 5'-[(2-methoxyethoxy)methoxy]-1',6-dimethyl-2'-oxo-[2,4'-bipyridine]-4-carboxylic acid methyl ester (370 mg, 1.02 mmol, 1 equiv) and HCl (10 mL, 4 M in MeOH) was stirred at room temperature under nitrogen atmosphere for 1.5 h. The mixture was concentrated under reduced pressure. The residue was treated with dichloromethane (30 mL) and NaHCO ₃The solution was worked up and filtered. The filtrate was concentrated under reduced pressure to give 260 mg of 5'-hydroxy-1',6-dimethyl-2'-oxo-[2,4'-bipyridine]-4-carboxylic acid methyl ester (INT-B11-8) as a yellow solid. This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=275.05. Step 9. 1',6-dimethyl-5'-{[(4 RPreparation of methyl 5-[(2-nitrophenyl)amino]pentyl]oxy}-2'-oxo-[2,4'-bipyridine]-4-carboxylate (INT-B11-9). 5'-Hydroxy-1',6-dimethyl-2'-oxo-[2,4'-bipyridine]-4-carboxylate (282 mg, 1.03 mmol, 1 equivalent), (4 RA mixture of 2-(tributyl-1^[5]-phosphinilidene)acetonitrile (1.00 g, 4.14 mmol, 4.00 equiv)-4-methyl-5-[(2-nitrophenyl)amino]pentan-1-ol (247 mg, 1.03 mmol, 1 equiv) and 2-(tributyl-1^[5]-phosphinilidene)acetonitrile (1.00 g, 4.14 mmol, 4.00 equiv) in toluene (10 mL) was stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/1) to give 400 mg of 1',6-dimethyl-5'-{[(4R)-4-methyl-5-[(2-nitrophenyl)amino]pentyl]oxy}-2'-oxo-[2,4'-bipyridine]-4-carboxylic acid methyl ester (INT-B11-9) (77%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=495.10. Step 10. Preparation of 5'-{[(4R)-5-[(2-aminophenyl)amino]-4-methylpentyl]oxy}-1',6-dimethyl-2'-oxo-[2,4'-bipyridine]-4-carboxylic acid methyl ester (INT-B11-10). To a stirred mixture of 1',6-dimethyl-5'-{[(4R)-4-methyl-5-[(2-nitrophenyl)amino]pentyl]oxy}-2'-oxo-[2,4'-bipyridine]-4-carboxylic acid methyl ester (400 mg, 0.80 mmol, 1 eq.) and ranyl nickel (34 mg, 0.40 mmol, 0.50 eq.) in methanol (10 mL) was added hydrazine hydrate (77 mg, 2.42 mmol, 3.00 eq.) at 0°C. The mixture was stirred at 0 °C for 2 h under nitrogen atmosphere. The mixture was filtered and the filter cake was washed with methanol (3×10 mL). The resulting solution was concentrated under reduced pressure. The residue was purified on prep-TLC using petroleum ether/ethyl acetate (1/1) to give 350 mg of 5'-{[(4 R)-5-[(2-aminophenyl)amino]-4-methylpentyl]oxy}-1',6-dimethyl-2'-oxo-[2,4'-bipyridine]-4-carboxylic acid methyl ester (INT-B11-10) (93%). LCMS: m/z (ESI), [M+H] ⁺=465.20. Step 11. 5'-{[(4 RPreparation of methyl 4-[(2-amino-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1',6-dimethyl-2'-oxo-[2,4'-bipyridine]-4-carboxylate (INT-B11-11). 5'-{[(4 RA mixture of methyl 5-[(2-aminophenyl)amino]-4-methylpentyl]oxy}-1',6-dimethyl-2'-oxo-[2,4'-bipyridine]-4-carboxylate (400 mg, 0.86 mmol, 1 equiv) and BrCN (182 mg, 1.722 mmol, 2.00 equiv) in ethanol (10 mL) was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on prep-TLC using dichloromethane/methanol (20/1) to give 350 mg of 5'-{[(4 R)-4-[(2-amino-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1',6-dimethyl-2'-oxo-[2,4'-bipyridine]-4-carboxylic acid methyl ester (INT-B11-11) (83%). LCMS: m/z (ESI), [M+H] ⁺=490.10. Step 12. 5'-{[(4 R)-4-[(2-amino-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1',6-dimethyl-2'-oxo-[2,4'-bipyridine]-4-carboxylic acid (INT-B11-12). 5'-{[(4 R)-4-[(2-amino-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1',6-dimethyl-2'-oxo-[2,4'-bipyridine]-4-carboxylic acid methyl ester (300 mg, 0.61 mmol, 1 equivalent) and LiOH ^.H ₂A mixture of O (44 mg, 1.83 mmol, 3 equiv.) in tetrahydrofuran/water (4 mL/1 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was subjected to C18 FLASH chromatography using a HPLC-MS/MS system containing 0.1% NH₃ ^.H ₂O and acetonitrile water as the mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 200 mg of 5'-{[(4 R)-4-[(2-amino-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1',6-dimethyl-2'-oxo-[2,4'-bipyridine]-4-carboxylic acid (INT-B11-12) (68%). LCMS: m/z (ESI), [M+H] ⁺= 476.10. Step 13. (12 R)-5,12,27-trimethyl-8-oxa-5,14,21,23,28-pentazapentacyclo[23.3.1.0^{2,7}.0^{14,22}.0^{15,20}]twenty-nine-1(29),2,6,15,17,19,21,25,27-nonene-4,24-dione (Example B11). 5'-{[(4 R)-4-[(2-amino-1,3-benzodiazol-1-yl)methyl]pentyl]oxy}-1',6-dimethyl-2'-oxo-[2,4'-bipyridine]-4-carboxylic acid (400 mg, 0.84 mmol, 1 equivalent), N,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (479 mg, 1.26 mmol, 1.5 equivalents) and N, N- A mixture of diisopropylethylamine (217 mg, 1.68 mmol, 2 equiv.) in 1,4-dioxane (10 mL) was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 186 mg (12 R)-5,12,27-trimethyl-8-oxa-5,14,21,23,28-pentazapentacyclic [23.3.1.0^{2,7}.0^{14,22}.0^{15,20}]twenty-nine-1(29),2,6,15,17,19,21,25,27-nonene-4,24-dione (Example B11) (48%). LCMS: m/z (ESI), [M+H] ⁺=458.25. ¹H NMR (DMSO-d ₆, 400 MHz) δ 0.93 (3H, d), 1.47-1.60 (1H, m), 1.66-1.80 (1H, m), 1.96-2.20 (2H, m), 2.25-2.37 (1H, m), 2.63 (3H, s), 3.48 (3H, s), 3.93-4.08 (3H, m), 4.18 (1H, dd), 7.12 (1H, s), 7.19-7.34 (2H, m), 7.53-7.61 (3H, m), 7.83 (1H, d), 8.92 (1H, d), 12.80 (1H, s). Example B12 (11 R)-18-[2-(dimethylamino)ethyl]-5,11,30-trimethyl-7-oxo-4,5,13,18,24,26,31-heptaazahexacyclic[26.3.1.0^{2,6}.0^{13,25}. 0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24, 28(32),29-nonan-27-one Step 1. 2,2,2-trifluoro-1-(5-{[(2 RPreparation of 2,2,2-trifluoro-1-(5-fluoro-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (INT-A102-3, 15 g, 51.34 mmol, 1 equivalent), N,N-diisopropylethylamine (19.9 g, 154.01 mmol, 3 equivalents) and (4 RA mixture of 5-amino-4-methylpentan-1-ol (M3-6, 6016 mg, 51.34 mmol, 1 equivalent) in acetonitrile (150 mL) was stirred at 80 °C for 2 h. The mixture was cooled to room temperature. The reaction was quenched with water (500 mL), and the mixture was extracted with dichloromethane (3×500 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by eluting with petroleum ether/ethyl acetate (1/1) on a silica gel column to give 10 g of 2,2,2-trifluoro-1-(5-{[(2R)-5-hydroxy-2-methylpentyl]amino}-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (INT-B12-1) (50%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=390.10. Step 2. (4 R)-4-methyl-5-[(6-nitro-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]pentan-1-ol (INT-B12-2). 2,2,2-trifluoro-1-(5-{[(2 R)-5-hydroxy-2-methylpentyl]amino}-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (10 g, 25.68 mmol, 1 equivalent) and K ₂CO ₃(10.6 g, 77.05 mmol, 3 equiv.) in methanol (80 mL) and H ₂O (40 mL) was stirred at room temperature for 5 h. The reaction was treated with water (500 mL), and the mixture was extracted with dichloromethane (3×500 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/1) to obtain 7 g (4 R)-4-methyl-5-[(6-nitro-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]pentan-1-ol (INT-B12-2) (93%). LCMS: m/z (ESI), [M+H] ⁺=294.15. ¹H NMR (DMSO-d ₆,400 MHz) δ 0.83-0.88 (3 H, m), 1.07-1.11 (1 H, m), 1.22-1.51 (3 H, m), 1.57-1.64 (1 H, m), 2.59 (2 H, t), 2.88-2.92 (3 H, m), 3.10-3.20 (1 H, m), 3.30-3.33 (2 H, m), 3.87 (2H, s), 4.37 (1 H, s), 6.56 (1 H, d), 6.69 (1 H, t), 7.26-7.37 (1 H, m), 7.70 (1 H, d). Step 3. 5-{[(2 RPreparation of tert-butyl 5-hydroxy-2-methylpentyl]amino}-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate (INT-B12-3). (4 RA mixture of )-4-methyl-5-[(6-nitro-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]pentan-1-ol (8 g, 27.27 mmol, 1 equiv), trimethylamine (5.5 g, 54.54 mmol, 2 equiv) and di-tert-butyl dicarbonate (7.1 g, 32.72 mmol, 1.2 equiv) in dichloromethane (100 mL) was stirred at room temperature for 2 h. The reaction was quenched with water (300 mL), and the mixture was extracted with dichloromethane (3×300 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/1) to give 6.5 g of 5-{[(2 R)-5-hydroxy-2-methylpentyl]amino}-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (INT-B12-3) (60%). LCMS: m/z (ESI), [M+H] ⁺=394.20. ¹H NMR (DMSO-d ₆400 MHz) δ 0.84 (3H, d), 1.03-1.17 (1H, m), 1.22-1.45 (2H, m), 1.45 (9H, s), 1.61 (1H, q), 2.75 (2H, t), 2.93-2.97 (1H, m), 3.08-3.12 (1H, m), 3.30-3.33 (2H, m), 3.51 (2H, t), 4.36 (1H, t), 4.52 (2H, s), 6.73 (1H, d), 6.83 (1H, s), 7.80 (1H, d) Step 4. 5-{[(2 RPreparation of tert-butyl 5-({4-[4-(methoxycarbonyl)-6-methylpyridin-2-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate (INT-B12-4). In a nitrogen atmosphere at 0 ° C, 5-{[(2 RTo a stirred mixture of tert-butyl 2-(5-hydroxy-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (1 g, 2.54 mmol, 1 eq.) and triphenylphosphine (2 g, 7.62 mmol, 3 eq.) in tetrahydrofuran (20 mL) were added methyl 2-(5-hydroxy-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (M1, 691 mg, 2.79 mmol, 1.1 eq.) and diisopropyl azodicarboxylate (1.5 g, 7.62 mmol, 3 eq.). The mixture was stirred at room temperature for 2 h. The reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×80 mL). The combined organic layers were washed with brine (3×80 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (2/3) to obtain 900 mg of 5-{[(2 R)-5-({4-[4-(methoxycarbonyl)-6-methylpyridin-2-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (INT-B12-4) (57%). LCMS: m/z (ESI), [M+H] ⁺=623.30. Step 5. 6-amino-5-{[(2 R)-5-({4-[4-(methoxycarbonyl)-6-methylpyridin-2-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (INT-B12-5). 5-{[(2 RA mixture of tert-butyl 5-({4-[4-(methoxycarbonyl)-6-methylpyridin-2-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate (500 mg, 0.80 mmol, 1 eq.) and Pd/C (10%, 30 mg) in methanol (10 mL) was stirred under hydrogen atmosphere for 1 h. The resulting mixture was filtered, and the filter cake was washed with methanol (3×50 mL). The resulting solution was concentrated under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (10/1) to give 360 mg of 6-amino-5-{[(2 R)-5-({4-[4-(methoxycarbonyl)-6-methylpyridin-2-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (INT-B12-5) (76%). LCMS: m/z (ESI), [M+H] ⁺=593.40. Step 6. 2-(5-{[(4 RPreparation of methyl pyridine-4-carboxylate (INT-B12-6). 6-amino-5-{[(2 RA mixture of tert-butyl 5-({4-[4-(methoxycarbonyl)-6-methylpyridin-2-yl]-2-methylpyrazol-3-yl}oxy)-2-methylpentyl]amino}-3,4-dihydro-1H-isoquinoline-2-carboxylate (350 mg, 0.59 mmol, 1 equiv) and BrCN (75 mg, 0.71 mmol, 1.2 equiv) in dichloromethane (4 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (60 mL), and the mixture was extracted with dichloromethane (3×60 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (11/1) to give 300 mg of 2-(5-{[(4 R)-4-{[2-amino-7-(tert-butoxycarbonyl)-6H,8H,9H-imidazo[4,5-f]isoquinolin-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid methyl ester (INT-B12-6) (82%). LCMS: m/z (ESI), [M+H] ⁺=618.35. Step 7. 2-(5-{[(4 RPreparation of 2-(5-{[(4 R)-4-{[2-amino-7-(tert-butoxycarbonyl)-6H,8H,9H-imidazo[4,5-f]isoquinolin-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid methyl ester (290 mg, 0.47 mmol, 1 eq.) and LiOH (30 mg, 0.70 mmol, 1.5 eq.) in tetrahydrofuran/H ₂The mixture in 400 mL/1 mL was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. The residue was purified by C18 flash chromatography using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 900 mg of 2-(5-{[(4 R)-4-{[2-amino-7-(tert-butoxycarbonyl)-6H,8H,9H-imidazo[4,5-f]isoquinolin-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B12-7) (71%). LCMS: m/z (ESI), [M+H] ⁺=604.30. Step 8. (11 RPreparation of tert-butyl ester (INT-B12-8) of 5,11,30-trimethyl-27-oxo-7-oxa-4,5,13, 18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14, 23}.0^{15,20}]tri-dodeca-1(31),2(6),3,14,20,22,24,28(32),29-nonene-18-carboxylate.R)-4-{[2-amino-7-(tert-butoxycarbonyl)-6H,8H,9H-imidazo[4,5-f]isoquinolin-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (200 mg, 0.33 mmol, 1 equivalent), N,N-Diisopropylethylamine (128 mg, 0.99 mmol, 3 equiv.) