EGFR inhibitors and uses thereof

Abstract

Disclosed herein are compounds or pharmaceutically acceptable salts thereof useful as EGFR inhibitors. Also disclosed are pharmaceutical compositions comprising such compounds and methods of using such compounds or compositions in the treatment of EGFR-related conditions (e.g., cancer).

Description

Technical Field

[0001] The present disclosure generally relates to novel compounds and pharmaceutically acceptable salts thereof that inhibit epidermal growth factor receptor (EGFR). The present disclosure also relates to pharmaceutical compositions comprising the compounds as active ingredients and uses of the compounds in treating EGFR-related disorders (including cancer). Background Art

[0002] Epidermal growth factor receptor (EGFR) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The EGFR family of receptor tyrosine kinases regulates cell proliferation, survival, adhesion, migration and differentiation. Inhibition of EGFR activity has been shown to have potential therapeutic applicability under a wide range of pathological conditions. Certain cancers are characterized by EGFR mutations, which 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 EGFR inhibitors and fourth-generation EGFR inhibitors such as WZ4002 has been reported.

[0004] There remains a need for novel compounds that inhibit EGFR, which can be used as pharmacological tools and are of considerable interest as drugs for the treatment of EGFR-related disorders such as cancer. Summary of the Invention

[0005] Disclosed herein are novel compounds capable of inhibiting EGFR. Therefore, the compounds disclosed herein can be used to treat EGFR-related diseases such as cancer.

[0006] In one aspect, the present disclosure provides a compound of formula (I):

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein:

[0009] Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0010] Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0011] L 1selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0012] L 2 Selected from the group consisting of: a bond, N(R A ), 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 replaced by one or more R B replace;

[0013] where R A 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 substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0014] Each R B independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0015] L 3 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0016] L 4 Selected from O, S or N(R C );

[0017] where R C selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0018] Each R 1 are independently selected from the group consisting of: hydroxy, halogen, cyano, amino, -N(R D)2, 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 replaced by one or more R E replace;

[0019] Each R D independently selected from the group consisting of hydrogen, 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 the group consisting of hydroxy, halogen, cyano, -N(R F )2OR-OR G ;

[0020] Each R E are independently selected from the group consisting of hydrogen, hydroxy, 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 the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino and alkyl;

[0021] where R F and R G each of which is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0022] Each R 2 independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, the heteroalkynyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0023] R 3selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0024] m is an integer from 0 to 5; and

[0025] n is an integer from 0 to 4.

[0026] In another aspect, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038] In another aspect, the present disclosure provides a compound of formula (II):

[0039]

[0040] or a pharmaceutically acceptable salt thereof, wherein:

[0041] Ring A 1 is a 7-12 membered cycloalkyl group, a 7-12 membered heterocyclyl group, a 7-12 membered aryl group or a 7-12 membered heteroaryl group;

[0042] Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0043] L 1selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0044] L 2 Selected from the group consisting of: a bond, N(R A ), 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 replaced by one or more R B replace;

[0045] where R A 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 substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0046] Each R B independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0047] L 3 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0048] L 4 Selected from O, S or N(R C );

[0049] where R C selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0050] Each R 1 are independently selected from the group consisting of: hydroxy, halogen, cyano, amino, -N(R D)2, 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 replaced by one or more R E replace;

[0051] Each R D independently selected from the group consisting of hydrogen, 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 the group consisting of hydroxy, halogen, cyano, -N(R F )2OR-OR G ;

[0052] Each R E are independently selected from the group consisting of hydrogen, hydroxy, 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 the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino and alkyl;

[0053] where R F and R G each of which is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0054] Each R 2 independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, the heteroalkynyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0055] Each R 3selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0056] m is an integer from 0 to 5;

[0057] n is an integer from 0 to 4; and

[0058] p is an integer from 0 to 3.

[0059] In another aspect, the present disclosure provides a compound of formula (III)

[0060]

[0061] or a pharmaceutically acceptable salt thereof, wherein:

[0062] Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0063] Ring B 1 is a 7-12 membered cycloalkyl group, a 7-12 membered heterocyclyl group, a 7-12 membered aryl group or a 7-12 membered heteroaryl group;

[0064] L 1 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0065] L 2 Selected from the group consisting of: a bond, N(R A ), 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 replaced by one or more R B replace;

[0066] where R Aselected 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 substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0067] Each R B independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0068] L 3 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0069] L 4 Selected from O, S or N(R C );

[0070] where R C selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0071] Each R 1 are independently selected from the group consisting of: hydroxy, halogen, cyano, amino, -N(R D )2, 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 replaced by one or more R E replace;

[0072] Each R D independently selected from the group consisting of hydrogen, 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 the group consisting of hydroxy, halogen, cyano, -N(R F )2OR-OR G ;

[0073] Each R E are independently selected from the group consisting of hydrogen, hydroxy, 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 the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino and alkyl;

[0074] where R F and R G each of which is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0075] Each R 2 independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, the heteroalkynyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0076] Each R 3 selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0077] m is an integer from 0 to 5;

[0078] n is an integer from 0 to 4; and

[0079] p is an integer from 0 to 3.

[0080] In another aspect, the present disclosure provides a compound of formula (IV):

[0081]

[0082] or a pharmaceutically acceptable salt thereof, wherein:

[0083] Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0084] Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0085] L 1 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0086] L 21 is a 7-12 membered cycloalkyl or a 7-12 membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally replaced by one or more R B replace;

[0087] Each R B independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0088] L 3 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0089] L 4 Selected from O, S or N(R C );

[0090] where R C selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0091] Each R 1 are independently selected from the group consisting of: hydroxy, halogen, cyano, amino, -N(R D )2, 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 replaced by one or more R E replace;

[0092] Each R Dindependently selected from the group consisting of hydrogen, 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 the group consisting of hydroxy, halogen, cyano, -N(R F )2OR-OR G ;

[0093] Each R E are independently selected from the group consisting of hydrogen, hydroxy, 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 the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino and alkyl;

[0094] where R F and R G each of which is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0095] Each R 2 independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, the heteroalkynyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0096] R 3 selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0097] m is an integer from 0 to 5;

[0098] n is an integer from 0 to 4; and

[0099] p is an integer from 0 to 3.

[0100] In another aspect, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0101]

[0102]

[0103]

[0104] 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.

[0105] In another aspect, the present disclosure provides a method for inhibiting EGFR activity in a subject in need thereof, 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.

[0106] In another aspect, the present disclosure provides a method for treating EGFR-related disorders, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure to a subject in need thereof.

[0107] In another aspect, the present disclosure provides 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-related disorder.

[0108] 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 use in treating an EGFR-related disorder. DETAILED DESCRIPTION

[0109] Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are shown in the accompanying structures and formulas. Although the present disclosure will be described in conjunction with the enumerated embodiments, it should be understood that the embodiments are not intended to limit the present disclosure to those embodiments. On the contrary, the present disclosure is intended to encompass all alternatives, modifications and equivalents, which may be included within the scope of the present disclosure as defined in the claims. Those skilled in the art will recognize many methods and materials that are similar or equivalent to the methods and materials described herein and that can be used when practicing 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 technology, etc.) are different from or contradictory to the present application, the present disclosure shall prevail. All references, patents, and patent applications cited in the present disclosure are hereby incorporated by reference in their entirety.

[0110] It should be understood that certain features of the present disclosure described in the context of separate embodiments for the sake of clarity may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure described in the context of a single embodiment for the sake of brevity may also be provided individually or in any suitable subcombination. It must be noted that, unless the context clearly indicates otherwise, as used in the specification and the appended claims, the singular forms "a or an" and "the" include their plural forms. Thus, for example, reference to "a compound" includes a plurality of compounds.

[0111] definition

[0112] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry as well as specific functional moieties and reactivities are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th ed., 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 ed., Cambridge University Press, Cambridge, 1987; the entire contents of each of the foregoing are incorporated herein by reference.

[0113] Throughout this disclosure, linking substituents are described. Where a structure clearly requires a linking group, the Markush variable listed for that group should be understood to refer to the linking group. For example, if a structure requires a linking group and the Markush group definition for that variable lists "alkyl," it should be understood that "alkyl" means a linking alkylene group.

[0114] In any variable (e.g., R i ) occurs more than once in any constituent or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if the group shown is replaced by 0 to 2 R i Partially substituted, the group may optionally be replaced by up to two R i Partially substituted, and R i Each occurrence is independently selected from Ri Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0115] As used herein, for convenience, a dash "-" is used before or at the end of a chemical group to indicate the point of attachment of a substituent. For example, -OH is attached through an oxygen atom; a chemical group can be depicted with one or more dashes or without one or more dashes without losing its general meaning. A wavy line drawn through a line in a structure indicates the point of attachment of a group. Unless chemically or structurally required, directionality does not indicate or imply the order in which the chemical groups are written or named. As used herein, a solid line extending from the center of a ring indicates that the point of attachment of a substituent on the ring can be at any ring atom. When substituents are listed, but it is not specified through which atom such substituent is bonded to the rest of the compound of a given formula, such substituent can be bonded through any atom in this formula. Combinations of substituents and / or variables are permitted, but only if such combinations result in stable compounds.

[0116] Unless otherwise indicated herein, the recitation of a range of values ​​is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated into the specification as if it were individually recited herein. As used herein, ranges include both limits of the range unless otherwise indicated. For example, the expression "n is an integer between 1 and 6" and "n is an integer from 1 to 6" both mean "n is 1, 2, 3, 4, 5, or 6."

[0117] 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.

[0118] As used herein, the term "C i-j " indicates 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 every integer point therebetween, and where j is greater than i. For example, C 1-6 Indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms. In some embodiments, the term "C 1-12 ” indicates 1 to 12 carbon atoms, especially 1 to 10 carbon atoms, especially 1 to 8 carbon atoms, especially 1 to 6 carbon atoms, especially 1 to 5 carbon atoms, especially 1 to 4 carbon atoms, especially 1 to 3 carbon atoms or especially 1 to 2 carbon atoms.

[0119] As used herein, the term "alkyl", whether used as part of another term or by itself, refers to a saturated straight or branched chain hydrocarbon group that may be optionally substituted independently with one or more substituents as described below. i-j "Alkyl" refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 9 carbon atoms. In some embodiments, the alkyl group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C 1-10 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1-6 Examples of "alkyl" are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like.

[0120] As used herein, the term "alkenyl", whether as part of another term or used independently, refers to a straight or branched hydrocarbon group with at least one carbon-carbon double bond that can be optionally independently substituted by one or more substituents described herein and includes groups with "cis" orientation and "trans" orientation or alternatively "E" orientation and "Z" orientation. In some embodiments, the alkenyl contains 2 to 12 carbon atoms. In some embodiments, the alkenyl contains 2 to 11 carbon atoms. In some embodiments, the 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, 2 to 3 carbon atoms, and in some embodiments, the alkenyl includes 2 carbon atoms. Examples of alkenyl include but are not limited to vinyl (ethylenyl or vinyl), propenyl (allyl), butenyl, pentenyl, 1-methyl-2-butene-1-yl, 5-hexenyl, etc.

[0121] As used herein, the term "alkynyl", whether used as part of another term or independently, refers to a straight or branched chain hydrocarbon group with at least one carbon-carbon triple bond that can be optionally independently substituted by one or more substituents described herein. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkynyl group includes 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, etc.

[0122] As used herein, the term "amino" refers to a -NH2 group. The amino group may also be substituted with one or more groups such as alkyl, alkenyl, alkynyl, aryl, carbonyl or other amino groups.

[0123] As used herein, the term "aryl", whether used as part of another term or independently, refers to monocyclic and polycyclic ring systems with a total of 5 to 20 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system includes 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, etc., which may carry one or more substituents. As used herein, the scope of the term "aryl" also includes groups in which an aromatic ring is fused to one or more additional rings. In the case of a polycyclic system, only one ring is required to be aromatic (e.g., 2,3-dihydroindole), but all rings can be aromatic (e.g., quinoline). The second ring can also be fused or bridged. Examples of polycyclic aryl groups include, but are not limited to, benzofuranyl, indanyl, phthalimido, naphthalimido, phenanthridinyl, or tetrahydronaphthyl, etc. Aryl can be substituted by substituents as described above at one or more ring positions.

[0124] As used herein, the term "cyano" refers to -CN.

[0125] 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 and polycyclic system in which all ring atoms are carbon and the system includes at least three ring-forming carbon atoms. In some embodiments, the cycloalkyl group may contain 3 to 12 ring-forming carbon atoms, 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, 3 to 8 ring-forming carbon atoms, 3 to 7 ring-forming carbon atoms, 3 to 6 ring-forming carbon atoms, 3 to 5 ring-forming carbon atoms, 4 to 12 ring-forming carbon atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming carbon atoms, 4 to 8 ring-forming carbon atoms, 4 to 7 ring-forming carbon atoms, 4 to 6 ring-forming carbon atoms, 4 to 5 ring-forming carbon atoms. Cycloalkyl groups can be saturated or partially unsaturated. Cycloalkyl groups can be substituted. In some embodiments, the cycloalkyl group can be a saturated cyclic alkyl group. In some embodiments, cycloalkyl can be a partially unsaturated cyclic alkyl group that includes at least one double bond or triple bond in its ring system. In some embodiments, cycloalkyl can be monocyclic or polycyclic. In the case of polycyclic systems, fused, spiro and bridged ring systems are included within the scope of this definition. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Examples of polycyclic cycloalkyls include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro[3.6]-decyl, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, etc.

[0126] As used herein, the term "halogen" refers to an atom selected from the group consisting of fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo).

[0127] 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-oxides).

[0128] As used herein, the term "heteroalkyl" refers to an alkyl group in which at least one of its carbon atoms is replaced by a heteroatom selected from N, O or S. A heteroalkyl group can be a carbon group or a heteroatom group (i.e., a heteroatom can appear in the middle or at a terminal end of the group) and can be optionally substituted independently with one or more substituents described herein. The term "heteroalkyl" encompasses alkoxy and heteroalkoxy groups.

[0129] As used herein, the term "heteroalkenyl" refers to an alkenyl group in which at least one of its carbon atoms is replaced by a heteroatom selected from N, O, or S. A heteroalkenyl group can be carbonyl or heteroatom-based (i.e., the heteroatom can occur in the middle or at a terminal end of the group) and can be optionally substituted independently with one or more substituents described herein.

[0130] As used herein, the term "heteroalkynyl" refers to an alkynyl group in which at least one of its carbon atoms is replaced by a heteroatom selected from N, O, or S. A heteroalkynyl group can be carbonyl or heteroatom-based (i.e., the heteroatom can occur in the middle or at a terminal end of the group) and can be optionally substituted independently with one or more substituents described herein.

[0131] As used herein, the term "heteroaryl", whether used as part of another term or independently, refers to an aryl group having one or more heteroatoms in addition to carbon atoms. Heteroaryl can be monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. Heteroaryl also includes a polycyclic group to which a heteroaromatic ring is fused to one or more aryl, cycloalkyl, or heterocyclyl rings, wherein a linking group or point of attachment is located on the heteroaromatic ring. Examples of polycyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo[1,3]dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0132] As used herein, the term "heterocyclic radical" refers to a saturated or partially unsaturated carbocyclic radical, wherein one or more ring atoms are heteroatoms independently selected from oxygen, sulphur, nitrogen, phosphorus, etc., and the remaining ring atoms are carbon, wherein one or more ring atoms can optionally be independently substituted by one or more substituents. In some embodiments, the heterocyclic radical is a saturated heterocyclic radical. In some embodiments, the heterocyclic radical is a partially unsaturated heterocyclic radical with one or more double bonds in its ring system. In some embodiments, the heterocyclic radical can include any oxidized form of carbon, nitrogen, sulphur or phosphorus and any quaternized form of basic nitrogen. "Heterocyclic radical" also includes a group in which the heterocyclic radical is fused to a saturated, partially unsaturated or completely unsaturated (i.e., aromatic) carbocyclic ring or heterocyclic ring. Where possible, the heterocyclic radical can be carbon-connected or nitrogen-connected. In some embodiments, the heterocycle is carbon-connected. In some embodiments, the heterocycle is nitrogen-connected. For example, the group derived from pyrrole can be pyrrole-1-yl (nitrogen-connected) or pyrrole-3-yl (carbon-connected). Further, the group derived from imidazole may be imidazol-1-yl (nitrogen-attached) or imidazol-3-yl (carbon-attached).

[0133] 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 a polycyclic system, fused, spiro, and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, 1,1-dioxothietane, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazinonyl, pyrrolidinyl, triazinonyl, etc. Examples of fused heterocyclic groups include, but are not limited to, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, hexahydro-1H-pyrrolizinyl, 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. Examples of spiroheterocyclyl groups include, but are not limited to, spiropyranyl, spirooxazinyl, 2,6-diazaspiro[3.3]heptanyl, 2,5-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 5-oxa-2,8-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, and the like. Examples of bridged heterocyclic groups include, but are not limited to, morphinyl, 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.

[0134] As used herein, the term "hydroxyl" or "hydroxy" refers to -OH.

[0135] As used herein, the term "partially unsaturated" refers to a group that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

[0136] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances where the event or circumstance does not occur. As used herein, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. It should be understood that "substituted" or "substituted by" includes the implicit proviso that such substitution is consistent with the allowed valences of the substituted atom and that the substitution produces a stable or chemically feasible compound, e.g., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. Unless otherwise stated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituent may be the same or different at each position. Substitution can include but is not limited to alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclic radical, hydroxyl, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, mercaptan, thioketone or its combination. It will be understood by those skilled in the art that, if appropriate, the substituent itself can be substituted. Unless specifically stated as "unsubstituted", reference to chemical moieties herein should be understood to include substituted variants. For example, reference to "aryl" groups or moieties implicitly includes both substituted variants and unsubstituted variants.

[0137] As used herein, the term "substituted", whether or not there is the term "optionally" in front, means that one or more hydrogens of the designated portion are replaced by a suitable substituent. It should be understood that "substituted" or "substituted by..." includes implicit prerequisites, i.e., such substitutions are consistent with the allowed valence of the substituted atom, and the substitution produces a stable or chemically feasible compound, for example, a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. Unless otherwise indicated, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a designated group, at each position, the substituent can be the same or different. It will be understood by those skilled in the art that, if appropriate, the substituent itself can be substituted. Unless specifically stated as "unsubstituted", reference to a chemical moiety herein should be understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0138] The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom. The isomer descriptors "R" and "S" are used as described herein to indicate the configuration of atoms relative to the core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68: 2193-2222 (1996)).

[0139] Compound

[0140] In one aspect, the present disclosure provides compounds of formula (I):

[0141]

[0142] or a pharmaceutically acceptable salt thereof,

[0143] in,

[0144] Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0145] Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0146] L 1 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0147] L 2Selected from the group consisting of: a bond, N(R A ), 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 replaced by one or more R B replace;

[0148] where R A 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 substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0149] Each R B independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0150] L 3 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0151] L 4 Selected from O, S or N(R C );

[0152] where R C selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0153] Each R 1 are independently selected from the group consisting of: hydroxy, halogen, cyano, amino, -N(R D )2, 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 replaced by one or more R E replace;

[0154] Each R Dindependently selected from the group consisting of hydrogen, 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 the group consisting of hydroxy, halogen, cyano, -N(R F )2OR-OR G ;

[0155] Each R E are independently selected from the group consisting of hydrogen, hydroxy, 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 the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino and alkyl;

[0156] where R F and R G each of which is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0157] Each R 2 independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, the heteroalkynyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0158] R 3 selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0159] m is an integer from 0 to 5; and

[0160] n is an integer from 0 to 4.

[0161] In some embodiments, Ring A is aryl. In certain 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 certain embodiments, Ring A is phenyl.

[0162] In some embodiments, Ring A is heteroaryl. In certain embodiments, Ring A is 5-12 membered heteroaryl, 5-11 membered heteroaryl, 5-10 membered heteroaryl, 5-9 membered heteroaryl, 5-8 membered heteroaryl, 5-7 membered heteroaryl, or 5-6 membered heteroaryl.

[0163] In certain embodiments, Ring A is selected from the group consisting of furanyl, thiophenyl, pyrrolyl, pyridyl, pyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, and tetrahydroisoquinolinyl.

[0164] In certain embodiments, Ring A is selected from the group consisting of:

[0165] In some embodiments, Ring B is aryl. In certain 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 certain embodiments, Ring B is phenyl.

[0166] In some embodiments, Ring B is a heteroaryl. In certain embodiments, Ring B is a 5-12 membered heteroaryl, a 5-11 membered heteroaryl, a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, a 5-8 membered heteroaryl, a 5-7 membered heteroaryl, or a 5-6 membered heteroaryl. In certain embodiments, Ring B is a pyridyl or pyrazolyl group.

[0167] In certain embodiments, Ring B is selected from the group consisting of:

[0168] In some embodiments, L 1 It is a key.

[0169] In some embodiments, L 1 In certain embodiments, L 1 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 alkyl.

