RU2800153C2 - Heterocyclic compound, intermediate compound, a method of its production and its use - Google Patents

Abstract

FIELD: heterocyclic compounds.

SUBSTANCE: invention relates to heterocyclic compounds of formula I

, where represents ; m is 1, 2, 3 or 4; R³ is H, halogen, C₁-C₆ haloalkyl or C₁-C₆ alkyl; when m is not equal to 1, R³ is independently the same or different; W is a single bond; is phenyl; n is either 1, 2, 3 or 4; R¹ is independently H, halogen, unsubstituted or substituted C₁-C₆ alkyl; where the specified substituted C₁-C₆ alkyl substituted by one to three halogens; and when n is not equal to 1, R¹ is independently the same or different; Q is -NH-C(=O)-R^1-1, -S(=O)₂-N(R^1-9R^1-10), -N(R^1-14R^1-15), -NH-S(=O)₂-R^1-16, unsubstituted or substituted C₃-C₄ cycloalkyl, unsubstituted or substituted C₃-C₆ heterocycloalkyl, or unsubstituted or substituted 5–6-membered heteroaryl; where the specified C₃-C₆ heterocycloalkyl contains 1–3 heteroatoms selected from one or more of O and N; the specified 5–6-membered heteroaryl contains 1–3 heteroatoms selected from N; the said substituted C₃-C₄ cycloalkyl, substituted C₃-C₆ heterocycloalkyl, or substituted 5–6-membered heteroaryl are substituted with one or more substituents independently selected from halo, -OH, and -CN; R² is independently ; where R^2-1 and R^2-2 each independently represents H, unsubstituted C₁-C₆ alkyl; X and Y are each independently methylene, -O-, -N(R^2-3)- or ; R^2-3 and R^2-4 are each independently H or unsubstituted C₁-C₆ alkyl-O-, intermediates and methods of their preparation and use.

EFFECT: obtaining new heterocyclic compounds of formula I which have a high P2X3 antagonistic activity and good selectivity.

26 cl, 8 dwg, 9 tbl, 192 ex

Description

This application claims priority to Chinese Patent Application CN 201811642319.9 filed on December 29, 2018, Chinese Patent Application CN 201910440214.3 filed on May 24, 2019, and Chinese Patent Application CN 201911016158.7 filed on October 24, 2018. 019, which are included in this document by reference in full.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound, an intermediate and a method for its preparation and use.

BACKGROUND OF THE ART

ATP receptors are classified into two main families: P2Y purinoceptors and P2X purinoceptors, according to their molecular structure, transduction mechanism, and pharmacological properties. P2X purinoceptors are a family of ATP-dependent cation channels, and several subtypes have been cloned, including six homomeric receptors (P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7) and three heteromeric receptors (P2X2/3, P2X4/6, and P2X1/ 5). The P2X3 receptor has been found to be expressed particularly in primary afferent nerve fibers of “hollow viscera” such as the lower urinary tract and respiratory tract.

Cough is the main symptom of respiratory diseases and is observed in 70-80% of patients in respiratory outpatient departments. With the increasing prevalence of COPD, HPD, etc. There is also a growing demand for treatment of cough, as it is the main manifestation of most respiratory diseases. Coughing, as a protective nervous reflex of the body, is useful for removing respiratory secretions and harmful factors. However, frequent and severe cough will seriously affect patients' work, life and social activities.

Few P2X3 antagonists have been developed that specifically target cough, and one project that is currently developing rapidly is Roche's AF-219 project, which in a recently completed phase II clinical trial demonstrates relatively good efficacy in refractory cough but produces severe dysgeusia.

There are currently no drugs on the market that can treat various conditions, including chronic cough, by inhibiting P2X3. Therefore, the development of new compounds capable of inhibiting P2X3 activity is of great importance for the treatment of diseases.

SHORT DESCRIPTION

The present invention addresses the technical problem of the lack of P2X3 antagonist in the prior art and thus provides a heterocyclic compound, an intermediate and a method for its preparation and use. The heterocyclic compound described herein has high P2X3 antagonistic activity, good selectivity, low toxicity, good metabolic stability and little effect on taste.

The present invention solves the above problem by the following technical embodiments of the invention.

The present invention provides a heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof,

Where represents

represents

m represents 1, 2, 3 or 4;

R ³ represents H, halogen, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ alkyl; when m is not equal to 1, R ³ is independently the same or different;

W represents a single bond;

is phenyl;

n is 1, 2, 3 or 4;

R ¹ independently represents H, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl; wherein said substituted C ₁ -C ₆ alkyl is substituted with one to three halogens; and when n is not equal to 1, R ¹ is independently the same or different;

Q represents -NH-C(=O)-R ^1-1 , -S(=O) ₂ -N(R ^1-9 R ^1-10 ), -N(R ^1-14 R ^1-15 ), -NH-S(=O) ₂ -R ^1-16 , unsubstituted or substituted C ₃ -C ₄ cycloalkyl, unsubstituted or substituted C ₃ -C ₆ heterocycloalkyl, or unsubstituted or substituted 5-6-membered heteroaryl; wherein said C ₃ -C ₆ heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O and N; said 5-6 membered heteroaryl contains 1-3 heteroatoms selected from N; said substituted C ₃ -C ₄ cycloalkyl, substituted C ₃ -C ₆ heterocycloalkyl, or substituted 5-6 membered heteroaryl is substituted with one or more substituents independently selected from the following: halogen, -OH and -CN;

where R ^1-1 , R ^1-9 , R ^1-10 , R ^1-14 , R ^1-15 , and R ^1-16 are each independently H, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted C ₂ -C ₃ alkenyl, unsubstituted or substituted C ₃ -C ₆ cycloalkyl, unsubstituted or substituted C ₄ -C ₆ heterocycloalkyl, or unsubstituted or substituted phenyl; where said C ₃ -C ₉ heterocycloalkyl contains 1 heteroatom selected from O; and said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₆ heterocycloalkyl, phenyl are substituted with one or two substituents independently selected from the following: halogen, -COOH, -COOCH ₃ , -NH ₂ and =O ;

R ² independently represents

where R ^2-1 and R ^2-2 each independently represent H, unsubstituted C ₁ -C ₆ alkyl;

X and Y are each independently methylene, -O-, -N(R ^2-3 )- or

R ^2-3 and R ^2-4 each independently represent H or unsubstituted C ₁ -C ₆ alkyl-O-.

In the present invention, certain substituents on the heterocyclic compound of Formula I may be defined below, and substituents that are not mentioned have the definitions described in any of the above embodiments.

In a preferred embodiment of the present invention is a 5-membered heteroaryl or 5-membered heterocycloalkenyl; wherein the 5-membered heteroaryl contains 1-2 heteroatoms selected from one or more of N, O and S, and the 5-membered heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of N, O and S;

is phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl; wherein the 5-6 membered heterocycloalkyl contains 1-3 heteroatoms selected from one or more of N, O and S, the 5-6 membered heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of N, O and S, and A 5-6 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O and S;

Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , Z ⁷ , Z ⁸ and Z ⁹ independently represent a ring atom; and when is 5-membered heterocycloalkyl, 5-membered heterocycloalkenyl or 5-membered heteroaryl, Z ⁶ or Z ⁹ represents a single bond;

m represents 1, 2, 3 or 4;

R ³ represents H, halogen, -OH, C ₁ -C ₆ haloalkyl, -CN or C ₁ -C ₆ alkyl; when m is not equal to 1, R ³ is independently the same or different; or when two adjacent R ³ are present, they, together with the ring atom with which they directly bond, form C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, C ₃ -C ₉ heterocycloalkyl, C ₃ -C ₉ heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; where C ₃ -C ₉ heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S and N, C ₃ -C ₉ heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S and N, and A 5-6 membered heteroaryl contains 1-3 heteroatoms selected from one or more of O, S and N;

W represents a single bond or -C(=O)-NH-;

represents phenyl, 5-6-membered heteroaryl or C ₃ -C ₉ heterocycloalkyl; where the 5-6 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O and S, and the C ₃ -C ₉ heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O, S and N;

n is 1, 2, 3 or 4;

R ¹ independently represents H, halogen, -OH, -CN, unsubstituted or substituted C ₁ -C ₆ alkyl, or unsubstituted or substituted C ₁ -C ₆ alkyl-O-; wherein the substituted C ₁ -C ₆ alkyl or substituted C ₁ -C ₆ alkyl-O- is substituted with one or more substituents independently selected from the following: halogen, -OH, -CF ₃ , -CN, -COOH, -C(=O )NH ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or =O (i.e. two geminal hydrogens on the carbon atom are replaced by an O group); when multiple substituents are present, they are the same or different; and when n is not 1, R ¹ is independently the same or different;

Q represents H, halogen, -OH, -CF ₃ , -CN, -NH-C(=O)-R ^1-1 , -C (=O)-R ^1-2 , -O-C (=O )-N(R ^1-3 R ^1-4 ), -C(=O)-N(R ^1-5 R ^1-6 ), -C(=NH)-N(R ^1-7 R ^1-8 ), -S(=O) ₂ -N(R ^1-9 R ^1-10 ), -S(=O)-N(R ^1-11 R ^1-12 ), -OC(=O)-R ^{1 -13} , -N(R ^1-14 R ^1-15 ), -NH-S(=O) ₂ -R ^1-16 , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl -O-, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkenyl-O-, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkenyl, unsubstituted or substituted C ₆ -C ₁₀ aryl or unsubstituted or substituted 5-10 membered heteroaryl; where C ₃ -C ₉ heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S and N, C ₃ -C ₉ heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S and N, 5 -10-membered heteroaryl contains 1-3 heteroatoms selected from one or more of O, S and N; and substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl-O-, substituted C ₃ -C ₁₀ cycloalkyl, substituted C ₆ -C ₁₀ aryl, substituted C ₃ -C ₉ heterocycloalkyl, substituted C ₃ -C ₉ heterocycloalkenyl or substituted 5-10 membered heteroaryl is substituted with one or more substituents independently selected from the following: halogen, -OH, -CF ₃ , -CN , -COOH, -C(=O)NH ₂ , =O (i.e. two geminal hydrogens on the carbon atom are replaced by an O group), -N(R ^1-21 R ^1-22 ), -C(=O) -N(R ^1-23 R ^1-24 ), -S(=O) ₂ -N(R ^1-25 R ^1-26 ), -C(=O)-OR ^1-27 and C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or C ₃ -C ₆ cycloalkyl, which is unsubstituted or substituted by one or more R ^a ; where, if there are multiple R ^{a ,} they are the same or different and each R ^a is halogen, -OH, =O, -CF ₃ , -CN, -COOH or -C(=O)NH ₂ ; and when multiple substituents are present, they are the same or different;

