EGFR inhibitors and their uses

Abstract

The present invention discloses compounds or pharmaceutically acceptable salts thereof that are useful as EGFR inhibitors. Pharmaceutical compositions containing such compounds and methods for treating EGFR-related diseases (e.g., cancer) with such compounds or compositions are also disclosed.

Description

[Technical Field]

[0001] This disclosure generally relates to novel compounds and pharmaceutically acceptable salts thereof that inhibit the epidermal growth factor receptor (EGFR). This disclosure also relates to pharmaceutical compositions containing the compounds as active ingredients, and to the use of the compounds in the treatment of EGFR-associated diseases, including cancer. [Background technology]

[0002] The epidermal growth factor receptor (EGFR) is a transmembrane protein that is the receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The EGFR receptor tyrosine kinase family regulates cell proliferation, survival, adhesion, migration, and differentiation. Inhibition of EGFR activity has proven to have potential therapeutic applications in a wide range of pathological conditions. Some cancers are characterized by EGFR mutations that result in increased cell proliferation.

[0003] 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-sparing EGFR inhibitors such as WZ4002 and fourth-generation EGFR inhibitors has been reported.

[0004] There remains a need for new compounds that inhibit EGFR, which can be used as pharmacological tools and are of great interest as drugs to treat EGFR-associated diseases such as cancer. Summary of the Invention

[0005] Disclosed herein are novel compounds that can inhibit EGFR, and thus are useful for treating EGFR-related diseases, such as cancer.

[0006] In one aspect, the present disclosure provides a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 1 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 2 is the bond, N(R A ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R B is replaced by R A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; Each R Bis independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 3 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 4 is O, S or N(R C ) and R C is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 1 are independently hydroxy, halogen, cyano, amino, -N(R D )2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R E is replaced by Each R D are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of hydroxyl, halogen, cyano, -N(RF )2 OR -OR G and is substituted with one or more groups independently selected from Each R E are independently 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, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, and alkyl; R F and R G each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 2 are independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; R 3is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; m is an integer from 0 to 5, and n is an integer from 0 to 4; The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0007] In another aspect, the present disclosure provides a method for producing a pharmaceutical composition comprising: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0008] In another aspect, the present disclosure provides a compound of formula (II) [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A 1 is a 7- to 12-membered cycloalkyl, a 7- to 12-membered heterocyclyl, a 7- to 12-membered aryl, or a 7- to 12-membered heteroaryl; Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 1 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 2 is the bond, N(R A ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R B is replaced by R A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; Each RB is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 3 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 4 is O, S or N(R C ) and R C is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 1 are independently hydroxy, halogen, cyano, amino, -N(R D )2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R E is replaced by Each R Dare independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of hydroxyl, halogen, cyano, -N(R F )2 OR -OR G and is substituted with one or more groups independently selected from Each R E are independently 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, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, and alkyl; R F and R G each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 2are independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; Each R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; 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; The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0009] In another aspect, the present disclosure provides a compound of formula (III) [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring B 1 is a 7- to 12-membered cycloalkyl, a 7- to 12-membered heterocyclyl, a 7- to 12-membered aryl, or a 7- to 12-membered heteroaryl; L 1is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 2 is the bond, N(R A ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R B is replaced by R A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; Each R B is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 3is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 4 is O, S or N(R C ) and R C is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 1 are independently hydroxy, halogen, cyano, amino, -N(R D )2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R E is replaced by Each R D are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of hydroxyl, halogen, cyano, -N(R F )2 OR -OR G and is substituted with one or more groups independently selected from Each R E are independently hydrogen, hydroxyl, halogen, cyano, amino, -N(RF )2,-Alkyl-N(R F )2, -C(O)OR G , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, and alkyl; R F and R G each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 2 are independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; Each R 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, and said heterocyclyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; 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; The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0010] In another aspect, the present disclosure provides a compound of formula (IV) [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 1 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 21 is a 7- to 12-membered cycloalkyl or a 7- to 12-membered heterocyclyl, and the cycloalkyl and heterocyclyl are optionally joined by one or more R B is replaced by Each R B is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 3is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 4 is O, S or N(R C ) and R C is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 1 are independently hydroxy, halogen, cyano, amino, -N(R D )2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R E is replaced by Each R D are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of hydroxyl, halogen, cyano, -N(R F )2 OR -OR G and is substituted with one or more groups independently selected from Each R E are independently hydrogen, hydroxyl, halogen, cyano, amino, -N(RF )2,-Alkyl-N(R F )2, -C(O)OR G , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, and alkyl; R F and R G each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 2 are independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; 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; The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: [Table 1-1] [Table 1-2] or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0013] In another aspect, the present disclosure provides a method for inhibiting EGFR activity in a subject in need of treatment, comprising administering to the subject an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0014] In another aspect, the present disclosure provides a method for treating an EGFR-associated condition, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0015] In another aspect, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, in the preparation of a medicament for treating an EGFR-associated condition.

[0016] In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for treating an EGFR-associated disease. DETAILED DESCRIPTION OF THE INVENTION

[0017] Reference will now be made in detail to several embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. While the present disclosure will be described with reference to the enumerated embodiments, it should be understood that they are not intended to limit the disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications, and equivalents included within the scope of the present disclosure, as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present disclosure. The present 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.) differs from or contradicts this application, the present disclosure shall control. All references, patents, and patent applications cited in this disclosure are incorporated by reference in their entirety.

[0018] It should be understood that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single exemplary embodiment, may also be provided alone or in any suitable subcombination. It should be noted that, as used in the specification and the appended claims, the singular forms "a" and "an" and "the" include the plural forms unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of compounds. definition

[0019] Definitions of certain functional groups and chemical terminology are explained in more detail below. For purposes of this disclosure, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover, and certain functional groups are generally defined as set forth herein. Additionally, general principles of organic chemistry and specific functional moieties and reactivities are explained 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, 1987, the entire contents of which are incorporated herein by reference.

[0020] Linking substituents are described in each section of this disclosure. When a structure explicitly requires a linking group, the Markush variable listed for that group should be understood to be the linking group. For example, when a structure requires a linking group and "alkyl" is listed in the Markush group definition for that variable, it is understood that "alkyl" represents a linking alkylene.

[0021] Any variable (e.g., R i When a group R occurs several times in any constituent or formula of a compound, its definitions on each occurrence are independent of each other. Thus, for example, a group R i When partially substituted with, said group may optionally be substituted with up to two R i may be partially substituted with, and each R i are each independently R i Further, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0022] As used herein, for convenience, a dash "-" is used at the front or end of a chemical group to indicate the point of attachment of a substituent. For example, -OH is attached through an oxygen atom, and a chemical group can be drawn with one or more dashes or without one or more dashes without losing its general meaning. Wavy lines drawn by lines in a structure indicate the point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the depiction or naming order of a chemical group. As used herein, a solid line emanating from the center of a ring indicates that the point of attachment of a substituent on the ring may be at any ring atom. When a substituent is listed but does not specify through which atom such substituent is attached to the remainder of a compound of a given formula, such substituent may be attached through any atom in the formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0023] Unless otherwise indicated herein, the description of a range of values ​​is intended merely as a shorthand method for individually referring to each value within the range, and each value is incorporated herein as if it were individually set forth herein. Unless otherwise stated, ranges used herein include the two limits of the range. For example, the expressions "n is an integer between 1 and 6" and "n is an integer between 1 and 6" both mean "n is 1, 2, 3, 4, 5, or 6."

[0024] As used herein, the term "compounds provided herein," or "compounds disclosed herein," or "compounds of the disclosure" refers to compounds of formula (I), (II), (III), and (IV), as well as specific compounds disclosed herein.

[0025] As used herein, the term "C i-j " denotes a range of carbon atoms, where i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and each integer point therebetween, where j is greater than i. For example, C 1-6 indicates a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some embodiments, the term "C 1-12 " denotes 1 to 12 carbon atoms, particularly 1 to 10 carbon atoms, particularly 1 to 8 carbon atoms, particularly 1 to 6 carbon atoms, particularly 1 to 5 carbon atoms, particularly 1 to 4 carbon atoms, particularly 1 to 3 carbon atoms, or particularly 1 to 2 carbon atoms.

[0026] As used herein, the term "alkyl," whether used as part of another term or independently, refers to a saturated straight-chain or branched hydrocarbon group that may be optionally and independently substituted with one or more substituents described below. i-j"Alkyl" refers to an alkyl having i to j carbon atoms. In some embodiments, an alkyl contains 1 to 10 carbon atoms. In some embodiments, an alkyl contains 1 to 9 carbon atoms. In some embodiments, an alkyl 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 1-10 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1-6 Illustrative examples of "alkyl" include 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, and the like.

[0027] The term "alkenyl," as used herein, whether used as part of another term or independently, refers to a straight-chain or branched hydrocarbon group having at least one carbon-carbon double bond, which may be optionally substituted with one or more substituents independently described herein, and includes groups having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In some embodiments, an alkenyl contains 2 to 12 carbon atoms. In some embodiments, an alkenyl contains 2 to 11 carbon atoms. In some embodiments, an alkenyl 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, or 2 to 3 carbon atoms. Also, in some embodiments, an alkenyl contains 2 carbon atoms. Illustrative examples of alkenyl include, but are not limited to, vinyl (ethylenyl or vinyl), propenyl (allyl), butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, and the like.

[0028] The term "alkynyl," as used herein, whether used as part of another term or independently, refers to a straight-chain or branched hydrocarbon group having at least one carbon-carbon triple bond, which may be optionally and independently substituted with one or more substituents described herein. In some embodiments, alkenyl contains 2 to 12 carbon atoms. In some embodiments, alkynyl contains 2 to 11 carbon atoms. In some embodiments, alkynyl 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, or 2 to 3 carbon atoms. In some embodiments, alkynyl contains 2 carbon atoms. Illustrative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0029] The term "amino" as used herein refers to the group -NH. Amino may be substituted with one or more groups such as alkyl, alkenyl, alkynyl, aryl, carbonyl, or another amino.

[0030] As used herein, the term "aryl," whether used as part of another term or independently, refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, in which at least one ring in the system is aromatic, and each ring in the system contains 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthracene, and the like, which may bear one or more substituents. The term "aryl," as used herein, also includes groups in which an aromatic ring is fused to one or more additional rings. In polycyclic ring systems, only one ring need be aromatic (e.g., 2,3-dihydroindole), but all rings may be aromatic (e.g., quinoline). The second ring may be fused or bridged. Examples of polycyclic aryls include, but are not limited to, benzofuranyl, indenyl, indenyl, naphthaleneimide, phenanthridine, or tetrahydronaphthyl. An aryl may be substituted at one or more ring positions with the substituents described above.

[0031] As used herein, the term "cyano" refers to --CN.

[0032] As used herein, the term "cycloalkyl," whether used as part of another term or independently, refers to a monovalent non-aromatic, saturated or partially unsaturated, monocyclic or polycyclic ring system, wherein all ring atoms are carbon and the system contains at least three ring-forming carbon atoms. In some embodiments, a cycloalkyl 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, or 4 to 5 ring-forming carbon atoms. A cycloalkyl may be saturated or partially unsaturated. A cycloalkyl may be substituted. In some embodiments, a cycloalkyl may be a saturated cyclic alkyl group. In some embodiments, cycloalkyl may be a partially unsaturated cyclic alkyl whose ring system contains at least one double or triple bond. In some embodiments, cycloalkyl may be monocyclic or polycyclic. In the case of polycyclic ring systems, fused, spiral, and bridged ring systems are included within the scope of this definition. Illustrative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexyldiakenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Illustrative examples of multicyclic cycloalkyls include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro[3.6]-decanyl, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, and the like.

[0033] As used herein, the term "halogen" refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo), and iodine (or iodo).

[0034] 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 a basic nitrogen (including N-oxide).

[0035] As used herein, the term "heteroalkyl" refers to an alkyl having at least one of its carbon atoms replaced with a heteroatom selected from N, O, or S. A heteroalkyl may be a carbon or heteroatom group (i.e., the heteroatom may be located in the middle or at the end of the group), and may be optionally and independently substituted with one or more substituents described herein. The term "heteroalkyl" includes alkoxy and heteroalkoxy.

[0036] As used herein, the term "heteroalkenyl" refers to an alkenyl having at least one of its carbon atoms replaced with a heteroatom selected from N, O, or S. A heteroalkenyl may be a carbon or heteroatom group (i.e., the heteroatom may be located in the middle or at the end of the group), and may be optionally substituted independently with one or more substituents described herein.

[0037] As used herein, the term "heteroalkynyl" refers to an alkynyl having at least one of its carbon atoms replaced with a heteroatom selected from N, O, or S. The heteroalkynyl may be a carbon or heteroatom group (i.e., the heteroatom may be located at the middle or end of the group), and may be optionally substituted independently with one or more substituents described herein.

[0038] As used herein, the term "heteroaryl," whether used as part of another term or independently, refers to an aryl having one or more heteroatoms in addition to carbon atoms. Heteroaryls may be monocyclic. Examples of monocyclic heteroaryls include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. Heteroaryls also include polycyclic groups in which a heteroaromatic ring is fused with one or more aryl, cycloalkyl, or heterocyclyl rings, where the connecting group or point is located on the heteroaromatic ring. Illustrative examples of polycyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo[1,3]dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0039] As used herein, the term "heterocyclyl" 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 may optionally be independently substituted with one or more substituents. In some embodiments, a heterocyclyl is a saturated heterocyclyl. In some embodiments, a heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system. In some embodiments, a heterocyclyl may contain any oxidized form of carbon, nitrogen, sulfur, or phosphorus, and any quaternized form of a basic nitrogen. "Heterocyclyl" further includes groups in which the heterocyclyl is fused to a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. Where possible, a heterocyclyl may be carbon- or nitrogen-linked. In some embodiments, a heterocyclyl is carbon-linked. In some embodiments, a heterocyclyl is nitrogen-linked. For example, a group derived from pyrrole may be pyrrol-1-yl (nitrogen-linked) or pyrrol-3-yl (carbon-linked), and a group derived from imidazole may be imidazol-1-yl (nitrogen-linked) or imidazol-3-yl (carbon-linked).

[0040] In some embodiments, the term "3- to 12-membered heterocyclyl" refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, sulfur, or phosphorus. In the case of polycyclic ring systems, fused, spiral, and bridged ring systems are also included within the scope of this definition. Illustrative examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, 1,1-dioxothietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like. Illustrative examples of fused heterocyclyls include quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolidinyl, quinozolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, and the like. These include, but are not limited to, zolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, hexahydro-1H-pyrrolidinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[4,3-a]pyridinyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, and the like. Illustrative examples of spiroheterocyclyl 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.Illustrative examples of bridged heterocyclyls include, but are not limited to, morphanyl, hexamethylenetetraminyl, 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, and the like.

[0041] As used herein, the term "hydroxyl" or "hydroxy" refers to --OH.

[0042] As used herein, the term "partially unsaturated" refers to a group that contains at least one double or triple bond. The term "partially unsaturated" is intended to include rings with multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

[0043] As used herein, the term "optionally" means that the described event or circumstance may or may not occur, and the description includes instances in which the event or circumstance occurs and instances in which 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 on the specified moiety have been replaced with a suitable substituent. It should be understood that "substituted" or "substituted with" includes the implicit assumption that such substitution is consistent with the allowed valence of the substituted atom and that the substitution results in a stable or chemically viable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when one or more positions in any given structure may be substituted with one or more substituents selected from a specified group, the substituents at each position may be the same or different. Substitutions include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonate, alkylsulfonyl, thiocyanate, thiol, thioketone, or combinations thereof. Those skilled in the art will understand that, where appropriate, the substituents themselves may be substituted. Unless specifically stated as "unsubstituted," chemical moieties referenced herein should be understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0044] As used herein, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens on the specified moiety have been replaced with a suitable substituent. It should be understood that "substituted" or "substituted with" includes the implicit assumption that such substitution is consistent with the allowed valence of the substituted atom and that the substitution results in a stable or chemically viable compound, e.g., a compound that does not spontaneously transform by rearrangement, cyclization, elimination, and the like. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and if one or more positions in any given structure may be substituted with one or more substituents selected from a specified group, the substituents may be the same or different at each position. Those of skill in the art should understand that, where appropriate, the substituents themselves may be substituted. Unless specifically stated as "unsubstituted," chemical moieties referred to herein should be understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0045] The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom. The isomeric descriptors "R" and "S" are used herein to refer to atomic configurations relative to a core molecule and are intended to be used as defined in the literature (IUPAC Recommendation 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)). compound

[0046] In one aspect, the present disclosure provides a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 1 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 2 is the bond, N(R A ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R B is replaced by R A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; Each R B is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 3is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 4 is O, S or N(R C ) and R C is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 1 are independently hydroxy, halogen, cyano, amino, -N(R D )2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R E is replaced by Each R D are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of hydroxyl, halogen, cyano, -N(R F )2 OR -OR G and is substituted with one or more groups independently selected from Each R E are independently hydrogen, hydroxyl, halogen, cyano, amino, -N(RF )2,-Alkyl-N(R F )2, -C(O)OR G , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, and alkyl; R F and R G each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 2 are independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; m is an integer from 0 to 5, and n is an integer from 0 to 4; The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, ring A is aryl. In some embodiments, ring A is C 6-12 Aryl, C 6-11 Aryl, C 6-10 Aryl, C 6-9 Aryl or C 6-8 In some embodiments, ring A is phenyl.

[0048] In some embodiments, ring A is heteroaryl. In some embodiments, ring A is a 5- to 12-membered heteroaryl, a 5- to 11-membered heteroaryl, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, a 5- to 8-membered heteroaryl, a 5- to 7-membered heteroaryl, or a 5- to 6-membered heteroaryl.

[0049] In some embodiments, Ring A is selected from the group consisting of furanyl, thiophenyl, pyrrolyl, pyridinyl, pyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, and tetrahydroisoquinolinyl.

[0050] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0051] In some embodiments, ring B is aryl. In some embodiments, ring B is C 6-12 Aryl, C 6-11 Aryl, C 6-10 Aryl, C 6-9 Aryl or C 6-8 In some embodiments, Ring B is phenyl.

[0052] 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 pyridinyl or pyrazolyl.

[0053] In some embodiments, ring B is [ka] is selected from the group consisting of:

[0054] In some embodiments, L 1 is a bond.

[0055] In some embodiments, L 1 is alkyl. In some embodiments, L 1 is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl.

[0056] In some embodiments, L 1 teeth, [ka] and L 1 The * end of 2 is connected to.

[0057] In some embodiments, L 2 is a bond.

[0058] In some embodiments, L 2 is N(R A ) and R Ais selected from alkyl or heterocyclyl, wherein said alkyl or said heterocyclyl is optionally substituted with one or more halogen or alkyl. 2 is N(R A ) and R A is ethyl, difluoroethyl, trifluoroethyl or oxetanyl.

[0059] In some embodiments, L 2 optionally one or more R B In some embodiments, L is cycloalkyl substituted with 2 is C 3-10 Cycloalkyl, C 3-9 Cycloalkyl, C 3-8 Cycloalkyl, C 3-7 Cycloalkyl, C 3-6 Cycloalkyl or C 3-5 cycloalkyl, each of which optionally has one or more R B is replaced by .

[0060] In some embodiments, L 2 optionally one or more R B replaced with [ka] is.

[0061] In some embodiments, L 2 optionally one or more R B In some embodiments, L is a heterocyclyl substituted with 2 is heterocyclyl containing one or more heteroatoms selected from N, O, or S. In some embodiments, L 2 is a 3- to 12-membered heterocyclyl, a 3- to 11-membered heterocyclyl, a 3- to 10-membered heterocyclyl, or a 3- to 9-membered heterocyclyl, each of which optionally is selected from the group consisting of one or more R B is replaced by .

[0062] In some embodiments, L 2 teeth, [ka] and a heterocyclyl selected from the group consisting of: B is substituted with L 2 The * end of 3 is connected to.