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)urea hexafluorophosphate (252 mg, 0.66 mmol, 2 equiv.) in dioxane (5 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (60 mL), and the mixture was extracted with dichloromethane (3×60 mL). The combined organic layers were washed with brine (3×40 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC eluting with dichloromethane/methanol (15/1) to give 160 mg (11 R)-5,11,30-trimethyl-27-dioxo-7-dioxa-4,5,13, 18,24,26,31-heptaazahexacyclic [26.3.1.0^{2,6}.0^{13,25}.0^{14, 23}.0^{15,20}]triacontidine-1(31),2(6),3,14,20,22,24,28(32),29-nonene-18-carboxylic acid tert-butyl ester (INT-B12-8) (82%). LCMS: m/z (ESI), [M+H] ⁺=586.30. Step 9. Preparation of (11R)-5,11,30-trimethyl-7-oxa-4,5,13,18,24,26, 31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15, 20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one (INT-B12-9). At room temperature, (11 RTo a stirred mixture of tert-butyl 5,11,30-trimethyl-27-oxo-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontria-1(31),2(6),3,14,20,22,24,28(32),29-nonene-18-carboxylate (120 mg, 0.21 mmol, 1 equiv) in 1,4-dioxane (0.5 mL) was added HCl solution (3 mL, 4 M in 1,4-dioxane). The mixture was stirred at room temperature for 2 h. The resulting mixture was treated with saturated NaHCO₃(aqueous solution) (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×70 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure to give 99 mg (11 R)-5,11,30-trimethyl-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one (INT-B12-9) (99%). This material was used in the next step without purification. LCMS: m/z (ESI), [M+H] ⁺=486.30. Step 10. (11 R)-18-[2-(dimethylamino)ethyl]-5,11,30-trimethyl-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclic [26.3.1.0^{2,6}. 0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14, 20,22,24,28(32),29-nonan-27-one (Example B12). At room temperature, to (11 R)-5,11,30-trimethyl-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one (99 mg, 0.20 mmol, 1 equivalent) and trimethylamine (62 mg, 0.61 mmol, 3 equivalents) in N,N-To the stirred mixture in dimethylformamide (5 mL), (2-bromoethyl)dimethylamine (56 mg, 0.37 mmol, 1.8 equiv) and KI (10 mg, 0.06 mmol, 0.3 equiv) were added. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (50 mL), and the mixture was extracted with dichloromethane (3×60 mL). The combined organic layers were washed with brine (3×40 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (20/1). The product was purified by prep-HPLC using an XBridge Prep OBD C18 column containing 10 mmol/L NH₄HCO ₃The product was further purified using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 9.3 mg (11 R)-18-[2-(dimethylamino)ethyl]-5,11,30-trimethyl-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one (Example B12) (8%). LCMS: m/z (ESI), [M+H] ⁺=557.30. ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.85 (3H, d), 1.41-1.53 (1H, m), 1.77-1.92 (1H, m), 1.95-2.08 (1H, m), 2.19 (6H, s), 2.21-2.29 (1H, m), 2.49-2.61 (5H, m), 2.72-2.86 (2H, m), 2.88-3.02 (1H, m), 3.10-3.27 (2H, m), 3.60-3.70 (2H, m), 3.73 (3H, s), 3.96-4.02 (1H, m), 4.22-4.28 (4H, m), 6.95 (1H, d), 7.39 (1H, d), 7.57 (1H, s), 7.93 (1H, s), 8.36 (1H, d), 12.75 (1H, s). Example B13 ( R)-11,26,7-trimethyl-57-(oxacyclobutane-3-yl)-56,57,58,59-tetrahydro-11H,51H-11-oxa-4-aza-5(2,1)-imidazo[4,5-f]isoquinoline-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one Step 1. (11 R)-11,26,7-trimethyl-57-(oxacyclobutane-3-yl)-56, 57,58,59-tetrahydro-11H,51H-11-oxa-4-aza-5(2,1)-imidazo[4,5-f]isoquinoline-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecane-3-one (Example B13). (11 RA mixture of 5,11,30-trimethyl-7-oxa-4,5,13,18, 24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontria-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one (INT-B12-9, 40 mg, 0.08 mmol, 1 eq) in dichloromethane (2 mL) was treated with 3-oxacyclobutanone (12 mg, 0.16 mmol, 2 eq) and trimethylamine (17 mg, 0.16 mmol, 2 eq) under nitrogen atmosphere at room temperature for 0.5 min. h, followed by addition of NaBH(AcO) at 0°C ₃(52 mg, 0.25 mmol, 3 equiv.). The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water (20 mL), and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×20 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 10.5 mg (11 R)-5,11,30-trimethyl-18-(oxacyclobutane-3-yl)-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one (Example B13) (22%). LCMS: m/z (ESI), [M+H] ⁺=542.20. ¹H NMR (DMSO- d ₆, 400 MHz) δ 0.86 (3H, d), 1.38-1.53 (1H, m), 1.79-1.93 (1H, m), 1.96-2.06 (1H, m), 2.16-2.28 (1H, m), 2.58 (3H, s), 2.58-2.73 (3H, m), 2.90-3.02 (1H, m), 3.15-3.26 (1H, m), 3.45-3.64 (3H, m), 3.73 (3H, s), 3.97-4.01 (1H, m), 4.14-4.38 (3H, m), 4.56 (2H, t), 4.65 (2H, t), 6.96 (1H, d), 7.41 (1H, d), 7.58 (1H, s), 7.93 (1H, s), 8.39 (1H, s), 12.78 (1H, s). Example B14 30-Methyl-11-oxa-8,9,17,24,26,31-hexaazahexacyclo[26.3.1.0^{2,10}.0^{3,8}.0^{17,25}.0^{18,23}]triacontac-1(31),2,4,6,9,18,20,22,24,28(32),29-undecane-27-one Step 1. Preparation of 1-(5-bromopentyl)-1,3-benzodiazol-2-amine (INT-B14-1). 2-aminobenzimidazole (4 g, 30.04 mmol, 1 equivalent), K ₂CO ₃A mixture of (12.46 g, 90.12 mmol, 3 equiv.) and 1,5-dibromopentane (27.63 g, 120.16 mmol, 4 equiv.) in acetonitrile (80 mL) was stirred at 60 °C for 5 h. The mixture was cooled to room temperature. The reaction was quenched with water (500 mL), and the mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (3×500 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using dichloromethane/methanol (10/1) to give 4 g of 1-(5-bromopentyl)-1,3-benzodiazol-2-amine (INT-B14-1) (47%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=283.95. Step 2. Preparation of 1-[5-({3-bromopyrazolo[1,5-a]pyridin-2-yl}oxy)pentyl]-1,3-benzodiazol-2-amine (INT-B14-2). 1-(5-bromopentyl)-1,3-benzodiazol-2-amine (3.97 g, 14.08 mmol, 1.5 equivalents), 3-bromopyrazolo[1,5-a]pyridin-2-ol (2 g, 9.38 mmol, 1.00 equivalents) and K ₂CO ₃(2.59 g, 18.77 mmol, 2 equiv.) in acetonitrile (80 mL) was stirred at 60 °C for 2 h. The mixture was cooled to room temperature. The reaction was quenched with water (500 mL), and the mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (3×500 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by C18 FLASH chromatography using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to dryness to give 2.3 g of 1-[5-({3-bromopyrazolo[1,5-a]pyridin-2-yl}oxy)pentyl]-1,3-benzodiazol-2-amine (INT-B14-2) (39%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=414.20. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 1.40-1.52 (2H, m), 1.63.175 (2H, m), 1.76-1.88 (2H, m), 3.92-4.03 (2H, m), 4.30 (2H, t), 6.37 (2H, s), 6.79-6.87 (2H, m), 6.88-6.94 (1H, m), 7.12 (2H, t), 7.26-7.39 (2H, m),8.54 (1H, d). Step 3. Preparation of 6-chloro-4-(methoxycarbonyl)pyridin-2-ylboronic acid) (M1-1). A mixture of bis(pinacol)diboron (1631.71 mg, 6.426 mmol, 1.5 eq) in methyl tert-butyl ether (20 mL) was warmed to 80 °C and stirred under nitrogen atmosphere for 0.5 h, then cooled to room temperature. To this mixture was added bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) (283.95 mg, 0.428 mmol, 0.1 eq) and 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine (229.95 mg, 0.857 mmol, 0.2 eq). The mixture was stirred at 25 °C for 0.5 h, then methyl 2-chloropyridine-4-carboxylate (735 mg, 4.284 mmol, 1 eq) was added. The reaction mixture was further stirred at 80°C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give 850 mg (crude) of 6-chloro-4-(methoxycarbonyl)pyridin-2-ylboronic acid (M1-1) as a brown oil. This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=216.05. Step 4. 2-(2-{[5-(2-amino-1,3-benzodiazol-1-yl)pentyl]oxy}pyrazolo[1,5-a]pyridin-3-yl)-6-chloropyridine-4-carboxylic acid methyl ester (INT-B14-3). Freshly prepared 6-chloro-4-(methoxycarbonyl)pyridin-2-ylboronic acid (850 mg crude, about 2.5 equivalents), 1-[5-({3-bromopyrazolo[1,5-a]pyridin-2-yl}oxy)pentyl]-1,3-benzodiazol-2-amine (654 mg, 1.58 mmol, 1.00 equivalents), Cs ₂CO ₃(1543 mg, 4.73 mmol, 3 equivalents), Pd ₂(dba) ₃(144 mg, 0.15 mmol, 0.1 eq.) and bis(adamantan-1-yl)(butyl)phosphine (57 mg, 0.16 mmol, 0.1 eq.) in H ₂A mixture of 20% O (4 mL) and toluene (20 mL) was stirred at 80 °C under nitrogen atmosphere for 2 h. The mixture was cooled to room temperature. The reaction was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column using petroleum ether/ethyl acetate (1/3) to give 250 mg of methyl 2-(2-{[5-(2-amino-1,3-benzodiazol-1-yl)pentyl]oxy}pyrazolo[1,5-a]pyridin-3-yl)-6-chloropyridine-4-carboxylate (INT-B14-3) (31%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=505.15 Step 5. Preparation of 2-(2-{[5-(2-amino-1,3-benzodiazol-1-yl)pentyl]oxy}pyrazolo[1,5-a]pyridin-3-yl)-6-methylpyridine-4-carboxylic acid methyl ester (INT-B14-4). 2-(2-{[5-(2-amino-1,3-benzodiazol-1-yl)pentyl]oxy}pyrazolo[1,5-a]pyridin-3-yl)-6-chloropyridine-4-carboxylic acid methyl ester (140 mg, 0.27 mmol, 1 equivalent), trimethyl-1,3,5,2,4,6-trioxatriboborohexane (69 mg, 0.55 mmol, 2 equivalents), Pd(dppf)Cl ₂ ^.CH ₂Cl ₂(3 mg, 0.01 mmol, 0.2 equivalent), K ₂CO ₃(76 mg, 0.55 mmol, 2 eq.) and PCy ₃HBF ₄A mixture of (30 mg, 0.08 mmol, 0.3 equiv) in 1,4-dioxane (10 mL) was stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on Prep-TLC using dichloromethane/methanol (20/1) to give 80 mg of methyl 2-(2-{[5-(2-amino-1,3-benzodiazol-1-yl)pentyl]oxy}pyrazolo[1,5-a]pyridin-3-yl)-6-methylpyridine-4-carboxylate (INT-B14-4) (59%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=485.25. Step 6. Preparation of 2-(2-{[5-(2-amino-1,3-benzodiazol-1-yl)pentyl]oxy}pyrazolo[1,5-a]pyridin-3-yl)-6-methylpyridine-4-carboxylic acid (INT-B14-5). 2-(2-{[5-(2-amino-1,3-benzodiazol-1-yl)pentyl]oxy}pyrazolo[1,5-a]pyridin-3-yl)-6-methylpyridine-4-carboxylic acid methyl ester (70 mg, 0.14 mmol, 1 equivalent) and LiOH ^.H ₂A mixture of O (18 mg, 0.43 mmol, 3 equiv.) in tetrahydrofuran (5 mL) and water (1.25 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 FLASH using water and acetonitrile as mobile phases. The fractions containing the desired compound were evaporated to dryness to give 30 mg of 2-(2-{[5-(2-amino-1,3-benzodiazol-1-yl)pentyl]oxy}pyrazolo[1,5-a]pyridin-3-yl)-6-methylpyridine-4-carboxylic acid (INT-B14-5) (44%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=471.30. Step 7. Preparation of 30-methyl-11-oxa-8,9,17,24,26,31-hexaazahexacyclo[26.3.1.0^{2,10}.0^{3,8}.0^{17,25}.0^{18,23}]triacontidine-1(31),2,4,6,9,18,20,22,24,28(32),29-undecane-27-one (Example B14). 