[0170] In certain embodiments, L 1 Selected from the group consisting of: Among them L 1 The * end and L 2 connect.

[0171] In some embodiments, L 2 Yes key.

[0172] In some embodiments, L 2 It is N(R A ), and R A is selected from alkyl or heterocyclic, wherein the alkyl or heterocyclic is optionally substituted with one or more halogen or alkyl. 2 It is N(R A ), and R A is ethyl, difluoroethyl, trifluoroethyl or oxetanyl.

[0173] In some embodiments, L 2 is optionally replaced by one or more R B In certain embodiments, L 2 It 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 is optionally substituted by one or more R B replace.

[0174] In certain embodiments, L 2 is optionally replaced by one or more R B Replaced

[0175] In some embodiments, L 2 is optionally replaced by one or more R B In certain embodiments, L 2 is a heterocyclic group containing one or more heteroatoms selected from N, O or S. In certain embodiments, L 2 is a 3-12 membered heterocyclyl, a 3-11 membered heterocyclyl, a 3-10 membered heterocyclyl or a 3-9 membered heterocyclyl, each of which is optionally substituted by one or more R B replace.

[0176] In certain embodiments, L 2 is a heterocyclic group selected from the group consisting of:

[0177] Each of which is optionally replaced by one or more R B Substituted, where L 2 The * end and L 3 connect.

[0178] In some embodiments, L 2 is one or more R B substituted cycloalkyl or heterocyclic group, and R B In certain embodiments, R B It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In certain embodiments, R B It's methyl.

[0179] In some embodiments, L 2 Selected from the group consisting of:

[0180] Among them L 2 The * end and L 3 connect.

[0181] In some embodiments, L 3 In some embodiments, L 3 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 alkyl.

[0182] In certain embodiments, L 3 It's ethyl.

[0183] In some embodiments, L 4 is O or NH.

[0184] In some embodiments, L 1 is the key, and L 2 is a bond or optionally replaced by one or more R B substituted heterocyclic group.

[0185] In some embodiments, L 1 is an alkyl group, and L 2 is a key, N(R A ) or optionally one or more R B Substituted cycloalkyl.

[0186] In some embodiments, -L 1 -L 2 -L 3 -L 4 - is -alkyl-O-. In certain embodiments, -L 1 -L 2 -L 3 -L 4 -Yes-(C 3-8 In certain embodiments, -L 1 -L 2 -L 3 -L 4 - is -CH2CH(CH3)(CH2)3-O- or -CH2CH(CH2CH3)(CH2)3-O-.

[0187] In some embodiments, -L 1 -L 2 -L 3 -L 4 -is -heterocyclyl-alkyl-O-, wherein the heterocyclyl is optionally substituted by one or more R B In certain embodiments, -L 1 -L 2 -L 3 -L 4 -is-(5-10 membered heterocyclyl)-(C 1-6 alkyl)-O-, wherein the 5-10 membered heterocyclic group is optionally replaced by one or more R B In certain embodiments, -L 1 -L 2 -L 3 -L 4 -Selected from the group consisting of: as well as

[0188] In some embodiments, -L 1 -L 2 -L 3 -L 4 -is-alkyl-N(R A )-alkyl-O-, wherein R A is selected from alkyl or heterocyclic, wherein the alkyl or heterocyclic is optionally substituted with one or more halogen or alkyl. 1 -L 2 -L 3 -L 4 -Yes-(C 1-6 alkyl)-N(R A )-(C 1-6alkyl)-O-, wherein R A Selected from C 1-6 alkyl or 3- to 6-membered heterocyclic group, wherein the alkyl or heterocyclic group is optionally substituted by one or more halogen or C 1-6 In certain embodiments, -L 1 -L 2 -L 3 -L 4 -yes

[0189] In some embodiments, -L 1 -L 2 -L 3 -L 4 -is -alkyl-cycloalkyl-alkyl-O-, wherein the cycloalkyl group is optionally replaced by one or more R B In certain embodiments, -L 1 -L 2 -L 3 -L 4 -Yes-(C 1-6 alkyl)-(C 3-6 Cycloalkyl)-(C 1-6 alkyl)-O-, wherein the C 3-6 The cycloalkyl group is optionally substituted with one or more R B In certain embodiments, -L 1 -L 2 -L 3 -L 4 -yes

[0190] In some embodiments, R 1 is hydroxy and m is 1.

[0191] In some embodiments, R 1 is halogen and m is 1. In certain embodiments, R 1 is bromine or fluorine, and m is 1.

[0192] In some embodiments, R 1 Yes-N(R D )2, and m is 1.

[0193] In some embodiments, R 1 Yes-N(R D )2, and each R D is independently hydrogen or optionally substituted by one or more independently selected from -N(R F )2OR-OR G In certain embodiments, R 1Yes-N(R D )2, and each R D is optionally selected from one or more independently selected from -N(R F )2OR-OR G C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In certain embodiments, R 1 Yes-N(R D )2, and each R D is independently methyl, methoxyethyl, N,N-dimethylaminoethyl, hydroxyethyl or N,N-dimethylaminopropyl.

[0194] In some embodiments, R 1 is optionally replaced by one or more R E substituted heterocyclyl, and m is 1. In certain embodiments, R 1 is optionally replaced by one or more R E a substituted 3- to 10-membered heterocyclic group, and m is 1.

[0195] In certain embodiments, R 1 Selected from the group consisting of:

[0196] Each of which is optionally replaced by one or more R E replace.

[0197] In some embodiments, R E It's a halogen.

[0198] In certain embodiments, R E It's F.

[0199] In certain 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.

[0200] In some embodiments, R F and R G In certain embodiments, each of R F and R G Each of them is independently C 1-6 Alkyl, C 1-5 Alkyl, C1-4 Alkyl, C 1-3 Alkyl or C 1-2 alkyl.

[0201] In certain embodiments, R F and R G Each of them is independently C 1-3 alkyl.

[0202] In certain embodiments, each R E Independently selected from the group consisting of F, -N(CH3)2, -C 1-3 Alkyl-N(CH3)2, -C(O)O(tert-butyl), methyl, ethyl or trifluoroethyl.

[0203] In certain embodiments, R E is cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more alkyl and / or halogen.

[0204] In certain embodiments, R E is selected from cyclopropyl, morpholine, piperazine, oxetanyl or azetidinyl, each of which is optionally substituted with one or more alkyl and / or halogen.

[0205] In certain 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, m is 2, R 1 One of them is a halogen, and the other R 1 is optionally replaced by one or more R E substituted heterocyclic group.

[0207] In certain embodiments, m is 2, R 1 One of them is a halogen, and the other R 1 is a heterocyclic group selected from the group consisting of:

[0208]

[0209] Each of which is optionally replaced by one or more R E replace.

[0210] In certain embodiments, each R E are independently selected from halogen, -N(R F )2, -alkyl-N(R F )2、-C(O)OR G or alkyl optionally substituted with one or more halogens.

[0211] In some embodiments, R 1 Selected from the group consisting of:

[0212] OH, F, Br,

[0213] In certain embodiments, R 2 is halogen, and n is 1 or 2.

[0214] In certain embodiments, R 2 It's F.

[0215] In some embodiments, R 2 is alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more or halogen. 2 It is C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally substituted with one or more halogens. 2 is methyl, ethyl, cyclopropyl or trifluoroethyl.

[0216] In some embodiments, R 3 is alkyl or cycloalkyl. In certain embodiments, R 3 It is C 1-6 Alkyl or C 3-6 In certain embodiments, R 3 is methyl, ethyl or cyclopropyl.

[0217] In some embodiments, m is 0, 1, or 2.

[0218] In some embodiments, n is 0 or 1.

[0219] Exemplary compounds of formula (I) are described below.

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231] In one aspect, the present disclosure provides a compound of formula (II):

[0232]

[0233] or a pharmaceutically acceptable salt thereof, wherein:

[0234] Ring A 1 is a 7-12 membered cycloalkyl group, a 7-12 membered heterocyclyl group, a 7-12 membered aryl group or a 7-12 membered heteroaryl group;

[0235] Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0236] L 1 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0237] L 2 Selected from the group consisting of: a bond, N(R A ), 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 replaced by one or more R B replace;

[0238] where R A 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 substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0239] Each R Bindependently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0240] L 3 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0241] L 4 Selected from O, S or N(R C );

[0242] where R C selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0243] Each R 1 are independently selected from the group consisting of: hydroxy, halogen, cyano, amino, -N(R D )2, 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 replaced by one or more R E replace;

[0244] Each R D independently selected from the group consisting of hydrogen, 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 the group consisting of hydroxy, halogen, cyano, -N(R F )2OR-OR G ;

[0245] Each R E are independently selected from the group consisting of hydrogen, hydroxy, 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 the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino and alkyl;

[0246] where R F and R G each of which is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0247] Each R 2 independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, the heteroalkynyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0248] Each R 3 selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0249] m is an integer from 0 to 5;

[0250] n is an integer from 0 to 4; and

[0251] p is an integer from 0 to 3.

[0252] In some embodiments, Ring A 1 It is a 7-12 membered heteroaryl group.

[0253] In certain embodiments, Ring A 1 It is tetrahydroisoquinolinyl.

[0254] In certain embodiments, Ring A 1 yes

[0255] In some embodiments, Ring B is aryl. In certain embodiments, Ring B is C 6-12 Aryl, C 6-11 Aryl, C6-10 Aryl, C 6-9 Aryl or C 6-8 In certain embodiments, Ring B is phenyl.

[0256] In some embodiments, Ring B is a heteroaryl. In certain embodiments, Ring B is a 5-12 membered heteroaryl, a 5-11 membered heteroaryl, a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, a 5-8 membered heteroaryl, a 5-7 membered heteroaryl, or a 5-12 membered heteroaryl. In certain embodiments, Ring B is a pyridyl or pyrazolyl group.

[0257] In certain embodiments, Ring B is selected from the group consisting of:

[0258] In some embodiments, L 1 In certain embodiments, L 1 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 alkyl.

[0259] In certain embodiments, wherein L 1 yes Among them L 1 The * end and L 2 connect.

[0260] In some embodiments, L 2 Yes key.

[0261] In some embodiments, L 1 is an alkyl group, and L 2 Yes key.

[0262] In some embodiments, L 3 In certain embodiments, L 3 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In certain embodiments, L 3 It's ethyl.

[0263] In some embodiments, L 4 is O or NH.

[0264] In some embodiments, -L 1 -L 2 -L 3 -L 4- is -alkyl-O-. In certain embodiments, -L 1 -L 2 -L 3 -L 4 -Yes-(C 3-8 In certain embodiments, -L 1 -L 2 -L 3 -L 4 - is -(CH2)5-O-, -CH2CH(CH3)(CH2)3-O- or -CH2CH(CH2CH3)(CH2)3-O-.

[0265] In a certain embodiment, m is 0.

[0266] In some embodiments, m is 1, and R 1 is optionally replaced by one or more R E In certain embodiments, m is 1, and R 1 is optionally replaced by one or more R E Substituted C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In certain embodiments, R 1 is optionally replaced by one or more R E Substituted ethyl.

[0267] In some embodiments, R E Yes-N(R F )2, and R F In certain embodiments, R E Yes-N(R F )2, and R F It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In certain embodiments, R E It is -N(CH3)2.

[0268] In some embodiments, m is 1, and R 1 is optionally replaced by one or more R E In certain 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 is optionally substituted by one or more RE In certain embodiments, R 1 In certain embodiments, R 1 yes

[0269] In some embodiments, n is 1.

[0270] In some embodiments, R 2 In certain embodiments, R 2 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In certain embodiments, R 2 It's methyl.

[0271] In some embodiments, n is 1, and R 2 In certain embodiments, n is 1, and R 2 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In certain embodiments, n is 1, and R 2 It's methyl.

[0272] In some embodiments, yes

[0273] In some embodiments, p is 1.

[0274] In some embodiments, R 3 In certain embodiments, R 3 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In certain embodiments, R 3 It's methyl.

[0275] In some embodiments, p is 1, and R 3 In certain embodiments, p is 1, and R 3 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In certain embodiments, p is 1, and R3 It's methyl.

[0276] In some embodiments, yes In certain embodiments, yes

[0277] In some embodiments, m is 0 or 1.

[0278] In some embodiments, n is 1.

[0279] In some embodiments, p is 1.

[0280] In another aspect, the present disclosure provides a compound of formula (III):

[0281]

[0282] or a pharmaceutically acceptable salt thereof, wherein:

[0283] Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0284] Ring B 1 is a 7-12 membered cycloalkyl group, a 7-12 membered heterocyclyl group, a 7-12 membered aryl group or a 7-12 membered heteroaryl group;

[0285] L 1 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0286] L 2 Selected from the group consisting of: a bond, N(R A ), 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 replaced by one or more R B replace;

[0287] where R Aselected 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 substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0288] Each R B independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0289] L 3 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0290] L 4 Selected from O, S or N(R C );

[0291] where R C selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0292] Each R 1 are independently selected from the group consisting of: hydroxy, halogen, cyano, amino, -N(R D )2, 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 replaced by one or more R E replace;

[0293] Each R D independently selected from the group consisting of hydrogen, 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 the group consisting of hydroxy, halogen, cyano, -N(R F )2OR-OR G ;

[0294] Each R E are independently selected from the group consisting of hydrogen, hydroxy, 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 the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino and alkyl;

[0295] where R F and R G each of which is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0296] Each R 2 independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, the heteroalkynyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0297] Each R 3 selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0298] m is an integer from 0 to 5;

[0299] n is an integer from 0 to 4; and

[0300] p is an integer from 0 to 3.

[0301] In some embodiments, Ring A is aryl. In certain 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 certain embodiments, Ring A is phenyl.

[0302] In some embodiments, Ring A is a heteroaryl. In certain embodiments, Ring A is a 5-12 membered heteroaryl, a 5-11 membered heteroaryl, a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, a 5-8 membered heteroaryl, a 5-7 membered heteroaryl, or a 5-6 membered heteroaryl. In certain embodiments, Ring A is selected from the group consisting of furanyl, thiophenyl, pyrrolyl, pyridyl, pyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, and tetrahydroisoquinolinyl.

[0303] In some embodiments, Ring B 1 It is a 7-12 membered heteroaryl group.

[0304] In certain embodiments, Ring B 1 It is pyrazolopyridinyl.

[0305] In certain embodiments, Ring B 1 yes

[0306] In some embodiments, L 1 It is a key.

[0307] In some embodiments, L 1 In certain embodiments, L 1 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 alkyl.

[0308] In certain embodiments, L 1 Selected from the group consisting of: Among them L 1 The * end and L 2 connect.

[0309] In some embodiments, L 2 It is a key.

[0310] In some embodiments, L 2 It is N(R A ), and R A is selected from alkyl or heterocyclic, wherein the alkyl or heterocyclic is optionally substituted with one or more halogen or alkyl. 2 It is N(R A ), and R A is ethyl, difluoroethyl, trifluoroethyl or oxetanyl.

[0311] In some embodiments, L 2 is optionally replaced by one or more R BIn certain embodiments, L 2 It 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 is optionally substituted by one or more R B replace.

[0312] In certain embodiments, L 2 is optionally replaced by one or more R B Replaced

[0313] In some embodiments, L 2 is optionally replaced by one or more R B In certain embodiments, L 2 is a heterocyclic group containing one or more heteroatoms selected from N, O or S. In certain embodiments, L 2 is a 3-12 membered heterocyclyl, a 3-11 membered heterocyclyl, a 3-10 membered heterocyclyl or a 3-9 membered heterocyclyl, each of which is optionally substituted by one or more R B replace.

[0314] In certain embodiments, L 2 is a heterocyclic group selected from the group consisting of:

[0315] Each of which is optionally replaced by one or more R B Substituted, where L 2 The * end and L 3 connect.

[0316] In some embodiments, L 2 is one or more R B substituted cycloalkyl or heterocyclic group, and R B In certain embodiments, R B It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In certain embodiments, R B It's methyl.

[0317] In some embodiments, L 2 Selected from the group consisting of:

[0318] Among them L2 The * end and L 3 connect.

[0319] In some embodiments, L 3 In some embodiments, L 3 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 alkyl.

[0320] In certain embodiments, L 3 It's ethyl.

[0321] In some embodiments, L 4 is O or NH.

[0322] In some embodiments, L 1 is a key, and L 2 is a bond or optionally replaced by one or more R B substituted heterocyclic group.

[0323] In some embodiments, L 1 is an alkyl group, and L 2 is a key, N(R A ) or optionally one or more R B Substituted cycloalkyl.

[0324] In some embodiments, -L 1 -L 2 -L 3 -L 4 - is -alkyl-O-. In certain embodiments, -L 1 -L 2 -L 3 -L 4 -Yes-(C 3-8 In certain embodiments, -L 1 -L 2 -L 3 -L 4 - is -(CH2)5-O-, -CH2CH(CH3)(CH2)3-O- or -CH2CH(CH2CH3)(CH2)3-O-.

[0325] In some embodiments, -L 1 -L 2 -L 3 -L 4 -is -heterocyclyl-alkyl-O-, wherein the heterocyclyl is optionally substituted by one or more R B In certain embodiments, -L1 -L 2 -L 3 -L 4 -is-(5-10 membered heterocyclyl)-(C 1-6 alkyl)-O-, wherein the 5-10 membered heterocyclic group is optionally replaced by one or more R B In certain embodiments, -L 1 -L 2 -L 3 -L 4 -Selected from the group consisting of: as well as

[0326] In some embodiments, -L 1 -L 2 -L 3 -L 4 -is-alkyl-N(R A )-alkyl-O-, wherein R A is selected from alkyl or heterocyclic, wherein the alkyl or heterocyclic is optionally substituted with one or more halogen or alkyl. 1 -L 2 -L 3 -L 4 -Yes-(C 1-6 alkyl)-N(R A )-(C 1-6 alkyl)-O-, wherein RA is selected from C 1-6 alkyl or 3- to 6-membered heterocyclic group, wherein the alkyl or heterocyclic group is optionally substituted by one or more halogen or C 1-6 In certain embodiments, -L 1 -L 2 -L 3 -L 4 -yes

[0327] In some embodiments, -L 1 -L 2 -L 3 -L 4 -is -alkyl-cycloalkyl-alkyl-O-, wherein the cycloalkyl group is optionally replaced by one or more R B In certain embodiments, -L 1 -L 2 -L 3 -L 4 -Yes-(C 1-6 alkyl)-(C 3-6 Cycloalkyl)-(C 1-6alkyl)-O-, wherein the C 3-6 The cycloalkyl group is optionally substituted with one or more R B In certain embodiments, -L 1 -L 2 -L 3 -L 4 -yes

[0328] In some embodiments, R 1 is halogen and m is 1.

[0329] In some embodiments, R 1 Yes-N(R D )2, and m is 1.

[0330] In some embodiments, R 1 Yes-N(R D )2, and each R D is optionally independently selected from one or more -N(R F )2OR-OR G In certain embodiments, R 1 Yes-N(R D )2, and each R D is optionally selected from one or more independently selected from -N(R F )2OR-OR G C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In certain embodiments, R 1 Yes-N(R D )2, and each R D is independently methyl, methoxyethyl, N,N-dimethylaminoethyl or N,N-dimethylaminopropyl.

[0331] In some embodiments, R 1 is optionally replaced by one or more R E substituted heterocyclyl, and m is 1. In certain embodiments, R 1 is optionally replaced by one or more R E a substituted 3- to 10-membered heterocyclic group, and m is 1.

[0332] In certain embodiments, R 1 Selected from the group consisting of:

[0333] Each of which is optionally replaced by one or more R E replace.

[0334] In some embodiments, R E It's a halogen.

[0335] In certain embodiments, R E It's F.

[0336] In certain embodiments, R E Yes-N(R F )2, -alkyl-N(R F )2、-C(O)OR G or alkyl optionally substituted with one or more halogens.

[0337] In some embodiments, R F and R G In certain embodiments, each of R F and R G Each of them is independently C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 alkyl.

[0338] In certain embodiments, R F and R G Each of them is independently C 1-3 alkyl.

[0339] In certain embodiments, R E Selected from the group consisting of: -N(CH3)2, -C 1-3 Alkyl-N(CH3)2, -C(O)O(tert-butyl), methyl, ethyl and trifluoroethyl.

[0340] In certain embodiments, R E is cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more alkyl and / or halogen.

[0341] In certain 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.

[0342] In certain 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.

[0343] In certain embodiments, R 2 is halogen, and n is 1 or 2.

[0344] In certain embodiments, R 2 It's F.

[0345] In some embodiments, R 2 is alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more or halogen. 2 It is C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally substituted with one or more halogens. 2 is methyl, ethyl, cyclopropyl or trifluoroethyl.

[0346] In some embodiments, yes

[0347] In some embodiments, R 3 is alkyl or cycloalkyl. In certain embodiments, R 3 It is C 1-6 Alkyl or C 3-6 In certain embodiments, R 3 is methyl, ethyl or cyclopropyl.