[0063] In some embodiments, L 2 is one or more R B is a cycloalkyl or heterocyclyl substituted with R B is alkyl. In some embodiments, R B is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In some embodiments, R B is methyl.

[0064] In some embodiments, L 2 teeth, [ka] and L 2 The * end of 3 is connected to.

[0065] In some embodiments, L 3 is alkyl. In some embodiments, L 3 is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl.

[0066] In some embodiments, L 3 is ethyl.

[0067] In some embodiments, L 4 is O or NH.

[0068] In some embodiments, L 1 is a bond and L 2 is a bond or optionally one or more R B and heterocyclyl substituted with

[0069] In some embodiments, L 1 is alkyl, and L 2 is a bond, N(R A ) or optionally one or more R B is a cycloalkyl substituted with

[0070] In some embodiments, -L 1 -L 2 -L 3 -L 4 - is -alkyl-O-. In some embodiments, -L 1 -L 2 -L 3 -L 4 -ha-(C 3-8 In some embodiments, -L 1 -L 2 -L 3 -L 4 - is -CH2CH(CH3)(CH2)3-O- or -CH2CH(CH2CH3)(CH2)3-O-.

[0071] In some embodiments, -L 1 -L 2 -L 3 -L 4 - is -heterocyclyl-alkyl-O-, wherein said heterocyclyl is optionally selected from one or more R B In some embodiments, -L 1 -L 2 -L 3 -L 4 -(5-10 membered heterocyclyl)-(C 1-6alkyl)-O-, wherein the 5- to 10-membered heterocyclyl is optionally one or more R B In some embodiments, -L 1 -L 2 -L 3 -L 4 -teeth, [ka] is selected from the group consisting of:

[0072] In some embodiments, -L 1 -L 2 -L 3 -L 4 - is - alkyl-N(R A )-alkyl-O-, and R A is selected from alkyl or heterocyclyl, wherein said alkyl or said heterocyclyl is optionally substituted with one or more halogen or alkyl. 1 -L 2 -L 3 -L 4 -ha-(C 1-6 alkyl)-N(R A )-(C 1-6 alkyl)-O-, and R A is C 1-6 alkyl or 3- to 6-membered heterocyclyl, said alkyl or heterocyclyl optionally containing one or more halogen or C 1-6 In some embodiments, -L 1 -L 2 -L 3 -L 4 -teeth, [ka] is.

[0073] In some embodiments, -L 1 -L 2 -L 3 -L 4- is -alkyl-cycloalkyl-alkyl-O-, wherein said cycloalkyl is optionally selected from one or more R B In some embodiments, -L 1 -L 2 -L 3 -L 4 -ha-(C 1-6 alkyl)-(C 3-6 Cycloalkyl)-(C 1-6 alkyl)-O-, 3-6 Cycloalkyl may optionally be one or more R B In some embodiments, -L 1 -L 2 -L 3 -L 4 -teeth [ka] is.

[0074] In some embodiments, R 1 is hydroxy and m is 1.

[0075] In some embodiments, R 1 is halogen and m is 1. In some embodiments, R 1 is bromo or fluoro and m is 1.

[0076] In some embodiments, R 1 -N(R D )2 and m is 1.

[0077] In some embodiments, R 1 -N(R D )2, and each R D are independently hydrogen or optionally -N(R F )2 OR -OR G In some embodiments, R is alkyl substituted with one or more groups independently selected from 1 -N(R D )2, and each R Dis optionally -N(R F )2 OR -OR G C substituted with one or more groups independently selected from 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In some embodiments, R 1 -N(R D )2, and each R D are independently methyl, methoxyethyl, N,N-dimethylaminoethyl, hydroxyethyl, or N,N-dimethylaminopropyl.

[0078] In some embodiments, R 1 optionally one or more R E and m is 1. In some embodiments, R 1 optionally one or more R E and m is 1.

[0079] In some embodiments, R 1 teeth, [ka] and each of which is optionally selected from the group consisting of one or more R E is replaced by .

[0080] In some embodiments, R E is a halogen.

[0081] In some embodiments, R E is F.

[0082] In some embodiments, each R E are independently halogen, -N(R F )2,-Alkyl-N(R F )2, -C(O)OR Gor alkyl optionally substituted with one or more halogens.

[0083] In some embodiments, R F and R G Each of is independently alkyl. In some embodiments, R F and R G Each of the is independently C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl.

[0084] In some embodiments, R F and R G Each of the is independently C 1-3 It is alkyl.

[0085] In some embodiments, each R E are independently F, -N(CH3)2, and -C 1-3 alkyl is selected from the group consisting of -N(CH3)2, -C(O)O(tert-butyl), methyl, ethyl or trifluoroethyl.

[0086] In some embodiments, R E is cycloalkyl or heterocyclyl, said cycloalkyl and heterocyclyl being optionally substituted with one or more alkyl and / or halogen.

[0087] In some embodiments, R E is selected from cyclopropyl, morpholine, piperazine, oxetyl, or azetidinyl, each of which is optionally substituted with one or more alkyl and / or halogen.

[0088] In some embodiments, R Eis selected from cyclopropyl, morpholinyl, piperazinyl, oxetyl, or azetidinyl, each of which is optionally substituted with one or more alkyl and / or halogen.

[0089] In some embodiments, m is 2 and R 1 One of the is a halogen and another R 1 optionally one or more R E and heterocyclyl substituted with

[0090] In some embodiments, m is 2 and R 1 One of the is a halogen and another R 1 teeth, [ka] is a heterocyclyl selected from the group consisting of each of which may optionally be one or more R E is replaced by .

[0091] In some embodiments, each R E are independently halogen, -N(R F )2,-Alkyl-N(R F )2, -C(O)OR G or alkyl optionally substituted with one or more halogens.

[0092] In some embodiments, R 1 teeth, [ka] is selected from the group consisting of:

[0093] In some embodiments, R 2 is a halogen and n is 1 or 2.

[0094] In some embodiments, R 2 is F.

[0095] In some embodiments, R 2 is alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more or halogen. 2 is C 1-6 Alkyl or C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 The cycloalkyl is optionally substituted with one or more halogens. In some embodiments, R 2 is methyl, ethyl, cyclopropyl or trifluoroethyl.

[0096] In some embodiments, R 3 is alkyl or cycloalkyl. In some embodiments, R 3 is C 1-6 Alkyl or C 3-6 In some embodiments, R 3 is methyl, ethyl or cyclopropyl.

[0097] In some embodiments, m is 0, 1, or 2.

[0098] In some embodiments, n is 0 or 1.

[0099] Exemplary compounds of formula (I) are described below. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0100] In one aspect, the present disclosure provides a compound of formula (II) [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A 1 is a 7- to 12-membered cycloalkyl, a 7- to 12-membered heterocyclyl, a 7- to 12-membered aryl, or a 7- to 12-membered heteroaryl; Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 1 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 2 is the bond, N(R A ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R Bis replaced by R A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; Each R B is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 3 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 4 is O, S or N(R C ) and R C is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 1 are independently hydroxy, halogen, cyano, amino, -N(R D)2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R E is replaced by Each R D are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of hydroxyl, halogen, cyano, -N(R F )2 OR -OR G and is substituted with one or more groups independently selected from Each R E are independently 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, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, and alkyl; R F and R Geach is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 2 are independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; Each R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; 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; The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, ring A 1 is a 7- to 12-membered heteroaryl.

[0102] In some embodiments, ring A 1 is tetrahydroisoquinolinyl.

[0103] In some embodiments, ring A 1 teeth [ka] is.

[0104] In some embodiments, Ring B is aryl. In some embodiments, Ring B is C 6-12 Aryl, C 6-11 Aryl, C 6-10 Aryl, C 6-9 Aryl or C 6-8 In some embodiments, Ring B is phenyl.

[0105] 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 pyridinyl or pyrazolyl.

[0106] In some embodiments, ring B is [ka] is selected from the group consisting of:

[0107] In some embodiments, L 1 is alkyl. In some embodiments, L 1 is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl.

[0108] In some embodiments, L 1 teeth [ka] and L 1 The * end of 2is connected to.

[0109] In some embodiments, L 2 is a bond.

[0110] In some embodiments, L 1 is alkyl, and L 2 is a bond.

[0111] In some embodiments, L 3 is alkyl. In some embodiments, L 3 is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In some embodiments, L 3 is ethyl.

[0112] In some embodiments, L 4 is O or NH.

[0113] In some embodiments, -L 1 -L 2 -L 3 -L 4 - is -alkyl-O-. In some embodiments, -L 1 -L 2 -L 3 -L 4 -ha-(C 3-8 In some embodiments, -L 1 -L 2 -L 3 -L 4 - is -(CH2)5-O-, -CH2CH(CH3)(CH2)3-O- or -CH2CH(CH2CH3)(CH2)3-O-.

[0114] In some embodiments, m is 0.

[0115] In some embodiments, m is 1 and R 1optionally one or more R E In some embodiments, m is 1 and R 1 optionally one or more R E C replaced with 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In some embodiments, R 1 optionally one or more R E is ethyl substituted with

[0116] In some embodiments, R E -N(R F )2 and R F is alkyl. In some embodiments, R E -N(R F )2 and R F is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In some embodiments, R E is -N(CH3)2.

[0117] In some embodiments, m is 1 and R 1 optionally one or more R E In some embodiments, m is 1 and R 1 is a 3- to 10-membered heterocyclyl, a 3- to 9-membered heterocyclyl, a 3- to 8-membered heterocyclyl, a 3- to 7-membered heterocyclyl, a 3- to 6-membered heterocyclyl, or a 3- to 5-membered heterocyclyl, each of which optionally is selected from the group consisting of one or more R E In some embodiments, R 1 is oxetanyl. In some embodiments, R 1 teeth [ka] is.

[0118] In some embodiments, n is 1.

[0119] In some embodiments, R 2 is alkyl. In some embodiments, R 2 is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In some embodiments, R 2 is methyl.

[0120] In some embodiments, n is 1 and R 2 is alkyl. In some embodiments, n is 1 and R 2 is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In some embodiments, n is 1 and R 2 is methyl.

[0121] In some embodiments, [ka] is.

[0122] In some embodiments, p is 1.

[0123] In some embodiments, R 3 is alkyl. In some embodiments, R 3 is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In some embodiments, R3 is methyl.

[0124] In some embodiments, p is 1 and R 3 is alkyl. In some embodiments, p is 1 and R 3 is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In some embodiments, p is 1 and R 3 is methyl.

[0125] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] is.

[0126] In some embodiments, m is 0 or 1.

[0127] In some embodiments, n is 1.

[0128] In some embodiments, p is 1.

[0129] In another aspect, the present disclosure provides a compound of formula (III) [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring B 1 is a 7- to 12-membered cycloalkyl, a 7- to 12-membered heterocyclyl, a 7- to 12-membered aryl, or a 7- to 12-membered heteroaryl; L 1 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 2 is the bond, N(R A ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R B is replaced by R A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; Each R B is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 3 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 4 is O, S or N(R C ) and R C is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 1 are independently hydroxy, halogen, cyano, amino, -N(R D )2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R E is replaced by Each R D are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of hydroxyl, halogen, cyano, -N(R F )2 OR -OR G and is substituted with one or more groups independently selected from Each R Eare independently 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, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, and alkyl; R F and R G each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 2 are independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; Each R 3is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, and said heterocyclyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; 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; The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, ring A is aryl. In some embodiments, ring A is C 6-12 Aryl, C 6-11 Aryl, C 6-10 Aryl, C 6-9 Aryl or C 6-8 In some embodiments, ring A is phenyl.

[0131] In some embodiments, ring A is heteroaryl. In some embodiments, ring A is a 5- to 12-membered heteroaryl, a 5- to 11-membered heteroaryl, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, a 5- to 8-membered heteroaryl, a 5- to 7-membered heteroaryl, or a 5- to 6-membered heteroaryl. In some embodiments, ring A is selected from the group consisting of furanyl, thiophenyl, pyrrolyl, pyridinyl, pyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, and tetrahydroisoquinolinyl.

[0132] In some embodiments, ring B 1 is a 7- to 12-membered heteroaryl.

[0133] In some embodiments, ring B 1 is pyrazolopyridinyl.

[0134] In some embodiments, ring B 1 teeth [ka] is.

[0135] In some embodiments, L 1 is a bond.

[0136] In some embodiments, L 1 is alkyl. In some embodiments, L 1 is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl.

[0137] In some embodiments, L 1 teeth, [ka] and L 1 The * end of 2 is connected to.

[0138] In some embodiments, L 2 is a bond.

[0139] In some embodiments, L 2 is N(R A ) and R A is selected from alkyl or heterocyclyl, wherein said alkyl or said heterocyclyl is optionally substituted with one or more halogen or alkyl. 2 is N(R A ) and R A is ethyl, difluoroethyl, trifluoroethyl or oxetanyl.

[0140] In some embodiments, L2 optionally one or more R B In some embodiments, L is cycloalkyl substituted with 2 is C 3-10 Cycloalkyl, C 3-9 Cycloalkyl, C 3-8 Cycloalkyl, C 3-7 Cycloalkyl, C 3-6 Cycloalkyl or C 3-5 cycloalkyl, each of which optionally has one or more R B is replaced by .

[0141] In some embodiments, L 2 optionally one or more R B replaced with [ka] is.

[0142] In some embodiments, L 2 optionally one or more R B In some embodiments, L is a heterocyclyl substituted with 2 is heterocyclyl containing one or more heteroatoms selected from N, O, or S. In some embodiments, L 2 is a 3- to 12-membered heterocyclyl, a 3- to 11-membered heterocyclyl, a 3- to 10-membered heterocyclyl, or a 3- to 9-membered heterocyclyl, each of which optionally is selected from the group consisting of one or more R B is replaced by .

[0143] In some embodiments, L 2 teeth, [ka] and a heterocyclyl selected from the group consisting of: B is substituted with L 2 The * end of 3 is connected to.

[0144] In some embodiments, L 2 is one or more R B is a cycloalkyl or heterocyclyl substituted with R B is alkyl. In some embodiments, R B is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In some embodiments, R B is methyl.

[0145] In some embodiments, L 2 teeth, [ka] and L 2 The * end of 3 is connected to.

[0146] In some embodiments, L 3 is alkyl. In some embodiments, L 3 is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl.

[0147] In some embodiments, L 3 is ethyl.

[0148] In some embodiments, L 4 is O or NH.

[0149] In some embodiments, L 1 is a bond and L 2 is a bond or optionally one or more R B and heterocyclyl substituted with

[0150] In some embodiments, L 1 is alkyl, and L 2 is a bond, N(R A ) or optionally one or more R B is a cycloalkyl substituted with

[0151] In some embodiments, -L 1 -L 2 -L 3 -L 4 - is -alkyl-O-. In some embodiments, -L 1 -L 2 -L 3 -L 4 -ha-(C 3-8 In some embodiments, -L 1 -L 2 -L 3 -L 4 - is -(CH2)5-O-, -CH2CH(CH3)(CH2)3-O- or -CH2CH(CH2CH3)(CH2)3-O-.

[0152] In some embodiments, -L 1 -L 2 -L 3 -L 4 - is -heterocyclyl-alkyl-O-, wherein said heterocyclyl is optionally selected from one or more R B In some embodiments, -L 1 -L 2 -L 3 -L 4 -(5-10 membered heterocyclyl)-(C 1-6 alkyl)-O-, wherein the 5- to 10-membered heterocyclyl is optionally one or more R B In some embodiments, -L 1 -L 2 -L 3 -L 4 -teeth, [ka] is selected from the group consisting of:

[0153] In some embodiments, -L 1 -L 2 -L 3 -L 4 - is - alkyl-N(R A )-alkyl-O-, and R A is selected from alkyl or heterocyclyl, wherein said alkyl or said heterocyclyl is optionally substituted with one or more halogen or alkyl. 1 -L 2 -L 3 -L 4 -ha-(C 1-6 alkyl)-N(R A )-(C 1-6 alkyl)-O-, and R A is C 1-6 alkyl or 3- to 6-membered heterocyclyl, said alkyl or heterocyclyl optionally containing one or more halogen or C 1-6 In some embodiments, -L 1 -L 2 -L 3 -L 4 -teeth [ka] is.

[0154] In some embodiments, -L 1 -L 2 -L 3 -L 4 - is -alkyl-cycloalkyl-alkyl-O-, wherein said cycloalkyl is optionally selected from one or more R B In some embodiments, -L 1 -L 2 -L 3 -L 4 -ha-(C 1-6 alkyl)-(C 3-6 Cycloalkyl)-(C 1-6 alkyl)-O-, 3-6Cycloalkyl may optionally be one or more R B In some embodiments, -L 1 -L 2 -L 3 -L 4 -teeth [ka] is.

[0155] In some embodiments, R 1 is a halogen and m is 1.

[0156] In some embodiments, R 1 -N(R D )2 and m is 1.

[0157] In some embodiments, R 1 -N(R D )2, and each R D are independently optionally -N(R F )2 OR -OR G In some embodiments, R is alkyl substituted with one or more groups independently selected from 1 -N(R D )2, and each R D is optionally -N(R F )2 OR -OR G C substituted with one or more groups independently selected from 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In some embodiments, R 1 -N(R D )2, and each R D are independently methyl, methoxyethyl, N,N-dimethylaminoethyl, or N,N-dimethylaminopropyl.

[0158] In some embodiments, R 1 optionally one or more RE and m is 1. In some embodiments, R 1 optionally one or more R E and m is 1.

[0159] In some embodiments, R 1 teeth, [ka] and each of which is optionally selected from the group consisting of one or more R E is replaced by .

[0160] In some embodiments, R E is a halogen.

[0161] In some embodiments, R E is F.

[0162] In some embodiments, R E is -N(R F )2,-Alkyl-N(R F )2, -C(O)OR G or alkyl optionally substituted with one or more halogens.

[0163] In some embodiments, R F and R G Each of is independently alkyl. In some embodiments, R F and R G Each of the is independently C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl.

[0164] In some embodiments, R F and R G Each of the is independently C 1-3 It is alkyl.

[0165] In some embodiments, R E is -N(CH3)2, -C 1-3 alkyl is selected from the group consisting of -N(CH3)2, -C(O)O(tert-butyl), methyl, ethyl and trifluoroethyl.

[0166] In some embodiments, R E is cycloalkyl or heterocyclyl, said cycloalkyl and heterocyclyl being optionally substituted with one or more alkyl and / or halogen.

[0167] In some embodiments, R E is selected from cyclopropyl, morpholinyl, piperazinyl, oxetanyl, or azetidinyl, each of which is optionally substituted with one or more alkyl and / or halogen.

[0168] In some embodiments, R E is selected from cyclopropyl, morpholinyl, piperazinyl, oxetanyl, or azetidinyl, each of which is optionally substituted with one or more alkyl and / or halogen.

[0169] In some embodiments, R 2 is a halogen and n is 1 or 2.

[0170] In some embodiments, R 2 is F.

[0171] In some embodiments, R 2 is alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more or halogen. 2 is C 1-6 Alkyl or C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6The cycloalkyl is optionally substituted with one or more halogens. In some embodiments, R 2 is methyl, ethyl, cyclopropyl or trifluoroethyl.

[0172] In some embodiments, [ka] is.

[0173] In some embodiments, R 3 is alkyl or cycloalkyl. In some embodiments, R 3 is C 1-6 Alkyl or C 3-6 In some embodiments, R 3 is methyl, ethyl or cyclopropyl.

[0174] In some embodiments, p is 1 and R 3 is alkyl. In some embodiments, p is 1 and R 3 is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In some embodiments, p is 1 and R 3 is methyl.

[0175] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] is.

[0176] In some embodiments, m is 0, 1, or 2.

[0177] In some embodiments, n is 0 or 1.

[0178] In some embodiments, p is 1.