2-(2-{[5-(2-amino-1,3-benzodiazol-1-yl)pentyl]oxy}pyrazolo[1,5-a]pyridin-3-yl)-6-methylpyridine-4-carboxylic acid (25 mg, 0.05 mmol, 1 equivalent), N,N-Diisopropylethylamine (20 mg, 0.15 mmol, 3 equivalents) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (30 mg, 0.08 mmol, 1.5 equiv.) in 1,4-dioxane (10 mL) was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC using an XBridge Prep OBD C18 column containing 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O was used for purification with water and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 9.4 mg of 30-methyl-11-oxa-8,9,17,24,26,31-hexaazahexacyclo[26.3.1.0^{2,10}.0^{3,8}.0^{17,25}.0^{18,23}]triacontac-1(31),2,4,6,9,18,20,22,24,28(32),29-undecane-27-one (Example B14) (39%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=453.20. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 1.91-2.12 (6H, m), 2.64 (3H, s), 4.23 (2H, t), 4.48 (2H, t), 6.91 (1H, t), 7.20-7.33 (2H, m), 7.42 (1H, t), 7.49 (1H, s), 7.55 (2H, d), 8.57-8.67 (2H, m), 9.04 (1H, s), 12.66 (1H, s). Example B15 30-Chloro-11-oxo-8,9,17,24,26,31-hexaazahexacyclo[26.3.1.0^{2,10}.0^{3,8}.0^{17,25}. 0^{18,23}]triacontidine-1(31),2,4,6,9,18,20,22,24,28(32),29-undecane-27-one Step 1. Preparation of 2-(2-{[5-(2-amino-1,3-benzodiazol-1-yl)pentyl]oxy}pyrazolo[1,5-a]pyridin-3-yl)-6-chloropyridine-4-carboxylic acid (INT-B15-1). 2-(2-{[5-(2-amino-1,3-benzodiazol-1-yl)pentyl]oxy}pyrazolo[1,5-a]pyridin-3-yl)-6-chloropyridine-4-carboxylic acid methyl ester (330 mg, 0.65 mmol, 1 equivalent) and LiOH ^.H2O (41 mg, 0.98 mmol, 1.5 equiv.) in tetrahydrofuran (10 mL) and H ₂The mixture in 20% O (2.5 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃of water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 134 mg of 2-(2-{[5-(2-amino-1,3-benzodiazol-1-yl)pentyl]oxy}pyrazolo[1,5-a]pyridin-3-yl)-6-chloropyridine-4-carboxylic acid (INT-B15-1) (41%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=491.15. Step 2. Preparation of 30-chloro-11-oxa-8,9,17,24,26,31-hexaazahexacyclo[26.3.1.0^{2,10}.0^{3,8}.0^{17,25}.0^{18,23}]triacontidine-1(31),2,4,6,9,18,20,22,24,28(32),29-undecane-27-one (Example B15). 2-(2-{[5-(2-amino-1,3-benzodiazol-1-yl)pentyl]oxy}pyrazolo[1,5-a]pyridin-3-yl)-6-chloropyridine-4-carboxylic acid (120 mg, 0.24 mmol, 1 equivalent), N,N-Diisopropylethylamine (94 mg, 0.73 mmol, 3 equiv.) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (139 mg, 0.36 mmol, 1.5 equiv) in 1,4-dioxane (10 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by prep-HPLC using an XBridge Prep OBD C18 column containing 10 mmol/L NH₄HCO ₃The mixture was purified by using water and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to obtain 3.9 mg of 30-chloro-11-oxa-8,9,17,24,26,31-hexaazahexacyclo[26.3.1.0^{2,10}.0^{3,8}.0^{17,25}.0^{18,23}]triacontidine-1(31),2,4,6,9,18,20,22,25, 28(32),29-undecane-27-one (Example B15) (3%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=473.10. ¹H NMR (DMSO-d ₆ , 400 MHz) δ 1.93-2.13 (6H, m), 4.24 (2H, t), 4.49 (2H, t), 6.96-7.02 (1H, m), 7.22-7.35 (2H, m), 7.48-7.61 (4H, m), 8.44 (1H, d), 8.67 (1H, d), 9.17 (1H, d), 12.76 (1H, s). Example B16 5,30-dimethyl-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one Step 1. Preparation of tert-butyl 5-((5-((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)pentyl)amino)-6-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate (INT-B16-1). To a stirred mixture of tert-butyl 5-[(5-hydroxypentyl)amino]-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.6 g, 0.79 mmol, 1 eq), triphenylphosphine (3 g, 2.37 mmol, 3 eq) and methyl 2-(5-hydroxy-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (1 g, 0.79 mmol, 1 eq) in tetrahydrofuran (50 mL) was added diisopropyl azodicarboxylate (2.5 g, 1.19 mmol, 3 eq) under nitrogen atmosphere at 0°C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h. The reaction was quenched with water (50 mL) and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (1/1) to give 900 mg of 5-{[5-({4-[4-(methoxycarbonyl)-6-methylpyridin-2-yl]-2-methylpyrazol-3-yl}oxy)pentyl]amino}-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (INT-B16-1) (36%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=609.20. Step 2. Preparation of tert-butyl 6-amino-5-((5-((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)pentyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (INT-B16-2). A mixture of tert-butyl 5-{[5-({4-[4-(methoxycarbonyl)-6-methylpyridin-2-yl]-2-methylpyrazol-3-yl}oxy)pentyl]amino}-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate (900 mg, 1.48 mmol, 1 eq) and Pd/C (15.73 mg, 0.148 mmol, 0.1 eq) in methanol (10 mL) was stirred under hydrogen atmosphere at room temperature for 1 h. The resulting mixture was filtered, and the filter cake was washed with methanol (3×10 mL). The resulting solution was concentrated under reduced pressure to give 570 mg of tert-butyl 6-amino-5-((5-((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)pentyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (INT-B16-2) (67%) as a yellow oil. The crude product mixture was used directly in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺=579.25. Step 3. Preparation of tert-butyl 2-amino-1-(5-((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)pentyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-f]isoquinoline-7-carboxylate (INT-B16-3). A mixture of tert-butyl 6-amino-5-{[5-({4-[4-(methoxycarbonyl)-6-methylpyridin-2-yl]-2-methylpyrazol-3-yl}oxy)pentyl]amino}-3,4-dihydro-1H-isoquinoline-2-carboxylate (570 mg, 0.99 mmol, 1 eq) and BrCN (115 mg, 1.08 mmol, 1.1 eq) in methanol (20 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water (20 mL), and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane/methanol (20/1) to give 500 mg of methyl 2-[5-({5-[2-amino-7-(tert-butoxycarbonyl)-6H,8H,9H-imidazo[4,5-f]isoquinolin-1-yl]pentyl}oxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (INT-B16-3) (84%) as an off-white solid. LCMS: m/z (ESI), [M+H] ⁺=604.20. Step 4. Preparation of 2-(5-((5-(2-amino-7-(tert-butoxycarbonyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-f]isoquinolin-1-yl)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid (INT-B16-4). 2-[5-({5-[2-amino-7-(tert-butoxycarbonyl)-6H,8H,9H-imidazo[4,5-f]isoquinolin-1-yl]pentyl}oxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid methyl ester (500 mg, 0.828 mmol, 1 equivalent) and LiOH ^.H ₂O (59.50 mg, 2.484 mmol, 3 equiv.) in MeOH (10 mL) and H ₂The mixture in 4% O (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h and concentrated under reduced pressure. The residue was purified by prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 150 mg of 2-[5-({5-[2-amino-7-(tert-butoxycarbonyl)-6H,8H,9H-imidazo[4,5-f]isoquinolin-1-yl]pentyl}oxy)-1-methylpyrazol-4-yl]pyridine-4-carboxylic acid (INT-B16-4) (31%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=590.25. Step 5. Preparation of tert-butyl 5,30-dimethyl-18-(tert-butoxycarbonyl)-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}. 0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20, 22,24,28(32),29-nonan-27-one (INT-B16-5). 2-[5-({5-[2-amino-7-(tert-butoxycarbonyl)-6H,8H,9H-imidazo[4,5-f]isoquinolin-1-yl]pentyl}oxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid (500 mg, 0.85 mmol, 1 equivalent), N,N-Diisopropylethylamine (219 mg, 1.7 mmol, 2 equivalents) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)urea hexafluorophosphate (644.8 mg, 1.7 mmol, 2 equiv.) in dioxane (20 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (10 mL), and the mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (3×10 mL), purified by anhydrous Na ₂SO ₄The residue was purified by silica gel column chromatography using dichloromethane/methanol (10/1) to give 200 mg of 5,30-dimethyl-18-(tert-butoxycarbonyl)-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24, 28(32),29-nonan-27-one (INT-B16-5) (41%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=572.30. ¹H NMR (CDCl ₃, 400 MHz) δ 1.64 (17H, s), 1.95 (2H, d), 2.10-2.15 (2H, m), 2.68 (3H, s), 3.24 (2H, s), 3.80 (5H, d), 4.20-4.29 (2H, m), 4.38-4.47 (2H, m), 4.72 (2H, s), 7.03 (1H, d), 7.22 (1H, d), 7.69 (1H, s), 8.21 (1H, s), 8.49 (1H, s), 12.00 (1H, s). Step 6. Preparation of 5,30-dimethyl-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one (Example B16). 1 ¹,2 ⁶-Dimethyl-3-oxo-5- ⁶,5 ⁷,5 ⁸,5 ⁹-Tetrahydrogen-1 ¹H,5 ¹H-11-oxa-4-aza-5(2,1)-imidazo[4,5-f]isoquinoline-2(2,4)-pyridine-1(4,5)-pyrazole cycloundecane-5 ⁷A mixture of tert-butyl formate (30 mg, 0.090 mmol, 1 eq.) and HCl in 1,4-dioxane (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was washed with saturated NaHCO₃(aqueous solution) was adjusted to pH 7, and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×10 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O was used for purification with water and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 1.5 mg of 5,30-dimethyl-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one (Example B16) (0.37%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=472.35. ¹H NMR (DMSO, 400 MHz) δ 1.74-1.82 (2H, m), 1.96-2.10 (4H, m), 2.55 (3H, s), 3.02-3.16 (4H, m), 3.72 (3H, s), 3.95 (2H, s), 4.21 (2H, t), 4.35 (1H, d), 6.91 (1H, d), 7.33 (1H, d), 7.56 (1H, s), 7.93 (1H, s), 8.40 (1H, s). Example B17 5,30-Dimethyl-18-(oxacyclobutane-3-yl)-7-oxa-4,5,13,18,24,26, 31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15, 20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one Step 1. Preparation of 5,30-dimethyl-18-(oxacyclobutan-3-yl)-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24, 28(32),29-nonan-27-one (Example B17). A stirred mixture of (25E)-5,30-dimethyl-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontria-1(31),2(6),3,14,20,22,25,28(32),29-nonan-27-one (Example B16, 30 mg, 0.06 mmol, 1 eq), 3-oxacyclobutanone (9.17 mg, 0.12 mmol, 2 eq) and trimethylamine (12.88 mg, 0.12 mmol, 2 eq) in dichloromethane (5 mL) was stirred under nitrogen atmosphere at room temperature for 30 minutes. Add NaBH(AcO) to the above mixture at room temperature ₃(40.45 mg, 0.18 mmol, 3 equiv.). The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched with water (10 mL), and the mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (3×10 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃.H ₂O was used as the mobile phase for purification with water and acetonitrile. The fractions containing the desired compound were evaporated to dryness to give 5.8 mg of 5,30-dimethyl-18-(oxacyclobutane-3-yl)-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one (Example B17) (17%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=528.20. ¹H NMR (DMSO- d ₆, 400 MHz) δ 1.71-1.85 (2H, m), 1.96-2.13 (4H, m), 2.56 (3H, s), 2.59-2.70 (2H, m), 3.22-3.30 (2H, m), 3.54 (2H, s), 3.57-3.65 (1H, m), 3.73 (3H, s), 4.21 (1H, t), 4.33 (2H, t), 4.55 (2H, t), 4.65 (2H, t), 6.96 (1H, d), 7.46 (1H, d), 7.57 (1H, s), 7.76 (1H, d), 7.98 (1H, s), 8.40 (1H, s). Example B18 5,30-Dimethyl-17-(oxacyclobutane-3-yl)-7-oxa-4,5,13,17,24,26, 31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}. 0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one Step 1. Preparation of 2-(2-bromo-5-fluorophenyl)ethylamine (INT-B18-1). 