[0348] In some embodiments, p is 1, and R 3 In certain embodiments, p is 1, and R 3 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In certain embodiments, p is 1, and R 3 It's methyl.

[0349] In some embodiments, yes In certain embodiments, yes

[0350] In some embodiments, m is 0, 1, or 2.

[0351] In some embodiments, n is 0 or 1.

[0352] In some embodiments, p is 1.

[0353] In another aspect, the present disclosure provides a compound of formula (IV):

[0354]

[0355] or a pharmaceutically acceptable salt thereof, wherein:

[0356] Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0357] Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0358] L 1 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0359] L 21 is a 7-12 membered cycloalkyl or a 7-12 membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally replaced by one or more R B replace;

[0360] Each R B independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0361] L 3 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0362] L 4 Selected from O, S or N(R C );

[0363] where R C selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0364] Each R 1 are independently selected from the group consisting of: hydroxy, halogen, cyano, amino, -N(R D)2, 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 replaced by one or more R E replace;

[0365] Each R D independently selected from the group consisting of hydrogen, 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 the group consisting of hydroxy, halogen, cyano, -N(R F )2OR-OR G ;

[0366] Each R E are independently selected from the group consisting of hydrogen, hydroxy, 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 the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino and alkyl;

[0367] where R F and R G each of which is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0368] Each R 2 independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, the heteroalkynyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0369] R 3selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0370] m is an integer from 0 to 5;

[0371] n is an integer from 0 to 4; and

[0372] p is an integer from 0 to 3.

[0373] In some embodiments, Ring A is aryl. In certain 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 certain embodiments, Ring A is phenyl.

[0374] In some embodiments, Ring A is a heteroaryl. In certain embodiments, Ring A is a 5-12 membered heteroaryl, a 5-11 membered heteroaryl, a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, a 5-8 membered heteroaryl, a 5-7 membered heteroaryl, or a 5-6 membered heteroaryl. In certain embodiments, Ring A is selected from the group consisting of furanyl, thiophenyl, pyrrolyl, pyridyl, pyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, and tetrahydroisoquinolinyl.

[0375] In some embodiments, Ring B is aryl. In certain 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 certain embodiments, Ring B is phenyl.

[0376] In some embodiments, Ring B is a heteroaryl. In certain embodiments, Ring B is a 5-12 membered heteroaryl, a 5-11 membered heteroaryl, a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, a 5-8 membered heteroaryl, a 5-7 membered heteroaryl, or a 5-6 membered heteroaryl. In certain embodiments, Ring B is a pyridyl or pyrazolyl group.

[0377] In certain embodiments, Ring B is selected from the group consisting of:

[0378] In some embodiments, L 1 It is a key.

[0379] In some embodiments, L 21 is a 7-10 membered heterocyclic group containing one or more heteroatoms selected from N or O.

[0380] In certain embodiments, L 21 Selected from the group consisting of: Among them L 21 The * end and L 3 connect.

[0381] In some embodiments, L 3 In certain embodiments, L 3 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 alkyl.

[0382] In certain embodiments, L 3 It's ethyl.

[0383] In some embodiments, L 4 is O or NH.

[0384] In some embodiments, -L 1 -L 21 -L 3 -L 4 -is -heterocyclyl-alkyl-O-, wherein the heterocyclyl is optionally substituted by one or more R B In certain embodiments, -L 1 -L 21 -L 3 -L 4 -is-(5-10 membered heterocyclyl)-(C 1-6 alkyl)-O-, wherein the 5-10 membered heterocyclic group is optionally replaced by one or more R B replace.

[0385] In certain embodiments, -L 1 -L 21 -L 3 -L 4 -Selected from the group consisting of:

[0386] In some embodiments, R 1 is halogen and m is 1.

[0387] In some embodiments, R 1 Yes-N(R D )2, and m is 1.

[0388] In some embodiments, R 1 Yes-N(R D )2, and each R D is optionally independently selected from one or more -N(R F )2OR-OR G In certain embodiments, R 1 Yes-N(R D )2, and each R D is optionally selected from one or more independently selected from -N(R F )2OR-OR G C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In certain embodiments, R 1 Yes-N(R D )2, and each R D is independently methyl, methoxyethyl or N,N-dimethylaminopropyl.

[0389] In some embodiments, R 1 is optionally replaced by one or more R E substituted heterocyclyl, and m is 1. In certain embodiments, R 1 is optionally replaced by one or more R E a substituted 3- to 10-membered heterocyclic group, and m is 1.

[0390] In certain embodiments, R 1 Selected from the group consisting of:

[0391] Each of which is optionally replaced by one or more R E replace.

[0392] In some embodiments, R E It's a halogen.

[0393] In certain embodiments, R E It's F.

[0394] In certain embodiments, R E Yes-N(R F )2, -alkyl-N(R F )2、-C(O)OR G or alkyl optionally substituted with one or more halogens.

[0395] In some embodiments, R F and R G In certain embodiments, each of R F and R G Each of them is independently C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 alkyl.

[0396] In certain embodiments, R F and R G Each of them is independently C 1-3 alkyl.

[0397] In certain embodiments, R E Selected from the group consisting of: -N(CH3)2, -C 1-3 Alkyl-N(CH3)2, -C(O)O(tert-butyl), methyl, ethyl and trifluoroethyl.

[0398] In certain embodiments, R E is cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more alkyl and / or halogen.

[0399] In certain 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.

[0400] In certain 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.

[0401] In certain embodiments, R 1 Selected from the group consisting of:

[0402]

[0403] In certain embodiments, R 2 is halogen, and n is 1 or 2.

[0404] In certain embodiments, R 2 It's F.

[0405] In some embodiments, R 2 is alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more or halogen. 2 It is C1-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally substituted with one or more halogens. 2 is methyl, ethyl, cyclopropyl or trifluoroethyl.

[0406] In certain embodiments, R 2 It's methyl.

[0407] In some embodiments, R 3 In certain embodiments, R 3 Each of the C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In certain embodiments, R 3 It's methyl.

[0408] In some embodiments, p is 1, and R 3 In certain embodiments, p is 1, and R 3 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 In certain embodiments, p is 1, and R 3 It's methyl.

[0409] In some embodiments, yes In certain embodiments, yes

[0410] In some embodiments, m is 1.

[0411] In some embodiments, n is 1.

[0412] In some embodiments, p is 1.

[0413] Illustrative compounds of the present disclosure are described below.

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420] The compounds provided herein are described with reference to both general formulae 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.

[0421] As used herein, the term "prodrug" refers to a compound or a pharmaceutically acceptable salt thereof that produces a desired active compound when metabolized or converted by solvolysis under physiological conditions. Prodrugs include, but are not limited to, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound. Typically, the prodrug is inactive or less active than the active compound, but may provide 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. In addition, some prodrugs are enzymatically activated to produce the active compound or to produce a compound of the active compound after further chemical reaction. The prodrug may be developed from the prodrug form to the active form in a single step, or may have one or more intermediate forms that may themselves be active or inactive. The preparation and use of prodrugs are discussed in the following references: T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series, Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; Prodrugs: Challenges and Rewards, ed. V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Springer Verlag New York, 2007, all of which are hereby incorporated by reference in their entirety.

[0422] As used herein, the term "metabolite", such as an active metabolite, overlaps with a prodrug as described above. Thus, such metabolites are pharmacologically active compounds or compounds that are further metabolized to pharmacologically active compounds, which are derivatives produced by metabolic processes in the subject. For example, such metabolites can be produced by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound or salt or prodrug. Among them, active metabolites are such pharmacologically active derivative compounds. For prodrugs, the prodrug compound is generally inactive or less active than the metabolite. For active metabolites, the parent compound can be the active compound or can be an inactive prodrug.

[0423] Prodrugs and active metabolites can be identified using conventional techniques known in the art. See, for example, Bertolini et al., 1997, J Med Chem 40:2011-2016; Shan et al., J Pharm Sci 86:756-757; Bagshawe, 1995, Drug Dev Res 34:220-230; Wermuth, supra.

[0424] As used herein, the term "pharmaceutically acceptable" indicates that a substance or composition is chemically and / or toxicologically compatible with the other ingredients making up the formulation and / or the subject being treated.

[0425] As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and are not undesirable biologically or otherwise. 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 in which they are administered. The preparation of such salts can facilitate pharmacological use by changing the physical properties of the compound without hindering it from exerting its physiological effects. Useful changes in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of the drug.

[0426] 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, cyclohexylsulfamate, and quinate. Pharmaceutically acceptable salts can be obtained 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, cyclohexylsulfamate, fumaric acid, and quinic acid.

[0427] When an acidic functional group such as a carboxylic acid or phenol is present, pharmaceutically acceptable salts also include base addition salts, such as base addition salts of benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, and zinc. See, for example, 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 bases.

[0428] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound can be dissolved in a suitable solvent (such as an aqueous or aqueous-alcoholic solution containing an appropriate acid) and then isolated by evaporating the solution. Thus, if the particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid; a pyranosyl acid such as glucuronic acid or galacturonic acid; an α-hydroxy acid such as citric acid or tartaric acid; an amino acid such as aspartic acid or glutamic acid; an aromatic acid such as benzoic acid or cinnamic acid; a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid; and the like.

[0429] Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Illustrative examples of suitable salts include those derived from amino acids such as L-glycine, L-lysine and L-arginine; ammonia, primary, secondary and tertiary amines; and organic salts of cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0430] It will also be understood that the compounds of the present disclosure may exist in unsolvated forms, solvated forms (eg, hydrated forms), and solid forms (eg, crystalline forms or polymorphic forms), and that the present disclosure is intended to encompass all such forms.

[0431] As used herein, the term "solvate" or "solvated form" refers to a solvent addition form that includes a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with one molecule of a substance in which the water retains its molecular state as HO. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0432] 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 indicated, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compounds of the present disclosure is intended to also include their isotopes, such as, but not limited to, 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 1. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes 12 C and 13 C.

[0433] The compounds provided herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, thereby giving rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined as (R)-, (S)-, (D)-, or (L)- of an amino acid based on absolute stereochemistry, or as rel-(R)- or rel-(S)- based on relative configuration. The present disclosure includes all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared by chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing and isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When a compound is represented in its chiral form, it is understood that the embodiments include, but are not limited to, the specific diastereomer or enantiomerically enriched form. Where chirality is not specified but exists, it is understood that the embodiments are intended to include the particular diastereomer or enantiomerically enriched form; or racemic or scalemic mixture of such compounds.

[0434] The term "stereoisomer" refers to compounds containing the same atoms joined by the same bonds but with different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0435] The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers in a ratio other than 1:1 is a "non-racemic" mixture.

[0436] The term "diastereomers" refers to stereoisomers that have at least two asymmetric atoms, but which are not mirror images of one another.

[0437] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted through a low energy barrier. The presence and concentration of isomeric forms will depend on the environment in which the compound is located and can vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution. For example, proton tautomers (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerization, and cyclic forms in which protons can occupy two or more positions of a heterocyclic ring system. Valence tautomers include interconversions performed by reorganization of some bonding electrons. Tautomers can be in equilibrium or spatially locked into one form by appropriate substitution. Unless otherwise stated, compounds disclosed herein that are identified as a specific tautomeric form by name or structure are intended to include other tautomeric forms.

[0438] When the compounds provided herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0439] Synthesis method

[0440] 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 pathways.

[0441] The reaction for preparing the compound of the present disclosure can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. Suitable solvent can be substantially unreactive with starting material (reactant), intermediate or product at a temperature that reacts, for example, ranging from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in a solvent or a mixture of more than one solvent. According to the specific reactions step, the suitable solvent for the specific reactions step can be selected by those skilled in the art.

[0442] The preparation of compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The demand 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, for example, the following references: TW Greene and PGM Wuts, " Protective Groups in Organic Synthesis ", 3rd edition, John Wiley & Sons Publishing Company, New York, (1999); P. Kocienski, " Protective Groups ", Georg Thieme Verlag, 2003; and Peter G.M. Wuts, " Protective Groups in Organic Synthesis ", 5th edition, Wiley, 2014, the references are incorporated herein by reference in their entirety.

[0443] The reaction can be monitored by any suitable method known in the art. For example, the reaction can be monitored by methods such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS) or thin layer chromatography (TLC) to monitor product formation. Those skilled in the art can purify the compound by various methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization" Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs, "Journal of Combinatorial Chemistry (J. Combi. Chem.)" 2004, 6 (6), 874-883, which is incorporated herein by reference in its entirety) and normal phase silica gel chromatography.

[0444] Pharmaceutical composition

[0445] In another aspect, a pharmaceutical composition is provided, comprising one or more compounds of the present disclosure or a pharmaceutically acceptable salt 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.

[0446] In another aspect, a pharmaceutical composition is provided, comprising one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.

[0447] 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 a pharmaceutically acceptable salt thereof.

[0448] 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.

[0449] As used herein, the term "therapeutically effective amount" refers to an amount of a molecule, compound, or composition comprising the molecule or compound that treats, ameliorates, or prevents an identified disease or condition, or shows a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The 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 treatment or combination of treatments selected for administration; and the judgment of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0450] 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 administration, rectal administration, topical administration, parenteral (including subcutaneous, intramuscular and intravenous) administration, sublingual administration, ophthalmic administration, transdermal administration or nasal administration, but the most appropriate route in any given case will depend on the nature and severity of the condition to which the active ingredient is administered and the specific host. Pharmaceutical compositions can be conveniently presented in unit dosage form and can be prepared by any method well known in the pharmaceutical field.

[0451] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and biologically and otherwise desirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used herein, a "pharmaceutically acceptable excipient" includes one and more than one such excipient. The term "pharmaceutically acceptable excipient" also encompasses a "pharmaceutically acceptable carrier" and a "pharmaceutically acceptable diluent."

[0452] The specific excipient used will depend on the means and purpose for which the compounds of the present disclosure are to be used. Solvents are typically selected based on solvents that are considered safe by those skilled in the art for use in mammals, including humans. Typically, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and the like, and mixtures thereof.

[0453] In some embodiments, suitable excipients may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl alcohol, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins , such as serum albumin, gelatin or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextran; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn protein complexes); and / or nonionic surfactants such as TWEEN TM 、PLURONICS TM or polyethylene glycol (PEG).

[0454] In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, aromatics, flavorings and other known additives to provide the best presentation of the drug (i.e., compound of the present disclosure or its pharmaceutical composition) or to help manufacture the drug product (i.e., drug). Active pharmaceutical ingredients can also be embedded in microcapsules prepared, for example, by coacervation technology or by interfacial polymerization, such as hydroxymethyl cellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in coarse emulsions. Such technology is disclosed in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. ed. (1980). "Liposomes" are small vesicles that can be used to deliver drugs (such as compounds disclosed herein and optionally chemotherapeutic agents) to mammals, including humans, including various types of lipids, phospholipids and / or surfactants. The components of liposomes are typically arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.

[0455] The pharmaceutical compositions provided herein can be in any form that permits administration of the composition to a subject, including but not limited to humans, and allows formulation of the composition compatible with the intended route of administration.

[0456] The pharmaceutical composition provided herein has been considered to have multiple approaches, and therefore the pharmaceutical composition provided herein can be supplied in bulk or unit dosage form depending on the expected route of administration. For example, for oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, soft capsules and caplets can be acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions and solutions can be acceptable as liquid dosage forms. For injection, emulsions and suspensions can be acceptable as liquid dosage forms, and powders suitable for reconstitution with suitable solutions can be acceptable as solid dosage forms. For inhalation, solution, sprays, dry powder and aerosol can be acceptable dosage forms. For local (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, emulsifiable pastes, lotions, gels, solutions and patches can be acceptable dosage forms. For vaginal administration, vaginal suppositories, tampons, emulsifiable pastes, gels, pastes, foams and sprays can be acceptable dosage forms.

[0457] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of formulations for oral administration.

[0458] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations. Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate, or calcium carbonate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid, or talc; preservatives such as ethylparaben or propylparaben; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or coated to regulate their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and / or appearance, in either case using conventional coating agents and procedures well known in the art.

[0459] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin; or in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil, such as peanut oil, liquid paraffin, or olive oil.

[0460] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension, which typically includes the active ingredient in finely divided form and one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic; a dispersant or wetting agent, such as lecithin or a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate); or a condensation product of ethylene oxide with a long-chain fatty alcohol, such as heptadecaethyleneoxycetanol; or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyoxyethylene sorbitan monooleate; or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate), antioxidants (such as ascorbic acid), coloring agents, flavoring agents and / or sweetening agents (such as sucrose, saccharin or aspartame).

[0461] In certain embodiments, the pharmaceutical composition of the present disclosure can be in the form of an oily suspension, which is generally comprised of a suspended active ingredient in a vegetable oil (such as peanut oil, castor oil, olive oil, sesame oil, or coconut oil) or a mineral oil (such as liquid paraffin). The oily suspension can also include a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those described above) and flavorings can be added to provide a palatable oral formulation. These compositions can be preserved by adding an antioxidant (such as ascorbic acid).

[0462] In certain embodiments, the pharmaceutical composition of the present disclosure can be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, such as olive oil or peanut oil; or a mineral oil, such as liquid paraffin; or a mixture of any of these oils. Suitable emulsifiers can be, for example, naturally occurring gums, such as gum arabic or gum tragacanth; naturally occurring phospholipids, such as soybeans, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate) and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion can also include sweeteners, flavorings, and preservatives.

[0463] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may include sweeteners, such as glycerol, propylene glycol, sorbitol, aspartame, or sucrose; demulcents; preservatives; flavorings, and / or coloring agents.

[0464] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of formulations for administration by injection.

[0465] In certain embodiments, the pharmaceutical composition of the present disclosure can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension can be formulated using those suitable dispersants or wetting agents and suspending agents mentioned above according to known techniques. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol or prepared as lyophilized powders. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils can conventionally be used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used to prepare injectables.

[0466] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for inhaled administration.

[0467] In certain embodiments, the pharmaceutical compositions of the present disclosure can be in the form of aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosols comprising any suitable solvent and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. Carriers and stabilizers vary with the requirements of the specific compound, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), innocuous proteins (such as serum albumin), sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols.

[0468] In some embodiments, the pharmaceutical compositions of the present disclosure can be in the form of formulations for topical or transdermal administration. In certain embodiments, the pharmaceutical compositions provided herein can be in the form of creams, ointments, gels, and aqueous or oily solutions or suspensions, which can generally be prepared by combining the active ingredient with conventional topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0469] In certain embodiments, the pharmaceutical compositions provided herein can be formulated for ophthalmic administration. In certain embodiments, the pharmaceutical compositions provided herein can be in the form of ophthalmic formulations, such as eye ointments, powders, solutions, etc. In certain embodiments, ophthalmic formulations are prepared under a comfortable pH and appropriate buffer system.

[0470] In addition to those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the present disclosure. Such excipients and carriers are described in, for example, Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991); Remington: The Science and Practice of Pharmacy, ed., University of the Sciences in Philadelphia, 21st ed., LWW (2005), which are incorporated herein by reference.

[0471] The dosage regimen of the compounds provided herein will vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health condition, physical condition and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and liver function, and the desired effect. A physician or veterinarian can determine and prescribe the effective amount of the drug needed to prevent, counter or arrest the progress of the condition.

[0472] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated so that 0.001 mg / kg body weight / day to 1000 mg / kg body weight / day, for example, 0.01 mg / kg body weight / day to 800 mg / kg body weight / day, 0.01 mg / kg body weight / day to 700 mg / kg body weight / day, 0.01 mg / kg body weight / day to 600 mg / kg body weight / day, 0.01 mg / kg body weight / day to 500 mg / kg body weight / day, 0.01 mg / kg body weight / day to 400 mg / kg body weight / day, 0.01 mg / kg body weight / day to 300 mg / kg body weight / day, 0.1 mg / kg body weight / day to 200 mg / kg body weight / day, 0.1 mg / kg body weight / day to 150 mg / kg body weight / day, 0.1 mg / kg body weight / day to 200 mg / kg body weight / day, 0.1 mg / kg body weight / day to 300 mg / kg body weight / day, 0.1 mg / kg body weight / day to 400 mg / kg body weight / day, 0.1 mg / kg body weight / day to 500 mg / kg body weight / day, 0.1 mg / kg body weight / day to 600 mg / kg body weight / day, 0.1 mg / kg body weight / day to 700 mg / kg body weight / day, 0.1 mg / kg body weight / day to 800 mg / kg body weight / day, 0.1 mg / kg body weight / day to 900 mg / kg body weight / day, 0.1 mg / kg body weight / day to 1000 mg / kg body weight / day, 0.1 mg / kg body weight / day to 1500 mg / kg body weight / day, 0.1 mg / kg body weight / day to 1000 mg / kg body weight / day, kg body weight / day to 100 mg / kg body weight / day, 0.5 mg / kg body weight / day to 100 mg / kg body weight / day, 0.5 mg / kg body weight / day to 80 mg / kg body weight / day, 0.5 mg / kg body weight / day to 60 mg / kg body weight / day, 0.5 mg / kg body weight / day to 50 mg / kg body weight / day, 1 mg / kg body weight / day to 50 mg / kg body weight / day, 1 mg / kg body weight / day to 45 mg / kg body weight / day, 1 mg / kg body weight / day to 40 mg / kg body weight / day, 1 mg / kg body weight / day to 35 mg / kg body weight / day, 1 mg / kg body weight / day to 30 mg / kg body weight / day, 1 mg / kg body weight / day to 25 mg / kg body weight / day of a compound provided herein, or a pharmaceutically acceptable salt thereof. In some cases, dosage levels below the lower limit of the aforementioned range may be more than adequate, while in other cases, larger doses may be employed without causing any deleterious side effects, provided that such larger doses are first divided into several smaller doses for administration throughout the day. For additional information on routes of administration and dosage regimens, see Comprehensive Medicinal Chemistry, Vol. 5, Chapter 25.3 (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press, 1990, which reference is specifically incorporated herein by reference.