[0179] In another aspect, the present disclosure provides a compound of formula (IV) [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 1 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 21 is a 7- to 12-membered cycloalkyl or a 7- to 12-membered heterocyclyl, and the cycloalkyl and heterocyclyl are optionally joined by one or more R B is replaced by Each R B is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 3is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 4 is O, S or N(R C ) and R C is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 1 are independently hydroxy, halogen, cyano, amino, -N(R D )2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R E is replaced by Each R D are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of hydroxyl, halogen, cyano, -N(R F )2 OR -OR G and is substituted with one or more groups independently selected from Each R E are independently hydrogen, hydroxyl, halogen, cyano, amino, -N(RF )2,-Alkyl-N(R F )2, -C(O)OR G , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, and alkyl; R F and R G each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 2 are independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; 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; The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, ring A is aryl. In some embodiments, ring A is C 6-12 Aryl, C 6-11 Aryl, C 6-10 Aryl, C 6-9 Aryl or C 6-8 In some embodiments, ring A is phenyl.

[0181] In some embodiments, ring A is heteroaryl. In some embodiments, ring A is a 5- to 12-membered heteroaryl, a 5- to 11-membered heteroaryl, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, a 5- to 8-membered heteroaryl, a 5- to 7-membered heteroaryl, or a 5- to 6-membered heteroaryl. In some embodiments, ring A is selected from the group consisting of furanyl, thiophenyl, pyrrolyl, pyridinyl, pyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, and tetrahydroisoquinolinyl.

[0182] In some embodiments, ring B is aryl. In some embodiments, ring B is C 6-12 Aryl, C 6-11 Aryl, C 6-10 Aryl, C 6-9 Aryl or C 6-8 In some embodiments, Ring B is phenyl.

[0183] 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 pyridinyl or pyrazolyl.

[0184] In some embodiments, ring B is [ka] is selected from the group consisting of:

[0185] In some embodiments, L 1 is a bond.

[0186] In some embodiments, L 21 is a 7-10 membered heterocyclyl containing one or more heteroatoms selected from N or O.

[0187] In some embodiments, L 21 teeth, [ka] and L 21 The * end of 3 is connected to.

[0188] In some embodiments, L 3 is alkyl. In some embodiments, L 3 is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl.

[0189] In some embodiments, L 3 is ethyl.

[0190] In some embodiments, L 4 is O or NH.

[0191] In some embodiments, -L 1 -L 21 -L 3 -L 4- is -heterocyclyl-alkyl-O-, wherein said heterocyclyl is optionally selected from one or more R B In some embodiments, -L 1 -L 21 -L 3 -L 4 -(5-10 membered heterocyclyl)-(C 1-6 alkyl)-O-, wherein the 5- to 10-membered heterocyclyl is optionally one or more R B is replaced by .

[0192] In some embodiments, -L 1 -L 21 -L 3 -L 4 -teeth, [ka] is selected from the group consisting of:

[0193] In some embodiments, R 1 is a halogen and m is 1.

[0194] In some embodiments, R 1 -N(R D )2 and m is 1.

[0195] In some embodiments, R 1 -N(R D )2, and each R D are independently optionally -N(R F )2 OR -OR G In some embodiments, R is alkyl substituted with one or more groups independently selected from 1 -N(R D )2, and each R D is optionally -N(R F )2 OR -OR G C substituted with one or more groups independently selected from 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C1-3 Alkyl or C 1-2 In some embodiments, R 1 -N(R D )2, and each R D are independently methyl, methoxyethyl, or N,N-dimethylaminopropyl.

[0196] In some embodiments, R 1 optionally one or more R E and m is 1. In some embodiments, R 1 optionally one or more R E and m is 1.

[0197] In some embodiments, R 1 teeth, [ka] and each of which is optionally selected from the group consisting of one or more R E is replaced by .

[0198] In some embodiments, R E is a halogen.

[0199] In some embodiments, R E is F.

[0200] In some embodiments, R E is -N(R F )2,-Alkyl-N(R F )2, -C(O)OR G or alkyl optionally substituted with one or more halogens.

[0201] In some embodiments, R F and R G Each of is independently alkyl. In some embodiments, R F and R GEach of the is independently C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl.

[0202] In some embodiments, R F and R G Each of the is independently C 1-3 It is alkyl.

[0203] In some embodiments, R E is -N(CH3)2, -C 1-3 alkyl is selected from the group consisting of -N(CH3)2, -C(O)O(tert-butyl), methyl, ethyl and trifluoroethyl.

[0204] In some embodiments, R E is cycloalkyl or heterocyclyl, said cycloalkyl and heterocyclyl being optionally substituted with one or more alkyl and / or halogen.

[0205] In some embodiments, R E is selected from cyclopropyl, morpholinyl, piperazinyl, oxetanyl, or azetidinyl, each of which is optionally substituted with one or more alkyl and / or halogen.

[0206] In some embodiments, R E is selected from cyclopropyl, morpholinyl, piperazinyl, oxetyl, or azetidinyl, each of which is optionally substituted with one or more alkyl and / or halogen.

[0207] In some embodiments, R 1 teeth, [ka] is selected from the group consisting of:

[0208] In some embodiments, R 2 is a halogen and n is 1 or 2.

[0209] In some embodiments, R 2 is F.

[0210] In some embodiments, R 2 is alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more or halogen. 2 is C 1-6 Alkyl or C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 The cycloalkyl is optionally substituted with one or more halogens. In some embodiments, R 2 is methyl, ethyl, cyclopropyl or trifluoroethyl.

[0211] In some embodiments, R 2 is methyl.

[0212] In some embodiments, R 3 is alkyl. In some embodiments, R 3 Each of the is independently C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In some embodiments, R 3 is methyl.

[0213] In some embodiments, p is 1 and R 3 is alkyl. In some embodiments, p is 1 and R 3 is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2In some embodiments, p is 1 and R 3 is methyl.

[0214] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] is.

[0215] In some embodiments, m is 1.

[0216] In some embodiments, n is 1.

[0217] In some embodiments, p is 1.

[0218] Exemplary compounds of the present disclosure are described below. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

[0219] The compounds provided herein are described with reference to both generic formulas and specific compounds. Additionally, the compounds of the present disclosure 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 isotopic derivatives, all of which are within the scope of the present disclosure.

[0220] As used herein, the term "prodrug" refers to a compound or a pharmaceutically acceptable salt thereof that produces the desired active compound when metabolized under physiological conditions or converted by solvolysis. Prodrugs include, but are not limited to, esters, amides, urethanes, carbonates, ureas, solvates, or hydrates of the active compound. Generally, prodrugs are inactive or less active than the active compound, but may offer one or more advantageous processing, administration, and / or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolism, the ester group is cleaved to produce the active drug. Some prodrugs are also activated by enzymes to produce the active compound or a compound that produces the active compound upon further chemical reaction. A prodrug can become active from the prodrug form in a single step, or it can have one or more intermediate forms that may or may not themselves be active. A discussion of the preparation and use of prodrugs is provided by the following references: T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, Bioreversible Carriers in Drug Design, Edward B. Roche (ed.), American Pharmaceutical Association and Pergamon Press, 1987; Prodrugs: Challenges and Rewards, V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley (eds.), Springer Verlag New York, 2007, all of which are hereby incorporated by reference in their entireties.

[0221] The term "metabolite," e.g., active metabolite, as used herein overlaps with the prodrug described above. Thus, such metabolites are pharmacologically active compounds that are derivatives resulting from metabolic processes in the subject's body, or compounds that are metabolized to further pharmacologically active compounds. For example, such metabolites can be produced by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic degradation, etc., of an administered compound or salt or prodrug. Here, active metabolites are derivative compounds that have pharmacological activity. For prodrugs, the prodrug compound is generally inactive or less active than its metabolic product. For active metabolites, the parent compound may be an active compound or an inactive prodrug.

[0222] 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, ibid.

[0223] As used herein, the term "pharmaceutically acceptable" means that a substance or composition is chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the subject being treated.

[0224] As used herein, the term "pharmaceutically acceptable" includes, unless otherwise specified, salts that retain the biological effectiveness of the free acids and bases of the particular 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 non-toxic in the amounts and concentrations administered. The preparation of such salts can facilitate pharmacological uses without inhibiting physiological activity by altering the physical properties of the compound. Useful changes in physical properties include lowering the melting point to facilitate administration via mucous membranes and increasing solubility to facilitate the administration of higher drug concentrations.

[0225] Pharmaceutically acceptable salts include acid addition salts such as sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylaminosulfonate, and quinate. Pharmaceutically acceptable salts can be derived from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid, fumaric acid, and quinic acid.

[0226] When an acidic functional group, such as a carboxylic acid or a phenol, is present, pharmaceutically acceptable salts also include base addition salts with benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, zinc, and the like. 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 can be prepared using the appropriate corresponding base.

[0227] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of a compound can be isolated by dissolving it in a suitable solvent (e.g., an aqueous or aqueous-alcoholic solution containing a suitable acid) and then evaporating the solution. Thus, if a particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, such as treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid; an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, or salicylic acid; a pyranosidyl acid such as glucuronic acid or galactosaldehyde acid; an α-hydroxyl 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; or a sulfonic acid such as p-toluenesulfonic acid or ethylsulfonic acid.

[0228] Similarly, if a particular compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, treating the free base with an inorganic or organic base such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide. Illustrative examples of suitable salts include organic salts derived from amino acids such as L-glycine, L-lysine, and L-arginine, ammonia, primary amines, secondary amines, tertiary amines, and cycloamines such as hydroxyethylpyrrolidine, piperidine, morpholine, or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0229] It should also be understood that the compounds of the present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystalline or polycrystalline forms), and that the present disclosure is intended to encompass all such forms.

[0230] The term "solvate" or "solvate form" as used herein refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state to form a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with a molecule of a substance in which water maintains its molecular state as HO. Examples of solvents that form solvates include, but are not limited to, water, isopropyl alcohol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0231] The present disclosure is also intended to include all isotopic forms of the compounds provided herein. Isotopes of an atom include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compounds of the present disclosure are isotopes of those atoms. 1 H, 2 H, 3 H, 11 C. 12 C. 13 C. 14 C. 14 N, 15 N, 16 O. 17 O. 18 O. 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I and 131 It is meant to further include isotopes such as, but not limited to, I. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes 12 C and 13 Contains C.

[0232] The compounds provided herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry as (R)- or (S)- or (D)- or (L)- of an amino acid, or based on relative configuration as rel-(R)- or rel-(S)-. The present disclosure includes all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared by chiral synthesizers or chiral reagents or resolved by conventional techniques, such as chromatography and stepwise crystallization. Conventional techniques for preparing and separating individual enantiomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using chiral high-pressure liquid chromatography (HPLC). Whether or not a compound is represented in its chiral form, it should be understood that the embodiments include, but are not limited to, the particular diastereomerically or enantiomerically enriched forms. Where chirality is not specified but chirality is present, it should be understood that the embodiments are intended to include the particular diastereomerically or enantiomerically enriched form, or racemic or scalaminic mixtures of such compounds.

[0233] The term "stereoisomers" refers to compounds containing the same atoms connected by the same bonds but having different three-dimensional structures, and are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0234] The term "enantiomer" 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 that is not in a 1:1 ratio is a "scalic" mixture.

[0235] The term "diastereomers" means stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0236] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. The existence and concentration of isomeric forms depends on the environment in which the compound is found and can vary depending on whether the compound is a solid or in an organic or aqueous solution. For example, proton tautomers (also called proton isomeric tautomers) include interconversions via proton migration, such as ketone-enol, amide-imidic acid, lactam-lactim, and imine-enamine isomerizations, as well as cyclic forms in which a proton can occupy more than one position in a heterocyclic ring system. Valence tautomers include interconversions via recombination of some bond-forming electrons. Tautomers may be in equilibrium or spatially locked as one form by appropriate substitution. Unless otherwise specified, compounds identified as a particular tautomeric form according to name or structure in this disclosure are intended to include other tautomeric forms.

[0237] When the compounds provided herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds include both E and Z geometric isomers. Synthesis method

[0238] The compounds provided herein can be prepared using any known organic synthesis technique and can be synthesized according to any of a variety of possible synthetic routes.

[0239] The reaction for preparing the compounds of the present disclosure can be carried out in a suitable solvent that can be easily selected by a person skilled in the art of organic synthesis. A suitable solvent may be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, for example, at a temperature ranging 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 one or more solvents. Depending on the specific reaction step, a suitable solvent for a particular reaction step can be selected by a person skilled in the art.

[0240] The preparation of the compounds of the present disclosure 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 easily determined by those skilled in the art. The chemistry of protecting groups can be found in references such as TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Edition, John Wiley & Sons, New York, (1999); P. Kocienski, "Protecting Groups", Georg Thieme Verlag, 2003; and Peter GM Wuts, "Greene's Protective Groups in Organic Synthesis", 5th Edition, Wiley, 2014, which are incorporated herein by reference in their entirety.

[0241] The reaction can be monitored by any suitable method known in the art, for example, nuclear magnetic resonance spectroscopy (e.g., 1 H or 13Product formation can be monitored by spectroscopic means, such as spectroscopy (e.g., infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or chromatographic methods, such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). One skilled in the art can purify compounds by a variety of 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, J. Combi. Chem. 2004, 6(6), 874-883, the entirety of which is incorporated herein by reference) and normal-phase silica chromatography. Drug Composition

[0242] In another aspect, there is provided a pharmaceutical composition comprising one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition of the present disclosure comprises a first compound provided herein or a pharmaceutically acceptable salt thereof and one or more additional compounds of the same formula, but the first compound and the additional compound are not the same molecule.

[0243] In another aspect, there is provided a pharmaceutical composition comprising one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.

[0244] In some embodiments, the pharmaceutical compositions of the present disclosure comprise a therapeutically effective amount of one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0245] In some embodiments, the pharmaceutical compositions of the present disclosure comprise a therapeutically effective amount of one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.

[0246] As used herein, the term "therapeutically effective amount" refers to an amount of a molecule, compound, or composition containing a molecule or compound that treats, ameliorate, or prevent an identified disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any measurement method known in the art. The precise 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 therapeutic or combination of therapeutics selected for administration, and the judgment of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0247] As used herein, the term "pharmaceutical composition" refers to a formulation comprising a molecule or compound of the present disclosure in a form suitable for administration to a subject. Pharmaceutical compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), sublingual, ophthalmic, transdermal, or nasal administration, although the most suitable route in any given situation will depend on the particular host and the nature and severity of the condition for which the active ingredient is being administered. Pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0248] As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient that is generally safe, non-toxic, and used in the preparation of pharmaceutical compositions, whether biologically or otherwise required, and includes excipients that are acceptable for use in veterinary and human medicine. As used herein, "pharmaceutically acceptable excipient" includes one or more such excipients. The term "pharmaceutically acceptable excipient" also encompasses "pharmaceutically acceptable carriers" and "pharmaceutically acceptable diluents."

[0249] The specific excipient used depends on the means and purpose of using the compounds of the present disclosure. Solvents are generally selected based on solvents that are considered safe by those skilled in the art to be administered to mammals, including humans. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), etc., and mixtures thereof.

[0250] In some embodiments, suitable excipients include buffers (e.g., phosphates, citrates, and other organic acids), antioxidants including ascorbic acid and methionine, preservatives (e.g., octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butanol, or benzyl alcohol, alkylparabens such as methylparaben or propylparaben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol), low molecular weight (less than about 10 residues) polypeptides, and the like. The present invention relates to a soluble polymer, such as a soluble polymer, ... TM , PLURONICS TM or polyethylene glycol (PEG).

[0251] In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-blocking agents, glidants, processing aids, colorants, sweeteners, fragrances, flavor enhancers, and other known additives to provide an optimal form of the drug (i.e., a compound of the present disclosure or a drug composition thereof) or to aid in the preparation of a pharmaceutical product (i.e., a drug). The active drug ingredient may be embedded in microcapsules prepared, for example, by aggregation techniques or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions, respectively. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th Edition, edited by Osol, A. (1980). "Liposomes" are vesicles containing various types of lipids, phospholipids, lipids, and / or surfactants that can be used to deliver drugs (including the compounds disclosed herein and any chemotherapeutic agents) to mammals, including humans. The components of liposomes are generally arranged in a bilayer, similar to the lipid arrangement of a biofilm.

[0252] The pharmaceutical compositions provided herein may be in any form that allows for the composition to be administered to a subject, including but not limited to a human, and the composition can be formulated to be compatible with the desired route of administration.

[0253] Various routes are contemplated for the drug compositions provided herein, and therefore, the drug compositions provided herein may be supplied in bulk or in unit dosage form depending on the desired route of administration. For example, for oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gel capsules, and caplets are acceptable solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions are acceptable liquid dosage forms. For injectable administration, emulsions and suspensions are acceptable liquid dosage forms, and powders suitable for reconstitution with an appropriate solution are acceptable solid dosage forms. For inhalation administration, 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, pessaries, tampons, creams, gels, pastes, foams, and sprays may be acceptable dosage forms.

[0254] In some embodiments, the drug compositions of the present disclosure may be in the form of a formulation for oral administration.

[0255] In some embodiments, the pharmaceutical composition of the present disclosure may be in the form of a tablet formulation. Suitable pharmaceutically acceptable excipients for tablet formulations include inert diluents (e.g., lactose, sodium carbonate, calcium phosphate, or calcium carbonate), granulating and disintegrating agents (e.g., cornstarch or alginic acid), adhesives (e.g., starch), lubricants (e.g., magnesium stearate, stearic acid, or talc), preservatives (e.g., ethyl or propyl parahydroxybenzoate), and antioxidants (e.g., ascorbic acid). The tablet formulation may be uncoated or coated to modify its disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract or to improve its stability and / or appearance, in either case using conventional coating agents and processes well known in the art.

[0256] In some embodiments, the drug compositions of the present disclosure may be hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

[0257] In some embodiments, the drug compositions of the present disclosure may be in the form of an aqueous suspension, which generally comprises the active ingredient in finely divided form and one or more suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth, and gum arabic), dispersing or wetting agents (e.g., lecithin or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate)), or condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives (for example, ethyl or propyl parahydroxybenzoate), antioxidants (for example, ascorbic acid), coloring agents, flavoring agents, and / or sweetening agents (for example, sucrose, saccharin, or aspartame).

[0258] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an oily suspension, which typically comprises the active ingredient suspended in a vegetable oil (e.g., peanut oil, castor oil, olive oil, sesame oil, or coconut oil) or in a mineral oil (e.g., liquid paraffin). Oily suspensions may further contain a thickening agent such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents (such as those described above) and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant (e.g., ascorbic acid).

[0259] In some embodiments, the pharmaceutical composition of the present disclosure 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 these oils. Suitable emulsifiers may include, for example, naturally occurring gums (e.g., gum arabic or tragacanth), naturally occurring phospholipids (e.g., soybeans, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate)), and condensation products of such partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsion may further contain sweeteners, flavoring agents, and preservatives.

[0260] In some embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweetening agents (e.g., glycerin, propylene glycol, sorbitol, aspartame or sucrose), demulcents, preservatives, flavorings and / or coloring agents.

[0261] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for injectable administration.

[0262] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. Such suspensions can be formulated using suitable dispersing or wetting agents and suspending agents, as described above, according to known techniques. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, non-gastrointestinal-acceptable diluent or solvent, for example, 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. Sterile fixed oils are also commonly used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid, can also be used to prepare injectables.

[0263] In some embodiments, the drug compositions of the present disclosure may be in the form of a formulation for inhaled administration.

[0264] In some embodiments, the drug compositions of the present disclosure may be in the form of aqueous and non-aqueous (e.g., in fluorocarbon propellant) aerosols, which may contain any suitable solvent and any other compounds, such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. Carriers and stabilizers vary depending on the requirements of the particular compound, but generally include non-ionic surfactants (Tween, Pluronic, or polyethylene glycol), innocuous proteins (e.g., serum albumin), sorbitan esters, oleic acid, lecithin, amino acids (e.g., glycine), buffers, salts, sugars, or sugar alcohols.