2-(2-bromo-5-fluorophenyl)acetonitrile (10 g, 46.72 mmol, 1 equivalent) and BH ₃-Me ₂A mixture of S (10.65 g, 140.16 mmol, 3 equiv.) in tetrahydrofuran (100 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (800 mL) at 0 °C, and the mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by silica gel chromatography using dichloromethane/methanol (10/1) to give 8 g of 2-(2-bromo-5-fluorophenyl)ethylamine (Example INT-B18-1) (79%) as an off-white solid. LCMS: m/z (ESI), [M+H] ⁺= 220.10. Step 2. N-[2-(2-bromo-5-fluorophenyl)ethyl]-2,2,2-trifluoroacetamide (INT-B18-2) Preparation. A mixture of 2-(2-bromo-5-fluorophenyl)ethylamine (5 g, 23 mmol, 1 eq.), trifluoroacetic anhydride (5.3 g, 25 mmol, 1.1 eq.) and trimethylamine (4.64 g, 45.86 mmol, 2 eq.) in dichloromethane (100 mL) was stirred at 0 °C for 2 h under a nitrogen atmosphere. The reaction was quenched with water (200 mL), and the mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine (3×200 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (10/1) to obtain 4 g of white solid.N-[2-(2-bromo-5-fluorophenyl)ethyl]-2,2,2-trifluoroacetamide (INT-B18-2) (56%). ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.90-2.96 (2H, m), 3.45-3.50 (2H, m), 7.04-7.26 (2H, m), 7.65 (1H, d), 9.55 (1H, s). Step 3. Preparation of 1-(5-bromo-8-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone (INT-B18-3). N-[2-(2-bromo-5-fluorophenyl)ethyl]-2,2,2-trifluoroacetamide (6.8 g, 21.65 mmol, 1 equivalent) and paraformaldehyde (28.6 g, 64.95 mmol, 3 equivalents) in H ₂SO ₄A mixture of (25 ml) and AcOH (30 ml) was stirred at 0 °C overnight under nitrogen atmosphere. The reaction was quenched with water (200 mL) at 0 °C and adjusted to pH 7 with NaOH. The mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine (3×200 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (1/1) to give 5 g of 1-(5-bromo-8-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone (71%) as an off-white solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.85-2.92 (2H, m), 3.85-3.95 (2H, m), 4.77 (2H, d), 7.17 (1H, d), 7.63 (1H, d). Step 4. Preparation of 1-(5-bromo-8-fluoro-7-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone (INT-B18-4). 1-(5-bromo-8-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone (6.46 g, 19.81 mmol, 1 equivalent) and KNO ₃(2 g, 19.81 mmol, 1 equivalent) in H ₂SO ₄The mixture in (20 mL) was stirred at 0 °C for 0.5 h under nitrogen atmosphere. The reaction was quenched with water (200 mL) and adjusted to pH 9 with NaOH. The mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine (3×200 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (3/1) to give 775 mg of 1-(5-bromo-8-fluoro-7-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone (INT-B18-4) (12%) as a brownish yellow solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ 2.95-3.02 (2H, m), 3.81-3.96 (2H, m), 4.75-4.90 (2H, m), 8.07 (1H, t). Step 5. Preparation of 5-[(5-bromo-7-nitro-1,2,3,4-tetrahydroisoquinolin-8-yl)amino]pentan-1-ol (INT-B18-5). 1-(5-bromo-8-fluoro-7-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone (4.6 g, 12.4 mmol, 1 equivalent), K ₂CO ₃A mixture of (5.14 g, 37.2 mmol, 3 equiv.) and 5-aminopentanol (1.53 g, 14.88 mmol, 1.2 equiv.) in acetonitrile (50 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10/1) to give 600 mg of 5-[(5-bromo-7-nitro-1,2,3,4-tetrahydroisoquinolin-8-yl)amino]pentan-1-ol (INT-B18-5) (14%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=360.00. Step 6. Preparation of tert-butyl 5-bromo-8-((5-hydroxypentyl)amino)-7-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate (INT-B18-6). A mixture of 5-[(5-bromo-7-nitro-1,2,3,4-tetrahydroisoquinolin-8-yl)amino]pentan-1-ol (650 mg, 1.81 mmol, 1 eq.), di-tert-butyl dicarbonate (475 mg, 2.18 mmol, 1.2 eq.) and trimethylamine (367 mg, 3.63 mmol, 2 eq.) in dichloromethane (20 mL) was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 450 mg of tert-butyl 5-bromo-8-((5-hydroxypentyl)amino)-7-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate (INT-B18-6) (54%) as a yellow oil. LCMS: m/z (ESI), [M+H] ⁺=460.25. Step 7. Preparation of tert-butyl 5-bromo-8-{[5-({4-[4-(methoxycarbonyl)-6-methylpyridin-2-yl]-2-methylpyrazol-3-yl}oxy)pentyl]amino}-7-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate (INT-B18-7). To a stirred mixture of tert-butyl 5-bromo-8-((5-hydroxypentyl)amino)-7-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate (450 mg, 0.98 mmol, 1 eq.), triphenylphosphine (772 mg, 2.95 mmol, 3 eq.) in tetrahydrofuran (20 mL) under nitrogen atmosphere at 0° C. was added methyl 2-(5-hydroxy-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (267 mg, 1.08 mmol, 1.1 eq.) and diisopropyl azodicarboxylate (595 mg, 2.95 mmol, 3 eq.). The reaction mixture was stirred at 60° C. for 3 h under nitrogen atmosphere and cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by C18 FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to dryness to give 350 mg of 5-bromo-8-{[5-({4-[4-(methoxycarbonyl)-6-methylpyridin-2-yl]-2-methylpyrazol-3-yl}oxy)pentyl]amino}-7-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (INT-B18-7) (52%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=689.05. Step 8. Preparation of tert-butyl 7-amino-8-((5-((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)pentyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (INT-B18-8). A mixture of tert-butyl 5-bromo-8-{[5-({4-[4-(methoxycarbonyl)-6-methylpyridin-2-yl]-2-methylpyrazol-3-yl}oxy)pentyl]amino}-7-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate (330 mg, 0.48 mmol, 1 eq) and Pd/C (5.1 mg, 0.048 mmol, 0.1 eq) in methanol (20 mL) was stirred under hydrogen atmosphere at room temperature for 1 h. The resulting mixture was filtered and the filter cake was washed with methanol (3×30 mL). The resulting solution was concentrated under reduced pressure to give 172 mg of tert-butyl 7-amino-8-((5-((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)pentyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (INT-B18-8) as a yellow oil. This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=579.25. Step 9. Preparation of 2-[5-({5-[2-amino-5-bromo-8-(tert-butoxycarbonyl)-6H,7H,9H-imidazo[4,5-h]isoquinolin-1-yl]pentyl}oxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid methyl ester (INT-B18-9). A mixture of tert-butyl 7-amino-8-((5-((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)pentyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (135 mg, about 0.21 mmol, about 1 equivalent) and BrCN (33 mg, 0.31 mmol, 1.5 equivalents) in dichloromethane (5 mL) was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched with water (20 mL), and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane/methanol (10/1) to give 90 mg of 2-[5-({5-[2-amino-5-bromo-8-(tert-butoxycarbonyl)-6H,7H,9H-imidazo[4,5-h]isoquinolin-1-yl]pentyl}oxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid methyl ester (INT-B18-9) (64%) as a light yellow oil. LCMS: m/z (ESI), [M+H] ⁺=604.25. Step 10. Preparation of 2-[5-({5-[2-amino-8-(tert-butoxycarbonyl)-6H,7H,9H-imidazo[4,5-h]isoquinolin-1-yl]pentyl}oxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid (INT-B18-10). 2-[5-({5-[2-amino-5-bromo-8-(tert-butoxycarbonyl)-6H,7H,9H-imidazo[4,5-h]isoquinolin-1-yl]pentyl}oxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylate (90 mg, 0.15 mmol, 1 equivalent) and LiOH ^.H ₂O (19 mg, 0.45 mmol, 3 equiv.) in MeOH (2 ml) and H ₂The mixture in 400 μl (0.5 ml) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 50 mg of 2-[5-({5-[2-amino-8-(tert-butoxycarbonyl)-6H,7H,9H-imidazo[4,5-h]isoquinolin-1-yl]pentyl}oxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid (INT-B18-10) (57%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=590.50. Step 11. Preparation of tert-butyl 5,30-dimethyl-27-oxo-7-oxa-4,5,13,17,24,26, 31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15, 20}]triacontidine-1(31),2(6),3,14,20,22,24,28(32),29-nonene-17-carboxylate (INT-B18-11). 2-[5-({5-[2-amino-8-(tert-butoxycarbonyl)-6H,7H,9H-imidazo[4,5-h]isoquinolin-1-yl]pentyl}oxy)-1-methylpyrazol-4-yl]-6-methylpyridine-4-carboxylic acid (35 mg, 0.05 mmol, 1 equivalent), N,N-Diisopropylethylamine (19.26 mg, 0.15 mmol, 3 equivalents) and N,N,N,N-Tetramethyl- OA mixture of -(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (58.03 mg, 0.15 mmol, 3 equiv.) in dioxane (2 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (10 mL), and the mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (3×10 mL), purified by anhydrous Na ₂SO ₄The residue was purified by silica gel column chromatography and eluted with dichloromethane/methanol (10/1) to give 30 mg of 5,30-dimethyl-27-oxo-7-oxa-4,5,13,17,24, 26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonene-17-carboxylic acid tert-butyl ester (INT-B18-11) (93%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=670.55. Step 12. Preparation of 5,30-dimethyl-7-oxa-4,5,13,17,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one (INT-B18-12). A mixture of tert-butyl 5,30-dimethyl-27-oxo-7-oxa-4,5,13, 17,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14, 23}.0^{15,20}]triacontria-1(31),2(6),3,14,20,22,24,28(32),29-nonene-17-carboxylate (30 mg, 0.05 mmol, 1 eq.) in trifluoroacetic acid (1 mL) and dichloromethane (2 mL) was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column and a column containing 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O was used for purification with water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 2 mg of 5,30-dimethyl-7-oxa-4,5,13,17,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one (INT-B18-12) (8%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=472.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.79 (2H, s), 2.04 (4H, s), 2.56 (3H, s), 2.80 (2H, d), 2.97 (2H, t), 3.73 (3H, s), 4.20-4.29 (4H, m), 4.32 (2H, s), 6.95 (1H, d), 7.34 (1H, d), 7.57 (1H, d), 7.92 (1H, s), 8.39 (1H, s). Step 13. Preparation of 5,30-dimethyl-17-(oxacyclobutan-3-yl)-7-oxa-4,5, 13,17,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24, 28(32),29-nonan-27-one (Example B18). A mixture of 5,30-dimethyl-7-oxa-4,5,13,17,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontria-1(31),2(6),3,14,20, 22,24,28(32),29-nonan-27-one (7 mg, 0.015 mmol, 1 eq), 3-oxacyclobutanone (1.28 mg, 0.018 mmol, 1.2 eq) and trimethylamine (3 mg, 0.030 mmol, 2 eq) in dichloromethane (2 mL) was stirred under nitrogen atmosphere at room temperature for 30 min. Sodium acetoxyborohydride (9.44 mg, 0.045 mmol, 3 equiv.) was added to the above mixture in portions at room temperature. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched with water (10 mL), and the mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (3×10 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was passed through prep-HPLC using an XBridge Shield RP18 OBD column, using a HPLC-MS/HPLC-MS/HPLC-MS containing 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O was used for purification with water and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 1.8 mg of 5,30-dimethyl-17-(oxacyclobutane-3-yl)-7-oxa-4,5,13,17,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one (Example B18) (23%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=528.20. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.66-1.80 (2H, m), 1.86-2.11 (4H, m), 2.56 (3H, s), 2.87-2.98 (4H, m), 3.17 (2H, d), 3.73 (3H, s), 3.75-3.81 (1H, m), 4.04 (4H, s), 4.16-4.28 (4H, m), 4.61 (2H, t), 4.70 (2H, t), 7.01 (1H, d), 7.38 (1H, d), 7.57 (1H, s), 7.93 (1H, s), 8.40 (1H, s). Example B20 5,16,26-trimethyl-7-oxa-4,5,13,16,20,22,27-heptaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(27),2(6),3, 14(19),17,20,24(28),25-octaene-15,23-dione Step 1. Preparation of 4-methoxy-1-methyl-3-nitropyridin-2-one (INT-B20-1). 