R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R ^1-15 , R ^1-16 , R ^1-21 , R ^1-22 , R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 are each independently H, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl-O-, unsubstituted or substituted C ₂ - C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkenyl-O-, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkenyl, unsubstituted or substituted phenyl or unsubstituted or substituted 5-10 membered heteroaryl; where C ₃ -C ₉ heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S and N, C ₃ -C ₉ heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S and N, 5 -10-membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O and S, and substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl , substituted C ₂ -C ₆ alkenyl-O-, substituted C ₂ -C ₆ alkynyl, substituted C ₃ -C ₁₀ cycloalkyl, substituted C ₃ -C ₉ heterocycloalkyl, substituted C ₃ -C ₉ heterocycloalkenyl, substituted phenyl or substituted 5- A 10-membered heteroaryl is substituted with one or more substituents independently selected from the following: halogen, -OH, -CF ₃ , -CN, -COOH, -COOCH ₃ , -NH ₂ , =O (i.e. two geminal hydrogens on the carbon is substituted by an O group), and C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or C ₃ -C ₆ cycloalkyl, which is unsubstituted or substituted by one or more R ^d , where, when multiple R ^d are present, they are the same or different and R ^d is independently H, halogen, -OH, =O, -CF ₃ , -CN, -COOH or -C(=O)NH ₂ and when multiple substituents are present, they are the same or various; or

R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 , R ^1-11 and R ^1-12 , R ^1-14 and R ^1-15 , R ^1-21 and R ^1-22 , R ^1-23 and R ^1-24 , or R ^1-25 and R ^1-26 , independently together with the N atom with which they directly linked, form unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkenyl or unsubstituted or substituted 5-10-membered heteroaryl; where the C ₃ -C ₉ heterocycloalkyl does not contain a heteroatom or contains 1-2 heteroatoms selected from one or more of O, S and N, in addition to the existing N atom, the C ₃ -C ₉ heterocycloalkenyl does not contain a heteroatom or contains 1-2 heteroatom selected from one or more of O, S and N, in addition to the existing N atom, the 5-10 membered heteroaryl contains no heteroatom or contains 1-2 heteroatoms selected from one or more of O, S and N, in addition to an existing N atom, and the substituted C ₃ -C ₉ heterocycloalkyl, substituted C ₃ -C ₉ heterocycloalkenyl, or substituted 5-10 membered heteroaryl is substituted with one or more substituents independently selected from the following: halogen, -OH, -CF ₃ . -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O-, =O (i.e. two geminal hydrogens on the carbon atom are replaced by an O group), and C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or C ₃ -C ₆ cycloalkyl, which is unsubstituted or substituted by one or more ^Rb , where, when multiple ^Rb are present, they are the same or different, and each ^Rb is a halogen, -OH, = O, -CF ₃ , -CN, -COOH or -C(=O)NH ₂ ; and when multiple substituents are present, they are the same or different;

R ² represents itself or -C(=O)N(R ^2-5 R ^2-6 );

R ^2-1 and R ^2-2 are each independently H, halogen, -OH, -CN, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl-O- or =O (t .e. two geminal hydrogens on the carbon atom are replaced by an O group); wherein the substituted C ₁ -C ₆ alkyl or substituted C ₁ -C ₆ alkyl-O- is substituted with one or more substituents independently selected from the following: halogen, -OH, -CF ₃ , -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or =O (ie, the two geminal hydrogens on the carbon atom are replaced by an O group), and if multiple substituents are present, they are the same or different;

X and Y each independently represent a single bond, methylene, -O-, -N(R ^2-3 )- or

R ^2-3 , R ^2-4 , R ^2-5 and R ^2-6 are each independently H, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl-O-, or unsubstituted or substituted C ₁ -C ₆ alkyl-O-; wherein the substituted C ₁ -C ₆ alkyl, substituted C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl-O- or substituted C ₁ -C ₆ alkyl-O- is substituted with one or more substituents independently selected from the following: halogen , -OH, -CF ₃ , -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or =O (i.e. two geminal hydrogens on the carbon atom are replaced by an O group), and in the presence of multiple substituents they are the same or different.

In a heterocyclic compound of formula I or a stereoisomer, geometric isomer, tautomer, nitric oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug disclosed herein, certain substituents may be defined below, and substituents that not mentioned have the definitions described in any of the embodiments of the invention.

In a preferred embodiment of the present invention, Z ⁶ represents a single bond and Z ⁹ represents NH, O or S; or Z ⁹ is a single bond and Z ⁶ is NH, O or S.

In a preferred embodiment of the present invention, when is a 5-membered heteroaryl, the 5-membered heteroaryl is pyrrolyl (e.g. ), furanyl (for example, ), pyrazolyl (e.g. ), thienyl (for example, ) or imidazolyl (e.g. ). (In the structural formula, the right bond is associated with W)

According to a preferred embodiment of the present invention, when is a 5-membered heterocycloalkenyl, the 5-membered heterocycloalkenyl contains 1-2 heteroatoms selected from one or more of N, O and S, and is preferably 2,3-dihydro-1H-pyrazolyl (e.g. ). (In the structural formula, the right bond is connected to W)

In a preferred embodiment of the present invention, when is a 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl is a 6-membered heterocycloalkyl; where the 6-membered heterocycloalkyl contains 1-3 N heteroatoms; and the 5-6 membered heterocycloalkyl is preferably piperazinyl (e.g. ) or piperidinyl (eg. ). (In the structural formula, a right-handed carbon-nitrogen bond represents the position condensed with )

In a preferred embodiment of the present invention, when is a 5-6 membered heterocycloalkenyl, 5-6 membered heterocycloalkenyl is a 6-membered heterocycloalkenyl; where the 6-membered heterocycloalkenyl contains 1-3 N heteroatoms; and the 5-6 membered heterocycloalkenyl is preferably 1,2-dihydropyridinyl (e.g. ) or 1,6-dihydropyrimidinyl (e.g. ). (In the structural formula, a right-handed carbon-nitrogen bond represents the position condensed with )

In a preferred embodiment of the present invention, when is a 5-6 membered heteroaryl, the 5-6 membered heteroaryl is a 6-membered heteroaryl; where the 6-membered heteroaryl contains 1-3 N heteroatoms (for example, pyridinyl or pyrimidinyl); and the 5-6 membered heteroaryl is preferably pyridinyl (e.g. ). (In the structural formula, a right-handed carbon-carbon double bond represents the position condensed with )

In a preferred embodiment of the present invention represents

In a preferred embodiment of the present invention represents

According to a preferred embodiment of the present invention, m is 1 or 2;

In a preferred embodiment of the present invention, Z ⁷ is substituted with R ³ , Z ⁸ is unsubstituted or substituted with R ³ , Z ⁶ and Z ⁹ are unsubstituted; when multiple R ³ are present, they are the same or different; and preferably Z ⁷ is substituted with R ³ and Z ⁶ , Z ⁸ and Z ⁹ are unsubstituted.

In a preferred embodiment of the present invention, when R ³ is halogen, the halogen is fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the present invention, when R ³ is C ₁ -C ₆ alkyl (for example, methyl, ethyl, propyl, butyl, pentyl or hexyl), C ₁ -C ₆ alkyl is C ₁ -C ₄ alkyl (for example , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) and preferably methyl.

In a preferred embodiment of the present invention, when R ³ is a C ₁ -C ₆ haloalkyl, the halogen is fluorine, chlorine, bromine or iodo, and preferably chlorine.

In a preferred embodiment of the present invention, when R ³ is a C ₁ -C ₆ haloalkyl, it contains one or more (eg 1, 2, 3, 4 or 5) halogens and preferably 1, 2 or 3 halogens.

In a preferred embodiment of the present invention, R ³ is -CF ₃ , -CH ₂ F or -CHF ₂ .

In a preferred embodiment of the present invention, when two adjacent R ³ are present and they, together with the ring atom to which they directly bond, form a C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl .

In a preferred embodiment of the present invention, when two adjacent R ³ are present and they, together with the ring atom to which they directly bond, form a C ₃ -C ₆ cycloalkenyl, the C ₃ -C ₆ cycloalkenyl is cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cyclohexadienyl.

In a preferred embodiment of the present invention, when two adjacent R ³ are present and they, together with the ring atom to which they directly bond, form a C ₃ -C ₉ heterocycloalkyl, the C ₃ -C ₉ heterocycloalkyl is a C ₄ -C ₅ heterocycloalkyl; where C ₄ -C ₅ heterocycloalkyl contains 1-2 heteroatoms selected from one or more of N, O and S.

In a preferred embodiment of the present invention, when two adjacent R ³ are present and they, together with the ring atom to which they directly bond, form a C ₃ -C ₉ heterocycloalkenyl, the C ₃ -C ₉ heterocycloalkenyl is a C ₄ -C ₅ heterocycloalkenyl; where C ₄ -C ₅ heterocycloalkenyl contains 1-2 heteroatoms selected from one or more of N, O and S.

In a preferred embodiment of the present invention, when two adjacent R ³ are present and they, together with the ring atom to which they directly bond, form a 5-6 membered heteroaryl, the 5-6 membered heteroaryl contains 1-2 heteroatoms selected from one or more of N, O and S.

In a preferred embodiment of the present invention, represents (as described above, R ³ is the same or different).

In a preferred embodiment of the present invention represents (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ) or (For example, ). (In the structural formula, a right-handed carbon-nitrogen bond condensed with ).

In a preferred embodiment of the present invention represents (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ) or (For example, ). (In the structural formula, a right-handed carbon-nitrogen bond or condensed with )

In a preferred embodiment of the present invention represents (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ) or (For example, ). (In the structural formula, the right-handed carbon-nitrogen bond or carbon-carbon double bond condensed with )

In a preferred embodiment of the present invention represents (For example, ), (For example, ), (For example, ), (For example, ), or (For example, ). (In the structural formula, a right-handed carbon-nitrogen bond condensed with )

In a preferred embodiment of the present invention represents (For example, ) or (For example, ). (In the structural formula, the right-handed carbon-nitrogen bond or carbon-carbon double bond condensed with )

In a preferred embodiment of the present invention represents

In a preferred embodiment of the present invention represents

In a preferred embodiment of the present invention represents

In a preferred embodiment of the present invention represents

In a preferred embodiment of the present invention represents

In a preferred embodiment of the present invention represents

In a preferred embodiment of the present invention, n is 1 or 2.

In a preferred embodiment of the present invention, each R ¹ is independently located at the α position (ortho Z ² position) or β position (meta Z ² position) of the bond between and Z ² .

In a preferred embodiment of the present invention, at least one R ¹ is located at the α position of the bond between and Z ² ; and preferably, when n is 2, each R ¹ is independently located at the α position of the bond between and Z ² .

In a preferred embodiment of the present invention, when R ¹ is halogen, the halogen is fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the present invention, when R ¹ is unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl (for example, methyl, ethyl, propyl, butyl, pentyl or hexyl) is independently C ₁ -C ₄ alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) and is preferably methyl.

In a preferred embodiment of the present invention, when R ¹ is a substituted C ₁ -C ₆ alkyl or a substituted C ₁ -C ₆ alkyl-O-, and each substituent is independently a halogen, the halogen is fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the present invention, when R ¹ is a substituted C ₁ -C ₆ alkyl or a substituted C ₁ -C ₆ alkyl-O-, the substituent is independently a C ₁ -C ₆ alkyl or a C ₁ -C ₆ alkyl-O -, and C ₁ -C ₆ alkyl (for example, methyl, ethyl, propyl, butyl, pentyl or hexyl) in the substituent is independently C ₁ -C ₄ alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl or tert-butyl) and preferably methyl.

In a preferred embodiment of the present invention, when R ¹ is a substituted C ₁ -C ₆ alkyl or a substituted C ₁ -C ₆ alkyl-O-, the number of substituents is independently 1, 2 or 3.