[0265] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for topical or transdermal administration. In some embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels, and aqueous or oily solutions or suspensions, which can generally be obtained by blending the active ingredient with conventional topically acceptable excipients (e.g., animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof).

[0266] In some embodiments, the drug compositions provided herein may be formulated for ophthalmic administration. In some embodiments, the drug compositions provided herein may be in the form of an ophthalmic formulation, such as an eye drop paste, powder, or solution. In some embodiments, the ophthalmic formulation is prepared at a comfortable pH and with an appropriate buffer system.

[0267] In addition to the exemplary 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 the following references: "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991); "Remington: The Science and Practice of Pharmacy," edited by University of the Sciences in Philadelphia, 21st ed., LWW (2005), which are incorporated herein by reference.

[0268] Dosage schemes for the compounds provided herein will vary depending on known factors, such as the pharmacological characteristics of the particular drug and its method and route of administration, the recipient's species, age, sex, health, physical condition and weight, the nature and severity of symptoms, type of concurrent treatment, frequency of treatment, route of administration, the patient's renal and hepatic 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 progression of the condition.

[0269] In some embodiments, the pharmaceutical compositions of the present disclosure provide a compound provided herein or a pharmaceutically acceptable salt thereof in an amount ranging from 0.001 mg / kg body weight / day to 1000 mg / kg body weight / day, for example, from 0.01 mg / kg body weight / day to 800 mg / kg body weight / day, from 0.01 mg / kg body weight / day to 700 mg / kg body weight / day, from 0.01 mg / kg body weight / day to 600 mg / kg body weight / day, from 0.01 mg / kg body weight / day to 500 mg / kg body weight / day, from 0.01 mg / kg body weight / day to 400 mg / kg body weight / day, from 0.01 mg / kg body weight / day to 300 mg / kg body weight / day, from 0.1 mg / kg body weight / day to 200 mg / kg body weight / day, from 0.1 mg / kg body weight / day to 150 mg / kg body weight / day, from 0.1 mg / kg body weight / day to 100 mg / kg body weight / day, or from 0.5 mg / kg body weight / day to 100 It can be formulated to be administered at doses ranging from 0.5 mg / kg body weight / day to 80 mg / kg body weight / day, from 0.5 mg / kg body weight / day to 60 mg / kg body weight / day, from 0.5 mg / kg body weight / day to 50 mg / kg body weight / day, from 1 mg / kg body weight / day to 50 mg / kg body weight / day, from 1 mg / kg body weight / day to 45 mg / kg body weight / day, from 1 mg / kg body weight / day to 40 mg / kg body weight / day, from 1 mg / kg body weight / day to 35 mg / kg body weight / day, from 1 mg / kg body weight / day to 30 mg / kg body weight / day, and from 1 mg / kg body weight / day to 25 mg / kg body weight / day. In some cases, dosage levels below the lower end of the above ranges may be tolerated, while in other cases, larger doses can be used without causing adverse side effects, provided that such larger doses are first divided into several smaller doses to be administered throughout the day. For details of routes of administration and dosage schemes, see Comprehensive Medicinal Chemistry, Vol. 5, Chapter 25.3 (Corwin Hansch, Editor-in-Chief), Pergamon Publishers, 1990, which is expressly incorporated herein by reference.

[0270] In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated as a single dosage form. The amount of a compound provided herein in a single dosage form will vary depending on the subject being treated and the particular mode of administration.

[0271] In some embodiments, dosage forms suitable for administration can contain from about 1 mg to about 1000 mg of the active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient is generally present in an amount of about 0.1-95% by weight, based on the total weight of the composition.

[0272] In some embodiments, the drug compositions of the present disclosure may be formulated as short-acting, fast-releasing, long-acting, or sustained-releasing forms. Thus, the drug formulations of the present disclosure may be formulated for controlled or sustained release.

[0273] In some embodiments, a fixed dose of a compound provided herein or a pharmaceutical composition provided herein is administered to a subject daily, 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 desired, the daily effective dose of the active compound can be administered as two, three, four, five, six, or more subdoses administered singly at appropriate intervals throughout the day, optionally in unit dosage form. In some embodiments, a fixed dose of a compound provided herein or a pharmaceutical composition provided herein is administered over a period of 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 more.

[0274] In another aspect, there is further provided a veterinary composition comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier. The veterinary carrier is a material for administering the composition and may be a solid, liquid, or gaseous material that is 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.

[0275] Pharmaceutical or veterinary compositions can be packaged in a variety of ways depending on the method of drug administration. For example, a product for distribution can include a container holding the composition in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), drug packets, ampoule bottles, plastic bags, and metal tubes. The container may further include a tamper-evident assembly to prevent easy access to the contents of the package. The container also carries a label describing the contents of the container. The label may include appropriate warnings. The compositions may be packaged in unit-dose or multi-dose containers, such as sealed ampoule bottles and vials, and can be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, e.g., water for injection, immediately prior to use. Injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the type described above.

[0276] In some embodiments, the pharmaceutical compositions of the present disclosure comprising one or more compounds provided herein or pharmaceutically acceptable salts thereof further comprise one or more additional therapeutically active agents.

[0277] The additional therapeutically active agents have complementary activities to the compounds provided herein so that they do not adversely affect each other, and such agents are present in any combination in amounts that are effective for the desired purpose.

[0278] In some embodiments, the additional therapeutic agent is selected from an EGFR TKI, an EGFR antibody, a MEK inhibitor, a c-MET inhibitor, a mitotic kinase inhibitor, an immunotherapeutic agent, an anti-angiogenic agent, an apoptosis inducer, an mTOR inhibitor, a histone deacetylase inhibitor, an IL6 inhibitor, or a JAK inhibitor.

[0279] Examples of EGFR TKIs include, but are not limited to, for example, afatinib, erlotinib, gefitinib, lapatinib, dacomitinib, osimertinib, olmutinib, nazartinib, and AC0010.

[0280] Examples of EGFR antibodies include, for example, cetuximab, panitumumab, and necitumumab.

[0281] Examples of MEK inhibitors include trametinib, cobimetinib, binimetinib, selumetinib, and refametinib.

[0282] Examples of c-MET inhibitors include, for example, savolitinib, cabozantinib, foretinib, and MET antibodies (eg, emibetuzumab).

[0283] Examples of mitotic kinase inhibitors include CDK4 / 6 inhibitors, such as palbociclib, ribociclib, and abemaciclib.

[0284] 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, and PDR-001, and immunomodulatory agents such as CD73 inhibitors or CD73 inhibitor antibodies.

[0285] Examples of anti-angiogenic agents include, for example, bevacizumab and nintedanib.

[0286] Examples of cell apoptosis inducers include Bcl-2 inhibitors (e.g., venetoclax, obatoclax, navitoclax), Mcl-1 inhibitors (e.g., AZD-5991, AMG-176, S-64315).

[0287] Examples of mTOR inhibitors include, for example, rapamycin, temsirolimus, everolimus, and ridaforolimus.

[0288] Examples of histone deacetylase inhibitors include, for example, panobinostat, entinostat, romidepsin, and vorinostat.

[0289] Examples of IL6 inhibitors include, for example, tocilizumab, siltuximab, olokizumab, elsilimomab, clazakizumab, sirukumab, revilimab, ARGX-109, FE301, and FM101.

[0290] Illustrative examples of JAK inhibitors include, for example, baricitinib, ruxolitinib, tofacitinib, oclacitinib, baricitinib, peficitinib, fedratinib, upadacitinib, filgotinib, delgocitinib, and abrocitinib.

[0291] The one or more additional therapeutic agents can be administered simultaneously with or sequentially to the compounds provided herein. Sequential administration includes administration before or after the compounds provided herein. In some embodiments, the one or more additional therapeutic agents can be administered in the same composition as the compounds provided herein. In other embodiments, there can be a time interval between the administration of the additional therapeutic agent and the administration of the compounds provided herein.

[0292] In some embodiments, administering an additional therapeutic agent together with a compound provided herein allows for the other therapeutic agent to be administered at lower dosages and / or at less frequent intervals. Treatment method

[0293] The compounds of the present disclosure and pharmaceutical compositions containing the compounds can inhibit EGFR and can therefore be used to inhibit EGFR activity and prevent or treat EGFR-related diseases in subjects in need of such treatment.

[0294] In another aspect, the present disclosure provides a method for treating an EGFR-associated condition, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0295] As used herein, the terms "treating" or "therapy" are intended to have their normal meaning of addressing a disease to completely or partially ameliorate one, some, or all of its symptoms or to correct or compensate for an underlying pathology, thereby achieving a beneficial or desired clinical result. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, amelioration of symptoms, reduction in the extent of disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, improvement or palliation and remission (either partial or total) of the disease state, which may be detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not treated. Conditions in need of treatment include those suffering from a disease state or condition, those susceptible to a disease state or condition, and those in which a disease state or condition is to be prevented.

[0296] As used herein, the term "preventing," "prevention," or "prophylaxis" is intended to have its normal meaning and includes primary prevention, which prevents the progression of disease, and secondary prevention, which temporarily or permanently protects a patient from progression or worsening of the disease or the development of new symptoms associated with the disease as the disease progresses.

[0297] In some embodiments, the compounds or pharmaceutically acceptable salts thereof and compositions provided herein can be used to treat various EGFR-associated conditions, including cancer, autoimmune diseases, and the like.

[0298] In some embodiments, the compounds or pharmaceutically acceptable salts thereof and compositions provided herein can be used to treat cancer, including lung cancer (e.g., non-small cell 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).

[0299] In some embodiments, the compounds or pharmaceutically acceptable salts thereof and compositions 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 afflictions.

[0300] The dosage and route of administration to a subject will vary depending on the EGFR-related condition being treated. In some embodiments, the administration is by a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intraspinal, intramuscular, intravitreal, intravenous, intraarterial, oral, buccal, sublingual, transdermal, topical, intratracheal, rectal, subcutaneous, and ocular administration.

[0301] Embodiments of each aspect provided in the present disclosure are also described in any of the following paragraphs.

[0302] In embodiment 1, a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 1is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 2 is the bond, N(R A ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R B is replaced by R A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; Each R B is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 3is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 4 is O, S or N(R C ) and R C is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 1 are independently hydroxy, halogen, cyano, amino, -N(R D )2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R E is replaced by Each R D are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of hydroxyl, halogen, cyano, -N(R F )2 OR -OR G and is substituted with one or more groups independently selected from Each R E are independently hydrogen, hydroxyl, halogen, cyano, amino, -N(RF )2,-Alkyl-N(R F )2, -C(O)OR G , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, and alkyl; R F and R G each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 2 are independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; m is an integer from 0 to 5, and n is an integer from 0 to 4.

[0303] Embodiment 2. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein ring A is aryl or heteroaryl.

[0304] Embodiment 3. The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of furanyl, thiophenyl, pyrrolyl, phenyl, pyridinyl, pyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, and tetrahydroisoquinoline.

[0305] Embodiment 4. The compound of embodiment 3, or a pharmaceutically acceptable salt thereof, wherein ring A is [ka] is selected from the group consisting of:

[0306] Embodiment 5. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein ring B is aryl or heteroaryl.

[0307] Embodiment 6. A compound according to embodiment 5, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or pyrazolyl.

[0308] Embodiment 7. The compound of embodiment 6, or a pharmaceutically acceptable salt thereof, wherein ring B is: [ka] is.

[0309] Embodiment 8. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein L 1 is a bond.

[0310] Embodiment 9. A compound according to embodiment 8, or a pharmaceutically acceptable salt thereof, wherein L1 is alkyl.

[0311] Embodiment 10. A compound according to embodiment 9, or a pharmaceutically acceptable salt thereof, wherein L 1 teeth, [ka] and L 1 The * end of 2 is connected to.

[0312] Embodiment 11. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein L 2 is a bond.

[0313] Embodiment 12. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein L 2 is N(R A ) and R A is selected from alkyl or heterocyclyl, said alkyl or said heterocyclyl optionally substituted with one or more halogen or alkyl.

[0314] Embodiment 13. A compound of embodiment 12, or a pharmaceutically acceptable salt thereof, wherein R A is ethyl, difluoroethyl, trifluoroethyl or oxetanyl.

[0315] Embodiment 14. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein L 2 optionally one or more R B is a cycloalkyl substituted with

[0316] Embodiment 15. A compound according to embodiment 14, or a pharmaceutically acceptable salt thereof, wherein L 2 teeth [ka] and optionally one or more R B is replaced by .

[0317] Embodiment 16. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein L 2 optionally one or more R B and heterocyclyl substituted with

[0318] Embodiment 17. The compound of Embodiment 16, or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl is: [ka] is selected from the group consisting of each of which may optionally be one or more R B is substituted with L 2 The * end of 3 is connected to.

[0319] Embodiment 18. A compound according to embodiment 16 or 17, or a pharmaceutically acceptable salt thereof, wherein R B is alkyl.

[0320] Embodiment 19. A compound of embodiment 19 or a pharmaceutically acceptable salt thereof, wherein R B is methyl.

[0321] Embodiment 20. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein L 2 teeth, [ka] and L 2 The * end of 3 is connected to.

[0322] Embodiment 21. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein L 3 is alkyl.

[0323] Embodiment 22. A compound according to embodiment 21 or a pharmaceutically acceptable salt thereof, wherein L 3 is ethyl.

[0324] Embodiment 23. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein L 4 is O or NH.

[0325] Embodiment 24. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein L 1 is a bond and L 2 is a bond or optionally one or more R B and heterocyclyl substituted with

[0326] Embodiment 25. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein L 1 is alkyl, and L 2 is a bond, N(R A ) or optionally one or more R B is a cycloalkyl substituted with

[0327] Embodiment 26. A compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is a halogen and m is 1.

[0328] Embodiment 27. A compound of Embodiment 26 or a pharmaceutically acceptable salt thereof, wherein R 1 is bromo.

[0329] Embodiment 28. A compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 1 -N(R D )2 and m is 1.

[0330] Embodiment 29. A compound of Embodiment 28 or a pharmaceutically acceptable salt thereof, wherein each R D are independently optionally -N(R F )2 OR -OR Gand alkyl substituted with one or more groups independently selected from:

[0331] Embodiment 30. A compound of Embodiment 29 or a pharmaceutically acceptable salt thereof, wherein each R D are independently methyl, methoxyethyl, or N,N-dimethylaminopropyl.

[0332] Embodiment 31. A compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 1 optionally one or more R E and m is 1.

[0333] Embodiment 32. The compound of Embodiment 31, or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl is: [ka] is selected from the group consisting of each of which may optionally be one or more R E is replaced by .

[0334] Embodiment 33. A compound of Embodiment 31 or a pharmaceutically acceptable salt thereof, wherein R E is a halogen.

[0335] Embodiment 34. A compound of Embodiment 32 or a pharmaceutically acceptable salt thereof, wherein R E is F.

[0336] Embodiment 35. A compound of Embodiment 31 or a pharmaceutically acceptable salt thereof, wherein R E is -N(R F )2,-Alkyl-N(R F )2, -C(O)OR G or alkyl optionally substituted with one or more halogens.

[0337] Embodiment 36. A compound of Embodiment 35, or a pharmaceutically acceptable salt thereof, wherein R F and R G Each of is alkyl.

[0338] Embodiment 37. A compound of Embodiment 35, or a pharmaceutically acceptable salt thereof, wherein R F and R G Each of the C 1-3 It is alkyl.

[0339] Embodiment 38. A compound of Embodiment 35 or a pharmaceutically acceptable salt thereof, wherein R E is -N(CH3)2, -C 1-3 alkyl is selected from the group consisting of -N(CH3)2, -C(O)O(tert-butyl), methyl, ethyl or trifluoroethyl.

[0340] Embodiment 39. A compound of Embodiment 31 or a pharmaceutically acceptable salt thereof, wherein R E is cycloalkyl or heterocyclyl, said cycloalkyl and said heterocyclyl being optionally substituted with one or more alkyl or halogen.

[0341] Embodiment 40. A compound of Embodiment 39 or a pharmaceutically acceptable salt thereof, wherein R E is selected from cyclopropyl, morpholinyl, piperazinyl, oxetyl, or azetidinyl, each of which is optionally substituted with one or more alkyl or halogen.

[0342] Embodiment 41. A compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, [ka] is selected from the group consisting of:

[0343] Embodiment 42. A compound of Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein R2 is a halogen and n is 1 or 2.

[0344] Embodiment 43. A compound of Embodiment 42 or a pharmaceutically acceptable salt thereof, wherein R 2 is F.

[0345] Embodiment 44. A compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is alkyl or cycloalkyl, said alkyl and cycloalkyl being optionally substituted with one or more halogens.

[0346] Embodiment 45. A compound of Embodiment 44 or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl, ethyl, cyclopropyl or trifluoroethyl.

[0347] Embodiment 46. A compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 3 is alkyl or cycloalkyl.

[0348] Embodiment 47. A compound of Embodiment 46, or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl, ethyl or cyclopropyl.

[0349] Embodiment 48. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

[0350] Embodiment 49. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

[0351] Embodiment 50. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0352] 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.

[0353] Embodiment 52. A method of inhibiting EGFR activity in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound of any one of Embodiments 1 to 50 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 51.

[0354] Embodiment 53. A method for treating an EGFR-related condition in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of Embodiments 1 to 50 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 51.

[0355] Embodiment 54 The method of embodiment 53, wherein the EGFR-associated disease is an autoimmune disease or cancer.

[0356] Embodiment 55. The method of 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 metastases (particularly brain metastases).

[0357] Embodiment 56 The method of any one of Embodiments 53 to 55, wherein the compound is administered simultaneously, alone, or sequentially with one or more additional therapeutic agents.

[0358] Embodiment 57. The method of embodiment 56, wherein the one or more additional therapeutic agents are selected from the group consisting of an EGFR TKI, an EGFR antibody, a MEK inhibitor, a c-MET inhibitor, a mitotic kinase inhibitor, an immunotherapeutic agent, an anti-angiogenic agent, an apoptosis inducer, an mTOR inhibitor, a histone deacetylase inhibitor, an IL6 inhibitor, and a JAK inhibitor.

[0359] Embodiments of each aspect provided in this disclosure are also described in any of the following paragraphs.

[0360] Item 1. Compound of formula (II) [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A 1 is a 7- to 12-membered cycloalkyl, a 7- to 12-membered heterocyclyl, a 7- to 12-membered aryl, or a 7- to 12-membered heteroaryl; Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 1is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 2 is the bond, N(R A ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R B is replaced by R A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; Each R B is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 3is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 4 is O, S or N(R C ) and R C is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 1 are independently hydroxy, halogen, cyano, amino, -N(R D )2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R E is replaced by Each R D are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of hydroxyl, halogen, cyano, -N(R F )2 OR -OR G and is substituted with one or more groups independently selected from Each R E are independently hydrogen, hydroxyl, halogen, cyano, amino, -N(RF )2,-Alkyl-N(R F )2, -C(O)OR G , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, and alkyl; R F and R G each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 2 are independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; Each R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; 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.

[0361] Item 2. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein ring A 1 is a 7- to 12-membered heteroaryl.

[0362] Item 3. The compound according to Item 2 or a pharmaceutically acceptable salt thereof, wherein ring A 1 is tetrahydroisoquinolinyl.

[0363] Item 4. The compound according to Item 3 or a pharmaceutically acceptable salt thereof, wherein ring A 1 teeth [ka] is.

[0364] Item 5. The compound according to any one of the preceding items or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0365] Item 6. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0366] Item 7. The compound according to Item 6 or a pharmaceutically acceptable salt thereof, wherein R 1 optionally one or more N(R F ) 2-substituted alkyl.

[0367] Item 8. The compound according to Item 7 or a pharmaceutically acceptable salt thereof, wherein R 1 optionally one or more N(R F ) 2-substituted ethyl.