[0473] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated into a single dosage form. The amount of the compound provided herein in a single dosage form will vary depending on the subject being treated and the particular mode of administration.

[0474] In some embodiments, dosage forms suitable for administration may contain from about 1 mg to about 1000 mg of active ingredient per dosage unit.In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1-95% by weight based on the total weight of the composition.

[0475] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated into short-acting, fast-release, long-acting, and sustained-release forms. Thus, the pharmaceutical formulations of the present disclosure can also be formulated for controlled release or slow release.

[0476] In some embodiments, a certain dose of compound provided herein or pharmaceutical composition provided herein is applied to the subject every day, every other day, every two days, every three days, once a week, twice a week, three times a week or once every two weeks. If necessary, the effective daily dose of the active compound can be used as a single dose at appropriate intervals in one day, optionally in two, three, four, five, six or more sub-doses administered in unit dosage form. In some embodiments, a certain dose of compound provided herein or pharmaceutical composition provided herein is applied for 2 days, 3 days, 5 days, 7 days, 14 days, 21 days, 1 month, 2 months, 2.5 months, 3 months, 4 months, 5 months, 6 months or longer.

[0477] In another aspect, veterinary compositions are provided, comprising one or more molecules or compounds of the present disclosure, or pharmaceutically acceptable salts thereof, and a veterinary carrier. A veterinary carrier is a material useful for the purpose of administering the composition and can be a solid, liquid, or gaseous material that is otherwise inert or acceptable in the veterinary art and compatible with the active ingredient. These veterinary compositions can be administered parenterally, orally, or by any other desired route.

[0478] Pharmaceutical compositions or veterinary compositions can be packaged in various ways depending on the method for administering the drug. For example, the product for distribution can include a container for storing 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), medicine capsules, ampoules, plastic bags, metal cylinders, etc. The container can also include an anti-tamper assembly to prevent easy access to the contents of the package. In addition, the container has a label for the contents of the description container placed thereon. The label can also include appropriate warnings. The composition can also be packaged in unit dose or multidose containers, such as sealed ampoules and vials, and can be stored in freeze-dried (lyophilized) conditions that only require the addition of a sterile liquid carrier immediately before use, such as water for injection. Extemporaneous injection solutions and suspensions are prepared by sterile powders, granules, and tablets of the types described previously.

[0479] 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.

[0480] The additional therapeutically active agents have activities complementary to those of the compounds provided herein such that they do not adversely affect each other. Such agents are suitably present together in amounts effective for their intended purpose.

[0481] In certain embodiments, the additional therapeutic agent is selected from: EGFR TKI, EGFR antibody, MEK inhibitor, c-MET inhibitor, mitotic kinase inhibitor, immunotherapeutic agent, anti-angiogenic agent, apoptosis inducer, mTOR inhibitor, histone deacetylase inhibitor, IL6 inhibitor, JAK inhibitor.

[0482] Examples of EGFR TKIs include, but are not limited to, afatinib, erlotinib, gefitinib, lapatinib, dacomitinib, osimertinib, olmutinib, nazartinib, and AC0010.

[0483] Examples of EGFR antibodies include, for example, cetuximab, panitumumab, and necitumumab.

[0484] Examples of MEK inhibitors include trametinib, cobimetinib, binimetinib, selumetinib, and refametinib.

[0485] Examples of c-MET inhibitors include, for example, savolitinib, cabozantinib, foretinib, and MET antibodies such as emibetuzumab.

[0486] Examples of mitotic kinase inhibitors include CDK4 / 6 inhibitors, such as palbociclib, ribociclib, and abemaciclib.

[0487] Examples of immunotherapeutic agents include immune checkpoint inhibitors such as anti-CTLA4 mAb, anti-PD1 mAb, anti-PD-L1 mAb, anti-PD-L2 mAb, anti-LAG3 mAb, anti-TM3 mAb, preferably anti-PD1 mAb, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 and immunomodulators such as CD73 inhibitors or CD73 inhibitory antibodies.

[0488] Examples of anti-angiogenic agents include, for example, bevacizumab and nintedanib.

[0489] Examples of apoptosis inducers include Bcl-2 inhibitors (eg, venetoclax, obatoclax, navitoclax), Mcl-1 inhibitors (eg, AZD-5991, AMG-176, S-64315).

[0490] Examples of mTOR inhibitors include, for example, rapamycin, temsirolimus, everolimus, ridaforolimus.

[0491] Examples of histone deacetylase inhibitors include, for example, panobinostat, entinostat, romidepsin, and vorinostat.

[0492] Examples of IL6 inhibitors include, e.g., tocilizumab, siltuximab, olokizumab, elsilimomab, clazakizumab, sirukumab, levilimab, ARGX-109, FE301, FM101.

[0493] Examples of JAK inhibitors include, e.g., baricitinib, ruxolitinib, tofacitinib, oclacitinib, baricitinib, peficitinib, fedratinib, upadacitinib, filgotinib, delgocitinib, abrocitinib.

[0494] One or more other therapeutic agents can be used simultaneously or sequentially with the compound provided herein. Sequentially, use can be used before or after the compound provided herein. In some embodiments, the one or more other therapeutic agents can be used in the same composition as the compound provided herein. In other embodiments, there can be a time interval between the use of another therapeutic agent and the compound provided herein.

[0495] In some embodiments, administering an additional therapeutic agent with a compound provided herein can enable the other therapeutic agent to be administered at a lower dose and / or at less frequent intervals.

[0496] Methods used for treatment

[0497] The compounds disclosed herein and pharmaceutical compositions comprising the compounds are capable of inhibiting EGFR and thus can be used to inhibit EGFR activity in subjects in need thereof, as well as to prevent or treat EGFR-related disorders.

[0498] In another aspect, the present disclosure provides a method of treating an EGFR-related disorder, comprising administering to a subject in need thereof an effective amount of a compound provided herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0499] As used herein, the term "treating / treatment" or "therapy" is intended to have its normal meaning, that is, to treat a disease so as to fully or partially alleviate one, some or all of its symptoms, or to correct or compensate for underlying pathology, thereby achieving a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms, alleviation of the extent of the disease, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or alleviation of the disease state, and relief (whether partial or complete), whether detectable or undetectable. "Treatment" can also mean an extension of survival compared to the expected survival in the absence of therapy. Situations requiring therapy include situations in which a condition or illness is already present, as well as situations in which a condition or illness is prone to being present, or situations in which a condition or illness is to be prevented.

[0500] As used herein, the terms "preventing," "prevention," or "prophylaxis" are intended to have their normal meaning and include primary prevention, which is used to prevent the development of a disease, and secondary prevention, which is used after a disease has developed and to protect a patient, temporarily or permanently, from exacerbating or worsening the disease or developing new symptoms associated with the disease.

[0501] In some embodiments, the compounds or pharmaceutically acceptable salts and compositions provided herein can be used to treat a variety of EGFR-related disorders, including cancer, autoimmune diseases, and the like.

[0502] In certain embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, and compositions thereof, can be used to treat cancers, 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 (particularly brain metastases), and the like.

[0503] In certain embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, and compositions 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.

[0504] The administration concentration and administration route of the subject will vary depending on the EGFR related condition to be treated. In certain embodiments, the administration is carried out by a route selected from the group consisting of: parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreal injection, intravenous injection, intraarterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, rectal, subcutaneous, and ocular administration.

[0505] Implementations of various aspects provided by the present disclosure are also described in any of the following paragraphs.

[0506] Embodiment 1: A compound of formula (I):

[0507]

[0508] or a pharmaceutically acceptable salt thereof, wherein:

[0509] Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0510] Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0511] L 1 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0512] L 2 Selected from the group consisting of: a bond, N(R A ), 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 replaced by one or more R B replace;

[0513] where R A 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 substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0514] Each R B independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0515] L 3selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0516] L 4 Selected from O, S or N(R C );

[0517] where R C selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0518] Each R 1 are independently selected from the group consisting of: hydroxy, halogen, cyano, amino, -N(R D )2, 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 replaced by one or more R E replace;

[0519] Each R D independently selected from the group consisting of hydrogen, 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 the group consisting of hydroxy, halogen, cyano, -N(R F )2OR-OR G ;

[0520] Each R E are independently selected from the group consisting of hydrogen, hydroxy, 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 the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino and alkyl;

[0521] where R F and RG each of which is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0522] Each R 2 independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, the heteroalkynyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0523] R 3 selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0524] m is an integer from 0 to 5; and

[0525] n is an integer from 0 to 4.

[0526] Embodiment 2. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein ring A is aryl or heteroaryl.

[0527] Embodiment 3. The compound of embodiment 2 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of furanyl, phenylthio, pyrrolyl, phenyl, pyridinyl, pyranyl, pyrimidinyl, pyridazinyl, pyrazinyl and tetrahydroisoquinolinyl.

[0528] Embodiment 4. The compound according to embodiment 3 or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of:

[0529] Embodiment 5. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein ring B is aryl or heteroaryl.

[0530] Embodiment 6. The compound according to embodiment 5, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or pyrazolyl.

[0531] Embodiment 7. The compound according to embodiment 6 or a pharmaceutically acceptable salt thereof, wherein ring B is

[0532] Embodiment 8. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein L 1 It is a key.

[0533] Embodiment 9. The compound according to embodiment 8 or a pharmaceutically acceptable salt thereof, wherein L 1 It is an alkyl group.

[0534] Embodiment 10. The compound according to embodiment 9 or a pharmaceutically acceptable salt thereof, wherein L 1 Selected from the group consisting of: Among them L 1 The * end and L 2 connect.

[0535] Embodiment 11. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein L 2 It is a key.

[0536] Embodiment 12. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein L 2 It is N(R A ), and R A is selected from alkyl or heterocyclyl, wherein the alkyl or heterocyclyl is optionally substituted with one or more halogen or alkyl.

[0537] Embodiment 13. The compound according to embodiment 12 or a pharmaceutically acceptable salt thereof, wherein R A is ethyl, difluoroethyl, trifluoroethyl or oxetanyl.

[0538] Embodiment 14. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein L 2 is optionally replaced by one or more R B Substituted cycloalkyl.

[0539] Embodiment 15. The compound according to embodiment 14 or a pharmaceutically acceptable salt thereof, wherein L 2 yes which are optionally replaced by one or more R B replace.

[0540] Embodiment 16. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein L 2 is optionally replaced by one or more R B substituted heterocyclic group.

[0541] Embodiment 17. The compound of embodiment 16 or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group is selected from the group consisting of:

[0542]

[0543] Each of which is optionally replaced by one or more R B Substituted, where L 2 The * end and L 3 connect.

[0544] Embodiment 18. The compound according to embodiment 16 or 17, or a pharmaceutically acceptable salt thereof, wherein R B It is an alkyl group.

[0545] Embodiment 19. The compound according to embodiment 19 or a pharmaceutically acceptable salt thereof, wherein R B It's methyl.

[0546] Embodiment 20. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein L 2 Selected from the group consisting of:

[0547] Among them L 2 The * end and L 3 connect.

[0548] Embodiment 21. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein L 3 It is an alkyl group.

[0549] Embodiment 22. The compound according to embodiment 21 or a pharmaceutically acceptable salt thereof, wherein L 3 It's ethyl.

[0550] Embodiment 23. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein L 4 is O or NH.

[0551] Embodiment 24. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is a key, and L 2 is a bond or optionally replaced by one or more R B substituted heterocyclic group.

[0552] Embodiment 25. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is an alkyl group, and L 2 is a key, N(R A ) or optionally one or more R B Substituted cycloalkyl.

[0553] Embodiment 26. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is halogen, and m is 1.

[0554] Embodiment 27. The compound according to embodiment 26 or a pharmaceutically acceptable salt thereof, wherein R 1 It's bromine.

[0555] Embodiment 28. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Yes-N(R D )2, and m is 1.

[0556] Embodiment 29. The compound according to embodiment 28, or a pharmaceutically acceptable salt thereof, wherein each R D is optionally independently selected from one or more -N(R F )2OR-OR G An alkyl group substituted with a group.

[0557] Embodiment 30. The compound according to embodiment 29 or a pharmaceutically acceptable salt thereof, wherein each R D is independently methyl, methoxyethyl or N,N-dimethylaminopropyl.

[0558] Embodiment 31. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more R E substituted heterocyclic group, and m is 1.

[0559] Embodiment 32. The compound of embodiment 31 or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group is selected from the group consisting of:

[0560]

[0561] Each of which is optionally replaced by one or more R E replace.

[0562] Embodiment 33. The compound according to embodiment 31 or a pharmaceutically acceptable salt thereof, wherein R E It's a halogen.

[0563] Embodiment 34. The compound according to embodiment 32, or a pharmaceutically acceptable salt thereof, wherein R E It's F.

[0564] Embodiment 35. The compound according to embodiment 31 or a pharmaceutically acceptable salt thereof, wherein R E Yes-N(R F)2, -alkyl-N(R F )2、-C(O)OR G or alkyl optionally substituted with one or more halogens.

[0565] Embodiment 36. The compound according to embodiment 35, or a pharmaceutically acceptable salt thereof, wherein R F and R G Each of is an alkyl group.

[0566] Embodiment 37. The compound according to embodiment 35, or a pharmaceutically acceptable salt thereof, wherein R F and R G Each of them is C 1-3 alkyl.

[0567] Embodiment 38. The compound according to embodiment 35, or a pharmaceutically acceptable salt thereof, wherein R E Selected from the group consisting of: -N(CH3)2, -C 1-3 Alkyl-N(CH3)2, -C(O)O(tert-butyl), methyl, ethyl or trifluoroethyl.

[0568] Embodiment 39. The compound according to embodiment 31 or a pharmaceutically acceptable salt thereof, wherein R E is cycloalkyl or heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with one or more alkyl or halogen.

[0569] Embodiment 40. The compound according to embodiment 39 or a pharmaceutically acceptable salt thereof, wherein R E is selected from cyclopropyl, morpholinyl, piperazinyl, oxetanyl or azetidinyl, each of which is optionally substituted with one or more alkyl or halogen.

[0570] Embodiment 41. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

[0571]

[0572] Embodiment 42. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is halogen, and n is 1 or 2.

[0573] Embodiment 43. The compound according to embodiment 42, or a pharmaceutically acceptable salt thereof, wherein R 2 It's F.

[0574] Embodiment 44. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein R2 is alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more halogens.

[0575] Embodiment 45. The compound according to embodiment 44, or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl, ethyl, cyclopropyl or trifluoroethyl.

[0576] Embodiment 46. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is an alkyl group or a cycloalkyl group.

[0577] Embodiment 47. The compound according to embodiment 46, or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl, ethyl or cyclopropyl.

[0578] Embodiment 48. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2.

[0579] Embodiment 49. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

[0580] Embodiment 50. The compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592] 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.

[0593] Embodiment 52. A method of inhibiting EGFR activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1 to 50 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 51.

[0594] Embodiment 53. A method of treating an EGFR-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of embodiments 1 to 50 or a pharmaceutically acceptable salt thereof, or administering to the subject a pharmaceutical composition according to embodiment 51.

[0595] Embodiment 54. The method of embodiment 53, wherein the EGFR-related disorder is an autoimmune disease or cancer.

[0596] Embodiment 55. A method according to embodiment 54, wherein the cancer is selected from the group consisting of lung cancer, brain cancer, colorectal cancer, bladder cancer, urothelial cancer, breast cancer, prostate cancer, ovarian cancer, head and neck cancer, pancreatic cancer, gastric cancer and mesothelioma, including metastases (particularly brain metastases), etc.

[0597] Embodiment 56. The method of any one of embodiments 53 to 55, wherein the compound is administered simultaneously, separately or sequentially with one or more additional therapeutic agents.

[0598] Embodiment 57. The method of embodiment 56, wherein the one or more additional therapeutic agents are selected from the group consisting of: EGFR TKI, EGFR antibody, MEK inhibitor, c-MET inhibitor, mitotic kinase inhibitor, immunotherapeutic agent, anti-angiogenic agent, apoptosis inducer, mTOR inhibitor, histone deacetylase inhibitor, IL6 inhibitor and JAK inhibitor.

[0599] Furthermore, embodiments of various aspects provided by the present disclosure are also described in any of the following paragraphs.

[0600] Item 1. A compound of formula (II)

[0601]

[0602] or a pharmaceutically acceptable salt thereof, wherein:

[0603] Ring A 1is a 7-12 membered cycloalkyl group, a 7-12 membered heterocyclyl group, a 7-12 membered aryl group or a 7-12 membered heteroaryl group;

[0604] Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0605] L 1 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0606] L 2 Selected from the group consisting of: a bond, N(R A ), 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 replaced by one or more R B replace;

[0607] where R A 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 substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0608] Each R B independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0609] L 3 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0610] L 4 Selected from O, S or N(R C );

[0611] where R Cselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0612] Each R 1 are independently selected from the group consisting of: hydroxy, halogen, cyano, amino, -N(R D )2, 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 replaced by one or more R E replace;

[0613] Each R D independently selected from the group consisting of hydrogen, 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 the group consisting of hydroxy, halogen, cyano, -N(R F )2OR-OR G ;

[0614] Each R E are independently selected from the group consisting of hydrogen, hydroxy, 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 the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino and alkyl;

[0615] where R F and R G each of which is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0616] Each R 2independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, the heteroalkynyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0617] Each R 3 selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0618] m is an integer from 0 to 5;

[0619] n is an integer from 0 to 4; and

[0620] p is an integer from 0 to 3.

[0621] Item 2. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein Ring A 1 It is a 7-12 membered heteroaryl group.

[0622] Item 3. The compound according to Item 2 or a pharmaceutically acceptable salt thereof, wherein Ring A 1 It is tetrahydroisoquinolinyl.

[0623] Item 4. The compound according to Item 3 or a pharmaceutically acceptable salt thereof, wherein Ring A 1 yes

[0624] Item 5. The compound according to any one of the preceding items or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0625] Item 6. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0626] Item 7. The compound according to Item 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more N(R F )2 substituted alkyl.

[0627] Item 8. The compound according to Item 7 or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more N(RF )2 substituted ethyl.

[0628] Item 9. The compound according to Item 7 or 8 or a pharmaceutically acceptable salt thereof, wherein R F It is an alkyl group.

[0629] Item 10. The compound according to Item 9 or a pharmaceutically acceptable salt thereof, wherein R F It's methyl.

[0630] Item 11. The compound according to Item 6 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a heterocyclic group.

[0631] Item 12. The compound according to Item 11 or a pharmaceutically acceptable salt thereof, wherein R 1 It is an oxetane group.

[0632] Item 13. The compound according to Item 12 or a pharmaceutically acceptable salt thereof, wherein R 1 yes

[0633] Item 14. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein L 1 It is an alkyl group.

[0634] Item 15. The compound according to Item 14 or a pharmaceutically acceptable salt thereof, wherein L 1 yes Among them L 1 The * end and L 2 connect.

[0635] Item 16. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein L 2 It is a key.

[0636] Item 17. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein L 3 It is an alkyl group.

[0637] Item 18. The compound according to Item 11 or a pharmaceutically acceptable salt thereof, wherein L 3 It's ethyl.

[0638] Item 19. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein L 4 is O or NH.

[0639] Item 20. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein Ring B is an aryl group or a heteroaryl group.

[0640] Item 21. The compound according to Item 20 or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl, pyridyl or pyrazolyl.

[0641] Item 22. The compound according to Item 21 or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of:

[0642] Item 23. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0643] Item 24. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is an alkyl group.

[0644] Item 25. The compound according to Item 24 or a pharmaceutically acceptable salt thereof, wherein R 2 It's methyl.

[0645] Item 26. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein R 3 It is an alkyl group.

[0646] Item 27. The compound according to Item 26 or a pharmaceutically acceptable salt thereof, wherein R 3 It's methyl.