In a preferred embodiment of the present invention, when R ¹ is a substituted C ₁ -C ₆ alkyl or a substituted C ₁ -C ₆ alkyl-O- and each of the substituents independently represents a halogen, a substituted C ₁ -C ₆ alkyl in a substituted C ₁ -C ₆ alkyl or substituted C ₁ -C ₆ alkyl-O- is independently -CF ₃ .

In a preferred embodiment of the present invention, Q is located at the β or γ position of the bond between and W.

In a preferred embodiment of the present invention, when is a 5-6 membered heteroaryl, the 5-6 membered heteroaryl is a 5-membered heteroaryl, wherein the 5-membered heteroaryl contains 1-2 heteroatoms selected from one or more of N, O and S, and is preferably imidazolyl (For example, (For example, )), thienyl (for example, (For example, or )), furanyl (for example, (For example, )) or pyrrolyl (e.g. (For example, )). (In the structural formula, the left bond is connected to W, and the right bond is connected to Q)

In a preferred embodiment of the present invention, when is a 5-6 membered heteroaryl, 5-6 membered heteroaryl is a 6 membered heteroaryl; wherein the 6-membered heteroaryl contains 1-2 heteroatoms selected from one or more of N, O and S, and is preferably pyridinyl (e.g. (For example, )) or pyrazinil (e.g. (For example, )). (In the structural formula, the left bond is associated with W, and the right bond is associated with Q)

In a preferred embodiment of the present invention, when represents C ₃ -C ₉ heterocycloalkyl, C ₃ -C ₉ heterocycloalkyl represents C ₃ -C ₅ heterocycloalkyl, where C ₃ -C ₅ heterocycloalkyl contains 1-3 heteroatoms selected from one or more N, O and S; C ₃ -C ₉ heterocycloalkyl is preferably C ₄ -C ₅ heterocycloalkyl, wherein the C ₄ -C ₅ heterocycloalkyl contains 1-2 heteroatoms selected from one or more of N, O and S; and C ₃ -C ₉ heterocycloalkyl is preferably piperidinyl (for example , (For example, )). (In the structural formula, the left bond is connected to W, and the right bond is connected to Q)

In a preferred embodiment of the present invention, R ¹ is located at the β position of the bond between and Z ² . Preferably, when m is 2, each R ¹ is independently located at the β position of the bond between and Z ² .

In a preferred embodiment of the present invention, when is phenyl, represents or and preferably where R ^1' has the definition as described for R ¹ , and R ^1' is the same or different from R ¹ . (In the structural formula, the left bond is associated with W, and the right bond is associated with Q)

In a preferred embodiment of the present invention, when is phenyl, represents and preferably where R ^1' has the definition as described for R ¹ , and R ^1' is the same or different from R ¹ . (In the structural formula, the left bond is associated with W and the right bond is associated with Q)

In a preferred embodiment of the present invention, when is phenyl, represents (For example, (For example, ). (In the structural formula, the left bond is associated with W and the right bond is associated with Q)

In a preferred embodiment of the present invention, when is phenyl, represents (For example, ), (For example, ), (For example, ), (For example, ) or (For example, ). (In the structural formula, the left bond is connected to Z ² , and the right bond is connected to Q)

In a preferred embodiment of the present invention, when is phenyl, represents preferably and more preferably where R ^1' has the definition as described for R ¹ , and R ^1' is the same or different from R ¹ . (In the structural formula, the left bond is associated with Z ² , and the right bond is associated with Q)

In a preferred embodiment of the present invention represents preferably and more preferably where R ^1' has the definition as described for R ¹ , and R ^1' is the same or different from R ¹ . (In the structural formula, the left bond is associated with Z ² , and the right bond is associated with Q)

In a preferred embodiment of the present invention, represents

In a preferred embodiment of the present invention represents

In a preferred embodiment of the present invention, when is a 5-6 membered heteroaryl, represents (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ) or (For example, ). (In the structural formula, the left bond is connected to W, and the right bond is connected to Q)

In a preferred embodiment of the present invention, when is a 5-6 membered heteroaryl, represents (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ) or (For example, ). (In the structural formula, the left bond is associated with W and the right bond is associated with Q)

In a preferred embodiment of the present invention, when is a 5-6 membered heteroaryl, represents (For example, ) (For example, ), (For example, ), (For example, ) or (For example, ). (In the structural formula, the left bond is associated with W, and the right bond is associated with Q)

In a preferred embodiment of the present invention, when is a 5-6 membered heteroaryl, represents (For example, ) or (For example, ). (In the structural formula, the left bond is associated with W, and the right bond is associated with Q)

In a preferred embodiment of the present invention represents

In a preferred embodiment of the present invention represents

In a preferred embodiment of the present invention, when represents C ₃ -C ₅ heterocycloalkyl, represents (For example, ). (In the structural formula, the left bond is associated with W, and the right bond is associated with Q)

In a preferred embodiment of the present invention, when Q is halogen, the halogen is fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the present invention, when Q is unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl (e.g., methyl, ethyl, propyl, butyl , pentyl or hexyl) is independently C ₁ -C ₄ alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

In a preferred embodiment of the present invention, when Q is unsubstituted or substituted C ₂ -C ₆ alkenyl or unsubstituted or substituted C ₂ -C ₆ alkenyl-O-, C ₂ -C ₆ alkenyl is C ₂ -C ₄ alkenyl (eg , ethenyl, propenyl (eg 1-propenyl or 2-propenyl) or butenyl (eg 2-butenyl, 1-butenyl or butadienyl)).

In a preferred embodiment of the present invention, when Q is unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

In a preferred embodiment of the present invention, when Q is unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, C ₃ -C ₉ heterocycloalkyl is C ₃ -C ₅ heterocycloalkyl, wherein C ₃ -C ₅ heterocycloalkyl contains 1-3 heteroatoms selected one or more of O, S and N; C ₃ -C ₉ heterocycloalkyl is preferably C ₄ -C ₅ heterocycloalkyl, wherein the C ₄ -C ₅ heterocycloalkyl contains 1-2 heteroatoms selected from one or more of N, O and S; and C ₃ -C ₉ heterocycloalkyl is preferably glycidyl (for example, ), pyrrolidinyl (for example, ) or piperazinil (eg. ).

In a preferred embodiment of the present invention, when Q is unsubstituted or substituted C ₃ -C ₉ heterocycloalkenyl, the C ₃ -C ₉ heterocycloalkenyl is C ₃ -C ₅ heterocycloalkenyl, wherein the C ₃ -C ₅ heterocycloalkenyl contains 1-3 heteroatoms selected one or more of O, S and N; C ₃ -C ₉ heterocycloalkenyl is preferably C ₄ -C ₅ heterocycloalkenyl, wherein C ₄ -C ₅ heterocycloalkenyl contains 1-2 heteroatoms selected from one or more of N, O and S; and C ₃ -C ₉ heterocycloalkenyl is preferably preferably (For example, ), (For example, ), (For example, ) or (For example, ).

In a preferred embodiment of the present invention, when Q is unsubstituted or substituted C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl is phenyl.

In a preferred embodiment of the present invention, when Q is an unsubstituted or substituted 5-10 membered heteroaryl, the 5-10 membered heteroaryl is a 5-6 membered heteroaryl and preferably imidazolyl (e.g. ), oxazolyl (e.g. ), furanyl (for example, ), thienyl (for example, ), pyrrolyl (for example, ), pyrazolyl (e.g. ), isoxazolyl (for example, ), pyridinyl (for example, ), pyrimidinyl (for example, ), triazolyl (e.g. (For example, (For example (For example, )) or (For example, ).

In a preferred embodiment of the present invention, when Q is an unsubstituted or substituted 5-10 membered heteroaryl, the 5-10 membered heteroaryl is a 5-6 membered heteroaryl and preferably imidazolyl (e.g. ), oxazolyl (e.g. ), furanyl (for example, ), thienyl (for example, ), pyrrolyl (for example, ), pyrazolyl (e.g. ), isoxazolyl (for example, ), pyridinyl (for example, ), pyrimidinyl (for example, ), or triazolyl (for example, (For example, (For example, (For example,

In a preferred embodiment of the present invention, when Q is an unsubstituted or substituted 5-10 membered heteroaryl, the 5-10 membered heteroaryl is a 5-6 membered heteroaryl and preferably triazolyl (e.g. (For example, ), (For example, ), (For example, )) or

In a preferred embodiment of the present invention, when Q is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl-O-, substituted C ₃ -C ₁₀ cycloalkyl, substituted C ₆ -C ₁₀ aryl, substituted C ₃ -C ₉ heterocycloalkyl, substituted C ₃ -C ₉ heterocycloalkenyl or substituted 5-10-membered heteroaryl, the number of substituents is independently 1, 2, 3 or 4 .

In a preferred embodiment of the present invention, when Q is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl-O-, substituted C ₃ -C ₁₀ cycloalkyl, substituted C ₆ -C ₁₀ aryl, substituted C ₃ -C ₉ heterocycloalkyl, substituted C ₃ -C ₉ heterocycloalkenyl or substituted 5-10 membered heteroaryl, and the substituent is halogen, the halogen is independently fluorine , chlorine, bromine or iodine and preferably fluorine.

In a preferred embodiment of the present invention, C ₁ -C ₆ alkyl (for example, methyl, ethyl, propyl, butyl, pentyl or hexyl) in C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl-O-, which is unsubstituted or substituted one or more Ra is independently C ₁ -C ₄ alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), and preferably methyl or isopropyl.

In a preferred embodiment of the present invention, the C ₃ -C ₆ cycloalkyl in the C ₃ -C ₆ cycloalkyl that is unsubstituted or substituted by one or more ^Ra is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a preferred embodiment of the present invention, when R ^a is halogen, the halogen is independently fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the present invention, when each R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R 1-15, R ^1-16 , R ^1-21 , ^{R 1-22 ,} R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 is unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl or hexyl) is independently C ₁ -C ₄ alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) or tert-pentyl (1,1-dimethylpropyl).

In a preferred embodiment of the present invention, when each R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R 1-15, R ^1-16 , R ^1-21 , ^{R 1-22 ,} R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 is unsubstituted or substituted C ₂ -C ₆ alkenyl or unsubstituted or substituted C ₂ -C ₆ alkenyl-O-, C ₂ -C ₆ alkenyl is independently C ₂ -C ₄ alkenyl (eg ethenyl, propenyl (eg 1-propenyl or 2-propenyl) or butenyl (eg 2-butenyl 1-butenyl or butadienyl)) and preferably ethenyl.

In a preferred embodiment of the present invention, when each R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R ^{1-15, R 1-16} , R ^1-21 , ^{R 1-22 ,} R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 is unsubstituted or substituted C ₂ -C ₆ alkynyl, C ₂ -C ₆ alkynyl is C ₂ -C ₄ alkynyl ( for example ethynyl, propynyl (eg 1-propynyl or 2-propynyl) or butynyl (eg 2-butynyl, 1-butynyl or butadinyl)) and preferably ethynyl.