[0368] Item 9. The compound according to Item 7 or 8 or a pharmaceutically acceptable salt thereof, wherein R F is alkyl.

[0369] Item 10. The compound according to Item 9 or a pharmaceutically acceptable salt thereof, wherein R F is methyl.

[0370] Item 11. The compound according to Item 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is heterocyclyl.

[0371] Item 12. The compound according to Item 11 or a pharmaceutically acceptable salt thereof, wherein R 1 is oxetanyl.

[0372] Item 13. The compound according to Item 12 or a pharmaceutically acceptable salt thereof, wherein R 1 teeth [ka] is.

[0373] Item 14. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is alkyl.

[0374] Item 15. The compound according to Item 14 or a pharmaceutically acceptable salt thereof, wherein L 1 teeth [ka] and L 1 The * end of 2 is connected to.

[0375] Item 16. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein L 2 is a bond.

[0376] Item 17. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein L 3 is alkyl.

[0377] Item 18. The compound according to Item 11 or a pharmaceutically acceptable salt thereof, wherein L3 is ethyl.

[0378] Item 19. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein L 4 is O or NH.

[0379] Item 20. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein ring B is aryl or heteroaryl.

[0380] Item 21. The compound according to Item 20 or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl, pyridinyl, or pyrazolyl.

[0381] Item 22. The compound according to Item 21 or a pharmaceutically acceptable salt thereof, wherein ring B is [ka] is selected from the group consisting of:

[0382] Item 23. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0383] Item 24. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is alkyl.

[0384] Item 25. The compound according to Item 24 or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl.

[0385] Item 26. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is alkyl.

[0386] Item 27. The compound according to Item 26 or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl.

[0387] Item 28. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

[0388] Item 29. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0389] Item 30. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0390] Item 31. Compound of formula (III) [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring B 1 is a 7- to 12-membered cycloalkyl, a 7- to 12-membered heterocyclyl, a 7- to 12-membered aryl, or a 7- to 12-membered heteroaryl; L 1 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 2 is the bond, N(R A ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R B is replaced by R Ais selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; Each R B is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 3 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 4 is O, S or N(R C ) and R C is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 1 are independently hydroxy, halogen, cyano, amino, -N(R D)2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R E is replaced by Each R D are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of hydroxyl, halogen, cyano, -N(R F )2 OR -OR G and is substituted with one or more groups independently selected from Each R E are independently 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, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, and alkyl; R F and R Geach is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 2 are independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; Each R 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, and said heterocyclyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; 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.

[0391] Item 32. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein ring A is aryl or heteroaryl.

[0392] Item 33. The compound according to Item 32 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of furanyl, thiophenyl, pyrrolyl, phenyl, pyridinyl, pyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, and tetrahydroisoquinoline.

[0393] Item 34. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0394] Item 35. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 1 is a halogen and m is 1.

[0395] Item 36. The compound according to Item 35 or a pharmaceutically acceptable salt thereof, wherein R 1 is bromo.

[0396] Item 37. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 1 -N(R D )2 and m is 1.

[0397] Item 38. The compound according to Item 37 or a pharmaceutically acceptable salt thereof, wherein each R D are independently optionally -N(R F )2 OR -OR G and alkyl substituted with one or more groups independently selected from:

[0398] Item 39. The compound according to Item 38 or a pharmaceutically acceptable salt thereof, wherein each R D are independently methyl, methoxyethyl, or N,N-dimethylaminopropyl.

[0399] Item 40. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 1 optionally one or more R E and m is 1.

[0400] Item 41. The compound according to Item 40 or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl is [ka] is selected from the group consisting of each of which may optionally be one or more R E is replaced by .

[0401] Item 42. The compound according to Item 40 or a pharmaceutically acceptable salt thereof, wherein R E is a halogen.

[0402] Item 43. The compound according to Item 42 or a pharmaceutically acceptable salt thereof, wherein R E is F.

[0403] Item 44. The compound according to Item 40 or a pharmaceutically acceptable salt thereof, wherein R E is -N(R F )2,-Alkyl-N(R F )2, -C(O)OR G or alkyl optionally substituted with one or more halogens.

[0404] Item 45. The compound according to Item 44 or a pharmaceutically acceptable salt thereof, wherein R F and R G Each of is alkyl.

[0405] Item 46. The compound according to Item 45 or a pharmaceutically acceptable salt thereof, wherein R F and R G Each of the C 1-3 It is alkyl.

[0406] Item 47. The compound according to Item 44 or a pharmaceutically acceptable salt thereof, wherein R E is -N(CH3)2, -C 1-3 alkyl is selected from the group consisting of -N(CH3)2, -C(O)O(tert-butyl), methyl, ethyl or trifluoroethyl.

[0407] Item 48. The compound according to Item 40 or a pharmaceutically acceptable salt thereof, wherein R Eis cycloalkyl or heterocyclyl, said cycloalkyl and said heterocyclyl being optionally substituted with one or more alkyl or halogen.

[0408] Item 49. The compound according to Item 48 or a pharmaceutically acceptable salt thereof, wherein R E is selected from cyclopropyl, morpholine, piperazine, oxetyl, or azetidinyl, each of which is optionally substituted with one or more alkyl or halogen.

[0409] Item 50. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, [ka] is selected from the group consisting of:

[0410] Item 51. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein Ring B 1 is a 7- to 12-membered heteroaryl.

[0411] Item 52. The compound according to Item 51 or a pharmaceutically acceptable salt thereof, wherein Ring B 1 teeth [ka] is.

[0412] Item 53. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 2 is a halogen and n is 1 or 2.

[0413] Item 54. The compound according to Item 53 or a pharmaceutically acceptable salt thereof, wherein R 2 is F.

[0414] Item 55. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 2is alkyl or cycloalkyl, said alkyl and cycloalkyl being optionally substituted with one or more halogens.

[0415] Item 56. The compound according to Item 55 or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl, ethyl, cyclopropyl or trifluoroethyl.

[0416] Item 57. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein L 1 is alkyl.

[0417] Item 58. The compound according to Item 57 or a pharmaceutically acceptable salt thereof, wherein L 1 is propyl.

[0418] Item 59. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein L 2 is a bond.

[0419] Item 60. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein L 3 is alkyl.

[0420] Item 61. The compound according to Item 60 or a pharmaceutically acceptable salt thereof, wherein L 3 is ethyl.

[0421] Item 62. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein L 4 is O or NH.

[0422] Item 63. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 3 is alkyl.

[0423] Item 64. The compound according to Item 63 or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl.

[0424] Item 65. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 3 is a halogen.

[0425] Item 66. The compound according to Item 65 or a pharmaceutically acceptable salt thereof, wherein R 3 is Cl.

[0426] Item 67. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0427] Item 68. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0428] Item 69. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0429] Item 70. Compound of formula (IV) [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 1 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 21 is a 7- to 12-membered cycloalkyl or a 7- to 12-membered heterocyclyl, and the cycloalkyl and heterocyclyl are optionally joined by one or more R B is replaced by Each R B is independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L 3 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, and amino; L 4 is O, S or N(R C ) and R C is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 1 are independently hydroxy, halogen, cyano, amino, -N(R D )2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally selected from the group consisting of one or more R E is replaced by Each R Dare independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of hydroxyl, halogen, cyano, -N(R F )2 OR -OR G and is substituted with one or more groups independently selected from Each R E are independently 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, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, and alkyl; R F and R G each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 2are independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, said heteroalkynyl, said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl; 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.

[0430] Item 71. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein ring A is aryl.

[0431] Item 72. The compound according to Item 71 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.

[0432] Item 73. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein R 1 is a halogen and m is 1.

[0433] Item 74. The compound according to Item 73 or a pharmaceutically acceptable salt thereof, wherein R 1 is bromo.

[0434] Item 75. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein R 1 -N(R D )2 and m is 1.

[0435] Item 76. The compound according to Item 75 or a pharmaceutically acceptable salt thereof, wherein each R D are independently optionally -N(R F )2 OR -OR G and alkyl substituted with one or more groups independently selected from:

[0436] Item 77. The compound according to Item 76 or a pharmaceutically acceptable salt thereof, wherein each R D are independently methyl, methoxyethyl, or N,N-dimethylaminopropyl.

[0437] Item 78. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein R 1 optionally one or more R E and m is 1.

[0438] Item 79. The compound according to Item 78 or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl is [ka] is selected from the group consisting of each of which may optionally be one or more R E is replaced by .

[0439] Item 80. The compound according to Item 78 or a pharmaceutically acceptable salt thereof, wherein R E is a halogen.

[0440] Item 81. The compound according to Item 80 or a pharmaceutically acceptable salt thereof, wherein R E is F.

[0441] Item 82. The compound according to Item 78 or a pharmaceutically acceptable salt thereof, wherein R E is -N(R F )2,-Alkyl-N(R F )2, -C(O)OR G or alkyl optionally substituted with one or more halogens.

[0442] Item 83. The compound according to Item 82 or a pharmaceutically acceptable salt thereof, wherein R F and R G Each of is alkyl.

[0443] Item 84. The compound according to Item 83 or a pharmaceutically acceptable salt thereof, wherein R F and R G Each of the C 1-3 It is alkyl.

[0444] Item 85. The compound according to Item 82 or a pharmaceutically acceptable salt thereof, wherein R E is -N(CH3)2, -C 1-3 alkyl is selected from the group consisting of -N(CH3)2, -C(O)O(tert-butyl), methyl, ethyl or trifluoroethyl.

[0445] Item 86. The compound according to Item 78 or a pharmaceutically acceptable salt thereof, wherein R E is cycloalkyl or heterocyclyl, said cycloalkyl and said heterocyclyl being optionally substituted with one or more alkyl or halogen.

[0446] Item 87. The compound according to Item 86 or a pharmaceutically acceptable salt thereof, wherein R E is selected from cyclopropyl, morpholine, piperazine, oxetyl, or azetidinyl, each of which is optionally substituted with one or more alkyl or halogen.

[0447] Item 88: The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, [ka] is selected from the group consisting of:

[0448] Item 89. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein ring B is aryl or heteroaryl.

[0449] Item 90. The compound according to Item 89 or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl, pyridinyl, or pyrazolyl.

[0450] Item 91. The compound according to Item 90 or a pharmaceutically acceptable salt thereof, wherein ring B is [ka] is selected from the group consisting of:

[0451] Item 92. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein L 1 is a bond.

[0452] Item 93. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein L 21 is a 7-10 membered heterocyclyl containing one or more heteroatoms selected from N or O.

[0453] Item 94. The compound according to Item 93 or a pharmaceutically acceptable salt thereof, wherein L 21 teeth, [ka] and L 21 The * end of 3 is connected to.

[0454] Item 95. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein L 3 is alkyl.

[0455] Item 96. The compound according to Item 95 or a pharmaceutically acceptable salt thereof, wherein L 3 is ethyl.

[0456] Item 97. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein L 4 is O or NH.

[0457] Item 98. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein R 1 optionally one or more R E and m is 1.

[0458] Item 99. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein R 3 is alkyl.

[0459] Item 100. The compound according to Item 99 or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl.

[0460] Item 101. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

[0461] Item 102. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0462] Item 103. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0463] Item 104. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is [Table 3-1] [Table 3-2]

[0464] 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.

[0465] Item 106. A method for inhibiting EGFR activity in a subject in need of treatment, 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.

[0466] Item 107. A method for treating an EGFR-related disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound described in any one of items 1 to 104 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in item 105.

[0467] Item 108. The method according to Item 107, wherein the EGFR-associated disease is an autoimmune disease or cancer.

[0468] 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, and includes metastasis (particularly brain metastasis), etc.

[0469] Item 110. The method of any one of items 107 to 109, wherein the compound is administered simultaneously, alone, or sequentially with one or more additional therapeutic agents.

[0470] Item 111. The method of Item 110, wherein the one or more additional therapeutic agents are selected from an EGFR TKI, an EGFR antibody, a MEK inhibitor, a c-MET inhibitor, a mitotic kinase inhibitor, an immunotherapeutic agent, an anti-angiogenic agent, an apoptosis inducer, an mTOR inhibitor, a histone deacetylase inhibitor, an IL6 inhibitor, and a JAK inhibitor. [Example]

[0471] The general method of the present disclosure will be further described 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 will be described below. However, these do not limit the preparation methods of the compounds of the present disclosure. Synthesis Examples

[0472] For illustrative purposes, the following examples are included. The embodiments provided herein describe the synthesis of compounds disclosed herein and intermediates for preparing said compounds. However, it should be understood that these examples do not limit the disclosure, but merely demonstrate a method of practicing the disclosure. Those skilled in the art will recognize that the described chemical reactions can be easily adapted to prepare several other compounds of the disclosure, and alternative methods for preparing compounds of the disclosure are considered to be within the scope of the disclosure. For example, the synthesis of non-exemplary compounds according to the disclosure can be successfully achieved through modifications obvious to those skilled in the art, such as appropriately protecting interfering groups, utilizing other suitable reagents and components known in the art other than those described, and / or generally changing reaction conditions. Those skilled in the art will also recognize that each step described herein or in a separate group of compounds may be combined. Alternatively, other reactions disclosed herein or known in the art are considered suitable for preparing other compounds of the disclosure. Therefore, the following description is not intended to limit the scope of the disclosure, which is defined by the appended claims. Chemistry, Materials and General Methods

[0473] Unless otherwise noted, all reagents and solvents were purchased from commercial suppliers, such as PharmaBlock, Bide Pharmatech, Shanghai Send Pharm, Aldrich, and Sigma, and used without further purification. Dry organic solvents (e.g., THF, DMF, 1,4-dioxane) 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 a nitrogen atmosphere. 1H NMR spectra were recorded at ambient temperature on a Bruker AV III HD 400 MHz or Bruker AV NEO 400 MHz spectrometer. Chemical shifts are reported in parts per million (ppm, δ units). Data are reported as chemical shift, proton number, and multiplicity (s = singlet, d = doublet, dd = double doublet, dt = double triplet, t = triplet, q = quartet, br = broad, m = multiplet). 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 min) method used a Shimadzu 20AD spectrometer, Shim-pack Scepter C18-120, 3.3 x 33 mm, 3.0 μm, 30 °C, with a flow rate of 1.5 mL / min. Solvent A: water + 6.5 mM NH4HCO3 + ammonium hydroxide (pH = 10), Solvent B: acetonitrile. From 0.0 to 1.7 min, 30% B to 70% B, from 1.7 to 2.3 min, 70% B to 95% B, from 2.3 to 2.8 min, 95% B, from 2.8 to 3.0 min, 10% B. The flow from the UV detector was split (1:3) to an MS detector equipped with an electrospray ionization source. The CHIRAL method used the following: column CHIRALPAK IC-3, 0.46 * 5 cm, 3 μm, 25 °C, flow rate 1.0 ml / min, methyl tert-butyl ether (0.2% diethylamine) / (ethanol / dichloromethane = 1 / 1) = 20 / 80. The SFC method used the column (R, R)-WHELK-01-Kromasil, 5 * 25 cm, 5 μm, mobile phase A CO2, mobile phase B methanol / acetonitrile = 1 / 1.

[0474] The abbreviations used in the synthesis of the compounds provided herein are listed below. [Table 4-1] [Table 4-2] [Table 4-3] Synthesis of intermediates Intermediate M1 Methyl 2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate [ka]

[0475] Step 1. Preparation of 2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (M1-1). Under a nitrogen atmosphere, to a stirred solution of 2-methyl-1H-pyrazol-3-one (100 g, 1019 mmol, 1 equiv) and K2CO3 (352 g, 2548 mmol, 2.5 equiv) in acetonitrile (1000 mL) at 0 °C 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 dried over anhydrous Na2SO4. 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. 1 H NMR (DMSO - d6, 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).

[0476] 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 a nitrogen atmosphere, N-iodosuccinimide (50.93 g, 226.39 mmol, 1.1 equiv) was added. The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 1 h. 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 dried over anhydrous Na2SO4. 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. 1 H NMR (DMSO-d6, 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).

[0477] 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, after which 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 (crude) of methyl 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-4-carboxylate (M1-3) as a brown oil. This crude material was carried on to the next step without purification. LCMS: m / z (ESI), [M + H] + = 216.05.

[0478] 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 methyl 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-4-carboxylate (104 g crude, ca. 349 mmol, ca. 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)phosphane (12.58 g, 35.088 mmol, 0.1 equiv), CsCO (228.65 g, 701.754 mmol, 2 equiv), and Pd(dba) (9.6 g, 10.4 mmol, 0.03 The mixture of (equiv) was stirred at 80 °C under a nitrogen atmosphere for 2 h. 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified on a silica gel column eluted with petroleum ether / ethyl acetate (1 / 4) to afford 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.

[0479] 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). 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)Cl2 (3677 mg, 5.02 mmol, 0.05 equiv), PCy3 in 1,4-dioxane (500 mL) at room temperature under a nitrogen atmosphere. . To a stirred mixture of HBF (10.5 g, 28.64 mmol, 0.3 equiv) and KCO (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), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified on a silica gel column eluted with 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. 1 H NMR (DMSO-d6, 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).

[0480] 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 under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with saturated NaHCO3 (aq) solution (300 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (3 x 500 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 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. 1 H NMR (DMSO-d6, 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 [ka]

[0481] Step 1. Preparation of methyl 5-bromo-1-methyl-6-oxopyridine-3-carboxylate (M2-1). To a mixture of methyl 5-bromo-6-hydroxypyridine-3-carboxylate (20 g, 86.19 mmol, 1 equiv) in N,N-dimethylformamide (100 mL) at 0 °C, NaH (60%) (4.14 g, 172.39 mmol, 2 equiv) was added. The mixture was stirred at 0 °C for 60 min under a nitrogen atmosphere. CHCl (13.46 g, 94.81 mmol, 1.1 equiv) was slowly 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 dried over anhydrous NaSO. 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. 1 H NMR (DMSO-d6, 400 MHz) δ 3.59 (3H, s), 3.81 (3H, s), 8.18 (1H, d), 8.62 (1H, d).

[0482] Step 2. Preparation of (5-(methoxycarbonyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)boronic acid (M2-2). Methyl 5-bromo-1-methyl-6-oxopyridine-3-carboxylate (30 g, 121.92 mmol, 1 equiv), Pd(dppf)Cl2 in 1,4-dioxane (600 mL) . A mixture of CH2Cl2 (8.92 g, 12.2 mmol, 0.1 equiv), bis(pinacolato)diboron (46.44 g, 182.88 mmol, 1.5 equiv) and KOAc (35.90 g, 365.76 mmol, 3 equiv) was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction mixture was carried on directly to the next step without workup. LCMS: m / z (ESI), [M + H] += 212.00.

[0483] 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). 4-Iodo-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (43 g, 121.37 mmol, 1.00 equiv), Pd(dppf)Cl.CHCl (7.91 g, 9.71 mmol, 0.08 equiv), KCO (50.33 g, 364.14 mmol, 3 equiv), and HO (150 mL) were added to the mixture freshly prepared from the above reaction at room temperature. The mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. 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 dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column eluted with petroleum ether / ethyl acetate (1 / 8) to afford 30 g of methyl 1-methyl-5-(2-methyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-6-oxopyridine-3-carboxylate (M2-3) (62%) as a brown solid. LCMS: m / z (ESI), [M + H] + = 394.10. 1 H NMR (DMSO-d6, 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).