[0647] Item 28. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

[0648] Item 29. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0649] Item 30. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0650] Item 31. A compound of formula (III):

[0651]

[0652] or a pharmaceutically acceptable salt thereof, wherein:

[0653] Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0654] Ring B 1 is a 7-12 membered cycloalkyl group, a 7-12 membered heterocyclyl group, a 7-12 membered aryl group or a 7-12 membered heteroaryl group;

[0655] L 1selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0656] L 2 Selected from the group consisting of: a bond, N(R A ), 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 replaced by one or more R B replace;

[0657] where R A 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 substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0658] Each R B independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0659] L 3 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0660] L 4 Selected from O, S or N(R C );

[0661] where R C selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0662] Each R 1 are independently selected from the group consisting of: hydroxy, halogen, cyano, amino, -N(R D)2, 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 replaced by one or more R E replace;

[0663] Each R D independently selected from the group consisting of hydrogen, 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 the group consisting of hydroxy, halogen, cyano, -N(R F )2OR-OR G ;

[0664] Each R E are independently selected from the group consisting of hydrogen, hydroxy, 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 the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino and alkyl;

[0665] where R F and R G each of which is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0666] Each R 2 independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, the heteroalkynyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0667] Each R 3selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0668] m is an integer from 0 to 5;

[0669] n is an integer from 0 to 4; and

[0670] p is an integer from 0 to 3.

[0671] Item 32. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein Ring A is an aryl group or a heteroaryl group.

[0672] 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, phenylthio, pyrrolyl, phenyl, pyridinyl, pyranyl, pyrimidinyl, pyridazinyl, pyrazinyl and tetrahydroisoquinolinyl.

[0673] Item 34. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0674] Item 35. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 1 is halogen, and m is 1.

[0675] Item 36. The compound according to Item 35 or a pharmaceutically acceptable salt thereof, wherein R 1 It's bromine.

[0676] Item 37. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 1 Yes-N(R D )2, and m is 1.

[0677] Item 38. The compound according to Item 37 or a pharmaceutically acceptable salt thereof, wherein each R D is optionally independently selected from one or more -N(R F )2OR-OR G An alkyl group substituted with a group.

[0678] Item 39. The compound according to Item 38 or a pharmaceutically acceptable salt thereof, wherein each R D is independently methyl, methoxyethyl or N,N-dimethylaminopropyl.

[0679] Item 40. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more R E substituted heterocyclic group, and m is 1.

[0680] Item 41. The compound according to Item 40 or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group is selected from the group consisting of:

[0681]

[0682] Each of which is optionally replaced by one or more R E replace.

[0683] Item 42. The compound according to Item 40 or a pharmaceutically acceptable salt thereof, wherein R E It's a halogen.

[0684] Item 43. The compound according to Item 42 or a pharmaceutically acceptable salt thereof, wherein R E It's F.

[0685] Item 44. The compound according to Item 40 or a pharmaceutically acceptable salt thereof, wherein R E Yes-N(R F )2, -alkyl-N(R F )2、-C(O)OR G or alkyl optionally substituted with one or more halogens.

[0686] Item 45. The compound according to Item 44 or a pharmaceutically acceptable salt thereof, wherein R F and R G Each of is an alkyl group.

[0687] Item 46. The compound according to Item 45 or a pharmaceutically acceptable salt thereof, wherein R F and R G Each of them is C 1-3 alkyl.

[0688] Item 47. The compound according to Item 44 or a pharmaceutically acceptable salt thereof, wherein R E Selected from the group consisting of: -N(CH3)2, -C 1-3 Alkyl-N(CH3)2, -C(O)O(tert-butyl), methyl, ethyl or trifluoroethyl.

[0689] Item 48. The compound according to Item 40 or a pharmaceutically acceptable salt thereof, wherein R E is cycloalkyl or heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with one or more alkyl or halogen.

[0690] Item 49. The compound according to Item 48 or a pharmaceutically acceptable salt thereof, wherein R E is selected from cyclopropyl, morpholine, piperazine, oxetanyl or azetidinyl, each of which is optionally substituted with one or more alkyl or halogen.

[0691] Item 50. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 1 Select from the group consisting of

[0692]

[0693] Item 51. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein Ring B 1 It is a 7-12 membered heteroaryl group.

[0694] Item 52. The compound according to Item 51 or a pharmaceutically acceptable salt thereof, wherein Ring B 1 yes

[0695] Item 53. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 2 is halogen, and n is 1 or 2.

[0696] Item 54. The compound according to Item 53 or a pharmaceutically acceptable salt thereof, wherein R 2 It's F.

[0697] Item 55. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 2 is alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more halogens.

[0698] Item 56. The compound according to Item 55 or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl, ethyl, cyclopropyl or trifluoroethyl.

[0699] Item 57. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein L 1 It is an alkyl group.

[0700] Item 58. The compound according to Item 57 or a pharmaceutically acceptable salt thereof, wherein L 1 It is propyl.

[0701] Item 59. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein L 2 It is a key.

[0702] Item 60. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein L 3 It is an alkyl group.

[0703] Item 61. The compound according to Item 60 or a pharmaceutically acceptable salt thereof, wherein L 3 It's ethyl.

[0704] Item 62. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein L 4 is O or NH.

[0705] Item 63. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 3 It is an alkyl group.

[0706] Item 64. The compound according to Item 63 or a pharmaceutically acceptable salt thereof, wherein R 3 It's methyl.

[0707] Item 65. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R 3 It's a halogen.

[0708] Item 66. The compound according to Item 65 or a pharmaceutically acceptable salt thereof, wherein R 3 It's Cl.

[0709] Item 67. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0710] Item 68. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0711] Item 69. The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0712] Item 70. A compound of formula (IV):

[0713]

[0714] or a pharmaceutically acceptable salt thereof, wherein:

[0715] Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0716] Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0717] L 1selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0718] L 21 is a 7-12 membered cycloalkyl or a 7-12 membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally replaced by one or more R B replace;

[0719] Each R B independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0720] L 3 selected from the group consisting of a bond, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, and a heteroalkynyl, wherein said alkyl, said alkenyl, said alkynyl, said heteroalkyl, said heteroalkenyl, and said heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, and amino;

[0721] L 4 Selected from O, S or N(R C );

[0722] where R C selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0723] Each R 1 are independently selected from the group consisting of: hydroxy, halogen, cyano, amino, -N(R D )2, 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 replaced by one or more R E replace;

[0724] Each R D independently selected from the group consisting of hydrogen, 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 the group consisting of hydroxy, halogen, cyano, -N(RF )2OR-OR G ;

[0725] Each R E are independently selected from the group consisting of hydrogen, hydroxy, 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 the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino and alkyl;

[0726] where R F and R G each of which is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0727] Each R 2 independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, the heteroalkynyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0728] R 3 selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halogen, cyano, amino, alkyl, and haloalkyl;

[0729] m is an integer from 0 to 5;

[0730] n is an integer from 0 to 4; and

[0731] p is an integer from 0 to 3.

[0732] Item 71. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein Ring A is an aryl group.

[0733] Item 72. The compound according to Item 71 or a pharmaceutically acceptable salt thereof, wherein Ring A is a phenyl group.

[0734] Item 73. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein R 1 is halogen, and m is 1.

[0735] Item 74. The compound according to Item 73 or a pharmaceutically acceptable salt thereof, wherein R 1 It's bromine.

[0736] Item 75. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein R 1 Yes-N(R D )2, and m is 1.

[0737] Item 76. The compound according to Item 75 or a pharmaceutically acceptable salt thereof, wherein each R D is optionally independently selected from one or more -N(R F )2OR-OR G An alkyl group substituted with a group.

[0738] Item 77. The compound according to Item 76 or a pharmaceutically acceptable salt thereof, wherein each R D is independently methyl, methoxyethyl or N,N-dimethylaminopropyl.

[0739] Item 78. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more R E substituted heterocyclic group, and m is 1.

[0740] Item 79. The compound according to Item 78 or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group is selected from the group consisting of:

[0741]

[0742] Each of which is optionally replaced by one or more R E replace.

[0743] Item 80. The compound according to Item 78 or a pharmaceutically acceptable salt thereof, wherein R E It's a halogen.

[0744] Item 81. The compound according to Item 80 or a pharmaceutically acceptable salt thereof, wherein R E It's F.

[0745] Item 82. The compound according to Item 78 or a pharmaceutically acceptable salt thereof, wherein RE Yes-N(R F )2, -alkyl-N(R F )2、-C(O)OR G or alkyl optionally substituted with one or more halogens.

[0746] Item 83. The compound according to Item 82 or a pharmaceutically acceptable salt thereof, wherein R F and R G Each of is an alkyl group.

[0747] Item 84. The compound according to Item 83 or a pharmaceutically acceptable salt thereof, wherein R F and R G Each of them is C 1-3 alkyl.

[0748] Item 85. The compound according to Item 82 or a pharmaceutically acceptable salt thereof, wherein R E Selected from the group consisting of: -N(CH3)2, -C 1-3 Alkyl-N(CH3)2, -C(O)O(tert-butyl), methyl, ethyl or trifluoroethyl.

[0749] Item 86. The compound according to Item 78 or a pharmaceutically acceptable salt thereof, wherein R E is cycloalkyl or heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with one or more alkyl or halogen.

[0750] Item 87. The compound according to Item 86 or a pharmaceutically acceptable salt thereof, wherein R E is selected from cyclopropyl, morpholine, piperazine, oxetanyl or azetidinyl, each of which is optionally substituted with one or more alkyl or halogen.

[0751] Item 88: The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein R 1 Select from the group consisting of

[0752]

[0753]

[0754] Item 89. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein Ring B is an aryl group or a heteroaryl group.

[0755] Item 90. The compound according to Item 89 or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl, pyridyl or pyrazolyl.

[0756] Item 91. The compound according to Item 90 or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of:

[0757] Item 92. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein L 1 It is a key.

[0758] Item 93. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein L 21 is a 7-10 membered heterocyclic group containing one or more heteroatoms selected from N or O.

[0759] Item 94. The compound according to Item 93 or a pharmaceutically acceptable salt thereof, wherein L 21 Select from the group consisting of

[0760] Among them L 21 The * end and L 3 connect.

[0761] Item 95. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein L 3 It is an alkyl group.

[0762] Item 96. The compound according to Item 95 or a pharmaceutically acceptable salt thereof, wherein L 3 It's ethyl.

[0763] Item 97. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein L 4 is O or NH.

[0764] Item 98. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more R E substituted heterocyclic group, and m is 1.

[0765] Item 99. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein R 3 It is an alkyl group.

[0766] Item 100. The compound according to Item 99 or a pharmaceutically acceptable salt thereof, wherein R 3 It's methyl.

[0767] Item 101. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

[0768] Item 102. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0769] Item 103. The compound according to Item 70 or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0770] Item 104. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0771]

[0772]

[0773] Item 105. A pharmaceutical composition comprising the compound according to any one of Items 1 to 104 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0774] Item 106. A method of inhibiting EGFR activity in a subject in need thereof, 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.

[0775] Item 107. A method for treating an EGFR-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of Items 1 to 104 or a pharmaceutically acceptable salt thereof, or administering to the subject a pharmaceutical composition according to Item 105.

[0776] Item 108. The method according to Item 107, wherein the EGFR-related disorder is an autoimmune disease or cancer.

[0777] Item 109. A method according to Item 108, wherein the cancer is selected from the group consisting of lung cancer, brain cancer, colorectal cancer, bladder cancer, urothelial cancer, breast cancer, prostate cancer, ovarian cancer, head and neck cancer, pancreatic cancer, gastric cancer and mesothelioma, including metastases (especially brain metastases), etc.

[0778] Item 110. The method according to any one of Items 107 to 109, wherein the compound is administered simultaneously, separately or sequentially with one or more additional therapeutic agents.

[0779] Item 111. The method according to Item 110, wherein the one or more additional therapeutic agents are selected from the group consisting of: EGFR TKI, EGFR antibody, MEK inhibitor, c-MET inhibitor, mitotic kinase inhibitor, immunotherapeutic agent, anti-angiogenic agent, apoptosis inducer, mTOR inhibitor, histone deacetylase inhibitor, IL6 inhibitor, JAK inhibitor.

[0780] Example

[0781] The general methods of the present disclosure are further explained below. The compounds of the present disclosure can be prepared by methods known in the art. The following describes detailed preparation methods of preferred compounds of the present disclosure. However, these in no way limit the preparation methods of the compounds of the present disclosure.

[0782] Synthesis Example

[0783] The following examples are included for illustrative purposes. The examples provided herein describe the synthesis of the compounds disclosed herein and the intermediates used to prepare the compounds. However, it should be understood that these examples do not limit the present disclosure and are only intended to illustrate methods for practicing the present disclosure. Those skilled in the art will recognize that the chemical reactions described can be easily adapted to prepare a variety of other compounds of the present disclosure, and alternative methods for preparing the compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, non-exemplary compounds according to the present disclosure can be successfully synthesized by modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art in addition to the reagents and building blocks described, and / or by making conventional modifications to the reaction conditions. In addition, those skilled in the art will also understand that the various steps described herein or in separate batches of compounds can be combined. Alternatively, other reactions disclosed herein or known in the art will be considered to be applicable to the preparation of other compounds of the present disclosure. Therefore, the following description is not intended to limit the scope of the present disclosure, but is specified by the appended claims.

[0784] Chemistry, Materials, and General Methods

[0785] Unless otherwise noted, all reagents and solvents were obtained from commercial suppliers such as PharmaBlock, Bide Pharmatech, Shanghai Send Pharm, Aldrich, and Sigma and used without further purification. Dry organic solvents (THF, DMF, 1,4-dioxane, etc.) were purchased from Anhui Senrise Technology, Beijing Innochem Science & Technology, and J&K Scientific and packaged in Sure / Seal bottles under nitrogen. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere. 1H NMR spectra were recorded on a Bruker AVIII HD 400 MHz and Bruker AVNEO 400 MHz spectrometer at ambient temperature. Chemical shifts were reported in parts per million (ppm, δ units). Data were reported as follows: chemical shift, number of protons, and multiplicity (s = singlet, d = doublet, dd = double doublet, dt = double triplet, t = triplet, q = quartet, br = broad, m = multiplet). LCMS (Shimadzu 20AD) was used to monitor the reaction by UV detection at 254 nm and low resonance electrospray mode (ESI). As determined by LCMS (3 minutes), most final compounds were purified to a purity of >95%. The LCMS (3 minutes) method used the following: Shimadzu 20AD spectrometer, Shim-pack Scepter C18-120 3.3*33 mm, 3.0 μm, 30° C., with a flow rate of 1.5 ml / min; solvent A was water + 6.5 mM NH4HCO3 + ammonium hydroxide (pH = 10), solvent B was acetonitrile; 0.0-1.7 minutes, 30% B-70% B; 1.7-2.3 minutes, 70% B-95% B; 2.3-2.8 minutes, 95% B; 2.8-3.0 minutes, 10% B. The flow from the UV detector was split (1:3) to the MS detector, which was equipped with ESI as the ionization source. The CHIRAL method used the following: column: CHIRALPAK IC-3, 0.46 x 5 cm, 3 μm; flow rate: 1.0 ml / min at 25°C; methyl tert-butyl ether (0.2% diethylamine) / (ethanol / dichloromethane = 1 / 1) = 20 / 80. The SFC method used the following: column: (R,R)-WHELK-01-Kromasil, 5 x 25 cm, 5 μm; mobile phase A: CO2, mobile phase B: methanol / acetonitrile = 1 / 1.

[0786] Listed below are the abbreviations used in the synthesis of the compounds provided herein:

[0787]

[0788]

[0789]

[0790]

[0791] Synthesis of intermediates

[0792] Intermediate M1

[0793] 2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate

[0794]

[0795] Step 1. Preparation of 2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (M1-1). To a stirred solution of 2-methyl-1H-pyrazol-3-one (100 g, 1019 mmol, 1 equiv) and KCO (352 g, 2548 mmol, 2.5 equiv) in acetonitrile (1000 mL) at 0° C. under a nitrogen atmosphere was added 2-(trimethylsilyl)ethoxymethyl chloride (254 g, 1528 mmol, 1.5 equiv). 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 NaSO. 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-d6,400MHz)δ0.00(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).

[0796] 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 was added N-iodosuccinimide (50.93 g, 226.39 mmol, 1.1 equiv). The resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 1 h. The reaction was quenched with aqueous sodium thiosulfate (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 Na 2 SO 4 . 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-d6,400MHz)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).

[0797] Step 3. Preparation of (6-chloro-4-(methoxycarbonyl)pyridin-2-yl)boronic acid (M1-3). A mixture of bis(pinacolato)diboron (11.5 g, 453.7 mmol, 1.3 equiv) in methyl tert-butyl ether (100 mL) was heated to 80° C. and stirred for 0.5 h, then cooled to room temperature, and bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) (1.16 g, 17 mmol, 0.05 equiv) and 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine (1.4 g, 52 mmol, 0.15 equiv) were added. The mixture was stirred at 25° C. for 0.5 h, then methyl 2-chloropyridine-4-carboxylate (60 g, 349 mmol, 1.00 equiv) was added and stirred at 80° C. for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give 104 g of methyl 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-4-carboxylate (M1-3) (crude) as a brown oil. This crude material was used in the next step without purification. LCMS: m / z (ESI), [M+H] + =216.05.

[0798] 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, about 349 mmol, about 1 equiv), 4-iodo-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol- A mixture of 3-ketone (M1-2, 124.30 g, 350.877 mmol, 1 equiv), bis(adamantan-1-yl)(butyl)phosphine (12.58 g, 35.088 mmol, 0.1 equiv), CsCO (228.65 g, 701.754 mmol, 2 equiv) and Pd(dba) (9.6 g, 10.4 mmol, 0.03 equiv) in toluene (600 mL) and water (150 mL) was stirred at 80° C. for 2 h under 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 using petroleum ether / ethyl acetate (1 / 4) as eluent to give 38 g of methyl 2-chloro-6-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)isonicotinate (M1-4) (25%) as a yellow solid. LCMS: m / z (ESI), [M+H] + =398.05.

[0799] 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). To 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(d To a stirred mixture of (1,4-dioxane (500 mL) and (1,4-dioxane (500 mL)) (3677 mg, 5.02 mmol, 0.05 equiv), PCy 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 using petroleum ether / ethyl acetate (1 / 3) as eluent 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-d6,400MHz)δ0.05(9H,s),0.80-0.90(2H,m),2.53(3H,s),3.41(3 H,s),3.50(2H,t),3.89(3H,s),5.37(2H,s),7.44(1H,d),8.52-8.60(2H,m).

[0800] 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 NaHCO (aq) solution (300 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (3×500 mL), dried over anhydrous Na 2 SO 4 , 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, 400MHz) δ2.56(3H,s),3.48(3H,s),3.91(3H,s),7.31(1H,s),7.90-7.80(2H,m).

[0801] Intermediate M2

[0802] 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester

[0803]

[0804] Step 1. Preparation of 5-bromo-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M2-1). To a mixture of 5-bromo-6-hydroxypyridine-3-carboxylic acid methyl ester (20 g, 86.19 mmol, 1 eq) in N,N-dimethylformamide (100 mL) was added NaH (60%) (4.14 g, 172.39 mmol, 2 eq) at 0 ° C. The mixture was stirred at 0 ° C for 60 minutes under a nitrogen atmosphere. CHI (13.46 g, 94.81 mmol, 1.1 eq) 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 Na2SO4. 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-d6,400MHz) δ3.59(3H,s),3.81(3H,s),8.18(1H,d),8.62(1H,d).

[0805] Step 2. Preparation of (5-(methoxycarbonyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)boronic acid (M2-2). A mixture of methyl 5-bromo-1-methyl-6-oxopyridine-3-carboxylate (30 g, 121.92 mmol, 1 eq), Pd(dppf)Cl2·CHCl2 (8.92 g, 12.2 mmol, 0.1 eq), bis(pinacolato)diboron (46.44 g, 182.88 mmol, 1.5 eq) and KOAc (35.90 g, 365.76 mmol, 3 eq) in 1,4-dioxane (600 mL) was stirred at 80°C overnight under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction mixture was used directly in the next step without workup. LCMS: m / z (ESI), [M+H] + =212.00.

[0806] Step 3. Preparation of methyl 1-methyl-5-(2-methyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-6-oxopyridine-3-carboxylate (M2-3). To the mixture freshly prepared by the reaction described above was added 4-iodo-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (43 g, 121.37 mmol, 1.00 equiv), Pd(dppf)Cl2.CH2Cl2 (7.91 g, 9.71 mmol, 0.08 equiv), K2CO3 (50.33 g, 364.14 mmol, 3 equiv) and H2O (150 mL) 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether / ethyl acetate (1 / 8) as eluent to give 30 g of 1-methyl-5-(2-methyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-6-oxopyridine-3-carboxylic acid methyl ester (M2-3) (62%) as a brown solid. LCMS: m / z (ESI), [M+H] + =394.10. 1 H NMR(DMSO-d6,400MHz)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).