4-Hydroxy-3-nitro-1H-pyridin-2-one (10 g, 64.0 mmol, 1 equivalent), iodomethane (36.4 g, 256.2 mmol, 4 equivalents) and K ₂CO ₃(35.4 g, 256.2 mmol, 4 equivalents) in N,N-The mixture in dimethylformamide (100 mL) was stirred at 60 °C overnight under nitrogen atmosphere and cooled to room temperature. The reaction was quenched with water (500 mL), and the mixture was extracted with dichloromethane (3×500 mL). The combined organic layers were washed with brine (3×500 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by C18 FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to dryness to give 1600 mg of 4-methoxy-1-methyl-3-nitropyridin-2-one (INT-B20-1) (13%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=185.15. ¹H NMR (DMSO-d ₆, 400 MHz) δ 3.48 (3H, s), 3.96 (3H, s), 6.50 (1H, d), 8.03 (1H, d). Step 2. Preparation of 4-amino-1-methyl-3-nitropyridine-2-one (INT-B20-2). 4-Methoxy-1-methyl-3-nitropyridine-2-one (800 mg, 4.34 mmol, 1 equivalent) and NH ₃The mixture in methanol (20 mL) was stirred at room temperature for 4 h under nitrogen atmosphere. The precipitated solid was collected by filtration and washed with methanol (3×40 mL) to obtain 630 mg of 4-amino-1-methyl-3-nitropyridin-2-one (INT-B20-2) (85%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=170.05. ¹H NMR (DMSO-d ₆, 400 MHz) δ 3.28 (3H, s), 5.87 (1H, d), 7.55 (1H, d), 8.03 (2H, s). Step 3. Preparation of 3,4-diamino-1-methylpyridin-2-one (INT-B20-3). A mixture of 4-amino-1-methyl-3-nitropyridin-2-one (1 g, 5.91 mmol, 1 eq.) and Pd/C (0.31 g, 2.91 mmol, 0.49 eq.) in methanol (30 mL) was stirred at room temperature for 4 h under hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with methanol (3×40 mL). The organic solution was concentrated under reduced pressure to give 900 mg of 3,4-diamino-1-methylpyridin-2-one (INT-B20-3) as a black solid. This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺= 140.10. Step 4. Preparation of 2-amino-5-methyl-3H-imidazo[4,5-c]pyridin-4-one (INT-B20-4). A mixture of 3,4-diamino-1-methylpyridin-2-one (INT-B20-3, 800 mg, 5.74 mmol, 1 eq.) and BrCN (730.71 mg, 6.89 mmol, 1.20 eq.) in ethanol (15 mL) was stirred at room temperature for 3 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude product mixture was used directly in the next step without further purification. LCMS: m/z (ESI), [M+H] ⁺=165.15. Step 5. Preparation of 2-amino-3-(5-bromopentyl)-5-methylimidazo[4,5-c]pyridin-4-one (INT-B20-5). 2-amino-5-methyl-3H-imidazo[4,5-c]pyridin-4-one (INT-B20-4, 0.8 g, 4.87 mmol, 1 equivalent), 1,5-dibromopentane (5.6 g, 24.36 mmol, 5 equivalents) and K ₂CO ₃A mixture of (1.68 g, 12.13 mmol, 2.49 equiv) in acetonitrile (15 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere and cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using ethyl acetate to give 230 mg of 2-amino-3-(5-bromopentyl)-5-methylimidazo[4,5-c]pyridin-4-one (INT-B20-5) (15%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=313.10. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.38-1.52 (2H, m), 1.53-1.65 (2H, m), 1.74-1.85 (2H, m), 3.07-3.20 (2H, m), 3.28 (3H, s), 3.48-3.56 (2H, m), 5.76 (1H, d), 6.39 (2H, s), 7.34 (1H, d). Step 6. Preparation of 2-{5-[(5-{2-amino-5-methyl-4-oxoimidazolo[4,5-c]pyridin-3-yl}pentyl)oxy]-1-methylpyrazol-4-yl}-6-methylpyridine-4-carboxylic acid methyl ester (INT-B20-6). 2-Amino-3-(5-bromopentyl)-5-methylimidazo[4,5-c]pyridin-4-one (350 mg, 1.11 mmol, 1 equivalent), 2-(5-hydroxy-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid methyl ester (M1, 303 mg, 1.23 mmol, 1.10 equivalent) and K ₂CO ₃(386 mg, 2.79 mmol, 2.5 equiv) in acetonitrile (5 mL) was stirred at 60 °C for 4 h under nitrogen atmosphere and then cooled to room temperature. The reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (3×60 mL). The combined organic layers were washed with brine (3×50 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by Prep-TLC using dichloromethane/methanol (15/1) to give 160 mg of 2-{5-[(5-{2-amino-5-methyl-4-oxoimidazolo[4,5-c]pyridin-3-yl}pentyl)oxy]-1-methylpyrazol-4-yl}-6-methylpyridine-4-carboxylic acid methyl ester (INT-B20-6) (29%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=480.15. Step 7. Preparation of 2-{5-[(5-{2-amino-5-methyl-4-oxoimidazolo[4,5-c]pyridin-3-yl}pentyl)oxy]-1-methylpyrazol-4-yl}-6-methylpyridine-4-carboxylic acid (INT-B20-7). 2-{5-[(5-{2-amino-5-methyl-4-oxoimidazolo[4,5-c]pyridin-3-yl}pentyl)oxy]-1-methylpyrazol-4-yl}-6-methylpyridine-4-carboxylic acid methyl ester (160 mg, 0.33 mmol, 1 equivalent) and LiOH ^.H ₂O (28 mg, 0.66 mmol, 2 equiv.) in THF (1 mL) and H ₂O (0.25 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using acetonitrile and water to give 130 mg of 2-{5-[(5-{2-amino-5-methyl-4-oxoimidazolo[4,5-c]pyridin-3-yl}pentyl)oxy]-1-methylpyrazol-4-yl}-6-methylpyridine-4-carboxylic acid (INT-B20-7) (83%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=466.10. Step 8. Preparation of 5,16,26-trimethyl-7-oxa-4,5,13,16,20,22,27-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(27),2(6),3,14(19),17,20,24(28),25-octaene-15,23-dione (Example B20). 2-{5-[(5-{2-amino-5-methyl-4-oxoimidazolo[4,5-c]pyridin-3-yl}pentyl)oxy]-1-methylpyrazol-4-yl}-6-methylpyridine-4-carboxylic acid (105 mg, 0.22 mmol, 1 equivalent), N,N,N,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (128 mg, 0.33 mmol, 1.5 equivalents) and N,N- A mixture of diisopropylethylamine (87 mg, 0.67 mmol, 3 equiv.) in 1,4-dioxane (3 mL) was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water (60 mL), and the mixture was extracted with dichloromethane (3×40 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by trituration with DMF/DMSO (5 mL) to give 15 mg of 5,16,26-trimethyl-7-oxa-4,5,13,16,20,22,27-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(27),2(6),3,14(19),17,20,24(28),25-octaene-15,23-dione (Example B20) as a yellow solid (13%). LCMS: m/z (ESI), [M+H] ⁺=448.10. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.66-1.80 (2H, m), 1.86-2.11 (4H, m), 2.55 (3H, s), 3.53 (3H, s), 3.73 (3H, s), 4.40 (2H, t), 4.49 (2H, t), 6.58 (1H, d), 7.55 (1H, s), 7.60 (1H, d), 7.92 (1H, s), 8.38 (1H, s), 12.87 (1H, s). Example B21 5,16,26-trimethyl-7-oxa-4,5,13,16,17,20,22,27-octaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(27),2(6),3, 14(19),17,20,24(28),25-octaene-15,23-dione Step 1. Preparation of 4-hydroxy-2-methyl-5-nitrooxazin-3-one (INT-B21-1). 4,5-dichloro-2-methyloxazin-3-one (4.0 g, 22.34 mmol, 1 equivalent) and NaNO ₂(6.1 g, 89.38 mmol, 4.0 equivalents) in N,N- A mixture in dimethylformamide (20 mL) was stirred at 90 °C for 24 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in warm 4 M HCl (20 mL) and cooled to room temperature. The solid was filtered and triturated with ether (100 mL) to give 1.0 g of 4-hydroxy-2-methyl-5-nitrooxazin-3-one (INT-B21-1) (26%) as a yellow solid. ¹H NMR (DMSO-d ₆, 400 MHz) δ 3.56 (3H, s), 8.20 (1H, s). Step 2. Preparation of 4-amino-2-methyl-5-nitrooxazin-3-one (INT-B21-2). 4-Hydroxy-2-methyl-5-nitrooxazin-3-one (2.5 g, 14.61 mmol, 1 equivalent) and NH ₃The mixture in methanol (60 mL) was stirred at 60 °C for 20 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by C18 FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to obtain 800 mg of 4-amino-2-methyl-5-nitrooxazin-3-one (INT-B21-2) (32%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 3.60 (s, 3H), 8.26 (s, 1H), 8.83 (s, 2H). Step 3. Preparation of 4,5-diamino-2-methyloxazin-3-one (INT-B21-3). A mixture of 4-amino-2-methyl-5-nitrooxazin-3-one (340 mg, 2.00 mmol, 1 eq.) and Pd/C (106 mg, 1.00 mmol, 0.5 eq.) in methanol (15 mL) was stirred at room temperature for 3 h under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with methanol (50 mL). The solution was concentrated under reduced pressure to give 200 mg of 4,5-diamino-2-methyloxazin-3-one (INT-B21-3) (71%) as a light yellow solid. This material was used in the next reaction without purification. LCMS: m/z (ESI), [M+H] ⁺= 141.00. Step 4. Preparation of 2-amino-5-methyl-3H-imidazo[4,5-d]oxazin-4-one (INT-B21-4). A mixture of 4,5-diamino-2-methyloxazin-3-one (160 mg, 1.14 mmol, 1 eq.) and cyanogen bromide (181 mg, 1.71 mmol, 1.5 eq.) in ethanol (5 mL) was stirred at room temperature for 16 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was purified on Prep-TLC using dichloromethane/methanol (10/1) to give 160 mg of 2-amino-5-methyl-3H-imidazo[4,5-d]oxazin-4-one (INT-B21-4) (59%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺= 166.00. Step 5. Preparation of 2-amino-3-(5-bromopentyl)-5-methylimidazo[4,5-d]oxazin-4-one (INT-B21-5). 2-amino-5-methyl-3H-imidazo[4,5-d]oxazin-4-one (100 mg, 0.60 mmol, 1 eq.), 1,5-dibromopentane (409 mg, 1.78 mmol, 3.0 eq.) and K ₂CO ₃A mixture of (246.02 mg, 1.78 mmol, 3.0 equiv) in acetonitrile (10 mL) was stirred at 60 °C for 18 h under nitrogen atmosphere and cooled to room temperature. The reaction was quenched with water (30 mL), and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue is purified by C18FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound are evaporated to dryness to give 70 mg of 2-amino-3-(5-bromopentyl)-5-methylimidazo[4,5-d]oxazin-4-one (INT-B21-5) (37%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=315.95. Step 6. Preparation of 2-{5-[(5-{2-amino-6-methyl-7-oxoimidazo[4,5-d]oxazin-1-yl}pentyl)oxy]-1-methylpyrazol-4-yl}-6-methylpyridine-4-carboxylic acid methyl ester (INT-B21-6). 2-amino-3-(5-bromopentyl)-5-methylimidazo[4,5-d]oxazin-4-one (55 mg, 0.17 mmol, 1 equivalent), 2-(5-hydroxy-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid methyl ester (M1, 65 mg, 0.26 mmol, 1.5 equivalents) and K ₂CO ₃A mixture of (72 mg, 0.52 mmol, 3.0 equiv) in acetonitrile (2.0 mL) was stirred at 60 °C for 3 h under nitrogen atmosphere and then cooled to room temperature. The reaction was quenched with water (30 mL), and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by C18 FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 25 mg of 2-{5-[(5-{2-amino-6-methyl-7-oxoimidazolo[4,5-d]oxazin-1-yl}pentyl)oxy]-1-methylpyrazol-4-yl}-6-methylpyridine-4-carboxylic acid methyl ester (INT-B21-6) (29%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺=481.20. Step 7. Preparation of 2-{5-[(5-{2-amino-6-methyl-7-oxoimidazolo[4,5-d]oxazin-1-yl}pentyl)oxy]-1-methylpyrazol-4-yl}-6-methylpyridine-4-carboxylic acid (INT-B21-7). Methyl 2-{5-[(5-{2-amino-6-methyl-7-oxoimidazolo[4,5-d]oxazin-1-yl}pentyl)oxy]-1-methylpyrazol-4-yl}-6-methylpyridine-4-carboxylate (25 mg, 0.05 mmol, 1 equivalent) and LiOH ^.H ₂O (4.4 mg, 0.10 mmol, 2.0 equiv.) in methanol (0.5 mL) and H ₂The mixture in 4% ethyl acetate (1.0 mL) was stirred at 20 °C for 2 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by C18 FLASH using water and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 15 mg of 2-{5-[(5-{2-amino-6-methyl-7-oxoimidazolo[4,5-d]oxazin-1-yl}pentyl)oxy]-1-methylpyrazol-4-yl}-6-methylpyridine-4-carboxylic acid (INT-B21-7) (61%) as a light yellow solid. LCMS: m/z (ESI), [M+H] ⁺=467.15. Step 8. Preparation of 5,16,26-trimethyl-7-oxa-4,5,13,16,17,20,22,27-octaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(27),2(6),3,14(19),17,20,24(28),25-octaene-15,23-dione (Example B21). 