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R ^1-15 , R ^1-16 , R ^1-21 , R ^1-22 , R ^{1 -23} , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 are each unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl is C ₃ -C ₆ cycloalkyl and preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R ^1-15 , R ^1-16 , R ^1-21 , R ^1-22 , R ^{1 -23} , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 are each unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, C ₃ -C ₉ heterocycloalkyl is C ₃ -C ₅ heterocycloalkyl, where C ₃ -C ₅ heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O, S and N; C ₃ -C ₉ heterocycloalkyl is preferably C ₄ -C ₅ heterocycloalkyl, wherein the C ₄ -C ₅ heterocycloalkyl contains 1-2 heteroatoms selected from one or more of N, O and S; and C ₃ -C ₉ heterocycloalkyl is preferably glycidyl (for example, ), tetrahydrofuranyl (e.g. ) tetrahydropyranyl (e.g. ) or tetrahydrothienyl (for example, ).

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R ^1-15 , R ^1-16 , R ^1-21 , R ^1-22 , R ^{1 -23} , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 are each unsubstituted or substituted C ₃ -C ₉ heterocycloalkenyl, C ₃ -C ₉ heterocycloalkenyl is C ₃ -C ₅ heterocycloalkenyl, where C ₃ -C ₅ heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S and N; and C ₃ -C ₉ heterocycloalkenyl is preferably C ₄ -C ₅ heterocycloalkenyl, wherein C ₄ -C ₅ heterocycloalkenyl contains 1-2 heteroatoms selected from one or more of N, O and S.

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R ^1-15 , R ^1-16 , R ^1-21 , R ^1-22 , R ^{1 -23} , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 are each unsubstituted or substituted 5-10 membered heteroaryl, 5-10 membered heteroaryl is 5-6 membered heteroaryl, where the 5-6 membered heteroaryl contains 1-2 heteroatoms selected from one or two of N, O and S; and the 5-10 membered heteroaryl is preferably furanyl (e.g. ) or pyridinyl (

In a preferred embodiment of the present invention, when each R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R ^{1-15, R 1-16} , R ^1-21 , ^{R 1-22 ,} R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl-O-, substituted C ₂ -C ₆ alkynyl, substituted C ₃ -C ₁₀ cycloalkyl, substituted phenyl, substituted C ₃ -C ₉ heterocycloalkyl, substituted C ₃ -C ₉ heterocycloalkenyl or substituted 5 -10-membered heteroaryl, and the substituent is halogen, the halogen independently being fluorine, chlorine, bromine or iodine, and preferably fluorine.

In a preferred embodiment of the present invention, when R ^d is independently halogen, the halogen is independently fluorine, chlorine, bromine or iodine, and preferably fluorine.

In a preferred embodiment of the present invention, the amount of ^Rd is independently 1, 2, 3 or 4 and preferably 1 or 2.

In a preferred embodiment of the present invention, C ₁ -C ₆ alkyl (for example, methyl, ethyl, propyl, butyl, pentyl or hexyl) in C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl-O-, which is unsubstituted or substituted one or more R ^d is independently C ₁ -C ₄ alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

In a preferred embodiment of the present invention, the C ₃ -C ₆ cycloalkyl in the C ₃ -C ₆ cycloalkyl that is unsubstituted or substituted by one or more R ^d is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a preferred embodiment of the present invention, when each R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R ^{1-15, R 1-16} , R ^1-21 , ^{R 1-22 ,} R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl-O-, substituted C ₂ -C ₆ alkynyl, substituted C ₃ -C ₁₀ cycloalkyl, substituted phenyl, substituted C ₃ -C ₉ heterocycloalkyl, substituted C ₃ -C ₉ heterocycloalkenyl or substituted 5 -10-membered heteroaryl, the number of substituents is independently 1, 2, 3 or 4 and preferably 1 or 2.

In a preferred embodiment of the present invention, when R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 , R ^{1 -11} and R ^1-12 , R ^1-14 and R ^1-15 , R ^1-21 and R ^1-22 , R ^1-23 and R ^1-24 , or R ^1-25 and R ^1-26 , each independently together with the N atom with which they directly bond form an unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, the C ₃ -C ₉ heterocycloalkyl does not contain additional heteroatoms or contains one heteroatom selected from O, S and N, in addition to the existing N atom, and is preferably C ₃ -C ₅ heterocycloalkyl.

In a preferred embodiment of the present invention, when R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 , R ^{1 -11} and R ^1-12 , R ^1-14 and R ^1-15 , R ^1-21 and R ^1-22 , R ^1-23 and R ^1-24 , or R ^1-25 and R ^1-26 , each independently together with the N atom to which they are directly bonded form an unsubstituted or substituted C ₃ -C ₉ heterocycloalkenyl, the C ₃ -C ₉ heterocycloalkenyl does not contain additional heteroatoms or contains one heteroatom selected from O, S and N, in addition to the existing N atom, and is preferably C ₃ -C ₅ heterocycloalkenyl.

In a preferred embodiment of the present invention, when R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 , R ^{1 -11} and R ^1-12 , R ^1-14 and R ^1-15 , R ^1-21 and R ^1-22 , R ^1-23 and R ^1-24 , or R ^1-25 and R ^1-26 , each independently together with the N atom to which they directly bond form an unsubstituted or substituted 5-10 membered heteroaryl, the 5-10 membered heteroaryl contains no additional heteroatoms or contains one heteroatom selected from O, S and N, in addition to the existing N atom, and is preferably a 5-6 membered heteroaryl.

In a preferred embodiment of the present invention, when R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 , R ^{1 -11} and R ^1-12 , R ^1-14 and R ^1-15 , R ^1-21 and R ^1-22 , R ^1-23 and R ^1-24 , or R ^1-25 and R ^1-26 , each independently together with the N atom to which they are directly bonded form a substituted C ₃ -C ₉ heterocycloalkyl, a substituted C ₃ -C ₉ heterocycloalkenyl or a substituted 5-10 membered heteroaryl, and the substituent is halogen, the halogen is independently fluorine, chlorine , bromine or iodine.

In a preferred embodiment of the present invention, C ₁ -C ₆ alkyl (for example, methyl, ethyl, propyl, butyl, pentyl or hexyl) in C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl-O-, which is unsubstituted or substituted one or more Rb is independently C ₁ -C ₄ alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

In a preferred embodiment of the present invention, the C ₃ -C ₆ cycloalkyl in the C ₃ -C ₆ cycloalkyl that is unsubstituted or substituted by one or more R ^b is independently cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In a preferred embodiment of the present invention, when R ^b is halogen, the halogen is independently fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the present invention, when R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 , R ^{1 -11} and R ^1-12 , R ^1-14 and R ^1-15 , R ^1-21 and R ^1-22 , R ^1-23 and R ^1-24 , or R ^1-25 and R ^1-26 , each independently, together with the N atom to which they are directly bonded, they form a substituted C ₃ -C ₉ heterocycloalkyl, a substituted C ₃ -C ₉ heterocycloalkenyl or a substituted 5-10 membered heteroaryl, the number of substituents being independently 1, 2, 3 or 4 and preferably 1 or 2.

In a preferred embodiment of the present invention, when each R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R ^{1-15, R 1-16} , R ^1-21 , ^{R 1-22 ,} R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl is

In a preferred embodiment of the present invention, when each R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R ^{1-15, R 1-16} , R ^1-21 , ^{R 1-22 ,} R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl is

In a preferred embodiment of the present invention, when each R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R 1-15, R ^1-16 , R ^1-21 , ^{R 1-22 ,} R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 is substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl is

In a preferred embodiment of the present invention, when each R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R ^{1-15, R 1-16} , R ^1-21 , ^{R 1-22 ,} R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 is substituted C ₂ -C ₆ alkynyl, substituted C ₂ -C ₆ alkynyl is

In a preferred embodiment of the present invention, when each R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R ^{1-15, R 1-16} , R ^1-21 , ^{R 1-22 ,} R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 is substituted C ₃ -C ₁₀ cycloalkyl, substituted C ₃ -C ₁₀ cycloalkyl is (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ) or (For example, ).

In a preferred embodiment of the present invention, when each R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R ^{1-15, R 1-16} , R ^1-21 , ^{R 1-22 ,} R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 is substituted C ₃ -C ₉ heterocycloalkyl, substituted C ₃ -C ₉ heterocycloalkyl is (For example, ).

In a preferred embodiment of the present invention, when each R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R ^{1-15, R 1-16} , R ^1-21 , ^{R 1-22 ,} R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 is unsubstituted or substituted phenyl, substituted phenyl is (For example, ).

In a preferred embodiment of the present invention, when each R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 , R ^1-10 , R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 , R ^{1-15, R 1-16} , R ^1-21 , ^{R 1-22 ,} R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 is unsubstituted or substituted 5-10 membered heteroaryl, substituted 5-10 membered heteroaryl is (For example, ) or (For example, ).

In a preferred embodiment of the present invention, C ₁ -C ₆ alkyl substituted with one or more R ^a is

In a preferred embodiment of the present invention, C ₁ -C ₆ alkyl substituted with one or more R ^a is

In a preferred embodiment of the present invention, C ₃ -C ₆ cycloalkyl substituted with one or more ^Ra is (For example, ), (For example, ), (For example, ) or (For example, ).

In a preferred embodiment of the present invention, C ₃ -C ₆ cycloalkyl substituted with one or more ^Ra is (For example, ) or (For example, ).

In a preferred embodiment of the present invention, C ₃ -C ₆ cycloalkyl substituted with one or more R ^d is (For example, ) or (for example, ).

In a preferred embodiment of the present invention, -N(R ^1-21 R ^1-22 ) is -NHCH ₃ or -NH ₂ .

In a preferred embodiment of the present invention, -C(=O)-N(R ^1-23 R ^1-24 ) is -C(=O)-NH ₂ or -C(=O)-NHCH ₃ .

In a preferred embodiment of the present invention, -S(=O) ₂ -N(R ^1-25 R ^1-26 ) is -S(=O) ₂ -NH ₂ .

In a preferred embodiment of the present invention, -C(=O)-OR ^1-27 is -COOH, -COOCH ₃ or -COOC ₂ H ₅ .

In a preferred embodiment of the present invention, -C(=O)-OR ^1-27 is -COOH or -COOCH ₃ .

According to a preferred embodiment of the present invention, -NH-C(=O)-R ^1-1 is -NH-C(=O)-CH ₃ , -NH-C(=O)-O-CH ₃ ,

In a preferred embodiment of the present invention, -NH-C(=O)-R ^1-1 is

In a preferred embodiment of the present invention, -C(=O)-R ^1-2 is -C(=O)-CH ₃ or -C(=O)-O-CH ₃ .

In a preferred embodiment of the present invention, -OC(=O)-N(R ^1-3 R ^1-4 ) is -OC(=O)-NH-CH ₃ .

In a preferred embodiment of the present invention, -C(=O)-N(R ^1-5 R ^1-6 ) is -C(=O)-NH-CH ₃ .

In a preferred embodiment of the present invention, -C(=NH)-N(R ^1-7 R ^1-8 ) is -C(=NH)-NH-CH ₃ .

In a preferred embodiment of the present invention, -S(=O) ₂ -N(R ^1-9 R ^1-10 ) is -S(=O) ₂ -NH-CH ₃ or -SO ₂ NH ₂ .

In a preferred embodiment of the present invention, -OC(=O)-R ^1-13 is -OC(=O)-NH-CH ₃ .

In a preferred embodiment of the present invention, -N(R ^1-14 R ^1-15 ) is

In a preferred embodiment of the present invention, Q is -N(R ^1-14 R ^1-15 ), for example -NH ₂ .