[0807] Step 4. Preparation of methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2). A mixture of methyl 1-methyl-5-(2-methyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-6-oxopyridine-3-carboxylate (30 g, 76.23 mmol, 1 eq) and HCl in 1,4-dioxane (50 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and basified to pH 9 with K2CO3. 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 using dichloromethane / methanol (10 / 1) as eluent 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, 400MHz) δ3.52(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).

[0808] Intermediate M3

[0809] (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

[0810]

[0811] 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-propionyl-1,3-oxazolidin-2-one (100 g, 428.69 mmol, 1 eq) in tetrahydrofuran (640 mL) was added dropwise LiHMDS (471 mL, 471.56 mmol, 1.1 eq) and propenyl bromide (207.4 g, 1714.77 mmol, 4 eq) at -78°C under a nitrogen atmosphere. The resulting mixture was stirred at -50°C under a nitrogen atmosphere for 2 h and warmed to room temperature. The reaction mixture was treated with saturated NH4Cl(aq) solution (1000 mL) and extracted with CHCl (3×400 mL). The combined organic layers were washed with brine (3×500 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (40 / 1) as eluent to afford 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-d6,400MHz)δ1.00-1.12(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).

[0812] 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 eq) in tetrahydrofuran (800 mL) and H2O (200 mL) was added LiOH·H2O (46.05 g, 1097.56 mmol, 3 eq) and H2O2 (30%) (114.30 mL, 4906 mmol, 13.4 eq) at 0°C. The resulting mixture was stirred at 0°C under a nitrogen atmosphere for 3 h. The reaction was quenched with Na2S2O3 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 Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0813] Step 3. Preparation of (2R)-N,N-dibenzyl-2-methylpent-4-enoamide (M3-3). To a stirred solution of (2R)-2-methylpent-4-enoic acid (50 g, 219.02 mmol, 1 eq) and dibenzylamine (43.2 g, 219.022 mmol, 1 eq) in dioxane (200 mL) was added N,N-diisopropylethylamine (56.6 g, 438.04 mmol, 2 eq) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (99.94 g, 262.82 mmol, 1.2 eq) at room temperature under a nitrogen atmosphere. 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 Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether / ethyl acetate (40 / 1) as eluent to afford 55.6 g (2R)-N,N-dibenzyl-2-methylpent-4-enamide (M3-3) (86%) as a yellow oil. LCMS: m / z (ESI), [M+H] + =294.15. 1 H NMR(DMSO-d6,400MHz)δ1.01(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).

[0814] 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 eq) and 9-borabicyclo[3.3.1]nonane (852.05 mL, 426.02 mmol, 2.5 eq) in tetrahydrofuran (60 mL) was added dropwise NaOH (10 M) (220 mL) and H2O2 (30%) (151 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with Na2S2O4(aq) solution (500 mL). The mixture was extracted with CHCl (3×500 mL) and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether / ethyl acetate (1 / 1) as eluent to give 42.5 g (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-d6,400MHz)δ1.01(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).

[0815] Step 5. Preparation of (4R)-5-(dibenzylamino)-4-methylpentan-1-ol (M3-5). To a stirred mixture of LiAlH (6.73 g, 177.41 mmol, 1.3 equiv) in tetrahydrofuran (600 mL) was added (2R)-N,N-dibenzyl-5-hydroxy-2-methylpentanamide (42.5 g, 136.46 mmol, 1 equiv) at 0°C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (7 mL) and 15 mL of 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 using petroleum ether / ethyl acetate (10 / 1) as eluent to afford 27.9 g (4R)-5-(dibenzylamino)-4-methylpentan-1-ol (M3-5) (68%) as a yellow oil. LCMS: m / z(ESI),[M+H] + =298.15. 1H NMR(DMSO-d6,400MHz)δ0.81(3H,d),0.88-1.00(1H,m),1.13-1.46(3H,m),1.64-1.78(1H,m),2.03-2.27(2 H,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).

[0816] Step 6. Preparation of (4R)-5-amino-4-methylpentan-1-ol (M3-6). A mixture of (4R)-5-(dibenzylamino)-4-methylpentan-1-ol (18 g, 60.51 mmol, 1 eq) and Pd / C (1.29 g, 12.10 mmol, 0.2 eq) in methanol (200 mL) was stirred at room temperature under a hydrogen atmosphere for 6 h. The resulting mixture was filtered, and the filter cake was washed with methanol (3×70 mL). The resulting solution was concentrated under reduced pressure to give 6.5 g of (4R)-5-amino-4-methylpentan-1-ol (M3-6) (91%) as a yellow oil. 1 H NMR(DMSO-d6,400MHz)δ0.83(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).

[0817] Step 7. Preparation of (4R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentan-1-ol (M3-7). A mixture of 4-bromo-2-fluoro-1-nitrobenzene (10.00 g, 45.46 mmol, 1 eq), KCO (12.56 g, 90.91 mmol, 2 eq) and (4R)-5-amino-4-methylpentan-1-ol (6.39 g, 54.55 mmol, 1.2 eq) in acetonitrile (60 mL) was stirred at 60° C. for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature, treated with water (500 mL), and extracted with dichloromethane (3×500 mL). The combined organic layers were washed with brine (3×500 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure and purified by prep-TLC using petroleum ether / ethyl acetate (1 / 3) as eluent to give 11.7 g (4R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentan-1-ol (M3-7) as a yellow solid (81%). LCMS: m / z (ESI), [M+H] + =319.00. 1H NMR(400MHz,DMSO-d6)δ0.95(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).

[0818] 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 methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 2.67 g, 10 To a stirred mixture of 4-[(5-bromo-2-nitrophenyl)amino]-4-methylpentan-1-ol (3.21 g, 10.09 mmol, 1 eq) and triphenylphosphine (6.62 g, 25.22 mmol, 2.5 eq) in tetrahydrofuran (60 mL) were added diisopropyl azodicarboxylate (4.08 g, 20.18 mmol, 2 eq) and (4R)-5-[(5-bromo-2-nitrophenyl)amino]-4-methylpentan-1-ol (3.21 g, 10.09 mmol, 1 eq). 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 using petroleum ether / ethyl acetate (1 / 4) as eluent 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(400MHz,DMSO-d6)δ0.97(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).

[0819] 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 eq) and Raney nickel (200 mg, 2.33 mmol, 0.33 eq) in methanol (40 mL) was added NH2NH2·H2O (712 mg, 14.22 mmol, 2 eq) under nitrogen atmosphere at 0°C. After stirring at room temperature for 3h, the mixture was filtered, and the filter cake was washed with methanol (3×200mL). The organic solution was concentrated under reduced pressure, and the residue was purified by prep-TLC using dichloromethane / methanol (30 / 1) elution to obtain 3.65g 5-(5-{[(4R)-5-[(2-amino-5-bromophenyl)amino]-4-methylpentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl esters (M3-9) (96%) as a yellow solid. LCMS: m / z(ESI),[M+H] + =533.95.

[0820]

[0266] 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 eq) in dichloromethane (40 mL) was added cyanogen bromide (895 mg, 8.45 mmol, 1.5 eq) at room temperature. After stirring at room temperature for 2 h, the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC using dichloromethane / methanol (20 / 1) as eluent 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.

[0821] 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 eq) in tetrahydrofuran (100 mL) was added LiOH (307 mg, 12.83 mmol, 2 eq) in H2O (20 mL) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (10% to 40% acetonitrile / water) to give 3.5 g of 5-(5-{[(4R)-4-{[2-amino-6-(4-methylpiperazine-1-yl)-1,3-benzodiazol-1-yl]methyl}pentyl]oxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (M3-11) (97%) as a white solid. LCMS: m / z(ESI),[M+H] + =545.15.

[0822] 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}]octacos-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (M3). 5-(5-{[(4R)-4-[(2-amino-6-bromo-1,3 To a stirred mixture of 1-(7-azabenzotriazol-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) were added N,N-diisopropylethylamine (0.85 g, 6.62 mmol, 3 equiv) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.26 g, 3.31 mmol, 1.5 equiv). After stirring at 60 ° C. 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 using CH2Cl2 / methanol (40 / 1) as eluent to give 1.14 g (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}]octacos-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. 1 H NMR(DMSO-d6,400MHz)δ0.81(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),7.3 6(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).

[0823] Intermediates M4A and M4B

[0824] 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}]tritriacontac-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione, isomer 1 (M4A) and isomer 2 (M4B)

[0825]

[0826] Step 1. Preparation of benzylbis(ethoxymethyl)amine (M4-1). A mixture of benzylamine (500 g, 4666 mmol, 1 eq), POM (840.62 g, 9332 mmol, 2 eq) and KCO (644.88 g, 4666.mmol, 1 eq) 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 x 200 mL), and the organic solution was concentrated under reduced pressure to give 1200 g of benzylbis(ethoxymethyl)amine (M4-1) (80%) as a yellow oil. This crude material was used in Step 3 without further purification. 1 H NMR (DMSO-d6, 400MHz) δ1.01-1.19(6H,m),3.39-3.57(3H,m),3.90(2H,t),4.55-4.82(4H,m),7.27-7.39(5H,m).

[0827] Preparation of step 2.2-oxocyclopentane-1-carboxylic acid isopropyl ester (M4-2). A mixture of ethyl 2-oxocyclopentane-1-carboxylate (400 g, 2561 mmol, 1 eq) and DMAP (31.29 g, 256.11 mmol, 0.1 eq) 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 2-oxocyclopentane-1-carboxylic acid isopropyl ester (M4-2) (92%) as a yellow oil. LCMS: m / z (ESI), [MH] + =168.85. 1 H NMR(DMSO-d6,400MHz)δ1.26(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).

[0828] Preparation of step 3.3-benzyl-8-oxo-3-azabicyclo[3.2.1]octane-1-isopropyl carboxylate (M4-3). A solution of benzylbis(methoxymethyl)amine (M4-1, 601.1 g, 3078.5 mmol, 2.62 equivalents) in DMF (1.5 L) was treated with methyltrichlorosilane (400.4 g, 2679 mmol, 2.28 equivalents) at 0 ° C for 10 minutes under a nitrogen atmosphere, followed by the slow addition of 2-oxocyclopentane-1-isopropyl carboxylate (M4-2, 200 g, 1175 mmol, 1 equivalent) at 0 ° C. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched with water (3 L), basified to pH 7 with saturated NaHCO (aqueous solution) solution (3 L), and the mixture was extracted with ethyl acetate (3 × 2 L). The combined organic layers were washed with brine (3 × 2 L), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether: ethyl acetate (40 / 1) as eluent and concentrated under vacuum. The residue was further purified by Prep-HPLC using a C18 silica gel column by reverse flash chromatography. The fractions containing the desired compound were evaporated to dryness to give 110 g of 3-benzyl-8-oxo-3-azabicyclo[3.2.1]octane-1-carboxylic acid isopropyl ester (M4-3) (31%) as a yellow oil. LCMS: m / z (ESI), [M+H] + =470.15. 1 H NMR(DMSO-d6,400MHz)δ1.04-1.26(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)

[0829] Step 4. Preparation of isopropyl 3-benzyl-8-[(4-methylbenzenesulfonamido)imino]-3-azabicyclo[3.2.1]octane-1-carboxylate (M4-4). A solution of isopropyl 3-benzyl-8-oxo-3-azabicyclo[3.2.1]octane-1-carboxylate (100 g, 331.8 mmol, 1 eq) in methanol (1 L) was added portionwise at 0° C. to a solution of isopropyl 3-benzyl-8-oxo-3-azabicyclo[3.2.1]octane-1-carboxylate (100 g, 331.8 mmol, 1 eq) under nitrogen atmosphere. TsNHNH 2 (123.58 g, 663.5 mmol, 2.00 eq) was then added portionwise at 0° C. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. 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) as a white solid (51%). 1 H NMR(DMSO-d6,400MHz)δ0.99-1.15(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),2.62-2.7 3(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).

[0830] Step 5. Preparation of 3-benzyl-3-azabicyclo[3.2.1]octane-1-carboxylate (M4-5). To a stirred solution of 3-benzyl-8-[(4-methylbenzenesulfonamido)imino]-3-azabicyclo[3.2.1]octane-1-carboxylic acid isopropyl ester (100 g, 212.95 mmol, 1 eq) in methanol (2 L) was added NaBH4 (120.8 g, 3194.20 mmol, 15 eq) at 0°C under a nitrogen atmosphere. 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 Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with petroleum ether / ethyl acetate (5 / 1) to give 33.0 g of isopropyl 3-benzyl-3-azabicyclo[3.2.1]octane-1-carboxylate (M4-5) as a colorless oil (54%). LCMS: m / z (ESI), [M+H] + =288.05. 1H NMR(DMSO-d6,400MHz)δ1.14(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).

[0831] Step 6. Preparation of 3-benzyl-3-azabicyclo[3.2.1]octane-1-carboxylic acid (M4-6). A mixture of 3-benzyl-3-azabicyclo[3.2.1]octane-1-carboxylic acid isopropyl ester (33.0 g, 114.82 mmol, 1 eq) and LiOH (3.0 g, 126.30 mmol, 1.1 eq) in ethanol (400 mL) was stirred at 80° C. 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.

[0832] Preparation of step 7. 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 eq., 90%), DPPA (36.35 g, 132.07 mmol, 1.2 eq.) and triethylamine (33.41 g, 330.18 mmol, 3.0 eq.) in tetrahydrofuran (300 mL) was stirred at 80 ° C. for 2 h under 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 eq.) were added at 0 ° C. The mixture was stirred at 100 ° C. for 2 h under a nitrogen atmosphere and then cooled to room temperature. The reaction was quenched with water (1 L) and the mixture was extracted with ethyl acetate (3 × 1 L). The combined organic layers were washed with brine (3 × 1 L), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether / ethyl acetate (5 / 1) eluting to give 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-d6,400MHz)δ1.23(9H,s),1.38-1.60(3H,m),1.59-1.76(2H,m),1.7 5-2.25(5H,m),2.87(1H,d),3.38-3.56(2H,m),6.88(1H,s),7.17-7.37(5H,m)

[0833] Preparation of step 8.N-{3-azabicyclo[3.2.1]octan-1-yl}carbamic acid tert-butyl ester (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 eq) and Pd / C (7.57 g, 71.13 mmol, 1.50 eq) in methanol (300 mL) was stirred at room temperature for 2 h under a hydrogen atmosphere. 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-d6,400MHz)δ1.36(9H,d),1.45-1.60(2H,m),1.60-1.75(1H,m),1.73-1.91(1 H,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).

[0834] 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, about 44 mmol, about 1 eq), (2-bromoethoxy)(tert-butyl)dimethylsilane (21.14 g, 88.37 mmol, 2 eq), NaI (13.25 g, 88.37 mmol, 2 eq) and KCO (12.21 g, 88.37 mmol, 2 eq) in DMF (160 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 (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 prep-HPLC using water containing 0.1% NH4HCO3 and acetonitrile as mobile phases. The fractions containing the desired compound were evaporated to dryness to give 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-d6,400MHz)δ0.00(6H,s),0.82(9H,s),0.85(1H,s),1.32(9H,s),1.37-1.48(2H,m),1.53-1.64(2 H,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).

[0835]

[0146] 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), was used directly in the next step as an orange oil without further purification. LCMS: m / z (ESI), [M+H] + =285.15.

[0836] 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), KCO (21.56 g, 156.25 mmol, 5 eq) and 4-bromo-2-fluoro-1-nitrobenzene (20.53 g, 93.73 mmol, 3 eq) 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% NH4HCO3 and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 12 g of 2-[1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl]ethanol (M4-11) (76%) as an orange semisolid. LCMS: m / z (ESI), [M+H] + =371.95. 1H NMR(DMSO-d6,400MHz)δ1.68(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).

[0837] 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 2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]octan-3-yl}ethanol (8 g, 2 To a stirred mixture of 4-[ ... The residue was purified on a silica gel column using petroleum ether / ethyl acetate (1 / 3) as eluent to give 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.

[0838] Step 13. Preparation of methyl 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (M4-13). To a mixture of methyl 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (10.5 g, 17.06 mmol, 1 eq) and Raney nickel (2 g) in methanol (150 mL) was added hydrazine hydrate (2.19 g, 68.24 mmol, 1.5 eq) and stirred at 0° C. under nitrogen atmosphere for 2 h. 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 using dichloromethane / methanol (10 / 1) as eluent to afford 9.5 g of 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-carboxylic acid methyl ester (M4-13) (91%) as a brown oil. LCMS: m / z (ESI), [M+H] + =585.20. 1 H NMR(DMSO-d6,400MHz)δ1.45-1.60(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(1 H,m),6.50-6.56(1H,m),6.64(1H,d),7.97(1H,s),8.10(1H,d),8.43(1H,d).

[0839]

[0266] Step 14. Preparation of methyl 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M4-14). A solution of methyl 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-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 nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, and the residue was purified on a silica gel column using dichloromethane / methanol (20 / 1) as eluent 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.

[0840] 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). A racemic mixture of M4-14 (9 g, 14.74 mmol) was separated by chiral chromatography using a (R,R)-WHELK-01-Kromasil column (5*25 cm, 5 μm), CO2 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 minutes, Rt(isomer 2)=3.898 minutes.

[0841] 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 1-(4-nitro-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 LiOH (0.31 g, 13.10 mmol, 2 equiv) in HO (2 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure, and the residue was purified by Prep-HPLC by reverse-phase flash chromatography using a C18 silica gel column eluting with water and acetonitrile. The fractions containing the desired compound were evaporated to dryness to give 3.6 g of 5-(5-(2-(1-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (Isomer 1, M4-15A) as a white solid (92%). LCMS: m / z (ESI), [M+H] + =598.05.

[0842] 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}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (M4A). 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-aza]-1-[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ A mixture of bicyclo[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 equivalent), N,N,N,N-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (3.44 g, 9.05 mmol, 1.5 equivalents) and N,N-diisopropylethylamine (2.34 g, 18.10 mmol, 3 equivalents) 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 using dichloromethane / methanol (20 / 1) as eluent 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}]tritriacontac-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-d6,400MHz)δ1.56-1.81(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).

[0843] 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)-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 by reverse flash chromatography using a C18 silica gel column eluting with water and acetonitrile. The fractions containing the desired compound were evaporated to dryness to give 3.8 g of 5-(5-(2-(1-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (Isomer 2, M4-15B) as a white solid (92%). LCMS: m / z (ESI), [M+H] + =598.05.

[0844] Step 19. Preparation of 5-bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[24.4.1.1^{1,28}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tris-3,5,7,9,13,17(33),18(22),19-octaene-12,16-dione (isomer 2, M4B). 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3 -azabicyclo[3.2.1]octan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (M4-15B, 3.8 g, 6.37 mmol, 1 equivalent), N,N,N,N-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (3.63 g, 9.56 mmol, 1.5 equivalents) and N,N-diisopropylethylamine (2.47 g, 19.11 mmol, 3 equivalents) in 1,4-dioxane (80 mL) was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was quenched with water (300 mL) and the mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (3 × 300 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on a silica gel column using dichloromethane / methanol (20 / 1) as eluent 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}]tritriacontac-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-d6,400MHz)δ1.55-1.76(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(1 H,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)

[0845] Intermediate M5

[0846] 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}]tetracontriacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione

[0847]

[0848] Step 1. Preparation of ethyl 4-methylenecyclohexane-1-carboxylate (M5-1). To a mixture of methyltriphenylphosphonium bromide (314.81 g, 881.27 mmol, 1.5 equiv) and potassium tert-butoxide (131.85 g, 1175.03 mmol, 2 equiv) in tetrahydrofuran (500 mL) was added ethyl 4-oxocyclohexane-1-carboxylate (100 g, 587.51 mmol, 1 equiv) 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 NaSO 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-methylenecyclohexane-1-carboxylate (M5-1) (85%) as a yellow oil. 1H NMR(DMSO-d6,400MHz)δ1.18(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).

[0849] Step 2. Preparation of ethyl 1-(4-methylbenzenesulfonyl)-1-azaspiro[2.5]octane-6-carboxylate (M5-2). To a mixture of ethyl 4-methylenecyclohexane-1-carboxylate (80 g, 475.52 mmol, 1 eq) and chloramine-T (216.50 g, 951.04 mmol, 2 eq) in acetonitrile (800 mL) was added N,N,N-trimethylanilinium dibromoethane bromide (17.88 g, 47.55 mmol, 0.1 eq) at 0°C. 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 using petroleum ether / ethyl acetate (5 / 1) to give 60 g of ethyl 1-(4-methylbenzenesulfonyl)-1-azaspiro[2.5]octane-6-carboxylate (M5-2) (33%) as a white solid. LCMS: m / z (ESI), [M+H] + =338.05. 1 H NMR(DMSO-d6,400MHz)δ1.18(3H,t),1.54-1.58(1H,m),1.58-1.72(1H,m),1.72-1.93(4 H,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).