2-{5-[(5-{2-amino-6-methyl-7-oxoimidazolo[4,5-d]oxazin-1-yl}pentyl)oxy]-1-methylpyrazol-4-yl}-6-methylpyridine-4-carboxylic acid (15 mg, 0.03 mmol, 1 equivalent), N,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (24 mg, 0.06 mmol, 2.0 equiv) and N,NA mixture of 1-diisopropylethylamine (12 mg, 0.10 mmol, 3.0 equiv.) in 1,4-dioxane (1.0 mL) was stirred at room temperature under nitrogen atmosphere for 18 h. The mixture was concentrated under reduced pressure. The residue was treated with dimethyl sulfoxide (2 mL). The solid was collected by filtration and washed with methanol (3×5 mL) to give 14 mg of 5,16,26-trimethyl-7-oxa-4,5,13,16,17,20,22,27-octaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecano-1(27),2(6),3,14(19),17,20, 24(28),25-octaene-15,23-dione (Example B21) (99%) as a white solid. LCMS: m/z (ESI), [M+H] ⁺=449.15. ¹H NMR (CDCl ₃, 400 MHz) δ 1.72-1.82 (2H, m), 2.00-2.14 (4H, m), 2.56 (3H, s), 3.73 (3H, s), 3.76 (3H, s), 4.20 (2H, t), 4.47 (2H, t), 7.56 (1H, s), 7.92 (1H, s), 8.22 (1H, s), 8.37 (1H, s). Example B22 16-(2-Hydroxyethyl)-5,26-dimethyl-7-oxa-4,5,13,16,20,22,27-heptaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octadecene-1(27),2(6),3,14(19),17,20,24(28),25-octaene-15,23-dione Step 1. Preparation of 4-(2-{[(tert-butyldimethylsilyl)oxy]amino}ethoxy)-1-(2-{[(tert-butyldimethylsilyl)oxy]amino}ethyl)-3-nitropyridin-2-one (INT-B22-1). 4-Hydroxy-3-nitro-1H-pyridin-2-one (7 g, 44.84 mmol, 1 equivalent), cesium carbonate (43.8 g, 134.53 mmol, 3 equivalents) and (2-bromoethoxy)(tert-butyl)dimethylsilane (42.9 g, 179.38 mmol, 4 equivalents) were added to N,N-The mixture in dimethylformamide (100 mL) was stirred at 60 °C for 12 h. After cooling to room temperature, the reaction was treated with water (600 mL), and the mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (3×500 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (2/1) to give 8.6 g of 4-(2-{[(tert-butyldimethylsilyl)oxy]amino}ethoxy)-1-(2-{[(tert-butyldimethylsilyl)oxy]amino}ethyl)-3-nitropyridin-2-one (INT-B22-1) (37%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=473.30. ¹H NMR (400 MHz, DMSO-d ₆) δ 0-0.19 (12H, m), 0.69-0.97 (18H, m), 3.75-3.96 (4H, m), 3.98-4.15 (2H, m), 4.20-4.46 (2H, m), 6.47-6.61 (1H, m), 7.81-7.96 (1H, m). Step 2. Preparation of 4-amino-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-nitropyridine-2-one (INT-B22-2). 4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-nitropyridin-2-one (8.6 g, 18.01 mmol, 1 equivalent) and NH ₃The mixture in methanol (60 mL) was stirred at 60 °C for 12 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 5.6 g of 4-amino-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-nitropyridin-2-one (INT-B22-2) (96%) as a yellow solid. This material was used in the next reaction without further purification. LCMS: m/z (ESI), [M+H] ⁺=314.10. ¹H NMR (400 MHz, DMSO-d ₆) δ 0.05 (6H, s), 0.82 (9H, s), 3.72-3.78 (2H, m), 3.82-3.88 (2H, m), 5.84-5.89 (1H, m), 7.45 (1H, d), 8.04 (2H, s). Step 3. Preparation of 3,4-diamino-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyridin-2-one (INT-B22-3). To a stirred mixture of 4-amino-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-nitropyridin-2-one (4.4 g, 13.89 mmol, 1 eq.) and ranyl nickel (1.10 g, 12.79 mmol, 0.92 eq.) in methanol (200 mL) at 0 °C under nitrogen atmosphere was added hydrazine hydrate (4.26 g, 83.39 mmol, 6 eq.). The resulting mixture was stirred at room temperature for 4 h and filtered. The filter cake was washed with methanol (3×100 mL). The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum dichloromethane/methanol (10/1) to give 3.7 g of 3,4-diamino-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyridin-2-one (INT-B22-3) (93%) as a gray powder. LCMS: m/z (ESI), [M+H] ⁺=284.15. ¹H NMR (400 MHz, DMSO-d ₆) δ 0.07 (6H, s), 0.82 (9H, s), 3.74 (2H, t), 3.80-3.89 (4H, m), 5.11 (2H, s), 5.73 (1H, d), 6.79(1H, d). Step 4. Preparation of 2-amino-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3H-imidazo[4,5-c]pyridin-4-one (INT-B22-4). To a stirred mixture of 3,4-diamino-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyridin-2-one (3.7 g, 13.05 mmol, 1 eq) in ethanol (60 mL) was added cyanogen bromide (2.1 g, 19.58 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane/methanol (7/1) to give 6.6 g of 2-amino-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3H-imidazo[4,5-c]pyridin-4-one (INT-B22-4) (95%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=309.25. ¹H NMR (400 MHz, DMSO-d ₆) δ 0.14 (6H, s), 0.71 (9H, s), 3.95 (2H, t), 4.36(2H, t), 6.73 (1H, d), 7.88 (1H, d), 8.03(2H, s). Step 5. Preparation of 2-amino-3-(5-bromopentyl)-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}imidazo[4,5-c]pyridin-4-one (INT-B22-5). 2-amino-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3H-imidazo[4,5-c]pyridin-4-one (6.6 g, 21.40 mmol, 1 eq.) and K ₂CO ₃To a stirred mixture of 2-amino-3-(5-bromopentyl)-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}imidazo[4,5-c]pyridin-4-one (INT-B22-5) (21%) was added 1,5-dibromo-pentane (5.9 g, 42.79 mmol, 2 eq.) in acetonitrile (100 mL). The resulting mixture was stirred at 60 °C for 4 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane/methanol (10/1) to give 2.2 g of 2-amino-3-(5-bromopentyl)-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}imidazo[4,5-c]pyridin-4-one (INT-B22-5) (21%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=457.20. ¹H NMR (400 MHz, DMSO-d ₆) δ 0.12 (6H, s), 0.80 (9H, s), 1.31-1.43 (2H,m), 1.62-1.68 (2H, m), 1.78-1.84 (2H, m), 3.51 (2H, t), 3.80 (2H, t), 3.99 (2H,t), 4.19 (2H, t), 6.22 (1H, d), 6.50 (2H, s), 7.16 (1H, d). Step 6. Preparation of methyl 2-(5-{[5-(2-amino-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-4-oxoimidazolo[4,5-c]pyridin-3-yl)pentyl]oxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B22-6). 2-amino-3-(5-bromopentyl)-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}imidazo[4,5-c]pyridin-4-one (2.2 g, 4.81 mmol, 1 equivalent) and K ₂CO ₃To a stirred mixture of 2-(5-hydroxy-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid methyl ester (1.19 g, 4.81 mmol, 1 equiv.) (1.3 g, 9.62 mmol, 2 equiv.) in acetonitrile (20 mL) was added acetonitrile (5 mL). The resulting mixture was stirred at 60 °C for 12 h. After cooling to room temperature, the reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×100 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified on a silica gel column eluting with dichloromethane/methanol (10/1) to give 2.5 g of methyl 2-(5-{[5-(2-amino-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-4-oxoimidazolo[4,5-c]pyridin-3-yl)pentyl]oxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (INT-B22-6) (80%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=610.30. Step 7. Preparation of 2-(5-{[5-(2-amino-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-4-oxoimidazolo[4,5-c]pyridin-3-yl)pentyl]oxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B22-7). Under nitrogen atmosphere at room temperature, methyl 2-(5-{[5-(2-amino-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-4-oxoimidazolo[4,5-c]pyridin-3-yl)pentyl]oxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylate (2.5 g, 4.00 mmol, 1 equivalent) was added to tetrahydrofuran (20 mL) and H ₂Lithium hydroxide (336 mg, 8.01 mmol, 2 eq.) was added to the stirred mixture in 4% O (5 mL). The reaction mixture was stirred for 3 h. The resulting mixture was concentrated under reduced pressure and purified by reverse flash chromatography using 10% to 50% acetonitrile/water elution to give 2.0 g of 2-(5-{[5-(2-amino-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-4-oxoimidazolo[4,5-c]pyridin-3-yl)pentyl]oxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (INT-B22-7) (75%) as a brown solid. LCMS: m/z (ESI), [M+H] ⁺=610.30. Step 8. Preparation of 16-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-5,26-dimethyl-7-oxa-4,5,13,16,20,22,27-heptaazapentacyclic[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octaconic-1(27),2(6),3, 14(19),17,20,24(28),25-octaene-15,23-dione (INT-B22-8). 2-(5-{[5-(2-amino-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-4-oxoimidazolo[4,5-c]pyridin-3-yl)pentyl]oxy}-1-methylpyrazol-4-yl)-6-methylpyridine-4-carboxylic acid (20 mg, 0.03 mmol, 1 equivalent) and N,N,N,N-Tetramethyl- O-(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (18.71 mg, 0.05 mmol, 1.5 equivalents) was added to the stirred mixture in dioxane (4 mL) N,N-Diisopropylethylamine (12.72 mg, 0.10 mmol, 3 equiv.). After stirring at room temperature for 12 h, the reaction was quenched with water (100 mL), and the mixture was extracted with dichloromethane (2×80 mL). The combined organic layers were washed with brine (3×100 mL) and purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (10/1) to give 8 mg of 16-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-5,26-dimethyl-7-oxa-4,5,13,16,20,22,27-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(27),2(6),3, 14(19),17,20,24(28),25-octaene-15,23-dione (INT-B22-8) (39%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=592.35. ¹H NMR (400 MHz, CD ₃OD) δ 0.09 (6H, s), 0.83 (9H, s), 1.51-1.63 (2H, m), 1.76-1.91 (4H, m), 2.56 (3H, d), 3.72 (3H, s), 3.89-3.96 (2H, m), 4.09-4.16 (4H, m), 4.25-4.35 (2H, m), 6.39 (1H, d), 7.25 (1H, d),7.51 (1H, d), 7.84 (1H, s), 7.88-7.93 (1H, m). Step 9. 16-(2-Hydroxyethyl)-5,26-dimethyl-7-oxo-4,5,13,16,20,22,27-heptaazapentacyclic [22.3.1.0^{2,6}.0^{13,21}. 0^{14,19}]octacosa-1(27),2(6),3,14(19),17,20,24(28),25-octaene-15,23-dione (Example B22). 16-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-5,26-dimethyl-7-oxa-4,5,13,16,20,22,27-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(27),2(6),3,14(19),17,20,24(28),25-octaene-15,23-dione (40 mg, 0.068 mmol, 1 equivalent) and tetrabutylammonium fluoride (35.35 A mixture of 2-nitro-1-(2-nitro-4-yl)-6-nitropropene (6-nitropropene) (2.0 mg, 0.136 mmol, 2 eq.) in tetrahydrofuran (2 mL) was stirred at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using 10% to 100% MeOH/water to give 7.7 mg of 16-(2-hydroxyethyl)-5,26-dimethyl-7-oxa-4,5,13,16,20,22,27-heptaazapentacyclo[22.3.1.0^{2,6}. 0^{13,21}.0^{14,19}]octacos-1(27),2(6),3,14(19),17,20, 24(28),25-octaene-15,23-dione (Example B22) as a yellow solid (21%). LCMS: m/z (ESI), [M+H] ⁺=478.15. ¹H NMR (CD ₃OD, 400 MHz) δ 1.85-1.93 (2H, m), 2.11-2.23 (4H, m), 2.89 (3H, s), 3.87 (3H, s), 3.88-3.94 (2H, m), 4.22 (2H, t), 4.41 (2H, t), 4.60-4.69 (2H, m), 6.69 (1H, d), 7.59 (1H, d), 8.10 (1H, s), 8.36 (1H, s), 8.95 (1H, s). Example B23 18-[2-(dimethylamino)ethyl]-5,30-dimethyl-7-oxa-4,5,13, 18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14, 23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one Step 1. 18-[2-(dimethylamino)ethyl]-5,30-dimethyl-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24, 28(32),29-nonan-27-one (Example B23). 5,30-dimethyl-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}. 0^{14,23}.0^{15,20}] 32-1(31),2(6),3,14,20,22,24, 28(32),29-nonan-27-one (Example B16, 50 mg, 0.10 mmol, 1 equivalent), (2-bromoethyl)dimethylamine (32 mg, 0.21 mmol, 2 equivalents), trimethylamine (21 mg, 0.21 mmol, 2 equivalents) and NaI (3.1 mg, 0.02 mmol, 0.2 equivalents) in N,N-dimethylformamide (2 mL) was stirred at 60 °C for 6 h. The mixture was cooled to room temperature. The reaction was quenched with water (20 mL), and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×20 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Prep OBD C18 column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃ ^.