In a preferred embodiment of the present invention, -NH-S(=O) ₂ -R ^1-16 is -NH-S(=O) ₂ -CH ₃ .

In a preferred embodiment of the present invention, when Q is a substituted C ₁ -C ₆ alkyl, the substituted C ₁ -C ₆ alkyl is

In a preferred embodiment of the present invention, when Q is a substituted C ₃ -C ₁₀ cycloalkyl, the substituted C ₃ -C ₁₀ cycloalkyl is (For example, ), (For example, ) or (For example, ).

In a preferred embodiment of the present invention, when Q is substituted C ₃ -C ₉ heterocycloalkyl, the substituted C ₃ -C ₉ heterocycloalkyl is (For example, ), (For example, ), (For example, ), (For example, ) or (For example, ).

In a preferred embodiment of the present invention, when Q is substituted C ₃ -C ₉ heterocycloalkyl, the substituted C ₃ -C ₉ heterocycloalkyl is (For example, ), (For example, ) or (For example, ).

In a preferred embodiment of the present invention, when Q is a substituted C ₃ -C ₉ heterocycloalkenyl, the substituted C ₃ -C ₉ heterocycloalkenyl is (For example, ), (For example, ), (For example, ), (For example, ) or (For example, ).

In a preferred embodiment of the present invention, when Q is a substituted 5-10 membered heteroaryl, the substituted 5-10 membered heteroaryl is (For example, ), (For example, ), (For example, ), (For example, or ), (For example, ), (For example, ), (For example, or ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, , (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ) or (For example, ).

In a preferred embodiment of the present invention, when Q is a substituted 5-10 membered heteroaryl, the substituted 5-10 membered heteroaryl is (For example, ), (For example, ), (For example, ), (For example, or ), (For example, or ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ) or (For example,

In a preferred embodiment of the present invention, when Q is a substituted 5-10 membered heteroaryl, the substituted 5-10 membered heteroaryl is (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ), (For example, ) or (For example, ).

In a preferred embodiment of the present invention, Q is H, -OH, -CF ₃ , -CN, -NH ₂ , -NH-C(=O)-CH ₃ , -NH-C(=O)-O-CH ₃ ,

-C(=O)-CH ₃ , -C(=O)-C ₂ H ₅ , -C(=O)-O-CH ₃ , -O-C(=O)-NH-CH ₃ , -C (=O)-NH-CH ₃ , -C(=NH)-NH-CH ₃ , -S(=O) ₂ -NH-CH ₃ ,

In a preferred embodiment of the present invention, Q is H, -OH, -CF ₃ , -CN, -NH-C(=O)-CH ₃ , -NH-C(=O)-O-CH ₃ ,

-C(=O)-CH ₃ , -C(=O)-C ₂ H ₅ , -C(=O)-O-CH ₃ , -O-C(=O)-NH-CH ₃ , -C (=O)-NH-CH ₃ , -C(=NH)-NH-CH ₃ , -S(=O) ₂ -NH-CH ₃ ,

In a preferred embodiment of the present invention, Q is

In a preferred embodiment of the present invention, when R ^2-1 or R ^2-2 is halogen, the halogen is independently fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the present invention, when R ^2-1 or R ^2-2 is unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl (eg , methyl, ethyl, propyl, butyl, pentyl or hexyl) is independently C ₁ -C ₄ alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

In a preferred embodiment of the present invention, when R ^2-1 or R ^2-2 is a substituted C ₁ -C ₆ alkyl or a substituted C ₁ -C ₆ alkyl-O-, and the substituent is a halogen, the halogen is independently fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the present invention, when R ^2-1 or R ^2-2 is a substituted C ₁ -C ₆ alkyl or a substituted C ₁ -C ₆ alkyl-O-, and the substituent is a C ₁ -C ₆ alkyl or substituted The C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) substituent is independently C ₁ -C ₄ alkyl (e.g. methyl, ethyl, n -propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

In a preferred embodiment of the present invention, when R ^2-1 or R ^2-2 is substituted C ₁ -C ₆ alkyl or substituted C ₁ -C ₆ alkyl-O-, the number of substituents is independently 1, 2, 3 or 4 and preferably 1 or 2.

In a preferred embodiment of the present invention, when R ^2-3 , R ^2-4 , R ^2-5 or R ^2-6 is unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₁ -C ₆ alkyl-O -, C ₁ -C ₆ alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) is independently C ₁ -C ₄ alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl).

In a preferred embodiment of the present invention, when R ^2-3 , R ^2-4 , R ^2-5 or R ^2-6 is unsubstituted or substituted C ₃ -C ₈ cycloalkyl or unsubstituted or substituted C ₃ -C ₈ cycloalkyl-O -, C ₃ -C ₈ cycloalkyl is C ₃ -C ₆ cycloalkyl (eg cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl).

In a preferred embodiment of the present invention, when R ^2-3 , R ^2-4 , R ^2-5 or R ^2-6 is substituted C ₁ -C ₆ alkyl, substituted C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl-O- or substituted C ₁ -C ₆ alkyl-O-, and the substituent is halogen, the halogen independently being fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the present invention, when R ^2-3 , R ^2-4 , R ^2-5 or R ^2-6 is substituted C ₁ -C ₆ alkyl, substituted C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl-O- or substituted C ₁ -C ₆ alkyl-O-, and the substituent is C ₁ -C ₆ alkyl or substituted C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl (for example, methyl, ethyl, propyl, butyl, pentyl or hexyl) in the substituent is independently C ₁ -C ₄ alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) and preferably methyl or ethyl.

In a preferred embodiment of the present invention, when R ^2-3 , R ^2-4 , R ^2-5 or R ^2-6 is substituted C ₁ -C ₆ alkyl, substituted C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl-O- or substituted C ₁ -C ₆ alkyl-O-, and the substituent is C ₁ -C ₆ alkyl or substituted C ₁ -C ₆ alkyl-O-, the number of substituents is independently 1, 2, 3 or 4 , and preferably 1 or 2.

In a preferred embodiment of the present invention, when R ^2-7 is independently halogen, R ^2-7 is independently halogenated C ₁ -C ₆ alkyl, or R ^2-7 is independently halogenated C ₁ -C ₆ alkyl-O- , the halogen therein is independently fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the present invention, when R ^2-7 is independently unsubstituted or substituted C ₁ -C ₆ alkyl, or R ^2-7 is independently unsubstituted or substituted C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) therein is independently C ₁ -C ₄ alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

In a preferred embodiment of the present invention, when R ^2-8 or R ^2-9 is independently a halogenated C ₁ -C ₆ alkyl, the halogen therein is independently fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the present invention, when R ^2-8 or R ^2-9 independently represents unsubstituted or halogen-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl (for example, methyl, ethyl, propyl, butyl, pentyl or hexyl ) therein independently represents C ₁ -C ₄ alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

In a preferred embodiment of the present invention, -C(=O)N(R ^2-5 R ^2-6 ) is -C(=O)NH ₂ .

In a preferred embodiment of the present invention, -C(=O)N(R ^2-8 R ^2-9 ) is -C(=O)NHCH ₃ .

In a preferred embodiment of the present invention represents (For example, or ), where the carbon atom labeled ^"*" represents a chiral carbon atom in the S-configuration, R-configuration, or a mixture thereof; and preferably, the carbon atom labeled ^"*" is a chiral carbon atom in the form of one (R) or (S) enantiomer or in a form enriched with one enantiomer.

In a preferred embodiment of the present invention represents (where X represents methylene or -NH-).

In a preferred embodiment of the present invention, when R ² represents one of X and Y represents and the other is a single bond, methylene or -O- (e.g. , where X represents a single bond, methylene or -O-); preferably X is -O-, namely R ² is (For example, (For example, or )); and more preferably, R ² is (For example, (For example, or (For example, ) or (For example, (For example, or )).

In a preferred embodiment of the present invention, when R ² represents , X or Y is -N(R ^2-3 )-; preferably one of X and Y is -N(R ^2-3 )- and the other is -O-, -N(R ^2-3 )- or ; more preferably, R ² is (For example, (For example, or ) or ), (For example, or ), (For example, or (For example, ).

In a preferred embodiment of the present invention, R ² is or

In a preferred embodiment of the present invention, when R ² is independently unsubstituted or substituted 5-6 membered heteroaryl, the 5-6 membered heteroaryl is independently pyridinyl (e.g. (For example, )).

In a preferred embodiment of the present invention, when R ² independently represents a substituted 5-6 membered heteroaryl, which may be substituted with halogen, halogenated C ₁ -C ₆ alkyl, or halogenated C ₁ -C ₆ alkyl-O-, the halogen substituents are independently represents fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the present invention, when R ² independently represents a substituted 5-6 membered heteroaryl, which may be substituted with unsubstituted or halogenated C ₁ -C ₆ alkyl, or unsubstituted or halogenated C ₁ -C ₆ alkyl-O-, and C ₁ -C ₆ alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl or hexyl) substituents is independently C ₁ -C ₄ alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl).

In a preferred embodiment of the present invention, when R ² is independently unsubstituted or substituted 5-6 membered heteroaryl, the substituted 5-6 membered heteroaryl is independently (For example, or (For example,

In a preferred embodiment of the present invention is not

In a preferred embodiment of the present invention represents

In a preferred embodiment of the present invention, the heterocyclic compound of formula I has formula I-A, as shown below:

, Where represents

Preferably, the heterocyclic compound of formula I has formula IA-1, as shown below: where R ^1' has the definition as described for R ¹ , and R ^1' is the same or different from R ¹ ; W represents a single bond; And represents

more preferably, the heterocyclic compound of formula I is a compound of formula I-A-2, as shown below:

where R ^1' has the definition described for R ¹ and R ^1' is the same or different from R ¹ ; W represents a single bond; X represents a single bond, methylene or -O-; And represents

In a preferred embodiment of the present invention, the heterocyclic compound of formula I has formula I-B, as follows:

where R ² represents or -C(=O)N(R ^2-5 R ^2-6 ), X or Y is -N(R ^2-3 )-;

Preferably, the heterocyclic compound of formula I has formula IB-1, as shown below: wherein R ^1' has the definition as described for R ¹ and R ^1' is the same or different from R ¹ ; W represents a single bond; and R ² represents or -C(=O) N(R ^2-5 R ^2-6 ), where X or Y is -N(R ^2-3 )-; And

more preferably, the heterocyclic compound of formula I has formula IB-2, as follows: wherein R ^1' has the same definition as described for R ¹ and R ^1' is the same or different from R ¹ ; W represents a single bond; and R ² represents or -C(=O)N(R ^2-5 R ^2-6 ), where X or Y is -N(R ^2-3 )-.

In a preferred embodiment of the present invention, the heterocyclic compound of formula IQ is H, halogen, -OH, -CF ₃ , -CN, -NH-C(=O)-R ^1-1 , -C(=O)-R ^{1 -2} , -OC(=O)-N(R ^1-3 R ^1-4 ), -С(=NH)-N(R ^1-7 R ^1-8 ), -S(=O) ₂ -N (R ^1-9 R ^1-10 ), -S(=O)-N(R ^1-11 R ^1-12 ), -OC(=O)-R ^1-13 , -N(R ^1-14 R ^1-15 ), -NH-S(=O) ₂ -R ^1-16 , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl-O-, unsubstituted or substituted C _2-6 alkenyl, unsubstituted or substituted C ₂ -C ₆ alkenyl-O-, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkenyl, unsubstituted or substituted C ₆ -C ₁₀ aryl or unsubstituted or substituted 5-10 membered heteroaryl.