[0850]

[0266] Step 3. Preparation of ethyl 4-[(benzylamino)methyl]-4-(4-methylbenzenesulfonamide)cyclohexane-1-carboxylate (M5-3). A solution of ethyl 1-(4-methylbenzenesulfonyl)-1-azaspiro[2.5]octane-6-carboxylate (60 g, 177.81 mmol, 1 eq) and benzylamine (28.58 g, 266.72 mmol, 1.5 eq) in tetrahydrofuran (600 mL) was stirred at 80 ° C. 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 using petroleum ether / ethyl acetate (1 / 1) as eluent to give 60 g of ethyl 4-[(benzylamino)methyl]-4-(4-methylbenzenesulfonamide)cyclohexane-1-carboxylate (M5-3) (75%) as a white oil. LCMS: m / z (ESI), [M+H] +=445.20. 1 HNMR(DMSO-d6,400MHz)δ1.15(3H,t),1.31-1.44(2H,m),1.48-1.76(4H,m),2.00(1H,m),2.21-2.30(1H,m),2.3 0(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).

[0851]

[0266] Step 4. Preparation of lithium 4-((benzylamino)methyl)-4-((4-methylphenyl)sulfonamido)cyclohexane-1-carboxylate (M5-4). A mixture of ethyl 4-[(benzylamino)methyl]-4-(4-methylbenzenesulfonamido)cyclohexane-1-carboxylate (60 g, 134.95 mmol, 1 eq) and LiOH (6.46 g, 269.91 mmol, 2 eq) in ethanol (500 mL) was stirred at 80°C 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)sulfonamido)cyclohexane-1-carboxylate (M5-4) as a white solid. This material was used in the next step without further purification. LCMS: m / z (ESI), [M+H] + =417.10.

[0852]

[0266] Step 5. Preparation of N-{3-benzyl-4-oxo-3-azabicyclo[3.2.2]non-1-yl}-4-toluenesulfonamide (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)sulfonamido)cyclohexane-1-carboxylate (57 g, ca. 135 mmol, ca. 1 equiv) and N,N-diisopropylethylamine (52.37 g, 405.21 mmol, 3 equiv) in dichloromethane (150 mL) was stirred at room temperature overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (1 / 1) as eluent to give 50 g of N-{3-benzyl-4-oxo-3-azabicyclo[3.2.2]non-1-yl}-4-toluenesulfonamide (M5-5) (93%) as a white solid. LCMS: m / z (ESI), [M+H] + =399.15. 1H NMR(DMSO-d6,400MHz)δ1.64-1.74(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)

[0853] Step 6. Preparation of N-{3-benzyl-3-azabicyclo[3.2.2]nonan-1-yl}-4-toluenesulfonamide (M5-6). To a mixture of lithium aluminum hydride (7.62 g, 200.74 mmol, 2 equiv) in tetrahydrofuran (400 mL) was added N-{3-benzyl-4-oxo-3-azabicyclo[3.2.2]nonan-1-yl}-4-toluenesulfonamide (40 g, 100.37 mmol, 1 equiv) at 0°C and the mixture was stirred under nitrogen for 2 h. The reaction was quenched with water (7 mL) and 15 mL of NaOH (w / w, 30%) at 0°C. The mixture was dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether / ethyl acetate (1 / 1) as eluent to give 20 g of N-{3-benzyl-3-azabicyclo[3.2.2]non-1-yl}-4-toluenesulfonamide (M5-6) as a white solid (46%). LCMS: m / z (ESI), [M+H] + =385.15. 1 H NMR(DMSO-d6,400MHz)δ1.39-1.63(6H,m),1.71-1.77(1H,m),1.90-2.02(2H,m),2.36(3H,s),2.40(2 H,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).

[0854] Preparation of step 7.N-{3-azabicyclo[3.2.2]nonan-1-yl}-4-toluenesulfonamide (M5-7). A mixture of Pd / C (10%, 500 mg) and N-{3-benzyl-3-azabicyclo[3.2.2]nonan-1-yl}-4-toluenesulfonamide (20 g, 52.01 mmol, 1 equivalent) in methanol (200 mL) was stirred at room temperature under hydrogen pressure for 4 h. The resulting mixture was filtered. The filter cake was washed with methanol (3×70 mL) and the solution was concentrated under reduced pressure. The residue was purified on a silica gel column using dichloromethane / methanol (10 / 1) elution to give 15 g of N-{3-azabicyclo[3.2.2]nonan-1-yl}-4-toluenesulfonamide (M5-7) (93%) as a white solid. LCMS: m / z (ESI), [M+H] + =295.00. 1 H NMR(DMSO-d6,400MHz)δ1.35-1.60(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).

[0855] Step 8. Preparation of N-(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]non-1-yl)-4-toluenesulfonamide (M5-8). A mixture of N-{3-azabicyclo[3.2.2]non-1-yl}-4-toluenesulfonamide (15 g, 50.94 mmol, 1 eq), NaI (7.64 g, 50.94 mmol, 1 eq), KCO (21.12 g, 152.84 mmol, 3 eq) and (2-bromoethoxy)(tert-butyl)dimethylsilane (14.63 g, 61.13 mmol, 1.2 eq) 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 Na2SO4 and concentrated under reduced pressure. The residue was purified on a silica gel column using dichloromethane / methanol (10 / 1) elution to afford 20 g of N-(3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-azabicyclo[3.2.2]non-1-yl)-4-toluenesulfonamide (M5-8) (78%) as a yellow solid. LCMS: m / z (ESI), [M+H] + =453.30. 1H NMR(DMSO-d6,400MHz)δ0.00(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).

[0856]

[0266] 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-toluenesulfonamide (5 g, 11.04 mmol, 1 eq) and Mg (5.37 g, 220.88 mmol, 20 eq) in methanol (200 mL) was stirred at 70 °C overnight under 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 x 300 mL). The combined organic layers were washed with brine (3 x 400 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on a silica gel column using dichloromethane / methanol (5 / 1) as eluent 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-d6,400MHz)δ0.00(6H,s),0.82(9H,s),1.54-1.64(4H,m),1.79-1.83(1 H,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).

[0857] 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 eq), 4-bromo-2-fluoro-1-nitrobenzene (1.84 g, 8.37 mmol, 2.5 eq) and KCO (1.39 g, 10.05 mmol, 3 eq) 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 Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether / ethyl acetate (5 / 1) as eluent 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.

[0858] 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 eq) and tetrabutylammonium fluoride (1.57 g, 6.01 mmol, 2 eq) in tetrahydrofuran (15 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was quenched with saturated NaHCO (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 NaSO and concentrated under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane / methanol (10 / 1) as eluent to give 1.2 g of 2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethanol (M5-11) (93%) as a yellow oil. LCMS: m / z (ESI), [M+H] + =384.00.

[0859] Step 12. Preparation of methyl 5-[5-(2-{1-[(5-bromo-2-nitrophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (M5-12). To methyl 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M2, 0.66 g, 2 To a stirred mixture of 4-[ ... The residue was purified by Prep-TLC and eluted 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]non-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-d6,400MHz)δ1.58-1.76(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).

[0860] Step 13. Preparation of methyl 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (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]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (1.1 g, 1.74 mmol, 1 eq) in methanol (8 mL) was added NH2NH2.H2O (47 mg, 0.95 mmol, 2 eq) under nitrogen atmosphere at 0°C. The mixture was stirred at 0 ° C for 1 h. The resulting mixture was filtered. The filter cake was washed with methanol (2 × 20 mL), and the solution was concentrated under reduced pressure. The residue was purified by Prep-TLC and eluted with dichloromethane / methanol (10 / 1) to give 910 mg of 5- [5- (2- {1- [ (2- amino -5- bromophenyl) amino] -3- azabicyclo [3.2.2] nonan -3- bases} ethoxy) -1- methylpyrazol -4- bases] -1- methyl -6- oxopyridine -3- carboxylic acid methyl ester (M5-13) (76%) as a light yellow solid. LCMS: m / z (ESI), [M + H] + =599.20.

[0861]

[0266] Step 14. Preparation of methyl 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (M5-14). A mixture of methyl 5-[5-(2-{1-[(2-amino-5-bromophenyl)amino]-3-azabicyclo[3.2.2]non-3-yl}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (900 mg, 1.50 mmol, 1 eq) and BrCN (174 mg, 1.65 mmol, 1.1 eq) in ethanol (10 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was concentrated under vacuum. The residue was purified by Prep-TLC and eluted with dichloromethane / methanol (12 / 1) to give 640 mg of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M5-14) (68%) as a light yellow solid. LCMS: m / z (ESI), [M+H] +=624.10. 1 H NMR(DMSO-d6,400MHz)δ1.24(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).

[0862] Step 15. Preparation of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (M5-15). A mixture of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (620 mg, 0.99 mmol, 1 eq) and LiOH (28 mg, 1.19 mmol, 1.2 eq) 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 under vacuum to give 550 mg of 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl)-3-azabicyclo[3.2.2]non-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (M5-15) (90%) as a white solid. LCMS: m / z(ESI),[M+H] + =610.10.

[0863] 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}]tetracontriacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione (M5). 5-(5-{2-[1-(2-amino-6-bromo-1,3-benzodiazol-1-yl) -3-azabicyclo[3.2.2]nonan-3-yl]ethoxy}-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid (550 mg, 0.90 mmol, 1 eq), N,N,N,N-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (1027 mg, 2.70 mmol, 3 eq) and N,N-diisopropylethylamine (174 mg, 1.35 mmol, 1.5 eq) in dioxane (6 mL) was stirred at 60 ° C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by Prep-HPLC with an XBridge Prep OBD C18 column using water and acetonitrile containing 10 mmol / L NH4HCO3 as mobile phases. The fractions containing the desired compound were evaporated to dryness to give 500 mg of 5-bromo-15,21-dimethyl-23-oxa-2,9,11,15,20,21,26-heptaazaheptacyclo[26.2.2.1^{1,26}.1^{13,17}.0^{2,10}.0^{3,8}.0^{18,22}]tetracontriacontria-3,5,7,9,13,17(34),18(22),19-octaene-12,16-dione (M5) (88%) as a yellow solid. LCMS: m / z (ESI), [M+H] + =592.15.

[0864] Synthesis Example

[0865] Example A1

[0866] 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

[0867]

[0868] 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 eq), KCO (19.59 g, 141.742 mmol, 2 eq) and aminoethylethanolamine (14.76 g, 141.742 mmol, 2 eq) 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 NaSO and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with PE / EA (1:1) to give 8.5 g of 2-({2-[(2-nitrophenyl)amino]ethyl}amino)ethanol (INT-A1-1) (53%) as a yellow solid. 1 H NMR(DMSO-d6,400MHz)δ1.99(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).

[0869] 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 eq), N,N-diisopropylethylamine (2.30 g, 17.758 mmol, 2 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.47 g, 10.655 mmol, 1.2 eq) in N,N-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 (200 mL) and the mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with brine (3×200 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether / ethyl acetate (1 / 1) as eluent 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.

[0870] Step 3. Preparation of 1-methyl-5-{1-methyl-5-[2-({2-[(2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]pyrazol-4-yl}-6-oxopyridine-3-carboxylic acid methyl ester (INT-A1-3). To 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (M2, 0.5 To a stirred mixture of 4-[[(2-nitrophenyl)amino]ethyl]-1-[[(2-nitrophenyl)amino]ethyl]-1-[[(2-trifluoroethyl)amino]ethyl]-1-[[(2-nitrophenyl)amino]ethyl]-1-[[(2-nitrophenyl)amino]ethyl]-1-[[(2-nitrophenyl)amino]ethyl]-1-[[(2-nitrophenyl)amino]ethyl]-1-[[(2-nitrophenyl)amino]ethyl]-1-[[(2-nitrophenyl)amino]ethyl]-1-[[(2-nitrophenyl)amino]ethyl]-1-[[(2-nitrophenyl)amino]ethyl]-1-[[(2-nitrophenyl)amino]ethanol ... The residue was purified on Prep-TLC using petroleum ether / ethyl acetate (1 / 3) as eluent to give 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. 1 H NMR(DMSO-d6,400MHz)δ3.02(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)

[0871] Step 4. Preparation of methyl 5-{5-[2-({2-[(2-aminophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (INT-A1-4). To a stirred mixture of methyl 1-methyl-5-{1-methyl-5-[2-({2-[(2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]pyrazol-4-yl}-6-oxopyridine-3-carboxylate (1.1 g, 1.99 mmol, 1 eq) and Raney nickel (0.85 g, 9.95 mmol, 5 eq) in methanol (30 mL) was added hydrazine hydrate (0.15 g, 2.98 mmol, 1.5 eq) at 0° C. The mixture was stirred at 0° C. under nitrogen atmosphere for 30 min. The resulting mixture was filtered. The filter cake was washed with methanol (3×20 mL), and the solution was concentrated under reduced pressure to give 1 g of 5-{5-[2-({2-[(2-aminophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A1-4) (96%) as a brown solid. This material was used in the next reaction without further purification. LCMS: m / z (ESI), [M+H] + =523.10. 1 H NMR(DMSO-d6,400MHz)δ2.95(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),4.0 3(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).

[0872] 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, about 1.9 mmol, about 1 equiv) and BrCN (0.24 g, 2.29 mmol, 1.2 equiv) in CHCl (20 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC using CH2Cl2 / methanol (40 / 1) as eluent 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. 1 H NMR(DMSO-d6,400MHz)δ3.04(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).

[0873]

[0266] 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 eq) and LiOH.HO (23 mg, 0.55 mmol, 1.5 eq) in tetrahydrofuran (4 mL) and HO (1 mL) was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 FLASH using water and acetonitrile as mobile phases. The fractions containing the desired compound were evaporated to dryness to give 180 mg of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A1-6) (92%) as a white solid. LCMS: m / z (ESI), [M+H] + =534.10. 1 H NMR(DMSO-d6,400MHz)δ2.99(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)

[0874] 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}]octacos-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A1). 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](2 A mixture of [4-(2,2-trifluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (150 mg, 0.28 mmol, 1 eq), N,N,N,N-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (160 mg, 0.42 mmol, 1.5 eq) and N,N-diisopropylethylamine (109 mg, 0.84 mmol, 3 eq) in 1,4-dioxane (5 mL) was stirred at room temperature overnight 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 Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC using an XBridge Shield RP18 OBD column using water containing 10 mmol / L NH4HCO3 and 0.1% NH3.H2O and acetonitrile as mobile phases. The fractions containing the desired compound were evaporated to dryness to give 29.5 mg of 5,26-dimethyl-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A1) as a pink solid (20%). LCMS: m / z (ESI), [M+H] + =516.20. 1 H NMR(DMSO,400MHz)δ3.10(2H,t),3.27(2H,t),3.63(3H,s),3.59-3.69(2H,m),3.71(3H,s),4.19(2H,t),4.33( 2H,t),7.18-7.31(2H,m),7.49-7.56(1H,m),7.70(1H,d),8.25(1H,s),8.29(1H,d),8.89(1H,d),12.55(1H,s). 19F NMR(DMSO-d6,376MHz)δ69.23(s).

[0875] Example A2

[0876] 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

[0877]

[0878] 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 eq), aminoethylethanolamine (1.42 g, 13.63 mmol, 1.5 eq) and KCO (3 g, 27.27 mmol, 3 eq) 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 NaSO and concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane / methanol (10 / 1) as eluent 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-d6,400MHz)δ2.64(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).

[0879] 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 eq) and N,N-diisopropylethylamine (12 g, 98.63 mmol, 3 eq) in dimethylformamide (100 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (11 g, 49.31 mmol, 1.5 eq). The mixture was stirred at 60 °C under 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 Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by prep-TLC using petroleum ether / ethyl acetate (5 / 1) to give 3 g of 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethanol (INT-A2-2) as a yellow oil (21%). LCMS: m / z (ESI), [M+H] + =385.90 1 H NMR(DMSO-d6,400MHz)δ2.76(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).

[0880] Preparation of step 3.2-cyclopropylpyrazole-3-ol (INT-A2-3). A mixture of (2E)-3-methoxyprop-2-enoic acid methyl ester (1 g, 8.61 mmol, 1 equivalent) and cyclopropylhydrazine (621 mg, 8.61 mmol, 1 equivalent) 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 layer was washed with brine (3 × 300 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse flash chromatography using 0% to 15% acetonitrile / water elution to obtain 200 mg 2-cyclopropylpyrazole-3-ol (INT-A2-3) (18%) as a yellow oil. LCMS: m / z(ESI),[M+H] + =125.15. 1H NMR (DMSO-d6, 400MHz) δ1.08-0.93(4H,m),3.44-3.31(1H,m),5.64(1H,d),7.62(1H,d).

[0881] 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 eq) and 2-(trimethylsilyl)ethoxymethyl chloride (2.66 g, 15.95 mmol, 1.8 eq) in N,N-dimethylformamide (10 mL) was added sodium hydride (0.85 g, 17.72 mmol, 2 eq, 60%) in portions at room temperature under a nitrogen atmosphere. 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 using dichloromethane / methanol (10:1) as eluent. The product was further purified by reverse-phase flash chromatography using 0% to 100% acetonitrile / water as eluent 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

[0882] Step 5. Preparation of 2-cyclopropyl-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (INT-A2-5). A mixture of 2-cyclopropyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (4.5 g, 17.69 mmol, 1 eq) and NIS (5.97 g, 26.53 mmol, 1.5 eq) in acetonitrile (50 mL) was stirred at 0° C. for 2 h under nitrogen atmosphere. The reaction was quenched by 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 (3×100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 5.5 g of 2-cyclopropyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one as a yellow solid. 2-Cyclopropyl-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-one (INT-A2-5) (82%). LCMS: m / z (ESI), [M+H] + =380.95

[0883] 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). Freshly prepared 5-(methoxycarbonyl)-1-methyl-2-oxopyridin-3-ylboronic acid (M2-2, 800 mg, 3.8 mmol, 1 equiv), K2CO3 (1.31 g, 9 To the product was added 4-[[(2-(trimethylsilyl)ethoxy]methyl]pyrazol-3-one]-1-[ ... The residue was purified on a silica gel column using petroleum ether / ethyl acetate (1 / 1) as eluent to give 1 g of methyl 5-(2-cyclopropyl-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (INT-A22-4) (92%) as a brown solid. LCMS: m / z (ESI), [M+H] + =420.05.

[0884] 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 with K2CO3 to pH 7. 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 used in the next step without further purification. LCMS: m / z (ESI), [M+H] + =290.05

[0885] 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 methyl 5-(1-cyclopropyl-5-hydroxypyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylate (0.7 g, To a mixture of 4-[[(5-bromo-2-nitrophenyl)amino]ethyl]-2-[[(5-bromo-2-nitrophenyl)amino]ethyl]-2-[[(5-bromo-2-nitrophenyl)amino]ethyl]-2-[[(5-bromo-2-nitrophenyl)amino]ethyl]-2-[[(5-bromo-2-nitrophenyl)amino]ethyl]-2-[[(5-bromo-2-nitrophenyl)amino]ethyl]-2-[[(5-bromo-2-nitrophenyl)amino]ethyl]-2-[[(5-bromo-2-nitrophenyl)amino]ethyl]-2-[[(5-bromo-2-nitrophenyl)amino]ethyl]-2-[[(5-bromo-2-nitrophenyl)amino]ethanol ... 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) as an orange solid (25%). LCMS: m / z (ESI), [M+H] + =658.95. 1 H NMR(DMSO-d6,400MHz)δ0.92-1.03(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).

[0886] Step 9. Preparation of methyl 5-{5-[2-({2-[(2-amino-5-bromophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-cyclopropylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (INT-A2-9). To a mixture of methyl 5-{5-[2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-cyclopropylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (350 mg, 0.53 mmol, 1 eq.) and Raney nickel (365 mg, 4.26 mmol, 8 eq.) in methanol (5 mL) was added hydrazine hydrate (98%) (40 mg, 0.80 mmol, 1.5 eq.) under nitrogen atmosphere at 0°C. The resulting mixture was stirred for 2 h and filtered. The filter cake was washed with methanol (3 × 50 mL) and the solution was concentrated under reduced pressure to give 300 mg of 5-{5-[2-({2-[(2-amino-5-bromophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-cyclopropylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A2-9) (about 90%) as a brown solid. LCMS: m / z (ESI), [M+H] + =627.15. 1 H NMR(DMSO-d6,400MHz)δ0.91-1.03(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).

[0887]

[0266] Step 10. Preparation of methyl 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-cyclopropylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A2-10). A mixture of methyl 5-{5-[2-({2-[(2-amino-5-bromophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethoxy]-1-cyclopropylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (300 mg, 0.48 mmol, 1 eq) and BrCN (60 mg, 0.57 mmol, 1.2 eq) in dichloromethane (5 mL) was stirred at room temperature under nitrogen atmosphere for 2 h and concentrated under vacuum. The residue was purified on prep-TLC using dichloromethane / methanol (10 / 1) as eluent 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.