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 5.4 mg of 18-[2-(dimethylamino)ethyl]-5,30-dimethyl-7-oxa-4,5,13,18,24,26,31-heptaazahexacyclo[26.3.1.0^{2,6}.0^{13,25}.0^{14,23}.0^{15,20}]triacontac-1(31),2(6),3,14,20,22,24,28(32),29-nonan-27-one (Example B23) as a white solid (8%). LCMS: m/z (ESI), [M+H] ⁺=543.40. ¹H NMR (DMSO- d ₆, 400 MHz) δ 1.79-1.83 (2H, m), 2.02-2.06 (4H, m), 2.21 (6H, s), 2.56 (3H, s), 2.54-2.64 (2H, m), 2.77-2.81 (2H, m), 3.15-3.44 (4H, m), 3.67 (2H, s), 3.73 (3H, s), 4.22 (2H, t), 4.35 (2H, t), 6.94 (1H, d), 7.35 (1H, d), 7.57 (1H, s), 7.93 (1H, s), 8.41 (1H, s), 12.66 (1H, s). Example B27 5-[4-(dimethylamino)piperidin-1-yl]-15,21-dimethyl-23-oxo-2,9, 11,16,20,21,26-heptaazaheptacyclic[26.2.2.1^{1,26}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]triacontetrazol-3,5,7,9,13,15,17(34), 18(22),19-nonan-12-one Under nitrogen atmosphere at room temperature, 5-bromo-15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclic [26.2.2.1^{1,26}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,15,17(34), 18(22),19-nonan-12-one (INT-B2-5, 70 mg, 0.12 mmol, 1 equivalent) was added. N,N-dimethylpiperidin-4-amine (93 mg, 0.73 mmol, 6 equiv) and BrettPhos Pd G ₃To a stirred mixture of 2-nitropropene (33 mg, 0.04 mmol, 0.3 eq.) and 1,4-dioxane (6 mL) was added LiHMDS (1.5 mL, 1.45 mmol, 12 eq.) dropwise. The mixture was stirred at 60 °C under nitrogen atmosphere for 2 h and cooled to room temperature. The reaction was heated with saturated NH₄Cl(aq) (20 mL) was quenched at room temperature, and the mixture was washed with CH₂Cl ₂(3×50 mL) extraction. The combined organic layers were purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was purified by prep-TLC using dichloromethane/methanol (10:1). The product was purified by prep-HPLC using an XBridge Prep OBD C18 column containing 0.1% NH₄HCO ₃of water and acetonitrile. The fractions containing the desired compound were evaporated to dryness to give 20.4 mg of 5-[4-(dimethylamino)piperidin-1-yl]-15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13, 17}.0^{2,10}.0^{3,8}.0^{18,22}]triacontria-3,5,7,9,13,15, 17(34),18(22), 19-nonan-12-one (Example B27) (26%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=624.30 ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.47-1.60 (2H, m), 1.88-2.04 (6H, m), 2.06-2.15 (3H, m), 2.21-2.28 (7H, m), 2.54 (3H, s), 2.61-2.71 (2H, m), 2.81 (2H, d), 2.86 (2H, d), 3.46 (4H, d), 3.56 (2H, d), 3.76 (3H, s), 4.38 (2H, t), 6.94 (1H, dd), 7.36 (1H, d), 7.48 (1H, d), 7.61 (1H, d), 7.89 (1H, s), 8.76 (1H, s), 13.20 (1H, s). Examples B28-B39 (Table 3) were prepared using the same reaction conditions described above for the synthesis of Example B27 from INT-B2-5. Example B40A and Example B40B 5-[4-(dimethylamino)piperidin-1-yl]-15,21-dimethyl-23-oxa-2,9, 11,16,20,21,26-heptaazaheptacyclic[24.4.1.1^{1,28}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tritriacontah-3,5,7,9,13,15,17(33), 18(22),19-nonan-12-one (isomer 1, Example B40A) Under nitrogen atmosphere at room temperature, 5-bromo-15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,15,17(33), 18(22),19-nonan-12-one (isomer 1, INT-B9-5A, 80 mg, 0.142 mmol, 1 equivalent) was added.N,N-dimethylpiperidin-4-amine (54.71 mg, 0.426 mmol, 3 equiv) and BrettPhos Pd G ₃To a stirred mixture of 2-nitropropene (38.68 mg, 0.043 mmol, 0.3 equiv) and 1,4-dioxane (8 mL) was added LiHMDS (1.420 mmol, 10 equiv) dropwise. The mixture was stirred at 60 °C for 1 h and then cooled to room temperature. The reaction was heated with saturated NH₄Cl(aqueous solution) (10 mL) was quenched, and the mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×30 mL), purified by anhydrous Na ₂SO ₄Dry and concentrate under reduced pressure. The residue was subjected to prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol/L NH₄HCO ₃and 0.1% NH ₃.H ₂O water and acetonitrile as mobile phase for purification. The fractions containing the desired compound were evaporated to dryness to give 33.2 mg of 5-[4-(dimethylamino)piperidin-1-yl]-15,21-dimethyl-23-oxa-2,9,11, 16,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2, 10}.0^{3,8}.0^{18,22}]tritriacontac-3,5,7,9,13,15,17(33), 18(22),19-nonan-12-one (isomer 1, Example B40A) (37%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=610.35. ¹H NMR (DMSO- d ₆, 400 MHz) δ 1.65-1.78 (6H, m), 1.87-1.93 (2H, m), 1.96-2.12 (1H, d), 2.25 (6H, s), 2.45-2.49 (2H, m), 2.51-2.55 (4H, m), 2.65-2.69 (4H, m), 3.20-3.26 (2H, m), 3.35-3.45 (1H, m), 3.61-3.68 (2H, m), 3.74 (4H, s), 4.56 (1H, t), 4.70 (1H, d), 6.90-7.02 (1H, m), 7.21 (1H, d), 7.42 (1H, d), 7.56 (1H, s), 7.94 (1H, s), 8.42 (1H, s), 12.69 (1H, s). SFC-HPLC, Rt = 8.811 minutes. 5-[4-(Dimethylamino)piperidin-1-yl]-15,21-dimethyl-23-oxo-2,9,11,16,20,21,26-heptaazaheptacyclic[24.4.1.1^{1,28}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tritriacontahedral-3,5,7,9,13,15,17(33), 18(22), 19-nonan-12-one (isomer 2, Example B40B) Under nitrogen atmosphere at room temperature, 5-bromo-15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}. 0^{2,10}.0^{3,8}.0^{18,22}]tritriacontria-3,5,7,9,13,15,17(33), 18(22),19-nonan-12-one (isomer 2, INT-B9-5B, 80 mg, 0.14 mmol, 1 equivalent) and N,N-dimethylpiperidin-4-amine (109 mg, 0.85 mmol, 6 equiv) and BrettPhos Pd G ₃(38 mg, 0.04 mmol, 0.3 equiv) in 1,4-dioxane was added LiHMDS (3 mL, 3.00 mmol, 21.0 equiv) dropwise. The mixture was stirred at 60 °C for 1.5 h under nitrogen atmosphere. The mixture was cooled to room temperature and then quenched with saturated ammonium chloride (aqueous solution) (100 mL) at room temperature. The mixture was extracted with dichloromethane (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC eluting with dichloromethane/methanol (10/1). The product was purified by prep-HPLC using an XBridge Prep OBD C18 column (30*150 mm, 5μm) and water (10 mmol/L NH₄HCO ₃and 0.05% NH ₃H ₂O) Mobile phase A and acetonitrile mobile phase B were further purified to obtain 29.7 mg of 5-[4-(dimethylamino)piperidin-1-yl]-15,21-dimethyl-23-oxa-2,9,11,16,20,21,26-heptaazaheptacyclic [24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tritriacontac-3,5,7,9,13,15,17(33),18(22),19-nonan-12-one (isomer 2, Example B40B) (34%) as a yellow solid. LCMS: m/z (ESI), [M+H] ⁺=610.30. ¹H NMR (DMSO-d ₆, 400 MHz) δ 1.51-1.75 (5H, m), 1.87-1.93 (2H, m), 2.03-2.12 (2H, m), 2.26 (6H, s), 2.45-2.49 (2H, m), 2.51-2.55 (4H, m), 2.72 (4H, d), 3.20-3.26 (2H, m), 3.35-3.45 (1H, m), 3.61-3.68 (2H, m), 3.74 (4H, s), 4.52-4.60 (1H, m), 4.70 (1H, d), 6.93 (1H, d), 7.21 (1H, s), 7.42 (1H, d), 7.57 (1H, s), 7.94 (1H, s), 8.42 (1H, s), 12.70 (1H, s). SFC-HPLC, Rt=7.034, ee=100%. Rt1=3.894, Rt2=4.686. Example B41A, Example B42A, Example B43A, Example B44A, Example B44A1, Example B44A2, Example B45A, Example B46A, Example B47A, Example B48A, Example B49A, Example B50A, Example B51A, Example B52A, Example B53A, Example B54A, Example B55A, Example B56A, Example B57A, Example B58A, Example B59A (Table 4) were prepared using similar reaction conditions described above for the synthesis of Example B40A from INT-9B-5A. Example B41B, Example B42B, Example B43B, Example B44B, Example B44B1, Example B44B2, Example B45B, Example B46B, Example B47B, Example B48B, Example B49B, Example B50B, Example B51B, Example B52B, Example B53B, Example B54B, Example B55B, Example B56B, Example B57B, Example B58B, Example B59B (Table 4) were prepared using similar reaction conditions described above for the synthesis of Example B40B from INT-9B-5B. Biological Examples Exemplary compounds disclosed herein have been characterized in one or more of the following biological assays. Biological Example 1: Inhibition of EGFR WT and mutant enzyme activity Recombinant EGFR wild-type, L858R, L858R/T790M, Exon19Del, Exon19Del/T790M, EGFR[T790M/C797S/L858R], and EGFR[T790M/C797S/d746-750] were purchased from Carna Bio. EGFR(d746-750 C797S) and EGFR(C797S L858R) were purchased from Signalchem. The inhibitory potency of compounds against these enzymes was assessed using a homogeneous time-resolved fluorescence method (HTRF, CisBio. Catalog No. 62TK0PEJ). The inhibitory effect of compounds was determined by measuring the enzymatic activity of EGFR enzyme phosphorylating 1 μM TK substrate-biotin in the presence of 1 mM 5'-adenosine triphosphate (ATP) and different concentrations of test compounds. The enzyme reaction buffer contained 5 mM MgCl2, 1 mM MnCl2, 0.01% CHAPS, 1 mM dithiothreitol (DTT), 0.5% dimethyl sulfoxide (DMSO) and 1X supplemental enzyme buffer. WT and mutant EGFR enzymes (Synogencon) were added to the plate containing inhibitors, and the kinase reaction was subsequently initiated by adding ATP and peptide substrate. After incubation for 1 h at room temperature, the reaction was terminated by adding a detection reagent mixture containing EDTA. Fluorescence was measured at 615 nm and 665 nm, respectively, with an excitation wavelength at 320 nm. The calculated 665 nm/615 nm signal ratio is proportional to the kinase activity. The compound concentration that produces 50% inhibition of the corresponding kinase (IC ₅₀). Table 5 lists the data obtained through these measurements. Biological Example 2: Cell Proliferation Assay Ba/F3 cells expressing EGFR mutations were seeded at 5000 cells/well in RPMI1640 medium with 10% FBS in 384-well plates. PC-9 were seeded at 500 cells/well in RPMI1640 medium with 10% FBS in 384-well plates. After overnight incubation, the assay plates were dosed with a series of concentrations of compounds. In addition to dosing the assay plates, the day 0 plates were treated using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega) to measure the number of viable cells (G0). The assay plates were further incubated for 72 hours, and the number of viable cells (G3) was measured. The proliferation percentage was calculated as follows: Proliferation% = 100 × (G3 value of sample well - G0 value) / (G3 value of DMSO control - G0 value). XLFit software was used to further calculate the 50% proliferation inhibition (GI) in the best fitting curve.₅₀) concentrations of compounds in the presence of . Table 6 lists the data obtained from these assays. N/A = Not Available. The foregoing description is considered to be merely illustrative of the principles of the present disclosure. Further, since many modifications and variations will be apparent to those skilled in the art, it is not intended to limit the present invention to the exact construction and process shown as described above. Therefore, all suitable modifications and equivalents may be considered to fall within the scope of the present invention as defined by the appended claims.

Claims (61)