In a preferred embodiment of the present invention, the heterocyclic compound of formula I has formula I-C, as shown below:

, where Q represents H, halogen, -OH, -CF ₃ , -CN, -NH-C(=O)-R ^1-1 , -C(=O)-R ^1-2 , -OC(=O )-N(R ^1-3 R ^1-4 ), -C(=NH)-N(R ^1-7 R ^1-8 ), -S(=O) ₂ -N(R ^1-9 R ^{1- 10} ), -S(=O)-N(R ^1-11 R ^1-12 ), -OC(=O)-R ^1-13 , -N(R ^1-14 R ^1-15 ), -NH- S(=O) ₂ -R ^1-16 , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl-O-, unsubstituted or substituted C _2-6 alkenyl, unsubstituted or substituted C ₂ - C ₆ alkenyl-O-, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, unsubstituted or substituted C ₆ -C ₁₀ aryl or substituted 5- 10 heteroaryl;

Preferably, the heterocyclic compound of formula I has formula IC-1, as shown below: ; And

more preferably, the heterocyclic compound of formula I has formula IC-2, as shown below: where R ^1' has the definition described for R ¹ , R ^1' is the same or different from R ¹ , and X represents a single bond, methylene or -O-.

In a preferred embodiment of the present invention, the heterocyclic compound of formula I has formula I-D, as shown below:

, Where is a 5-6 membered heteroaryl or C ₃ -C ₅ heterocycloalkyl;

Preferably, the heterocyclic compound of formula I has formula ID-1, as shown below: , Where is a 5-6 membered heteroaryl or C ₃ -C ₅ heterocycloalkyl; And

more preferably, the heterocyclic compound of formula I has formula ID-2, as shown below: where X represents a single bond, methylene or -O-; W represents a single bond; And is a 5-6 membered heteroaryl or C ₃ -C ₅ heterocycloalkyl.

In a preferred embodiment of the present invention, the heterocyclic compound of formula I has formula I-E, as shown below:

; where R ² independently represents or unsubstituted or substituted 5-6 membered heteroaryl; for example, W represents a single bond;

Preferably, the heterocyclic compound of formula I has formula I-E-1, as shown below:

; For example, is phenyl or 6-membered heteroaryl; And

more preferably, a heterocyclic compound of formula I of formula I-E-2, as shown below:

; For example, is phenyl.

In a preferred embodiment of the present invention is a 5-membered heteroaryl;

is phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein the 5-6 membered heterocycloalkyl contains 1-3 heteroatoms selected from one or more of N, O and S, 5-6 membered heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of N, O and S, and 5-6 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O and S;

Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , Z ⁷ , Z ⁸ and Z ⁹ independently represent a ring atom; and when Z represents 5-membered heterocycloalkyl, 5-membered heterocycloalkenyl or 5-membered heteroaryl, Z ⁶ or Z ⁹ represents a single bond;

m represents 1, 2, 3 or 4;

R ³ represents H, halogen, -OH, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ alkyl;

W represents a single bond or -C(=O)-NH-;

is phenyl, 5-6 membered heteroaryl or C _3- C ₉ heterocycloalkyl;

n is 1, 2, 3 or 4;

R ¹ independently represents H, halogen, -OH, -CN or unsubstituted or substituted C ₁ -C ₆ alkyl;

Q represents H, halogen, -OH, -CN, -NH-C(=O)-R ^1-1 , -C(=O)-R ^1-2 , -O-C(=O)-N( R ^1-3 R ^1-4 ), -C(=O)-N(R ^1-5 R ^1-6 ), -C(=NH)-N(R ^1-7 R ^1-8 ), -S (=O) ₂ -N(R ^1-9 R ^1-10 ), -N(R ^1-14 R ^1-15 ), -NH-S(=O) ₂ -R ^1-16 , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkenyl or unsubstituted or substituted 5-10 membered heteroaryl;

R ² independently represents , -C(=O) N(R ^2-5 R ^2-6 ) or unsubstituted or substituted 5-6 membered heteroaryl;

preferably is phenyl, 6-membered heterocycloalkyl, 6-membered heterocycloalkenyl, or 6-membered heteroaryl;

m represents 1 or 2;

the substituent on R ¹ is independently one or more of the following substituents: halogen, -OH, -CN or -C(=O)NH ₂ ; and preferably halogen.

R ³ represents H, halogen, -OH, -CF ₃ or C ₁ -C ₆ alkyl;

R ² independently represents itself-C(=O)N(R ^2-5 R ^2-6 ).

In a preferred embodiment of the present invention is a 5-membered heteroaryl.

In a preferred embodiment of the present invention is phenyl, 6-membered heterocycloalkyl, 6-membered heterocycloalkenyl, or 6-membered heteroaryl.

According to a preferred embodiment of the present invention, m is 1 or 2.

In a preferred embodiment of the present invention, R ³ represents H, halogen, -OH, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ alkyl; and preferably R ³ is H, halogen, -OH, -CF ₃ or C ₁ -C ₆ alkyl.

In a preferred embodiment of the present invention, W is a single bond.

In a preferred embodiment of the present invention, n is 1 or 2.

In a preferred embodiment of the present invention, R ¹ is independently H, halogen, -OH, -CN or unsubstituted or substituted C ₁ -C ₆ alkyl, and preferably H, halogen or unsubstituted or substituted C ₁ -C ₆ alkyl.

In a preferred embodiment of the present invention, the substituent on R ¹ is independently one or more of the following substituents: halogen, -OH, -CN or -C(=O)NH ₂ ; and preferably halogen.

In a preferred embodiment of the present invention, Q is H, halogen, -OH, -CN, -NH-C(=O)-R ^1-1 , -C(=O)-R ^1-2 , -OC(=O )-N(R ^1-3 R ^1-4 ), -C(=O)-N(R ^1-5 R ^1-6 ), -C(=NH)-N(R ^1-7 R ^1-8 ), -S(=O) ₂ -N(R ^1-9 R ^1-10 ), -N(R ^1-14 R ^1-15 ), -NH-S(=O) ₂ -R ^1-16 , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkenyl or unsubstituted or substituted 5-10 membered heteroaryl.

In a preferred embodiment of the present invention, Q is H, halogen, -OH, -CF ₃ , -CN, -NH-C(=O)-R ^1-1 , -C(=O)-R ^1-2 , - OC(=O)-N(R ^1-3 R ^1-4 ), -C(=O)-N(R ^1-5 R ^1-6 ), -C(=NH)-N(R ^1-7 R ^1-8 ), -S(=O) ₂ -N(R ^1-9 R ^1-10 ), -S(=O)-N(R ^1-11 R ^1-12 ), -OC(=O )-R ^1-13 , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl-O-, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkenyl- O-, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkenyl, unsubstituted or substituted C ₆ -C ₁₀ aryl or unsubstituted or substituted 5-6-membered heteroaryl; And

preferably Q is H, halogen, -OH, -CN, -NH-C(=O)-R ^1-1 , -C(=O)-R ^1-2 , -O-C(=O)-N (R ^1-3 R ^1-4 ), -C(=O) -N(R ^1-5 R ^1-6 ), -C(=NH)-N(R ^1-7 R ^1-8 ), - S(=O) ₂ -N(R ^1-9 R ^1-10 ), unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkenyl or unsubstituted or substituted 5-10 membered heteroaryl.

In a preferred embodiment of the present invention, substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl-O-, substituted C ₆ -C ₁₀ aryl, substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl or substituted 5-6 membered heteroaryl is substituted with one or more substituents independently selected from the following: halogen, -OH, -CF ₃ , -CN, -COOH , -C(=O)NH ₂ , =O (i.e. two geminal hydrogens on the carbon atom are replaced by an O group), and C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or C ₃ -C ₆ cycloalkyl, which is unsubstituted or substituted by one or more ^Ra , wherein there are multiple ^Ras , they are the same or different, and each ^Ra is halogen, -OH, =O, -CF ₃ , -CN, -COOH or - C(=O)NH ₂ ; and when multiple substituents are present, they are the same or different.

In a preferred embodiment of the present invention, each R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1- 9} , R ^1-10 , R ^1-11 , R ^1-12 and R ^1-13 are independently H, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl-O-, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkenyl-O-, unsubstituted or substituted C ₃ -C ₆ cycloalkyl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkenyl, unsubstituted or substituted phenyl or unsubstituted or substituted 5-6 membered heteroaryl, where C ₃ -C ₅ heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S and N, C ₃ -C ₅ heterocycloalkenyl contains 1 -3 heteroatoms selected from one or more of O, S and N, 5-6 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O and S; and substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl-O-, substituted C ₃ -C ₆ cycloalkyl, substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl, substituted phenyl or substituted 5-6 membered heteroaryl is substituted with one or more substituents independently selected from the following: halogen, -OH, -CF ₃ , -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O-, C ₃ -C ₆ cycloalkyl, -COOH or =O, where in the presence of multiple substituents they are the same or different.

In a preferred embodiment of the present invention, R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 , or R ^{1- 11} and R ^1-12 , independently together with the N atom to which they directly bind, form an unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl, an unsubstituted or substituted C ₃ -C ₅ heterocycloalkenyl or an unsubstituted or substituted 5-6-membered heteroaryl, where the C ₃ -C ₅ heterocycloalkyl does not contain a heteroatom or contains 1-2 heteroatoms selected from one or more of O, S and N, in addition to the existing N atom, the C ₃ -C ₅ heterocycloalkenyl does not contain a heteroatom or contains 1-2 heteroatom selected from one or more of O, S and N, in addition to the existing N atom, the 5-6 membered heteroaryl contains no heteroatom or contains 1-2 heteroatoms selected from one or more of O, S and N, in addition to an existing N atom; and substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl or substituted 5-6 membered heteroaryl is substituted with one or more substituents independently selected from the following: halogen, -OH, -CF ₃ , -CN, and C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O-, =O (i.e. two geminal hydrogens on the carbon atom are replaced by an O group), and C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or C ₃ -C ₆ cycloalkyl, which is unsubstituted or substituted by one or more R ^a where, when multiple R ^b are present, they are the same or different and each R ^b is halogen, -OH, =O, -CF ₃ , -CN, -COOH or -C(=O)NH ₂ ; and when multiple substituents are present, they are the same or different.

In a preferred embodiment of the present invention, R ² is independently or -C(=O)N(R ^2-5 R ^2-6 ).