[0484] 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 equiv) 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 basified to pH 9 with KCO. 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 eluting 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. 1 H NMR (DMSO-d6, 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 (11R)-16-Bromo-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 [ka]

[0485] Step 1. Preparation of (4S)-4-benzyl-3-[(2R)-2-methylpent-4-enoyl]-1,3-oxazolidin-2-one (M3-1). To a stirred mixture of (4S)-4-benzyl-3-propanoyl-1,3-oxazolidin-2-one (100 g, 428.69 mmol, 1 equiv) in tetrahydrofuran (640 mL) at −78 °C under a nitrogen atmosphere, LiHMDS (471 mL, 471.56 mmol, 1.1 equiv) and allyl bromide (207.4 g, 1714.77 mmol, 4 equiv) were added dropwise, successively. The resulting mixture was stirred at −50 °C under a nitrogen atmosphere for 2 h and then allowed to warm to room temperature. The reaction mixture was treated with saturated NH4Cl(aq) solution (1000 mL) and extracted with CHCl2 (3 × 400 mL). The combined organic layers were washed with brine (3 x 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (40 / 1) to give 100 g of (4S)-4-benzyl-3-[(2R)-2-methylpent-4-enoyl]-1,3-oxazolidin-2-one (M3-1) (85%) as a colorless oil. LCMS: m / z (ESI), [M + H] + = 274.00. 1 H NMR (DMSO-d6, 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).

[0486] Step 2. Preparation of (2R)-2-methylpent-4-enoic acid (M3-2). To a stirred mixture of (4S)-4-benzyl-3-[(2R)-2-methylpent-4-enoyl]-1,3-oxazolidin-2-one (M3-1, 100 g, 365.85 mmol, 1 equiv) in tetrahydrofuran (800 mL) and HO (200 mL) at 0 °C, LiOH· HO (46.05 g, 1097.56 mmol, 3 equiv) and HO (30%) (114.30 mL, 4906 mmol, 13.4 equiv) were added. The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 3 h. The reaction was quenched with NaSO solution (250 mL), acidified to pH = 1 with HCl solution, and extracted with CHCl (3 × 400 mL). The combined organic layers were washed with brine (3 × 500 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was carried on directly to the next step without further purification.

[0487] Step 3. Preparation of (2R)-N,N-dibenzyl-2-methylpent-4-enamide (M3-3). To a stirred solution of (2R)-2-methylpent-4-enoic acid (50 g, 219.02 mmol, 1 equiv) and dibenzylamine (43.2 g, 219.022 mmol, 1 equiv) in dioxane (200 mL) at room temperature under a nitrogen atmosphere, 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) were added. The resulting mixture was stirred for 2 h. The reaction was quenched with water (1000 mL), and the mixture was extracted with CHCl (3×300 mL). The combined organic layers were washed with brine (3×500 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column eluted with petroleum ether / ethyl acetate (40 / 1) to afford 55.6 g of (2R)-N,N-dibenzyl-2-methylpent-4-enamide (M3-3) (86%) as a yellow oil. LCMS: m / z (ESI), [M + H] + = 294.15. 1H NMR (DMSO-d6, 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).

[0488] Step 4. Preparation of (2R)-N,N-dibenzyl-5-hydroxy-2-methylpentanamide (M3-4). To a stirred mixture of (2R)-N,N-dibenzyl-2-methylpent-4-enamide (50 g, 170.41 mmol, 1 equiv) and 9-borabicyclo[3.3.1]nonane (852.05 mL, 426.02 mmol, 2.5 equiv) in tetrahydrofuran (60 mL) at 0 °C, NaOH (10 M) (220 mL) and HO (30%) (151 mL) were added dropwise. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with NaSO (aq) solution (500 mL). The mixture was extracted with CHCl (3 × 500 mL), and the combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column eluted with petroleum ether / ethyl acetate (1 / 1) to give 42.5 g of (2R)-N,N-dibenzyl-5-hydroxy-2-methylpentanamide (M3-4) (68%) as a yellow oil. LCMS: m / z (ESI), [M + H] + = 312.10. 1 H NMR (DMSO-d6, 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).

[0489] Step 5. Preparation of (4R)-5-(dibenzylamino)-4-methylpent-1-ol (M3-5). To a stirred mixture of LiAlH (6.73 g, 177.41 mmol, 1.3 equiv) in tetrahydrofuran (600 mL) at 0 °C, (2R)-N,N-dibenzyl-5-hydroxy-2-methylpentanamide (42.5 g, 136.46 mmol, 1 equiv) was added. 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 dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column eluted with petroleum ether / ethyl acetate (10 / 1) to give 27.9 g of (4R)-5-(dibenzylamino)-4-methylpent-1-ol (M3-5) (68%) as a yellow oil. LCMS: m / z (ESI), [M + H] + = 298.15. 1 H NMR (DMSO-d6, 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).

[0490] Step 6. Preparation of (4R)-5-amino-4-methylpent-1-ol (M3-6). A mixture of (4R)-5-(dibenzylamino)-4-methylpent-1-ol (18 g, 60.51 mmol, 1 equiv) and Pd / C (1.29 g, 12.10 mmol, 0.2 equiv) 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 of (4R)-5-amino-4-methylpent-1-ol (M3-6) (91%) as a yellow oil. 1H NMR (DMSO-d6, 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).

[0491] Step 7. Preparation of (4R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpent-1-ol (M3-7). A mixture of 4-bromo-2-fluoro-1-nitrobenzene (10.00 g, 45.46 mmol, 1 equiv), K2CO3 (12.56 g, 90.91 mmol, 2 equiv), and (4R)-5-amino-4-methylpent-1-ol (6.39 g, 54.55 mmol, 1.2 equiv) in acetonitrile (60 mL) was stirred at 60 °C under a nitrogen atmosphere for 2 h. 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 dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by prep-TLC eluting with petroleum ether / ethyl acetate (1 / 3) to give 11.7 g of (4R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpent-1-ol (M3-7) (81%) as a yellow solid. LCMS: m / z (ESI), [M + H] + = 319.00. 1 H NMR (400 MHz, DMSO-d6) 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).

[0492] Step 8. Preparation of methyl 5-(5-{[(4R)-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) under a nitrogen atmosphere at 0 °C, diisopropyl azodicarboxylate (4.08 g, 20.18 mmol, 2 equiv) and (4R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpent-1-ol (3.21 g, 10.09 mmol, 1 equiv) were added. 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 dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC eluting with petroleum ether / ethyl acetate (1 / 4) to give 2.72 g of methyl 5-(5-{[(4R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M3-8) (48%) as a yellow solid. LCMS: m / z (ESI), [M + H] + = 564.10. 1H NMR (400 MHz, DMSO-d6) 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).

[0493] Step 9. Preparation of methyl 5-(5-{[(4R)-5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M3-9). To a stirred mixture of methyl 5-(5-{[(4R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (4.00 g, 7.11 mmol, 1 equiv) and Raney nickel (200 mg, 2.33 mmol, 0.33 equiv) in methanol (40 mL) under a nitrogen atmosphere at 0 °C was added NH · HO (712 mg, 14.22 mmol, 2 equiv) was added. 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 methyl 5-(5-{[(4R)-5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M3-9) (96%) as a yellow solid. LCMS: m / z (ESI), [M + H] + = 533.95.

[0494] Step 10. Preparation of methyl 5-(5-{[(4R)-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). To a stirred mixture of methyl 5-(5-{[(4R)-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) at room temperature 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 give 2.6 g of methyl 5-(5-{[(4R)-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) (83%) as a reddish-brown solid. LCMS: m / z (ESI), [M + H] + = 559.05.

[0495] Step 11. Preparation of 5-(5-{[(4R)-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-carboxylic acid (M3-11). To a stirred mixture of methyl 5-(5-{[(4R)-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 (3.71 g, 6.42 mmol, 1 equiv) in tetrahydrofuran (100 mL) at room temperature was added LiOH (307 mg, 12.83 mmol, 2 equiv) in HO (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 afford 3.5 g of 5-(5-{[(4R)-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-carboxylic acid (M3-11) (97%) as a white solid. LCMS: m / z (ESI), [M + H] + = 545.15.

[0496] Step 12. Preparation of (11R)-16-bromo-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 (M3). To a stirred mixture of 5-(5-{[(4R)-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 equiv) in dioxane (18 mL) at room temperature, 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) were added. After stirring at 60 °C under a nitrogen atmosphere for 3 h, the reaction mixture was cooled to room temperature, treated with water (300 mL), and extracted with CHCl (2 × 200 mL). The combined organic layers were washed with brine (3 × 300 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC eluting with CHCl / methanol (40 / 1) to give 1.14 g of (11R)-16-bromo-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 (M3) (98%) as a white solid. LCMS: m / z (ESI), [M + H] + = 525.15. 1H NMR (DMSO-d6, 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-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 1 (M4A) and Isomer 2 (M4B) [ka]

[0497] Step 1. Preparation of benzyl bis(ethoxymethyl)amine (M4-1). A mixture of benzylamine (500 g, 4666 mmol, 1 equiv), POM (840.62 g, 9332 mmol, 2 equiv), and K2CO3 (644.88 g, 4666 mmol, 1 equiv) in ethanol (1200 mL) was stirred at room temperature under a 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 benzyl bis(ethoxymethyl)amine (M4-1) (80%) as a yellow oil. This crude material was used in Step 3 without further purification. 1H NMR (DMSO-d6, 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).

[0498] Step 2. Preparation of isopropyl 2-oxocyclopentane-1-carboxylate (M4-2). A mixture of ethyl 2-oxocyclopentane-1-carboxylate (400 g, 2561 mmol, 1 equiv) and DMAP (31.29 g, 256.11 mmol, 0.1 equiv) in i-PrOH (500 mL) was stirred overnight at 80 °C under a 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 isopropyl 2-oxocyclopentane-1-carboxylate (M4-2) (92%) as a yellow oil. LCMS: m / z (ESI), [M - H] + = 168.85. 1 H NMR (DMSO-d6, 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).

[0499] Step 3. Preparation of isopropyl 3-benzyl-8-oxo-3-azabicyclo[3.2.1]octane-1-carboxylate (M4-3). A solution of benzyl bis(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 a 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 overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with water (3 L), basified to pH 7 with saturated NaHCO3 (aq) solution (3 L), and the mixture was extracted with ethyl acetate (3 × 2 L). The combined organic layers were washed with brine (3 x 2 L), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified on a silica gel column eluted with petroleum ether:ethyl acetate (40 / 1) and concentrated under vacuum. The residue was further purified by Prep-HPLC, 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 isopropyl 3-benzyl-8-oxo-3-azabicyclo[3.2.1]octane-1-carboxylate (M4-3) (31%) as a yellow oil. LCMS: m / z (ESI), [M + H] + = 470.15. 1 H NMR (DMSO-d6, 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)

[0500] Step 4. Preparation of isopropyl 3-benzyl-8-[(4-methylbenzenesulfonamido)imino]-3-azabicyclo[3.2.1]octane-1-carboxylate (M4-4). To a solution of isopropyl 3-benzyl-8-oxo-3-azabicyclo[3.2.1]octane-1-carboxylate (100 g, 331.8 mmol, 1 equiv) in methanol (1 L) was added TsNHNH2 (123.58 g, 663.5 mmol, 2.00 equiv) in portions under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred overnight at room temperature 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 isopropyl 3-benzyl-8-[(4-methylbenzenesulfonamido)imino]-3-azabicyclo[3.2.1]octane-1-carboxylate (M4-4) (51%) as a white solid. 1 H NMR (DMSO-d6, 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).

[0501] Step 5. Preparation of 3-benzyl-3-azabicyclo[3.2.1]octane-1-carboxylate (M4-5). To a stirred solution of isopropyl 3-benzyl-8-[(4-methylbenzenesulfonamido)imino]-3-azabicyclo[3.2.1]octane-1-carboxylate (100 g, 212.95 mmol, 1 equiv) in methanol (2 L) at 0 °C under a nitrogen atmosphere, NaBH (120.8 g, 3194.20 mmol, 15 equiv) was added. 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (5 / 1) to give 33.0 g of isopropyl 3-benzyl-3-azabicyclo[3.2.1]octane-1-carboxylate (M4-5) (54%) as a colorless oil. LCMS: m / z (ESI), [M + H] + = 288.05. 1 H NMR (DMSO-d6, 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).

[0502] Step 6. Preparation of 3-benzyl-3-azabicyclo[3.2.1]octane-1-carboxylic acid (M4-6). A mixture of isopropyl 3-benzyl-3-azabicyclo[3.2.1]octane-1-carboxylate (33.0 g, 114.82 mmol, 1 equiv) and LiOH (3.0 g, 126.30 mmol, 1.1 equiv) in ethanol (400 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 days. 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.

[0503] Step 7. Preparation of tert-butyl N-{3-benzyl-3-azabicyclo[3.2.1]octan-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 equiv, 90%), DPPA (36.35 g, 132.07 mmol, 1.2 equiv), and triethylamine (33.41 g, 330.18 mmol, 3.0 equiv) in tetrahydrofuran (300 mL) was stirred at 80 °C for 2 h under a 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) were added at 0 °C. The mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (5 / 1) to afford 15 g of tert-butyl N-{3-benzyl-3-azabicyclo[3.2.1]octan-1-yl}carbamate (M4-7) (43%) as a white solid. LCMS: m / z (ESI), [M + H] + = 317.15. 1H NMR (DMSO-d6, 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)

[0504] Step 8. Preparation of tert-butyl N-{3-azabicyclo[3.2.1]octan-1-yl}carbamate (M4-8). A mixture of tert-butyl N-{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 a 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 give 10 g of tert-butyl N-{3-azabicyclo[3.2.1]octan-1-yl}carbamate (M4-8) (93%) as a white solid. This material was used in the next step without further purification. LCMS: m / z (ESI), [M + H] + = 227.10. 1 H NMR (DMSO-d6, 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).

[0505] Step 9. Preparation of tert-butyl N-(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.1]octan-1-yl)carbamate (M4-9). A mixture of freshly prepared tert-butyl N-{3-azabicyclo[3.2.1]octan-1-yl}carbamate (10 g, approximately 44 mmol, approximately 1 equiv), (2-bromoethoxy)(tert-butyl)dimethylsilane (21.14 g, 88.37 mmol, 2 equiv), NaI (13.25 g, 88.37 mmol, 2 equiv), and KCO (12.21 g, 88.37 mmol, 2 equiv) in DMF (160 mL) was stirred at 60 °C for 2 h under a 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by prep-HPLC using water containing 0.1% NHHCO and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to afford 12 g of tert-butyl N-(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.1]octan-1-yl)carbamate (M4-9) (70%) as a colorless oil. LCMS: m / z (ESI), [M + H] + = 385.25. 1 H NMR (DMSO-d6, 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).

[0506] Step 10. Preparation of 2-(1-amino-3-azabicyclo[3.2.1]octan-3-yl)ethan-1-ol (M4-10). A mixture of tert-butyl N-(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 a 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), an orange oil, was carried directly to the next step without further purification. LCMS: m / z (ESI), [M + H] + = 285.15.

[0507] Step 11. Preparation of 2-[1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl]ethanol (M4-11). A mixture of 2-(1-amino-3-azabicyclo[3.2.1]octan-3-yl)ethan-1-ol (crude, M4-10), K2CO3 (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 a 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by prep-HPLC using water containing 0.1% NHHCO and acetonitrile as the mobile phase. 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 semi-solid. LCMS: m / z (ESI), [M + H] + = 371.95. 1H NMR (DMSO-d6, 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)。

[0508] Step 12. Preparation 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 (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 equiv) and triphenylphosphine (17.00 g, 64.82 mmol, 3 equiv) in tetrahydrofuran (500 mL) under a nitrogen atmosphere at 0 °C, diisopropyl azodicarboxylate (12.23 g, 60.50 mmol, 2.8 equiv) and methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (5.69 g, 21.61 mmol, 1 equiv) were slowly added. The resulting mixture was stirred under a nitrogen atmosphere at 0 °C 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 x 300 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified on a silica gel column eluted with petroleum ether / ethyl acetate (1 / 3) to afford 9.5 g 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 (M4-12) (71%) as an orange oil. LCMS: m / z (ESI), [M + H] + = 617.10.

[0509] Step 13. Preparation 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 (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 equiv) and Raney nickel (2 g) in methanol (150 mL) was added hydrazine hydrate (2.19 g, 68.24 mmol, 1.5 equiv) and stirred at 0° C. for 2 h under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with dichloromethane (3×200 mL). The organic solution was concentrated under reduced pressure. The residue was purified on a silica gel column eluting with dichloromethane / methanol (10 / 1) to give 9.5 g 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 (M4-13) (91%) as a brown oil. LCMS: m / z (ESI), [M + H] + = 585.20. 1 H NMR (DMSO-d6, 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).

[0510] Step 14. Preparation of methyl 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-carboxylate (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 equiv) and cyanogen bromide (2.17 g, 20.49 mmol, 1.20 equiv) in ethanol (200 mL) was stirred at room temperature overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, and the residue was purified on a silica gel column eluting with dichloromethane / methanol (20 / 1) to give 9.5 g of methyl 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-carboxylate (M4-14) (91%) as a brown solid. LCMS: m / z (ESI), [M + H] + = 612.05.

[0511] Step 15. Preparation of methyl 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-carboxylate, Isomer 1 (M4-14A) and Isomer 2 (M4-14B). The racemic mixture of M4-14 (9 g, 14.74 mmol) was separated by chiral chromatography on a (R,R)-WHELK-01-Kromasil column (5 * 25 cm, 5 μm) using CO as mobile phase A and methanol / acetonitrile (1 / 1) as mobile phase B to give 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.

[0512] 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 methyl 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-carboxylate (isomer 1, M4-14A, 4 g, 6.55 mmol, 1 equiv) in tetrahydrofuran (8 mL) was added HO (2 mL) containing LiOH (0.31 g, 13.10 mmol, 2 equiv). 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, reverse-phase flash chromatography, using a C18 silica gel column eluted with water and acetonitrile. 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.

[0513] Step 17. 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}]tritriaconta-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (M4A). A mixture 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 (M4-15A, 3.6 g, 6.03 mmol, 1 equiv), N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (3.44 g, 9.05 mmol, 1.5 equiv) and N,N-diisopropylethylamine (2.34 g, 18.10 mmol, 3 equiv) in 1,4-dioxane (80 mL) 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), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on a silica gel column eluting with 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}]tritriaconta-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-d6, 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)。

[0514] 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 methyl 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-carboxylate (isomer 2, M4-14B, 4.2 g, 6.88 mmol, 1 equiv) in tetrahydrofuran (80 mL) was added HO (20 mL) containing LiOH (0.33 g, 13.76 mmol, 2 equiv). 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, reverse-phase flash chromatography, using a C18 silica gel column eluted with water and acetonitrile. 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.

[0515] 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}]tritriaconta-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (isomer 2, M4B). A solution 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 (M4-15B, 3.8 g, 6.37 mmol, 1 equiv), N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (3.63 g, 9.56 mmol, 1.5 equiv), and N,N-diisopropylethylamine (2.47 g, 19.11 mmol, 3 equiv) in 1,4-dioxane (80 mL) 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), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on a silica gel column eluting with 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}]tritriaconta-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-d6, 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-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tetratriaconta-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione [ka]

[0516] Step 1. Preparation of ethyl 4-methylidenecyclohexane-1-carboxylate (M5-1). Ethyl 4-oxocyclohexane-1-carboxylate (100 g, 587.51 mmol, 1 equiv) was added to a mixture of methyltriphenylphosphanium 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. 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), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (5 / 1) to give 80 g of ethyl 4-methylidenecyclohexane-1-carboxylate (M5-1) (85%) as a yellow oil. 1 H NMR (DMSO-d6, 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).

[0517] Step 2. Preparation of ethyl 1-(4-methylbenzenesulfonyl)-1-azaspiro[2.5]octane-6-carboxylate (M5-2). At 0 °C, N,N,N-trimethylanilinium dibromanebromide (17.88 g, 47.55 mmol, 0.1 equiv) was added to a mixture of ethyl 4-methylidenecyclohexane-1-carboxylate (80 g, 475.52 mmol, 1 equiv) and chloramine-T (216.50 g, 951.04 mmol, 2 equiv) in acetonitrile (800 mL). The mixture was stirred at room temperature under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 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. 1 H NMR (DMSO-d6, 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).