[0888] 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 (2,2,2-trifluoroethyl)amino}ethoxy)-1-cyclopropylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (280 mg, 0.43 mmol, 1 eq) and LiOH HO (27 mg, 0.64 mmol, 1.5 eq) in THF (4 mL) and HO (1 mL) was stirred at room temperature for 2 h under a nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by prep-HPLC using an XBridge Shield RP18 OBD column using water and acetonitrile containing 10 mmol / L NH4HCO3 and 0.1% NH3 HO as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 135 mg of 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2,2-trifluoroethyl)amino}ethoxy)-1-cyclopropylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A2-11) as a brown solid (49%). LCMS: m / z (ESI), [M+H] + =638.10. 1 H NMR(DMSO-d6,400MHz)δ0.90-1.03(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)

[0889] Step 12. Preparation of 16-bromo-5-cyclopropyl-26-methyl-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacos-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A2-12). 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol- A mixture of [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 eq), N,N-diisopropylethylamine (67 mg, 0.52 mmol, 3 eq) and N,N,N,N-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (98 mg, 0.26 mmol, 1.5 eq) in 1,4-dioxane (5 mL) was stirred at room temperature for 2 h 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 × 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 using water containing 10 mmol / L NH4HCO3 and 0.1% NH3.H2O and acetonitrile as mobile phases. The fractions containing the desired compound were evaporated to dryness to give 60 mg of 16-bromo-5-cyclopropyl-26-methyl-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A2-12) as a brown solid (56%). LCMS: m / z (ESI), [M+H] + =622.05. 1H NMR(DMSO-d6,400MHz)δ0.96-1.04(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)。

[0890] Step 13. Preparation of 5-cyclopropyl-26-methyl-16-(4-methylpiperazin-1-yl)-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A2). 16-bromo-5-cyclopropyl-26-methyl-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}]octacos-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione was prepared under nitrogen atmosphere at room temperature. To a mixture of 2-methyl-2,6-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}]octacos-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (40 mg, 0.06 mmol, 1 eq), 1-methylpiperazine (26 mg, 0.256 mmol, 4 eq) and BrettPhos Pd G3 (18 mg, 0.02 mmol, 0.3 eq) in 1,4-dioxane (5 mL) was added LiHMDS (65 mg, 0.38 mmol, 6 eq). The mixture was stirred at 60° C. for 2 h and then cooled to room temperature. The reaction mixture was treated with NH4Cl (aqueous) solution (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC using a Shield RP18 OBD column using water containing 10 mmol / L NH4HCO3 and 0.1% NH3·H2O and acetonitrile as mobile phases. The fractions containing the desired compound were evaporated to dryness to give 2.7 mg of 5-cyclopropyl-26-methyl-16-(4-methylpiperazin-1-yl)-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacos-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A2) as a white solid (6%). LCMS: m / z (ESI), [M+H] + =640.35. 1H NMR(DMSO-d6,400MHz)δ0.96-1.04(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-d6,376MHz)δ69.26(s).

[0891] Example A3

[0892] 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

[0893]

[0894] 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). Triphenylphosphine (1324 mg, 5.04 mmol, 3 equiv.) and 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methylpyrazol-3-yl)-1-methylpyrazol-4-yl were reacted at 0°C. To a stirred mixture of methyl-6-oxopyridine-3-carboxylate (M2, 354 mg, 1.34 mmol, 0.8 eq) in tetrahydrofuran (9 mL) was added 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2,2-trifluoroethyl)amino)ethanol (650 mg, 1.68 mmol, 1 eq) and diisopropyl azodicarboxylate (1021 mg, 5.04 mmol, 3 eq). The mixture was stirred at 0 ° C. under a nitrogen atmosphere for 1 h. The reaction was quenched with water (50 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane / methanol (10 / 1) as eluent to give 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. 1 H NMR(DMSO-d6,400MHz)δ3.01(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).

[0895] 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 eq) and Raney nickel (30 mg) in methanol (6 mL) was added NH2NH2·H2O (57 mg, 1.80 mmol, 2 eq). The mixture was stirred at 0°C under nitrogen atmosphere 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) as a yellow oil (42%). LCMS: m / z (ESI), [M+H] + =601.05.

[0896] 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 eq) and BrCN (42 mg, 0.39 mmol, 1 eq) in ethanol (6 mL) was stirred at 0° C. for 1 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane / methanol (10 / 1) as eluent 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

[0897] 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 eq) in tetrahydrofuran (2 mL) was added LiOH·H2O (7.6 mg, 0.32 mmol, 2 eq) in H2O (0.5 mL). The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by a C18 column using water and acetonitrile as mobile phases. 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-d6,400MHz)δ2.98(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,).

[0898] 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}]octacos-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A3-5). To 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl] To a stirred mixture of (2,2,2-trifluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (65 mg, 0.10 mmol, 1 eq) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (60 mg, 0.15 mmol, 1.5 eq) in 1,4-dioxane (2 mL) was added N,N-diisopropylethylamine (41 mg, 0.31 mmol, 3 eq), and the mixture was stirred at 60° C. for 2 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane / methanol (10 / 1) as eluent 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}]octacos-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.

[0899] 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). To a stirred mixture 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 (50 mg, 0.08 mmol, 1 eq), BrettPhos Pd G3 (22 mg, 0.02 mmol, 0.3 eq) and piperazine, 1-methyl- (33 mg, 0.33 mmol, 4 eq) in 1,4-dioxane (2 mL) was added LiHMDS (0.48 mL, 0.48 mmol, 6 eq) dropwise at room temperature. The mixture was stirred at 60 ° C for 40 minutes under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (30 mL) and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with salt water (3 × 30 mL), dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by Prep-HPLC using an XBridge Shield RP18 OBD column using water containing 10 mmol / L NH HCO and 0.1% NH ·H O and acetonitrile as mobile phases. The fractions containing the desired compound were evaporated to dryness to give 3.1 mg of 5,26-dimethyl-16-(4-methylpiperazin-1-yl)-10-(2,2,2-trifluoroethyl)-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A3) as a yellow solid (5%). LCMS: m / z (ESI), [M+H] + =614.25. 1H NMR(DMSO-d6,400MHz)δ2.26(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-d6,376MHz)δ-69.31(s).

[0900] Example A4

[0901] 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

[0902]

[0903] 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 eq), N,N-diisopropylethylamine (2.55 g, 19.72 mmol, 3 eq) and 2,2-difluoroethyl trifluoromethanesulfonate (1.69 g, 7.89 mmol, 1.2 eq) in dimethylformamide (20 mL) was stirred at 60 °C under 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 using dichloromethane / methanol (10 / 1) as eluent to give 1.1 g of 2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethanol (INT-A4-1) (43%) as a yellow oil. LCMS: m / z (ESI), [M+H] + =366.00. 1H NMR(DMSO-d6,400MHz)δ2.71(2H,t),2.90(2H,t),2.99(2H,t),3.35-3.43(2H,m),3.46-3.64(2 H,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).

[0904] Step 2. Preparation of 5-{5-[2-({2-[(5-bromo-2-nitrophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A4-2). Triphenylphosphine (1.38 g, 5.29 mmol, 3 equiv.) and 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methylpyridine were added to the mixture at 0°C. To a mixture of methyl 6-oxopyridine-3-carboxylate (M2, 836 mg, 3.17 mmol, 1.8 equiv) in tetrahydrofuran (10 mL) was added 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). The mixture was stirred at 0 ° C. for 1 h under a nitrogen atmosphere. The reaction was quenched with water (80 mL) and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-TLC using petroleum ether / ethyl acetate (1 / 3) as eluent to give 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.

[0905]

[0266] 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 eq) and Raney nickel (72 mg) in methanol (5 mL) was added hydrazine (41 mg, 1.30 mmol, 2 eq) at 0°C. The mixture was stirred under nitrogen atmosphere at 0°C for 30 min. 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.

[0906]

[0266] Step 4. Preparation of methyl 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2-difluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylate (INT-A4-4). A mixture of methyl 5-{5-[2-({2-[(2-amino-5-bromophenyl)amino]ethyl}(2,2-difluoroethyl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylate (300 mg, 0.51 mmol, 1 eq) and BrCN (54 mg, 0.51 mmol, 1 eq) in ethanol (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane / methanol (10 / 1) as eluent 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.

[0907]

[0266] 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 eq) in tetrahydrofuran (4 mL) was added LiOH·H2O (19.6 mg, 0.82 mmol, 2.5 eq) in H2O (1 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was passed through C18FLASH using water and acetonitrile containing 10 mmol / L NH4HCO3 and 0.1% NH3.H2O as mobile phases. The fractions containing the desired compound were evaporated to dryness to give 175 mg of 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl)ethyl](2,2-difluoroethyl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (INT-A4-5) (80%) as a brown solid. LCMS: m / z (ESI), [M+H] + =594.10. 1 H NMR(DMSO-d6,400MHz)δ2.90(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).

[0908] 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}]octaconazol-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (INT-A4-6). 5-[5-(2-{[2-(2-amino-6-bromo-1,3-benzodiazol-1-yl]propane]-1,3-dione]propanediol ... A mixture of [4-(2-(2-(4-(2-(2-(4-(2-piperidin-1-yl)-1-methylpyrazol-4-yl)methyl)-1-methyl-6-oxopyridine-3-carboxylic acid) (160 mg, 0.26 mmol, 1 equiv), N,N,N,N-tetramethyl-O-(7-azabenzotriazole-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 for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water (30 mL) and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane / methanol (10 / 1) as eluent 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}]octacos-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;

[0909] 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). To a mixture 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}]octacos-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (100 mg, 0.17 mmol, 1 eq), BrettPhos Pd G3 (47 mg, 0.05 mmol, 0.3 eq) and [2-(dimethylamino)ethyl](methyl)amine (70 mg, 0.69 mmol, 4 eq) in 1,4-dioxane (3 mL) was added LiHMDS (0.7 mL, 1.02 mmol, 6 eq) dropwise at room temperature under atmospheric pressure. The mixture was stirred at 60 ° C for 2h under a nitrogen atmosphere and then cooled to room temperature. The reaction was quenched with saturated NH4Cl (aqueous solution) solution (5mL), and the mixture was extracted with ethyl acetate (3×200mL). The combined organic layer was washed with salt water (3×300mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC using XBridge Shield RP18 OBD column using water containing 10mmol / L NH4HCO3+0.1%NH3·H2O and acetonitrile as mobile phase. The fractions containing the desired compound were evaporated to dryness to give 1.2 mg of 10-(2,2-difluoroethyl)-16-{[2-(dimethylamino)ethyl](methyl)amino}-5,26-dimethyl-7-oxa-4,5,10,13,20,22,26-heptaazapentacyclo[22.3.1.0^{2,6}.0^{13,21}.0^{14,19}]octacosa-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A4) as a yellow solid (1%). LCMS: m / z (ESI), [M+H] + =598.25. 1H NMR(DMSO-d6,400MHz)δ2.19(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, 376MHz) δ 119.603 (s).

[0910] Example A5

[0911] 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

[0912]

[0913]

[0266] 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 eq), 3-oxetanone (383 mg, 5.33 mmol, 1.2 eq) and molecular sieves (20 mg) in dichloromethane (30 mL) was added sodium triacetoxyborohydride (1.88 g, 8.88 mmol, 2 eq) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere for 12 h. The reaction was quenched with water (80 mL) and the mixture was extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified by Prep-TLC using petroleum ether / ethyl acetate (1 / 1) to give 1.2 g of 2-({2-[(2-nitrophenyl)amino]ethyl}(oxetan-3-yl)amino)ethanol (INT-A5-1) (95%) as a red oil. LCMS: m / z (ESI), [M+H] + =282.10. 1H NMR(DMSO-d6,400MHz)δ2.56-2.65(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),4.4 2-4.48(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).

[0914] Step 2. Preparation of 1-methyl-5-{1-methyl-5-[2-({2-[(2-nitrophenyl)amino]ethyl}(oxetan-3-yl)amino)ethoxy]pyrazol-4-yl}-6-oxopyridine-3-carboxylic acid methyl ester (INT-A5-2). To 5-(5-hydroxy-1-methylpyrazol-4-yl)-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (308 mg, 1. To a stirred mixture of 4-[[(2-nitrophenyl)amino]ethyl]-3-oxetan-3-yl]amino]ethanol (300 mg, 1.07 mmol, 1 eq) and triphenylphosphine (839 mg, 3.20 mmol, 3 eq) in tetrahydrofuran (2 mL) was added diisopropyl azodicarboxylate (647 mg, 3.20 mmol, 3 eq) and 2-({2-[(2-nitrophenyl)amino]ethyl}(oxetan-3-yl)amino)ethanol (300 mg, 1.07 mmol, 1 eq). 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 using petroleum ether / ethyl acetate (1 / 1) as eluent 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-d6,400MHz)δ2.79-2.87(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).

[0915] 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 eq) and Raney nickel (30 mg, 0.35 mmol, 1.2 eq) in methanol (30 mL) was added NH2NH2.HO (90 mg) at 0°C. The mixture was stirred under 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 using dichloromethane / methanol (10 / 1) to give 120 mg of 5-{5-[2-({2-[(2-aminophenyl)amino]ethyl}(oxetan-3-yl)amino)ethoxy]-1-methylpyrazol-4-yl}-1-methyl-6-oxopyridine-3-carboxylic acid methyl ester (INT-A5-3) (73%) as a yellow solid. LCMS: m / z (ESI), [M+H] + =497.30.

[0916]

[0266] 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 eq) and cyanogen bromide (38 mg, 0.36 mmol, 1.5 eq) in ethanol (10 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC using dichloromethane / methanol (5 / 1) as eluent 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-d6,400MHz)δ2.77-2.86(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),4.2 9-4.36(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).

[0917]

[0266] 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 eq) and lithium hydroxide (13 mg, 0.31 mmol, 2 eq) in tetrahydrofuran (10 mL) and water (2.5 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by C18 FLASH using water containing 10 mmol / L NH4HCO3 and 0.1% NH3·H2O and acetonitrile as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 20 mg of 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl](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.

[0918] 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}]octacos-1(28),2(6),3,14,16,18,20,24-octaene-23,27-dione (Example A5). 5-[5-(2-{[2-(2-amino-1,3-benzodiazol-1-yl)ethyl] A mixture of (oxetan-3-yl)amino}ethoxy)-1-methylpyrazol-4-yl]-1-methyl-6-oxopyridine-3-carboxylic acid (20 mg, 0.04 mmol, 1 eq), N,N-diisopropylethylamine (15 mg, 0.12 mmol, 3 eq) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (22 mg, 0.06 mmol, 1.5 eq) in 1,4-dioxane (4 mL) was stirred at room temperature for 3 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC using an XBridge Prep OBD C18 column using water and acetonitrile containing 10 mmol / L NH4HCO3 and 0.1% NH3·H2O as the mobile phase. The fractions containing the desired compound were evaporated to dryness to give 8.8 mg 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}]octacos-1(28),2(6),3,1...

Claims

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

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of furanyl, phenylthio, pyrrolyl, phenyl, pyridyl, pyranyl, pyrimidinyl, pyridazinyl, pyrazinyl and tetrahydroisoquinolinyl.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of: The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring B is an aryl group or a heteroaryl group. The compound or pharmaceutically acceptable salt thereof according to claim 5, wherein Ring B is phenyl, pyridyl or pyrazolyl.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of:

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is the key.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein L 1 It is an alkyl group.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein L 1 Selected from the group consisting of: Where L 1 The * end and L 2 connect.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 2 is the key.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 2 is N(R A ), and R A is selected from alkyl or heterocyclyl, wherein the alkyl or heterocyclyl is optionally substituted by one or more halogen or alkyl.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein R A It is ethyl, difluoroethyl, trifluoroethyl or oxetanyl.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 2 is optionally replaced by one or more R B Substituted cycloalkyl.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein L 2 yes It is optionally replaced by one or more R B replace.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 2 is optionally replaced by one or more R B Substituted heterocyclic group.

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group is selected from the group consisting of: Each of which is optionally replaced by one or more R B Substitution, where L 2 The * end and L 3 connect.

18. The compound according to claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein R B It is an alkyl group.

19. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein R B It's methyl.

20. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 2 Selected from the group consisting of: Where L 2 The * end and L 3 connect.

21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 3 It is an alkyl group.

22. The compound according to claim 21 or a pharmaceutically acceptable salt thereof, wherein L 3 It is ethyl.

23. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 4 is O or NH.

24. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is a key, and L 2 is a bond or optionally one or more R B Substituted heterocyclic group.

25. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is an alkyl group, and L 2 is a key, N(R A ) or optionally one or more R B Substituted cycloalkyl.

26. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is a hydroxyl group, and m is 1.

27. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is halogen, and m is 1.

28. The compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein R 1 It is bromine or fluorine.

29. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Yes-N(R D )2, and m is 1.

30. The compound according to claim 29 or a pharmaceutically acceptable salt thereof, wherein each R D is independently hydrogen or optionally substituted by one or more independently selected from -N(R F )2OR G An alkyl group substituted with a group.

31. The compound according to claim 30 or a pharmaceutically acceptable salt thereof, wherein each R D and N,N-dimethylaminoethyl and N,N-dimethylaminopropyl are independently hydrogen, methyl, methoxyethyl, N,N-dimethylaminoethyl, hydroxyethyl or N,N-dimethylaminopropyl.

32. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more R E substituted heterocyclyl, and m is 1.

33. The compound according to claim 32 or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group is selected from the group consisting of: Each of which is optionally replaced by one or more R E replace.

34. The compound according to claim 32 or a pharmaceutically acceptable salt thereof, wherein R E It's a halogen.

35. The compound according to claim 33 or a pharmaceutically acceptable salt thereof, wherein R E It's F.

36. The compound according to claim 32 or a pharmaceutically acceptable salt thereof, wherein each R E are independently selected from halogen, -N(R F )2, -alkyl-N(R F )2. -C(O)OR G or alkyl optionally substituted by one or more halogens.

37. The compound according to claim 36 or a pharmaceutically acceptable salt thereof, wherein R F and R G Each of is independently an alkyl group.

38. The compound according to claim 36 or a pharmaceutically acceptable salt thereof, wherein R F and R G Each of these is independently C 1-3 alkyl.

39. The compound according to claim 36 or a pharmaceutically acceptable salt thereof, wherein each R E Independently selected from the group consisting of: F, -N(CH3)2, -C 1-3 Alkyl-N(CH3)2, -C(O)O(tert-butyl), methyl, ethyl or trifluoroethyl.

40. The compound according to claim 32 or a pharmaceutically acceptable salt thereof, wherein R E is cycloalkyl or heterocyclyl, wherein the cycloalkyl and the heterocyclyl are optionally substituted with one or more alkyl or halogen.

41. The compound according to claim 40 or a pharmaceutically acceptable salt thereof, wherein R E is selected from cyclopropyl, morpholinyl, piperazinyl, oxetinyl or azetidinyl, each of which is optionally substituted with one or more alkyl or halogen.

42. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 2, R 1 One of them is a halogen and the other R 1 is optionally replaced by one or more R E Substituted heterocyclic group.

43. The compound according to claim 42, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group is selected from the group consisting of: Each of which is optionally replaced by one or more R E replace.

44. The compound according to claim 43 or a pharmaceutically acceptable salt thereof, wherein each R E are independently selected from halogen, -N(R F )2, -alkyl-N(R F )2. -C(O)OR G or alkyl optionally substituted by one or more halogens.

45. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of: OH、F、Br、 46. ​​The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is halogen, and n is 1 or 2.

47. The compound according to claim 46 or a pharmaceutically acceptable salt thereof, wherein R 2 It's F.

48. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more halogens.

49. The compound according to claim 48 or a pharmaceutically acceptable salt thereof, wherein R 2 It is methyl, ethyl, cyclopropyl or trifluoroethyl.

50. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is an alkyl group or a cycloalkyl group.

51. The compound according to claim 50 or a pharmaceutically acceptable salt thereof, wherein R 3 It is methyl, ethyl or cyclopropyl.

52. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2.

53. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

54. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

55. A pharmaceutical composition comprising a compound according to any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

56. A method of inhibiting EGFR activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 55.

57. A method of treating an EGFR-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof or administering to the subject a pharmaceutical composition according to claim 55.

58. The method of claim 57, wherein the EGFR-related disorder is an autoimmune disease or cancer.

59. The method of claim 58, wherein the cancer is selected from the group consisting of lung cancer, brain cancer, colorectal cancer, bladder cancer, urothelial cancer, breast cancer, prostate cancer, ovarian cancer, head and neck cancer, pancreatic cancer, gastric cancer and mesothelioma, including metastases (particularly brain metastases), etc.

60. The method of any one of claims 57 to 59, wherein the compound is administered simultaneously, separately or sequentially with one or more additional therapeutic agents.

61. The method of claim 60, wherein the one or more additional therapeutic agents are selected from the group consisting of: EGFR TKI, EGFR antibodies, MEK inhibitors, c-MET inhibitors, mitotic kinase inhibitors, immunotherapeutics, anti-angiogenic agents, apoptosis inducers, mTOR inhibitors, histone deacetylase inhibitors, IL6 inhibitors, and JAK inhibitors.

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