In a preferred embodiment of the present invention, when Q is H, halogen, -OH, -CF ₃ , -CN, -NH-C(=O)-R ^1-1 , -C(=O)-R ^1-2 , -О-С(=O)-N(R ^1-3 R ^1-4 ), -C(=NH)-N(R ^1-7 R ^1-8 ), -S(=O) ₂ -N (R ^1-9 R ^1-10 ), -S(=O)-N(R ^1-11 R ^1-12 ), -OC(=O)-R ^1-13 , -N(R ^1-14 R ^1-15 ), -NH-S (=O) ₂ -R ^1-16 , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl-O-, unsubstituted or substituted C _2-6 alkenyl, unsubstituted or substituted C ₂ -C ₆ alkenyl-O-, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkenyl, unsubstituted or substituted C ₆ -C ₁₀ aryl, unsubstituted or substituted 5-10-membered heteropril, represents , or R ² represents , or 5-10 membered heteroaryl, where X and Y each independently represent a single bond, methylene, -O- or For example,

In a preferred embodiment of the present invention, when represents represents or R ² independently represents is -C(=O)N(R ^2-5 R ^2-6 ) or unsubstituted or substituted 5-6 membered heteroaryl, where X or Y is -N(R ^2-3 )-.

In a preferred embodiment of the present invention, R ² is independently , -C(=O)N(R ^2-5 R ^2-6 ) or unsubstituted or substituted 5-6 membered heteroaryl, where X or Y is -N(R ^2-3 )-.

In a preferred embodiment of the present invention, R ² is independently ; preferably X and Y are each independently a single bond, methylene, -O- or ; and more preferably, R ² is

In a preferred embodiment of the present invention represents

In a preferred embodiment of the present invention, R ³ represents halogen, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ alkyl;

Q represents -NH-C(=O)-R ^1-1 , -C(=O)-N(R ^1-5 R ^1-6 ), -S(=O) ₂ -N(R ^1-9 R ^1-10 ), -N(R ^1-14 R ^1-15 ), -NH-S(=O) ₂ -R ^1-16 , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₃ - C ₁₀ cycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkenyl or unsubstituted or substituted 5-10-membered heteroaryl, where C ₃ -C ₉ heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O, S and N, C ₃ -C ₉ heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S and N, 5-10 membered heteroaryl contains 1-3 heteroatoms selected from one or more from N, O and S; and substituted C ₁ -C ₆ alkyl, substituted C ₃ -C ₁₀ cycloalkyl, substituted C ₃ -C ₉ heterocycloalkyl, substituted C ₃ -C ₉ heterocycloalkenyl or substituted 5-10 membered heteroaryl is substituted with one or more substituents independently selected from the following : -OH, -CF ₃ , -CN, -N(R ^1-21 R ^1-22 ), -C(=O)-N(R ^1-23 R ^1-24 ), -S(=O) ₂ -N(R ^1-25 R ^1-26 ), -C(=O)-OR ^1-27 , =O (i.e. the two geminal hydrogens on the carbon atom are replaced by an O group), and C ₁ -C ₆ alkyl , C ₁ -C ₆ alkyl-O- or C ₃ -C ₆ cycloalkyl, which is unsubstituted or substituted by one or more R ^a , where, if there are multiple R ^a , they are the same or different and each R ^a is a halogen, - OH or -COOH; and when multiple substituents are present, they are the same or different;

R ² independently represents , -C(=O) N(R ^2-5 R ^2-6 ) or unsubstituted or substituted 5-6 membered heteroaryl; wherein the 5-6 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O and S, and the substituted 5-6 membered heteroaryl is substituted with one or more substituents independently selected from the following: halogen, -OH, - CN, unsubstituted or halogen-substituted C ₁ -C ₆ alkyl, unsubstituted or halogen-substituted C ₁ -C ₆ alkyl-O-, -C(=O)R ²⁷ or -C(=O)N(R ^2-8 R ^2-9 ), where in the presence of multiple substituents they are the same or different;

preferably Q is -S(=O) ₂ -N(R ^1-9 R ^1-10 );

W represents a single bond; is phenyl; And

R ² independently represents or unsubstituted or substituted 5-6 membered heteroaryl.

In a preferred embodiment of the present invention, R ³ represents halogen, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ alkyl;

Q represents -NH-C(=O)-R ^1-1 , -C(=O)-N(R ^1-5 R ^1-6 ), -N(R ^1-14 R ^1-15 ), - NH-S(=O) ₂ -R ^1-16 , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, unsubstituted or substituted C ₃ - C ₉ heterocycloalkenyl or unsubstituted or substituted 5-10-membered heteroaryl, where C ₃ -C ₉ heterocycloalkenyl contains 1-3 heteroatoms selected from O, S and N, C ₃ -C ₉ heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S and N, and the 5-10 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O and S; and substituted C ₁ -C ₆ alkyl, substituted C ₃ -C ₁₀ cycloalkyl, substituted C ₃ -C ₉ heterocycloalkyl, substituted C ₃ -C ₉ heterocycloalkenyl or substituted 5-10 membered heteroaryl is substituted with one or more substituents independently selected from the following : -OH, -CF ₃ , -CN, -N(R ^1-21 R ^1-22 ), -C(=O)-N(R ^1-23 R ^1-24 ), -S(=O) ₂ -N(R ^1-25 R ^1-26 ), -C(=O)-OR ^1-27 , =O (i.e. the two geminal hydrogens on the carbon atom are replaced by an O group), and C ₁ -C ₆ alkyl , C ₁ -C ₆ alkyl-O- or C ₃ -C ₆ cycloalkyl, which is unsubstituted or substituted by one or more ^Ra , where, when multiple ^Ra are present, they are the same or different, and each ^Ra is a halogen , -OH or -COOH; and when multiple substituents are present, they are the same or different;

R ^1-1 , R ^1-14 , R ^1-15 , R ^1-16 , R ^1-21 , R ^1-22 , R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 is each independently H, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl, unsubstituted or substituted phenyl or unsubstituted 5-10 membered heteroaryl, where C ₃ -C ₅ heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O, S and N, and 5 -10-membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O and S; and substituted C ₁ -C ₆ alkyl, substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkynyl, substituted C ₃ -C ₁₀ cycloalkyl, substituted C ₃ -C ₉ heterocycloalkyl, substituted phenyl or substituted 5-10-membered heteroaryl is substituted with one or more substituents independently selected from the following: halogen, -OH, -CF ₃ , -CN, -COOH, -C(=O)NH ₂ , -COOCH ₃ , -NH ₂ , =O and C ₁ - C ₆ alkyl, C ₁ -C ₆ alkyl-O- or C ₃ -C ₆ cycloalkyl, which is unsubstituted or substituted by one or more R ^d , where if there are multiple R ^d they are the same or different and each R ^d independently represents is H, halogen, -OH, =O, -CF ₃ , -CN, -COOH or -C(=O)NH ₂ ; and when multiple substituents are present, they are the same or different.

In a preferred embodiment of the present invention, R ³ represents halogen, -CHF ₂ , -CH ₂ F or C ₁ -C ₆ alkyl;

Q represents -NH-C(=O)-R ^1-1 , -N(R ^1-14 R ^1-15 ), -NH-S(=O) ₂ -R ^1-16 , unsubstituted or substituted with C ₁ -C ₆ alkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl or unsubstituted or substituted 5-10-membered heteroaryl, where C ₃ -C ₉ heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O, S and N, and the 5-10 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O and S; and substituted C ₁ -C ₆ alkyl, substituted C ₃ -C ₁₀ cycloalkyl, substituted C ₃ -C ₉ heterocycloalkyl or substituted 5-10 membered heteroaryl is substituted with one or more substituents independently selected from the following: -N(R ^1-21 R ^1-22 ), -C(=O)-N(R ^1-23 R ^1-24 ), -S(=O) ₂ -N(R ^1-25 R ^1-26 ) or -C(=O )-OR ^1-27 , where in the presence of multiple substituents, they are the same or different;

R ^1-1 , R ^1-14 , R ^1-15 , R ^1-16 , R ^1-21 , R ^1-22 , R ^1-23 , R ^1-24 , R ^1-25 , R ^1-26 and R ^1-27 is each independently H, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₃ -C ₉ heterocycloalkyl or unsubstituted or substituted 5-10 membered heteroaryl, where C ₃ -C ₉ heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O, S and N, and 5-10 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O and S; and substituted C ₁ -C ₆ alkyl, substituted C ₂ -C ₆ alkynyl, substituted C ₃ -C ₉ heterocycloalkyl or substituted 5-10 membered heteroaryl is substituted with one or more substituents independently selected from the following: halogen, -OH, -CN , =O, -COOH, -C(=O)NH ₂ , -COOCH ₃ , -NH ₂ and C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or C ₃ -C ₆ cycloalkyl, which is unsubstituted or substituted by one or more R ^d , where when multiple R d ^d are present, they are the same or different, and each R ^d independently represents H, halogen, -OH, =O, -CF ₃ , -CN, -COOH, or - C(=O)NH ₂ ; and when multiple substituents are present, they are the same or different.

In a preferred embodiment of the present invention is a 5-membered heteroaryl or 5-membered heterocycloalkenyl, wherein the 5-membered heteroaryl contains 1-2 heteroatoms selected from one or more of N, O and S, and the 5-membered heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of N, O and S;

is phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein the 5-6 membered heterocycloalkyl contains 1-3 heteroatoms selected from one or more of N, O and S, 5-6 membered heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of N, O and S, and 5-6 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O and S;

Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , Z ⁷ , Z ⁸ and Z ⁹ independently represent a ring atom; and when is 5-membered heterocycloalkyl, 5-membered heterocycloalkenyl or 5-membered heteroaryl, Z ⁶ or Z ⁹ represents a single bond;

m represents 1, 2, 3 or 4;

R ³ represents H, halogen, -OH, -CF ₃ , -CN or C ₁ -C ₆ alkyl; when m is not equal to 1, R ³ is independently the same or different; or when two adjacent R ³ are present, they, together with the ring atom with which they directly bond, form C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, C ₃ -C ₅ heterocycloalkyl, C ₃ -C ₅ heterocycloalkenyl, phenyl or 5-6 membered heteroaryl, where C ₃ -C ₅ heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O, S and N, C ₃ -C ₅ heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S and N, and the 5-6 membered heteroaryl contains 1-3 heteroatoms selected from one or more of O, S and N;

W represents a single bond or -C(=O)-NH-;

is phenyl, 5-6 membered heteroaryl or C ₃ -C ₅ heterocycloalkyl, wherein the 5-6 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O and S, and C ₃ -C ₅ heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O, S and N;

n is 1, 2, 3 or 4;

R ¹ independently represents H, halogen, -OH, -CN, unsubstituted or substituted C ₁ -C ₆ alkyl, or unsubstituted or substituted C ₁ -C ₆ alkyl-O-; wherein the substituted C ₁ -C ₆ alkyl or substituted C ₁ -C ₆ alkyl-O- is substituted with one or more substituents independently selected from the following: halogen, -OH, -CF ₃ , -CN, -COOH, -C(=O )NH ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or =O (i.e., two geminal hydrogens on the carbon atom are replaced by an O group); when multiple substituents are present, they are the same or different; and when n is not equal to 1, R ¹ is independently the same or different;