[0518] Step 3. Preparation of ethyl 4-[(benzylamino)methyl]-4-(4-methylbenzenesulfonamido)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 equiv) and benzylamine (28.58 g, 266.72 mmol, 1.5 equiv) in tetrahydrofuran (600 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 days. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (1 / 1) to afford 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. 1 H NMR (DMSO-d6, 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).

[0519] Step 4. Preparation of lithium 4-((benzylamino)methyl)-4-((4-methylphenyl)sulfonamino)cyclohexane-1-carboxylate (M5-4). A mixture of ethyl 4-[(benzylamino)methyl]-4-(4-methylbenzenesulfonamido)cyclohexane-1-carboxylate (60 g, 134.95 mmol, 1 equiv) and LiOH (6.46 g, 269.91 mmol, 2 equiv) in ethanol (500 mL) was stirred at 80 °C under a nitrogen atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure to give 57 g of lithium 4-((benzylamino)methyl)-4-((4-methylphenyl)sulfonamino)cyclohexane-1-carboxylate (M5-4) as a white solid. This material was carried on to the next step without further purification. LCMS: m / z (ESI), [M + H] + = 417.10.

[0520] Step 5. Preparation of N-{3-benzyl-4-oxo-3-azabicyclo[3.2.2]nonan-1-yl}-4-methylbenzenesulfonamide (M5-5). A mixture of N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (77.03 g, 202.60 mmol, 1.5 equiv), lithium 4-((benzylamino)methyl)-4-((4-methylphenyl)sulfonamino)cyclohexane-1-carboxylate (57 g, approximately 135 mmol, approximately 1 equiv), and N,N-diisopropylethylamine (52.37 g, 405.21 mmol, 3 equiv) in dichloromethane (150 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1 / 1) to give 50 g of N-{3-benzyl-4-oxo-3-azabicyclo[3.2.2]nonan-1-yl}-4-methylbenzenesulfonamide (M5-5) (93%) as a white solid. LCMS: m / z (ESI), [M + H] + = 399.15. 1H NMR (DMSO-d6, 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)

[0521] Step 6. Preparation of N-{3-benzyl-3-azabicyclo[3.2.2]nonan-1-yl}-4-methylbenzenesulfonamide methyl (M5-6). At 0 °C, N-{3-benzyl-4-oxo-3-azabicyclo[3.2.2]nonan-1-yl}-4-methylbenzenesulfonamide (40 g, 100.37 mmol, 1 equiv) was added to a mixture of lithium aluminum hydride (7.62 g, 200.74 mmol, 2 equiv) in tetrahydrofuran (400 mL), and the mixture was stirred under a 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 dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on a silica gel column eluted with petroleum ether / ethyl acetate (1 / 1) to give 20 g of N-{3-benzyl-3-azabicyclo[3.2.2]nonan-1-yl}-4-methylbenzenesulfonamide (M5-6) (46%) as a white solid. LCMS: m / z (ESI), [M + H] + = 385.15. 1 H NMR (DMSO-d6, 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).

[0522] Step 7. Preparation of N-{3-azabicyclo[3.2.2]nonan-1-yl}-4-methylbenzenesulfonamide (M5-7). A mixture of Pd / C (10%, 500 mg) and N-{3-benzyl-3-azabicyclo[3.2.2]nonan-1-yl}-4-methylbenzenesulfonamide (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 eluting with dichloromethane / methanol (10 / 1) to afford 15 g of N-{3-azabicyclo[3.2.2]nonan-1-yl}-4-methylbenzenesulfonamide (M5-7) (93%) as a white solid. LCMS: m / z (ESI), [M + H] + = 295.00. 1 H NMR (DMSO-d6, 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).

[0523] Step 8. Preparation of N-(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-yl)-4-methylbenzenesulfonamide (M5-8). A mixture of N-{3-azabicyclo[3.2.2]nonan-1-yl}-4-methylbenzenesulfonamide (15 g, 50.94 mmol, 1 equiv), NaI (7.64 g, 50.94 mmol, 1 equiv), KCO (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 a 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified on a silica gel column eluting with dichloromethane / methanol (10 / 1) to afford 20 g of N-(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-yl)-4-methylbenzenesulfonamide (M5-8) (78%) as a yellow solid. LCMS: m / z (ESI), [M + H] + = 453.30. 1 H NMR (DMSO-d6, 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).

[0524] Step 9. Preparation of 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (M5-9). A mixture of N-(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-yl)-4-methylbenzenesulfonamide (5 g, 11.04 mmol, 1 equiv) and Mg (5.37 g, 220.88 mmol, 20 equiv) in methanol (200 mL) was stirred at 70 °C overnight under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched by the addition of saturated NH4Cl(aq) solution (300 mL), and the mixture was extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with brine (3 × 400 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified on a silica gel column eluted with 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. 1 H NMR (DMSO-d6, 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).

[0525] Step 10. Preparation of N-(5-bromo-2-nitrophenyl)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (M5-10). A mixture of 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (1 g, 3.35 mmol, 1 equiv), 4-bromo-2-fluoro-1-nitrobenzene (1.84 g, 8.37 mmol, 2.5 equiv), and K2CO3 (1.39 g, 10.05 mmol, 3 equiv) in dimethyl sulfoxide (10 mL) was stirred at 120 °C for 4 h under a 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (5 / 1) to afford 1.5 g of N-(5-bromo-2-nitrophenyl)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]nonan-1-amine (M5-10) (85%) as a yellow oil. LCMS: m / z (ESI), [M + H] = 498.15.

[0526] Step 11. Preparation of 2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]nonan-3-yl}ethanol (M5-11). A solution of N-(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 equiv) and tetrabutylammonium fluoride (1.57 g, 6.01 mmol, 2 equiv) in tetrahydrofuran (15 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was quenched with saturated NaHCO3 (aq) solution (100 mL), and the mixture was extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane / methanol (10 / 1) to give 1.2 g of 2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]nonan-3-yl}ethanol (M5-11) (93%) as a yellow oil. LCMS: m / z (ESI), [M + H] + = 384.00.

[0527] Step 12. Preparation of methyl 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]nonan-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (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 equiv) and triphenylphosphine (2.46 g, 9.369 mmol, 3 equiv) in tetrahydrofuran (10 mL) at 0 °C, diisopropyl azodicarboxylate (1.89 g, 9.36 mmol, 3 equiv) and methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (0.66 g, 2.49 mmol, 0.8 equiv) were added. The mixture was stirred under a nitrogen atmosphere 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by prep-TLC eluting with petroleum ether / ethyl acetate (1 / 1) to give 1.2 g of methyl 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]nonan-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (M5-12) (57%) as a yellow oil. LCMS: m / z (ESI), [M + H] + = 629.25. 1 H NMR (DMSO-d6, 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).

[0528] Step 13. Preparation of methyl 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.2]nonan-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (M5-13). To a stirred mixture of Raney nickel (0.90 g) and methyl 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]nonan-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) under a nitrogen atmosphere at 0 °C, NH NH HO (47 mg, 0.95 mmol, 2 equiv) was added. 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 eluting with dichloromethane / methanol (10 / 1) to give 910 mg of methyl 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.2]nonan-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (M5-13) (76%) as a pale yellow solid. LCMS: m / z (ESI), [M + H] + = 599.20.

[0529] Step 14. Preparation of methyl 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]nonan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M5-14). A mixture of methyl 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.2]nonan-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (900 mg, 1.50 mmol, 1 equiv) and BrCN (174 mg, 1.65 mmol, 1.1 equiv) in ethanol (10 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h. The mixture was concentrated under vacuum. The residue was purified by prep-TLC eluting with dichloromethane / methanol (12 / 1) to give 640 mg of a pale yellow solid: methyl 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]nonan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M5-14) (68%). LCMS: m / z (ESI), [M + H] + = 624.10. 1 H NMR (DMSO-d6, 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).

[0530] Step 15. Preparation of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]nonan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (M5-15). A mixture of methyl 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]nonan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (620 mg, 0.99 mmol, 1 equiv) and LiOH (28 mg, 1.19 mmol, 1.2 equiv) in tetrahydrofuran / HO (4 mL / 1 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated in vacuo to give 550 mg of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]nonan-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.

[0531] Step 16. 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}]tetratriaconta-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione (M5). A mixture of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]nonan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (550 mg, 0.90 mmol, 1 equiv), N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1027 mg, 2.70 mmol, 3 equiv), and N,N-diisopropylethylamine (174 mg, 1.35 mmol, 1.5 equiv) in dioxane (6 mL) was stirred at 60° C. under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by Prep-HPLC using an XBridge Prep OBD C18 column with 10 mmol / L NH4HCO3 in water and acetonitrile as the mobile phase. Fractions containing the desired compound were evaporated to dryness to give 500 mg of a yellow solid: 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}]tetratriaconta-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione (M5) (88%). LCMS: m / z (ESI), [M + H] + = 592.15. Example Synthesis Example A1 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 [ka]

[0532] Step 1. Preparation of 2-((2-((2-nitrophenyl)amino)ethyl)amino)ethan-1-ol (INT-A1-1). A mixture of O-fluoronitrobenzene (10 g, 70.871 mmol, 1 equiv), K2CO3 (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 under a nitrogen atmosphere for 2 h. 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), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting 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. 1 H NMR (DMSO-d6, 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).

[0533] Step 2. Preparation of 2-({2-[(2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethanol (INT-A1-2). A mixture of 2-({2-[(2-nitrophenyl)amino]ethyl}amino)ethanol (INT-A1-1, 2 g, 8.879 mmol, 1 equiv), N,N-diisopropylethylamine (2.30 g, 17.758 mmol, 2 equiv), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.47 g, 10.655 mmol, 1.2 equiv) in N,N-dimethylformamide (20 mL) was stirred at 60 °C for 2 h under a 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 x 200 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (1 / 1) to afford 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.

[0534] Step 3. Preparation 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 (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 equiv) and triphenylphosphine (1.69 g, 6.44 mmol, 3 equiv) in tetrahydrofuran (20 mL) under a nitrogen atmosphere at 0 °C, diisopropyl azodicarboxylate (1.30 g, 6.44 mmol, 3 equiv) and 2-({2-[(2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethanol (0.66 g, 2.15 mmol, 1 equiv) were added. The mixture was stirred under a nitrogen atmosphere at 0 °C 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified on Prep-TLC eluting with petroleum ether / ethyl acetate (1 / 3) to afford 1.15 g 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 (INT-A1-3) (96%) as an orange oil. LCMS: m / z (ESI), [M + H] + = 553.25. 1H NMR (DMSO-d6, 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)

[0535] 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 equiv) and Raney nickel (0.85 g, 9.95 mmol, 5 equiv) in methanol (30 mL) at 0 °C was added hydrazine hydrate (0.15 g, 2.98 mmol, 1.5 equiv). The mixture was stirred at 0° C. under a nitrogen atmosphere for 30 minutes. 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 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) (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-d6, 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).

[0536] Step 5. Preparation of methyl 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-carboxylate (INT-A1-5). A mixture 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 (1 g, approximately 1.9 mmol, approximately 1 equiv) and BrCN (0.24 g, 2.29 mmol, 1.2 equiv) in CHCl (20 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC eluting with CHCl / methanol (40 / 1) to give 1 g of methyl 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-carboxylate (INT-A01-5) (95%) as a brown solid. LCMS: m / z (ESI), [M + H] + = 548.25. 1H NMR (DMSO-d6, 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).

[0537] 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). A mixture of methyl 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-carboxylate (200 mg, 0.36 mmol, 1 equiv) and LiOH·HO (23 mg, 0.55 mmol, 1.5 equiv) in tetrahydrofuran (4 mL) and HO (1 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 flash using water and acetonitrile as the mobile phase. 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-d6, 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)

[0538] Step 7. Preparation 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). A mixture 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 (150 mg, 0.28 mmol, 1 equiv), N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (160 mg, 0.42 mmol, 1.5 equiv), and N,N-diisopropylethylamine (109 mg, 0.84 mmol, 3 equiv) in 1,4-dioxane (5 mL) was stirred overnight at room temperature under a 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by prep-HPLC using an XBridge Shield RP18 OBD column with water and acetonitrile containing 10 mmol / L NHHCO and 0.1% NH.H0 as the mobile phase. 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) (20%) as a pink solid. 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). 19 F NMR (DMSO-d6, 376 MHz) δ 69.23 (s). Example A2 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 [ka]

[0539] Step 1. Preparation of 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}amino)ethanol (INT-A2-1). A mixture of 4-bromo-2-fluoro-1-nitrobenzene (2 g, 9.09 mmol, 1 equiv), aminoethylethanolamine (1.42 g, 13.63 mmol, 1.5 equiv), and K2CO3 (3 g, 27.27 mmol, 3 equiv) in acetonitrile (20 mL) was stirred at 60 °C under a nitrogen atmosphere for 2 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), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-TLC eluting with 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. 1 H NMR (DMSO-d6, 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).

[0540] Step 2. Preparation of 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethanol (INT-A2-2). To a stirred mixture of 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}amino)ethanol (INT-A2-1, 10 g, 32.87 mmol, 1 equiv) and N,N-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 under a nitrogen atmosphere for 2 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by prep-TLC eluting with 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 1 H NMR (DMSO-d6, 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).

[0541] 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 equiv) and cyclopropylhydrazine (621 mg, 8.61 mmol, 1 equiv) in methanol (4 mL) was stirred at 80 °C for 16 h under an air atmosphere. After cooling to room temperature, the reaction was quenched with saturated NH4Cl solution (300 mL), and the mixture was extracted with dichloromethane (3 × 200 mL). The combined organic layers were washed with brine (3 × 300 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography eluting with 0% to 15% acetonitrile / water to afford 200 mg of 2-cyclopropylpyrazol-3-ol (INT-A2-3) (18%) as a yellow oil. LCMS: m / z (ESI), [M + H] + = 125.15. 1 H NMR (DMSO-d6, 400 MHz) δ 1.08-0.93 (4H, m), 3.44-3.31 (1H, m), 5.64 (1H, d), 7.62 (1H, d).

[0542] Step 4. Preparation of 2-cyclopropyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (INT-A2-4). To a stirred mixture of 2-cyclopropylpyrazol-3-ol (1.1 g, 8.86 mmol, 1 equiv) and 2-(trimethylsilyl)ethoxymethyl chloride (2.66 g, 15.95 mmol, 1.8 equiv) in N,N-dimethylformamide (10 mL) at room temperature under a nitrogen atmosphere, sodium hydride (0.85 g, 17.72 mmol, 2 equiv, 60%) was added in portions. The mixture was stirred for 2 h. The reaction was quenched with saturated NH4Cl solution (300 mL), and the mixture was extracted with dichloromethane (3 × 200 mL). The combined organic layers were washed with brine (3 × 300 mL), dried over anhydrous Na2SO4, and concentrated 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

[0543] 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 equiv) and NIS (5.97 g, 26.53 mmol, 1.5 equiv) in acetonitrile (50 mL) was stirred at 0 °C for 2 h under a nitrogen atmosphere. The reaction was quenched by the addition of saturated sodium thiosulfate (aq) (100 mL), and the mixture was extracted with CHCl (3 × 50 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 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

[0544] Step 6. Preparation of methyl 5-(2-cyclopropyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A2-6). A mixture of freshly prepared 5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-ylboronic acid (M2-2, 800 mg, 3.8 mmol, 1 equiv), KCO (1.31 g, 9.48 mmol, 2.5 equiv), Pd(dppf)Cl (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 HO (2 mL) was stirred at 80 °C for 2 h under a 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 x 300 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified on a silica gel column eluted with petroleum ether / ethyl acetate (1 / 1) to afford 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.

[0545] Step 7. Preparation of methyl 5-(1-cyclopropyl-5-hydroxypyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A2-7). A solution of methyl 5-(2-cyclopropyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (750 mg, 1.79 mmol, 1 equiv) in 1,4-dioxane (10 mL) containing HCl was stirred at 60 °C for 5 h under a nitrogen atmosphere. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in methanol (10 mL) and neutralized to pH 7 with KCO. The mixture was filtered. The filter cake was washed with methanol (2 × 5 mL). The solution was concentrated 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 carried to the next step without further purification. LCMS: m / z (ESI), [M + H] + = 290.05

[0546] Step 8. Preparation 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 (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 equiv) and triphenylphosphine (1.9 g, 7.26 mmol, 3 equiv) in tetrahydrofuran (20 mL) under a nitrogen atmosphere at 0 °C, diisopropyl azodicarboxylate (1.4 g, 7.26 mmol, 3 equiv) 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 equiv) were added. 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 × 100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified on a C18 column using water containing 10 mmol / L NHHCO and 0.1% NH H0 and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 400 mg 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 (INT-A2-8) (25%) as an orange solid. LCMS: m / z (ESI), [M + H] + = 658.95. 1H NMR (DMSO-d6, 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).

[0547] 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 equiv) and Raney nickel (365 mg, 4.26 mmol, 8 equiv) in methanol (5 mL) under a nitrogen atmosphere at 0° C., hydrazine hydrate (98%) (40 mg, 0.80 mmol, 1.5 equiv) was added. The resulting mixture was stirred for 2 h and filtered. The filter cake was washed with methanol (3 x 50 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}(2,2,2-trifluoroethyl)amino)ethoxy]-1-cyclopropylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (INT-A2-9) (approximately 90%) as a brown solid. LCMS: m / z (ESI), [M + H] + = 627.15. 1H NMR (DMSO-d6, 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).

[0548] 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 equiv) and BrCN (60 mg, 0.57 mmol, 1.2 equiv) in dichloromethane (5 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h and concentrated in vacuo. The residue was purified on prep-TLC eluting with dichloromethane / methanol (10 / 1) to give 300 mg 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) (96%) as a brown solid. LCMS: m / z (ESI), [M + H] + = 654.10.

[0549] 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). A mixture 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 (280 mg, 0.43 mmol, 1 equiv) and LiOH·HO (27 mg, 0.64 mmol, 1.5 equiv) in THF (4 mL) and HO (1 mL) was stirred at room temperature under nitrogen atmosphere for 2 h and concentrated under reduced pressure. The residue was purified by prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol / L NH4HCO3 and 0.1% NH3 . The purification was carried out using water containing HO and acetonitrile as the mobile phase. 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. 1 H NMR (DMSO-d6, 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)

[0550] 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}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A2-12). A mixture 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 (110 mg, 0.17 mmol, 1 equiv), N,N-diisopropylethylamine (67 mg, 0.52 mmol, 3 equiv), and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (98 mg, 0.26 mmol, 1.5 equiv) in 1,4-dioxane (5 mL) was stirred at room temperature under a 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 x 50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol / L NH4HCO3 and 0.1% NH3 . The purification was carried out using water containing HO and acetonitrile as the mobile phase. 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-d6, 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)。

[0551] 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). A mixture 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 (40 mg, 0.06 mmol, 1 equiv), 1-methylpiperazine (26 mg, 0.256 mmol, 4 equiv), and BrettPhos Pd G3 (18 mg, 0.02 mmol, 0.3 equiv) in 1,4-dioxane (5 mL) was added to LiHMDS (65 mL) at room temperature under a nitrogen atmosphere. mg, 0.38 mmol, 6 equiv) was added. The mixture was stirred at 60 °C for 2 h and then cooled to room temperature. The reaction mixture was treated with NH4Cl(aq) solution (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC using a Shield RP18 OBD column with 10 mmol / L NH4HCO3 and 0.1% NH3 .The purification was carried out using water containing HO and acetonitrile as the mobile phase. 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) (6%) as a white solid. LCMS: m / z (ESI), [M + H] + = 640.35. 1 H NMR (DMSO-d6, 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). 19 F NMR (DMSO-d6, 376 MHz) δ 69.26 (s). Example A3 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 [ka]

[0552] 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 equiv) and methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 354 mg, 1.34 mmol, 0.8 equiv) in tetrahydrofuran (9 mL) at 0 °C, 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethanol (650 mg, 1.68 mmol, 1 equiv) and diisopropyl azodicarboxylate (1021 mg, 5.04 mmol, 3 equiv) were added. The mixture was stirred under a nitrogen atmosphere 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by prep-TLC eluting with dichloromethane / methanol (10 / 1) to afford 550 mg 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) (36%) as a yellow oil. LCMS: m / z (ESI), [M + H] + = 630.85. 1H NMR (DMSO-d6, 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).