A compound of formula (I) (I) or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl; Ring B is selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl; ^L1 is selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl and a heteroalkynyl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl and the heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of a hydroxyl, a halogen, a cyano and an amino; ^L2 is selected from the group consisting of a bond, N(R ^A ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more ^RB ; wherein R ^A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; wherein each ^RB is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclo, aryl and heteroaryl; L ^wherein L is selected from the group consisting of: a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, and the heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of: a hydroxyl, a halogen, a cyano, and an amino group; ^L is selected from O, S, or N(R ^C ); wherein R ^C is selected from the group consisting of: hydrogen, an alkyl, an alkenyl, an alkynyl, a halogenated alkyl, a heteroalkyl, a heteroalkenyl, a heteroalkynyl, a cycloalkyl, a heterocyclo, an aryl, and a heteroaryl group; each R ¹ is independently selected from the group consisting of: a hydroxyl, a halogen, a cyano, an amino group, -N(R ^D ) ₂ , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more R ^E ; wherein each R ^D is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, -N( ^RF ) ₂ or ^-ORG ; wherein each ^RE is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, -N( ^RF ) ₂ , -alkyl-N( ^RF ) ₂ , -C(O) ^ORG , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the following: hydroxyl, halogen, cyano, amino and alkyl; wherein each of ^RF and ^RG is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl; each R ^R is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclo, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl and halogenated alkyl; ³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclo are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl and halogenated alkyl; m is an integer from 0 to 5; and n is an integer from 0 to 4. The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein Ring A is an aryl group or a heteroaryl group. The compound or a pharmaceutically acceptable salt thereof as described in claim 2, wherein Ring A is selected from the group consisting of furanyl, phenylthio, pyrrolyl, phenyl, pyridyl, pyranyl, pyrimidinyl, oxazinyl, pyrazinyl and tetrahydroisoquinolinyl. The compound or a pharmaceutically acceptable salt thereof as described in claim 3, wherein Ring A is selected from the group consisting of: , , , , , , , , , and . The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein Ring B is an aryl group or a heteroaryl group. The compound or pharmaceutically acceptable salt thereof as described in claim 5, wherein Ring B is phenyl, pyridyl or pyrazolyl. The compound or a pharmaceutically acceptable salt thereof as described in claim 6, wherein Ring B is selected from the group consisting of: , , , , and . The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein L ¹ is a bond. The compound or pharmaceutically acceptable salt thereof as described in claim 8, wherein L ¹ is alkyl. The compound or a pharmaceutically acceptable salt thereof as described in claim 9, wherein ^L1 is selected from the group consisting of: , , , , , , and , where the * end of ^L1 is connected to ^L2 . The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein ^L2 is a bond. The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein L ² is N( ^RA ), and ^RA is selected from alkyl or heterocyclic groups, wherein the alkyl or heterocyclic group is optionally substituted with one or more halogens or alkyl groups. The compound or pharmaceutically acceptable salt thereof as described in claim 12, wherein ^RA is ethyl, difluoroethyl, trifluoroethyl or oxacyclobutane. The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein L ² is a cycloalkyl group optionally substituted by one or more ^RBs . The compound or pharmaceutically acceptable salt thereof as described in claim 14, wherein ^L2 is , which is optionally replaced by one or more ^RBs . The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein ^L2 is a heterocyclic group optionally substituted by one or more ^RB . The compound or a pharmaceutically acceptable salt thereof as described in claim 16, wherein the heterocyclic group is selected from the group consisting of: , , , , and , each of which is optionally replaced by one or more ^RB , wherein the * end of ^L2 is connected to ^L3 . The compound or pharmaceutically acceptable salt thereof as described in claim 16 or 17, wherein ^RB is alkyl. The compound or pharmaceutically acceptable salt thereof as described in claim 19, wherein ^RB is methyl. The compound or a pharmaceutically acceptable salt thereof as described in claim 1, wherein ^L2 is selected from the group consisting of: , , , , , , , , , , , and , where the * end of ^L2 is connected to ^L3 . The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein L ³ is alkyl. The compound or pharmaceutically acceptable salt thereof as described in claim 21, wherein L ³ is ethyl. The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein L ⁴ is O or NH. The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein L ¹ is a bond, and L ² is a bond or a heterocyclic group optionally substituted by one or more ^RBs . The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein L ¹ is alkyl, and L ² is a bond, N( ^RA ) or cycloalkyl optionally substituted by one or more ^RBs . The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein R ¹ is hydroxyl and m is 1. The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein R ¹ is halogen and m is 1. The compound or pharmaceutically acceptable salt thereof as described in claim 27, wherein R ¹ is bromine or fluorine. The compound or a pharmaceutically acceptable salt thereof as described in claim 1, wherein R ¹ is -N( ^RD ) ₂ and m is 1. The compound or pharmaceutically acceptable salt thereof as described in claim 29, wherein each ^RD is independently hydrogen or alkyl optionally substituted with one or more groups independently selected from -N( ^RF ) ₂ or ^-ORG . The compound or pharmaceutically acceptable salt thereof as described in claim 30, wherein each ^RD is independently hydrogen, methyl, methoxyethyl, N,N-dimethylaminoethyl, hydroxyethyl or N,N-dimethylaminopropyl. The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein R ¹ is a heterocyclic group optionally substituted by one or more ^RE , and m is 1. The compound or a pharmaceutically acceptable salt thereof as described in claim 32, wherein the heterocyclic group is selected from the group consisting of: , , , , , , , , , , , , , , , , , and , each of which is optionally replaced by one or more ^RE . The compound or pharmaceutically acceptable salt thereof as described in claim 32, wherein ^RE is a halogen. A compound or a pharmaceutically acceptable salt thereof as described in claim 33, wherein ^RE is F. The compound or pharmaceutically acceptable salt thereof as described in claim 32, wherein each ^{RE is} independently selected from halogen, -N( ^RF ) ₂ , -alkyl-N( ^RF ) ₂ , -C(O) ^ORG , or alkyl optionally substituted with one or more halogens. A compound or a pharmaceutically acceptable salt thereof as described in claim 36, wherein each of ^RF and ^RG is independently an alkyl group. A compound or a pharmaceutically acceptable salt thereof as described in claim 36, wherein each of ^RF and ^RG is independently a _C1-3 alkyl group. The compound or pharmaceutically acceptable salt thereof as described in claim 36, wherein each ^RE is independently selected from the group consisting of F, -N( _CH3 ) ₂ , _-C1-3alkyl -N( _CH3 ) ₂ , -C(O)O(tert-butyl), methyl, ethyl or trifluoroethyl. The compound or pharmaceutically acceptable salt thereof as described in claim 32, wherein ^RE is cycloalkyl or heterocyclic, wherein the cycloalkyl and the heterocyclic are optionally substituted with one or more alkyl or halogen. A compound or a pharmaceutically acceptable salt thereof as described in claim 40, wherein ^RE is selected from cyclopropyl, morpholinyl, piperazinyl, oxacyclobutenyl or azacyclobutanyl, each of which is optionally substituted with one or more alkyl or halogen groups. The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein m is 2, one of R ¹ is halogen, and the other R ¹ is a heterocyclic group optionally substituted by one or more ^RE . The compound or a pharmaceutically acceptable salt thereof as described in claim 42, wherein the heterocyclic group is selected from the group consisting of: , , , , , , , , , , , , , , , , , and , each of which is optionally replaced by one or more ^RE . The compound or pharmaceutically acceptable salt thereof as described in claim 43, wherein each ^{RE is} independently selected from halogen, -N( ^RF ) ₂ , -alkyl-N( ^RF ) ₂ , -C(O) ^ORG , or alkyl optionally substituted with one or more halogens. The compound or a pharmaceutically acceptable salt thereof as described in claim 1, wherein ^R1 is selected from the group consisting of: The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein ^R2 is a halogen and n is 1 or 2. A compound as described in claim 46 or a pharmaceutically acceptable salt thereof, wherein R ² is F. The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein R ² is alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more halogens. The compound or pharmaceutically acceptable salt thereof as described in claim 48, wherein R ² is methyl, ethyl, cyclopropyl or trifluoroethyl. The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein R ³ is alkyl or cycloalkyl. The compound or pharmaceutically acceptable salt thereof as described in claim 50, wherein R ³ is methyl, ethyl or cyclopropyl. A compound or a pharmaceutically acceptable salt thereof as described in claim 1, wherein m is 0, 1 or 2. The compound or pharmaceutically acceptable salt thereof as described in claim 1, wherein n is 0 or 1. The compound or a pharmaceutically acceptable salt thereof as described in claim 1, wherein the compound is selected from the group consisting of: and . A pharmaceutical composition comprising a compound as described in any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A method for inhibiting EGFR activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 54 or a pharmaceutical composition as described in claim 55. A method for treating an EGFR-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 54 or administering to the subject a pharmaceutical composition as described in claim 55. The method of claim 57, wherein the EGFR-related disorder is an autoimmune disease or cancer. A method as described in claim 58, wherein the cancer is selected from the group consisting of lung cancer, brain cancer, colorectal cancer, bladder cancer, urothelial cancer, breast cancer, prostate cancer, ovarian cancer, head and neck cancer, pancreatic cancer, gastric cancer and mesothelioma, including metastases (especially brain metastases), etc. A method as described in any one of claims 57 to 59, wherein the compound is administered simultaneously, separately or sequentially with one or more additional therapeutic agents. A method as described in claim 60, wherein the one or more additional therapeutic agents are selected from the group consisting of: EGFR TKI, EGFR antibody, MEK inhibitor, c-MET inhibitor, mitotic kinase inhibitor, immunotherapy, anti-angiogenic agent, apoptosis inducer, mTOR inhibitor, histone deacetylase inhibitor, IL6 inhibitor and JAK inhibitor.