[0553] Step 2. Preparation of methyl 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-carboxylate (INT-A3-2). To a stirred mixture 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 (570 mg, 0.90 mmol, 1 equiv) and Raney nickel (30 mg) in methanol (6 mL) was added NH2NH2·HO (57 mg, 1.80 mmol, 2 equiv). The mixture was stirred under a nitrogen atmosphere at 0 °C for 30 min. 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 methyl 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-carboxylate (INT-A3-2) (42%) as a yellow oil. LCMS: m / z (ESI), [M + H] + = 601.05.

[0554] Step 3. Preparation of methyl 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-carboxylate (INT-A3-3). A mixture of methyl 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-carboxylate (240 mg, 0.39 mmol, 1 equiv) and BrCN (42 mg, 0.39 mmol, 1 equiv) in ethanol (6 mL) was stirred at 0° C. under a nitrogen atmosphere for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC eluting with dichloromethane / methanol (10 / 1) to give 120 mg of methyl 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-carboxylate (INT-A3-3) (43%) as a brown solid. LCMS: m / z (ESI), [M + H] + = 626.05

[0555] 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 methyl 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-carboxylate (100 mg, 0.16 mmol, 1 equiv) in tetrahydrofuran (2 mL) was added LiOH·HO (7.6 mg, 0.32 mmol, 2 equiv) in HO (0.5 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was purified on a C18 column using water and acetonitrile as the 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. 1 H NMR (DMSO-d6, 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,).

[0556] 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). 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 (65 mg, 0.10 mmol, 1 equiv) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (60 mg, 0.15 mmol, 1.5 equiv) in 1,4-dioxane (2 mL), N,N-diisopropylethylamine (41 mg, 0.31 mmol, 3 equiv) was added, and the mixture was stirred at 60° C. under a nitrogen atmosphere for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC eluting with 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.

[0557] 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-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 (50 mg, 0.08 mmol, 1 equiv), BrettPhos Pd G3 (22 mg, 0.02 mmol, 0.3 equiv), and piperazine, 1-methyl- (33 mg, 0.33 mmol, 4 equiv) in 1,4-dioxane (2 mL) were dissolved in water at room temperature under a nitrogen atmosphere. To a stirred mixture of 10 mmol / L NH4HCO3 and 0.1% NH3 was added LiHMDS (0.48 mL, 0.48 mmol, 6 equiv). The mixture was stirred at 60 °C under nitrogen atmosphere for 40 min. 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), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol / L NH4HCO3 and 0.1% NH3 .The purification was carried out using water containing HO and acetonitrile as the mobile phase. Fractions containing the desired compound were evaporated to dryness to give 3.1 mg of a yellow solid: 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) (5%). LCMS: m / z (ESI), [M + H] + = 614.25. 1 H NMR (DMSO-d6, 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). 19 F NMR (DMSO-d6, 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-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 [ka]

[0558] Step 1. Preparation of 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethanol (INT-A4-1). A mixture of 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}amino)ethanol (2 g, 6.57 mmol, 1 equiv), N,N-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 under a nitrogen atmosphere for 2 h. 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by prep-TLC eluting with 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. 1 H NMR (DMSO-d6, 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).

[0559] Step 2. Preparation of methyl 5-{5-[2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (INT-A4-2). To a mixture of triphenylphosphine (1.38 g, 5.29 mmol, 3 equiv) and methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 836 mg, 3.17 mmol, 1.8 equiv) in tetrahydrofuran (10 mL) at 0 °C, 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethanol (650 mg, 1.76 mmol, 1 equiv) and diisopropyl azodicarboxylate (1.07 g, 5.29 mmol, 3 equiv) were added. The mixture was stirred under a nitrogen atmosphere at 0 °C 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by prep-TLC eluting with petroleum ether / ethyl acetate (1 / 3) to afford 400 mg of methyl 5-{5-[2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (INT-A4-2) (33%) as a yellow solid. LCMS: m / z (ESI), [M + H] + = 613.00.

[0560] Step 3. Preparation 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). To a stirred mixture of methyl 5-{5-[2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (400 mg, 0.65 mmol, 1 equiv) and Raney nickel (72 mg) in methanol (5 mL) at 0 °C, hydrazine (41 mg, 1.30 mmol, 2 equiv) was added. The mixture was stirred under a nitrogen atmosphere at 0 °C for 30 minutes. 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.

[0561] 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 equiv) and BrCN (54 mg, 0.51 mmol, 1 equiv) in ethanol (5 mL) was stirred at room temperature under a nitrogen atmosphere for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC eluting with dichloromethane / methanol (10 / 1) to give 250 mg 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) (71%) as a brown solid. LCMS: m / z (ESI), [M + H]+ = 608.05.

[0562] 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 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 (200 mg, 0.32 mmol, 1 equiv) in tetrahydrofuran (4 mL) was added LiOH·HO (19.6 mg, 0.82 mmol, 2.5 equiv) in HO (1 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by C18 flash with 10 mmol / L NH4HCO3 and 0.1% NH3 . The purification was carried out using water containing HO and acetonitrile as the mobile phase. 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. 1 H NMR (DMSO-d6, 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).

[0563] 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). A 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 (160 mg, 0.26 mmol, 1 equiv), N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (153 mg, 0.40 mmol, 1.5 equiv), and N,N-diisopropylethylamine (104 mg, 0.80 mmol, 3 equiv) in 1,4-dioxane (6 mL) was stirred at 60 °C under a nitrogen atmosphere for 2 h. 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The 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.

[0564] 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-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). 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 (100 mg, 0.17 mmol, 1 equiv), BrettPhos Pd G3 (47 mg, 0.05 mmol, 0.3 equiv), and [2-(dimethylamino)ethyl](methyl)amine (70 mg, 0.69 mmol, 4 equiv) were dissolved in 1,4-dioxane (3 mL) at room temperature under a nitrogen atmosphere. To a mixture of 10 mmol / L NH4HCO3 + 0.1% NH3 was added LiHMDS (0.7 mL, 1.02 mmol, 6 equiv). The mixture was stirred at 60 °C under nitrogen atmosphere for 2 h, then cooled to room temperature. The reaction was quenched with saturated NH4Cl(aq) solution (5 mL), and the mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC using an XBridge Shield RP18 OBD column with 10 mmol / L NH4HCO3 + 0.1% NH3 .The purification was carried out using water containing HO and acetonitrile as the mobile phase. Fractions containing the desired compound were evaporated to dryness to give 1.2 mg of a yellow solid: 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) (1%). LCMS: m / z (ESI), [M + H] + = 598.25. 1 H NMR (DMSO-d6, 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). 19 F NMR (DMSO-d6, 376 MHz) δ 119.603 (s). Example A5 5,26-Dimethyl-10-(oxetan-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 [ka]

[0565] Step 1. Preparation of 2-({2-[(2-nitrophenyl)amino]ethyl}(oxetan-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 equiv), 3-oxetanone (383 mg, 5.33 mmol, 1.2 equiv), and molecular sieves (20 mg) in dichloromethane (30 mL) at room temperature was added sodium triacetoxyborohydride (1.88 g, 8.88 mmol, 2 equiv). The mixture was stirred at room temperature under a nitrogen atmosphere for 12 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), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-TLC eluting with petroleum ether / ethyl acetate (1 / 1) to give 1.2 g of 2-({2-[(2-nitrophenyl)amino]ethyl}(oxetan-3-yl)amino)ethanol (INT-A5-1) (95%) as a red oil. LCMS: m / z (ESI), [M + H] + = 282.10. 1 H NMR (DMSO-d6, 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).

[0566] Step 2. Preparation of methyl 1-methyl-5-{1-methyl-5-[2-({2-[(2-nitrophenyl)amino]ethyl}(oxetan-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 equiv) and triphenylphosphine (839 mg, 3.20 mmol, 3 equiv) in tetrahydrofuran (2 mL) at 0 °C, diisopropyl azodicarboxylate (647 mg, 3.20 mmol, 3 equiv) and 2-({2-[(2-nitrophenyl)amino]ethyl}(oxetan-3-yl)amino)ethanol (300 mg, 1.07 mmol, 1 equiv) were added. The mixture was stirred at room temperature under a 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), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by prep-TLC eluting with petroleum ether / ethyl acetate (1 / 1) to give 200 mg of methyl 1-methyl-5-{1-methyl-5-[2-({2-[(2-nitrophenyl)amino]ethyl}(oxetan-3-yl)amino)ethoxy]pyrazol-4-yl}-6-oxopyridine-3-carboxylate (INT-A5-2) (30%) as a yellow solid. LCMS: m / z (ESI), [M + H] + = 527.20. 1H NMR (DMSO-d6, 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).

[0567] Step 3. Preparation of methyl 5-{5-[2-({2-[(2-aminophenyl)amino]ethyl}(oxetan-3-yl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (INT-A5-3). To a stirred mixture of methyl 1-methyl-5-{1-methyl-5-[2-({2-[(2-nitrophenyl)amino]ethyl}(oxetan-3-yl)amino)ethoxy]pyrazol-4-yl}-6-oxopyridine-3-carboxylate (150 mg, 0.29 mmol, 1 equiv) and Raney nickel (30 mg, 0.35 mmol, 1.2 equiv) in methanol (30 mL) at 0 °C, NH NH HO (90 mg) was added. The mixture was stirred under a nitrogen atmosphere at 0 °C for 1 h. 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 eluting with dichloromethane / methanol (10 / 1) to give 120 mg of methyl 5-{5-[2-({2-[(2-aminophenyl)amino]ethyl}(oxetan-3-yl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (INT-A5-3) (73%) as a yellow solid. LCMS: m / z (ESI), [M + H] + = 497.30.

[0568] Step 4. Preparation of methyl 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](oxetan-3-yl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A5-4). A mixture of methyl 5-{5-[2-({2-[(2-aminophenyl)amino]ethyl}(oxetan-3-yl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (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 under a nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC eluting with dichloromethane / methanol (5 / 1) to give 82 mg of methyl 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](oxetan-3-yl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A5-4) (65%) as a yellow solid. LCMS: m / z (ESI), [M + H] + = 522.25. 1 H NMR (DMSO-d6, 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).

[0569] Step 5. Preparation of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](oxetan-3-yl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A5-5). A mixture of methyl 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](oxetan-3-yl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (82 mg, 0.16 mmol, 1 equiv) and lithium hydroxide (13 mg, 0.31 mmol, 2 equiv) in tetrahydrofuran (10 mL) and water (2.5 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by C18 flash with 10 mmol / L NH4HCO3 and 0.1% NH3 . The purification was carried out using water containing HO and acetonitrile as the mobile phase. 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](oxetan-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.

[0570] Step 6. Preparation of 5,26-dimethyl-10-(oxetan-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). A mixture of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](oxetan-3-yl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (20 mg, 0.04 mmol, 1 equiv), N,N-diisopropylethylamine (15 mg, 0.12 mmol, 3 equiv), and N,N,N,N-tetramethyl-O-(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 under a nitrogen atmosphere for 3 h. The mixture was concentrated under reduced pressure. The resi...

Claims

1. Compound of formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl. Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl. L １ The group is selected from the group consisting of bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl, and the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano and amino. L ２ is a bond, N(R) Ａ ), selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be any one or more R Ｂ It has been replaced with, R Ａ The group is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl. Each R Ｂ These are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. L ３ The group is selected from the group consisting of bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl, and the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano and amino. L ４ is selected from O, S or N(R Ｃ ), R Ｃ This is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Each R １ These are independently hydroxy, halogen, cyano, amino, and -N(R) Ｄ ) ２ Selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be any one or more R Ｅ It has been replaced with, Each R Ｄ The elements are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally hydroxyl, halogen, cyano, -N(R) Ｆ ) ２ OR Ｇ It is replaced by one or more groups independently selected from the above, Each R Ｅ These are independently hydrogen, hydroxyl, halogen, cyano, amino, and -N(R) Ｆ ) ２ ,-alkyl-N(R Ｆ ) ２ , -C(O)OR Ｇ A group selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, and alkyl. R Ｆ and R Ｇ Each of these is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Each R ２ The group is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, and haloalkyl. R ３ The group is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclyl, and the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl and haloalkyl. m is an integer from 0 to 5, and n is an integer from 0 to 4. A compound or a pharmaceutically acceptable salt thereof.

2. (a) Ring A is aryl or heteroaryl; and / or (b) Ring B is aryl or heteroaryl; and / or (c) L1 is bonded or alkyl; and / or (d) L3 is alkyl and optionally ethyl; and / or (e) L 4 is O or NH; and / or (f) R3 is alkyl or cycloalkyl, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. (a) Ring A is selected from the group consisting of furanyl, thiophenyl, pyrrolyl, phenyl, pyridinyl, pyranyl, pyrimidinyl, pyridadinyl, pyrazinyl and tetrahydroisoquinoline; and / or (b) Ring B is phenyl, pyridinyl, or pyrazolyl, The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

4. (a) Ring A is 【Chemistry 2】 Selected from the group consisting of; and / or (b) Ring B is 【Transformation 3】 Selected from the group consisting of; and / or (c) L 1 is, 【Chemistry 4】 Selected from the group consisting of, the * end of L1 is connected to L2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. L ２ but, (a) is a bond; or (b) N(RA), where RA is selected from alkyl or heterocycline, and the alkyl or heterocycline is optionally substituted with one or more halogens or alkyls; or (c) A cycloalkyl compound optionally substituted with one or more R B groups; or (d) A heterocyclyl which is arbitrarily substituted with one or more R B The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. (i) L2 is N(RA), R Ａ is ethyl, difluoroethyl, trifluoroethyl or oxetanyl; or (ii) L 2 is 【Transformation 5】 and are replaced by any one or more R B; or (iii) L2 is a heterocycline, and the heterocycline is 【Transformation 6】 Selected from the group consisting of, Each of these is arbitrarily replaced by one or more R Bs, and the * end of L 2 is connected to L 3. The compound according to claim 5 or a pharmaceutically acceptable salt thereof.

7. R Ｂ The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein is alkyl and optionally R and B are methyl.

8. L ２ but, 【Transformation 7】 Selected from the group consisting of L ２ The * end is L ３ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, connected to a device.

9. (i) L １ is a bond, L ２ R is combined or any one or more R Ｂ It is a heterocyclyl substituted with; or (ii) L1 is alkyl and L2 is a cycloalkyl group bonded, N(RA) or optionally substituted with one or more RBs. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. (a) R １ is hydroxyl and m is 1; or (b) R1 is a halogen, m is 1, and R1 is optionally bromo or fluoro; or (c) R 1 is -N(RD) 2 and m is 1; or (d) R1 is a heterocyclyl in which R1 is arbitrarily substituted with one or more REs, and m is 1; or (e) m is 2, one of R1 is a halogen, and the other R1 is a heterocycline substituted with any one or more REs. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. (i) R 1 is -N(R D) 2, m is 1, and each R Ｄ This is independently hydrogen, or optionally -N(R) Ｆ ) ２ OR Ｇ It is an alkyl group substituted with one or more groups independently selected from; or (ii) R1 is a heterocyclyl in which R1 is arbitrarily substituted with one or more REs, m is 1, and the heterocyclyl is 【Transformation 8】 Selected from the group consisting of, Each of them is arbitrarily replaced by one or more REs; or (iii)m is 2, one of R1 is a halogen, and the other R1 is a heterocycline substituted with one or more REs, and the heterocycline is 【Chemistry 9】 Selected from the group consisting of, Each of them is arbitrarily replaced with one or more REs. The compound according to claim 10 or a pharmaceutically acceptable salt thereof.

12. (i) Each R Ｄ However, independently of hydrogen, methyl, methoxyethyl, N,N-dimethylaminoethyl, hydroxyethyl, or N,N-dimethylaminopropyl; or (ii) Each RE is independently selected from halogen, -N(RF)2, -alkyl-N(RF)2, -C(O)ORG, or alkyl substituted with any one or more halogens. The compound according to claim 10 or a pharmaceutically acceptable salt thereof.

13. (i) R Ｅ is halogen, and optionally RE is F; or (ii) Each of R F and R G is independently alkyl, and optionally each of R F and R G is independently C1-3 alkyl; or (iii) Each RE is independently selected from the group consisting of F, -N(CH3)2, -C1-3 alkyl-N(CH3)2, -C(O)O(tert-butyl), methyl, ethyl, or trifluoroethyl; or (iv) RE is a cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more alkyl or halogen groups, and RE is optionally selected from cyclopropyl, morpholinyl, piperazinyl, oxetyl or azetidinyl, each of which is optionally substituted with one or more alkyl or halogen groups. The compound according to claim 12 or a pharmaceutically acceptable salt thereof.

14. (i) R １ but, 【Chemistry 10】 Selected from the group consisting of; or (ii) R2 is a halogen, n is 1 or 2, and R2 is F of any choice; or (iii) R2 is alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more halogens, and R2 is optionally methyl, ethyl, cyclopropyl or trifluoroethyl; or (iv) R3 is alkyl or cycloalkyl, and optionally R3 is methyl, ethyl or cyclopropyl. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2; and / or n is 0 or 1.

16. The aforementioned compound, 【Chemistry 11-1】 【Chemistry 11-2】 【Chemistry 11-3】 【Chemistry 11-4】 【Chemistry 11-5】 【Chemistry 11-6】 【Chemistry 11-7】 【Chemistry 11-8】 【Chemistry 11-9】 【Chemistry 11-10】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following. 【Request Item 17】 【Chemistry 12】 A compound or a pharmaceutically acceptable salt thereof, selected from the above. 【Request Item 18】 【Chemistry 13】 A compound having the structure of or a pharmaceutically acceptable salt thereof. 【Request Item 19】 【Chemistry 14】 A compound having the structure. 【Request Item 20】 【Chemistry 15】 A compound having the structure of or a pharmaceutically acceptable salt thereof. 【Request Item 21】 【Chemistry 16】 A compound having the structure. 【Request Item 22】 【Chemistry 17】 A compound or a pharmaceutically acceptable salt thereof, selected from the above. 【Request Item 23】 【Chemistry 18】 A compound having the structure of or a pharmaceutically acceptable salt thereof. 【Request Item 24】 【Chemistry 19】 A compound having the structure. 【Request Item 25】 【Chemistry 20】 A compound having the structure of or a pharmaceutically acceptable salt thereof. 【Request Item 26】 【Chemistry 21】 A compound having the structure. 【Request Item 27】 【Chemistry 22】 A compound or a pharmaceutically acceptable salt thereof, selected from the above. 【Request Item 28】 【Chemistry 23】 A compound having the structure of or a pharmaceutically acceptable salt thereof. 【Request Item 29】 【Chemistry 24】 A compound having the structure. 【Request Item 30】 【Chemistry 25】 A compound having the structure of or a pharmaceutically acceptable salt thereof. 【Request Item 31】 【Chemistry 26】 A compound having the structure. 【Request Item 32】 【Chemistry 27】 A compound having the structure of or a pharmaceutically acceptable salt thereof. 【Request Item 33】 【Chemistry 28】 A compound having the structure.

34. A drug composition comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

35. A pharmaceutical composition for inhibiting EGFR activity in a subject as required, comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof.

36. A pharmaceutical composition for the treatment of EGFR-related disorders in subjects in need, comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof.

37. The pharmaceutical composition according to claim 36, wherein the EGFR-related disease is an autoimmune disease or cancer, and the cancer is optionally selected from the group consisting of 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, and includes metastasis (especially brain metastasis).

38. The pharmaceutical composition according to claim 35 or 36, wherein the compound is administered alone, sequentially, or simultaneously with one or more additional therapeutic agents.

39. The pharmaceutical composition according to claim 38, 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.

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