Q represents H, halogen, -OH, -CF ₃ , -CN, -NH ₂ , -NH-C(=O)-R ^1-1 , -C(=O)-R ^1-2 , -OC( =O)-N(R ^1-3 R ^1-4 ), -C(=O)-N(R ^1-5 R ^1-6 ), -C(=NH)-N(R ^1-7 R ^{1 -8} ), -S(=O) ₂ -N(R ^1-9 R ^1-10 ), -S(=O)-N(R ^1-11 R ^1-12 ), -OC(=O)- R ^1-13 , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl-O-, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkenyl-O- , unsubstituted or substituted C ₆ -C ₁₀ aryl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkenyl or unsubstituted or substituted 5-6-membered heteroaryl; where C ₃ -C ₅ heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S and N, C ₃ -C ₅ heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S and N, and A 5-6 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O and S; and substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl-O-, substituted C ₆ -C ₁₀ aryl, substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl or substituted 5-6 membered heteroaryl is substituted with one or more substituents independently selected from the following: halogen, -OH, -CF ₃ , -CN, -COOH, -C(= O)NH ₂ , =O (i.e. the two geminal hydrogens on the carbon atom are replaced by an O group), and C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or C ₃ -C ₆ cycloalkyl, which is unsubstituted or substituted with one or more R ^a , where multiple R ^a are the same or different and each R ^a is halogen, -OH, =O, -CF ₃ , -CN, -COOH or -C(=O)NH ₂ ; and when multiple substituents are present, they are the same or different;

R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 , R ^1-10 , R ^1-11 , R ^1-12 and R ^1-13 are each independently H, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl-O-, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkenyl-O-, unsubstituted or substituted C ₃ -C ₆ cycloalkyl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkenyl, unsubstituted or substituted phenyl , or unsubstituted or substituted 5-6 membered heteroaryl; where C ₃ -C ₅ heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S and N, C ₃ -C ₅ heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S and N, and A 5-6 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O and S; and substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl-O-, substituted C ₃ -C ₆ cycloalkyl, substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl, substituted phenyl or substituted 5-6 membered heteroaryl is substituted with one or more substituents independently selected from the following: halogen, -OH, -CF ₃ , -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O-, C ₃ -C ₆ cycloalkyl, -COOH or =O (i.e. two geminal hydrogens on the carbon atom are replaced by an O group), and in the presence of multiple substituents they are the same or various; or

R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 or R ^1-11 and R ^1-12 independently together with the N atom with which they directly bond, they form unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkenyl or unsubstituted or substituted 5-6-membered heteroaryl; where the C ₃ -C ₅ heterocycloalkyl does not contain a heteroatom or contains 1-2 heteroatoms selected from one or more of O, S and N, in addition to the existing N atom, the C ₃ -C ₅ heterocycloalkenyl does not contain a heteroatom or contains 1-2 a heteroatom selected from one or more of O, S and N, in addition to the existing N atom, and the 5-6 membered heteroaryl contains no heteroatom or contains 1-2 heteroatoms selected from one or more of O, S and N, in addition to the existing N atom; and substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl or substituted 5-6 membered heteroaryl is substituted with one or more substituents independently selected from the following: halogen, -OH, -CF ₃ , -CN, C ₁ - C ₆ alkyl, C ₁ -C ₆ alkyl-O-, =O (i.e. two geminal hydrogens on the carbon atom are replaced by an O group), and C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or C ₃ -C ₅ cycloalkyl, which is unsubstituted or substituted by one or more R ^b , where multiple R ^b are the same or different and each R ^b is halogen, -OH, =O, -CF ₃ , -CN, -COOH or -C(=O)NH ₂ ; and when multiple substituents are present, they are the same or different;

R ² represents or -C(=O)N(R ^2-5 R ^2-6 );

R ^2-1 and R ^2-2 are each independently H, halogen, -OH, -CN, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl-O- or =O (t .e. two geminal hydrogens on the carbon atom are replaced by an O group); wherein the substituted C ₁ -C ₆ alkyl or substituted C ₁ -C ₆ alkyl-O- is substituted with one or more substituents independently selected from the following: halogen, -OH, -CF ₃ , -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or =O (ie, the two geminal hydrogens on the carbon atom are replaced by an O group), and if multiple substituents are present, they are the same or different;

X and Y each independently represent a single bond, methylene, -O-, -N(R ^2-3 )- or

R ^2-3 , R ^2-4 , R ^2-5 and R ^2-6 are each independently H, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl-O-, or unsubstituted or substituted C ₁ -C ₆ alkyl-O-; wherein the substituted C ₁ -C ₆ alkyl, substituted C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl-O- or substituted C ₁ -C ₈ alkyl-O- is substituted with one or more substituents independently selected from the following: halogen , -OH, -CF ₃ , -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or =O (i.e., two geminal hydrogens on the carbon atom are replaced by an O group), and in the presence of multiple substituents they are the same or different.

In a preferred embodiment of the present invention, when is a 5-membered heteroaryl, a 5-membered heteroaryl is pyrrolyl (e.g. or ), furanyl (for example, ), pyrazolyl (e.g. ), thienyl (for example, ) or imidazolyl (for example ). (In the structural formula, the right bond is associated with W)

In a preferred embodiment of the present invention represents

In a preferred embodiment of the present invention, when two adjacent R ³ are present and they, together with the ring atom to which they directly bond, form a C ₃ -C ₅ heterocycloalkyl, the C ₃ -C ₅ heterocycloalkyl is a C ₄ -C ₅ heterocycloalkyl, where C ₄ -C ₅ heterocycloalkyl contains 1-2 heteroatoms selected from one or more of N, O and S.

In a preferred embodiment of the present invention, when two adjacent R ³ are present and they, together with the ring atom to which they directly bond, form a C ₃ -C ₅ heterocycloalkenyl, the C ₃ -C ₅ heterocycloalkenyl is a C ₄ -C ₅ heterocycloalkenyl, where C ₄ -C ₅ heterocycloalkenyl contains 1-2 heteroatoms selected from one or more of N, O and S.

In a preferred embodiment of the present invention, when is C ₃ -C ₅ heterocycloalkyl, C ₃ -C ₅ heterocycloalkyl is C ₄ -C ₅ heterocycloalkyl, wherein C ₄ -C ₅ heterocycloalkyl contains 1-2 heteroatoms selected from one or more of N, O and S, and preferably piperidinyl (e.g. (For example, )). (In the structural formula, the left bond is associated with W and the right bond is associated with Q)

In a preferred embodiment of the present invention, when Q is unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl, C ₃ -C ₅ heterocycloalkyl is C ₄ -C ₅ heterocycloalkyl, wherein C ₄ -C ₅ heterocycloalkyl contains 1-2 heteroatoms selected one or more of N, O and S, and is preferably pyrrolidinyl (e.g. ) or piperazinil (eg. ).

In a preferred embodiment of the present invention, when Q is unsubstituted or substituted C ₃ -C ₅ heterocycloalkenyl, the C ₃ -C ₅ heterocycloalkenyl is C ₄ -C ₅ heterocycloalkenyl, wherein the C ₄ -C ₅ heterocycloalkenyl contains 1-2 heteroatoms selected one or more of N, O and S; and C ₄ -C ₅ heterocycloalkenyl is preferably 2,5-dihydro-1H-pyrrolyl (for example, ).

In a preferred embodiment of the present invention, when Q is an unsubstituted or substituted 5-6 membered heteroaryl, the 5-6 membered heteroaryl is imidazolyl (e.g. or ), oxazolyl (e.g. ), furanyl (for example, ), thienyl (for example, ), pyrrolyl (for example, or ), pyrazolyl (e.g. or ), isoxazolyl (for example, ), pyridinyl (for example, ) or pyrimidinyl (for example, ).

In a preferred embodiment of the present invention, when Q is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl-O-, substituted C ₆ -C ₁₀ aryl, substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl or substituted 5-6-membered heteroaryl, the number of substituents is independently 1, 2, 3 or 4.

In a preferred embodiment of the present invention, when Q is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl-O-, substituted C ₆ -C ₁₀ aryl, substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl or substituted 5-6 membered heteroaryl, and the substituent is halogen, the halogen is independently fluorine, chlorine, bromine or iodine and preferably fluorine.

In a preferred embodiment of the present invention, when Q is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl-O-, substituted C ₆ -C ₁₀ aryl, substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl or substituted 5-6 membered heteroaryl, and the substituent is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl-O -, substituted with one or more ^Ra , C ₁ -C ₆ alkyl (for example, methyl, ethyl, propyl, butyl, pentyl or hexyl) in the substituent is independently a C ₁ -C ₄ alkyl (for example, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) and preferably methyl.

In a preferred embodiment of the present invention, when Q is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl-O-, substituted C ₆ -C ₁₀ aryl, substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl or substituted 5-6 membered heteroaryl, and the substituent is C ₃ -C ₆ cycloalkyl substituted with one or more R ^a , C _{The 3} -C ₆ cycloalkyl substituent (eg cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl) is cyclopropyl.

In a preferred embodiment of the present invention, when Q is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl-O-, substituted C ₆ -C ₁₀ aryl, substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl or substituted 5-6-membered heteroaryl, the substituent is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or C ₃ -C ₆ cycloalkyl substituted with one or more ^Ra , and ^Ra is halogen, the halogen independently being fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 or R ^1-13 is unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₁ -C ₆ alkyl-O-, C ₁ - C ₆ alkyl (eg, methyl, ethyl, propyl, butyl, pentyl or hexyl) is independently C ₁ -C ₄ alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) and preferably methyl or ethyl.

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 or R ^1-13 is unsubstituted or substituted C ₂ -C ₆ alkenyl or unsubstituted or substituted C ₂ -C ₆ alkenyl-O-, C ₂ - C ₆ alkenyl is C ₂ -C ₄ alkenyl {eg vinyl, propenyl (eg 1-propenyl or 2-propenyl) or butenyl (eg 2-butenyl, 1-butenyl or butadienyl)}, and preferably ethenyl.

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 or R ^1-13 is unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl, C ₃ -C ₅ heterocycloalkyl is C ₄ -C ₅ heterocycloalkyl, where C ₄ -C ₅ heterocycloalkyl contains 1-2 heteroatoms selected from one or more of N, O and S.

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 or R ^1-13 is unsubstituted or substituted C ₃ -C ₅ heterocycloalkenyl, C ₃ -C ₅ heterocycloalkenyl is C ₄ -C ₅ heterocycloalkenyl, where C ₄ -C ₅ heterocycloalkenyl contains 1-2 heteroatoms selected from one or more of N, O and S.

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 or R ^1-13 is an unsubstituted or substituted 5-6 membered heteroaryl, a 5-6 membered heteroaryl contains 1-2 heteroatoms selected from one or two of N, O and S.

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 or R ^1-13 is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl , substituted C ₂ -C ₆ alkenyl-O-, substituted phenyl, substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl or substituted 5-6 membered heteroaryl, and the substituent is halogen, the halogen is independently fluorine , chlorine, bromine or iodine, and preferably fluorine.

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 or R ^1-13 is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl , substituted C ₂ -C ₆ alkenyl-O-, substituted phenyl, substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl or substituted 5-6 membered heteroaryl, and the substituent is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl in a substituent (for example, methyl, ethyl, propyl, butyl, pentyl or hexyl) is independently C ₁ -C ₄ alkyl (for example, methyl, ethyl, n -propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 or R ^1-13 is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl , substituted C ₂ -C ₆ alkenyl-O-, substituted phenyl, substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl or substituted 5-6 membered heteroaryl, and the substituent is C ₃ -C ₆ cycloalkyl, The C ₃ -C ₆ cycloalkyl substituent (eg, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl) is cyclopropyl.

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 or R ^1-13 is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl-O-, substituted C ₂ -C ₆ alkenyl , substituted C ₂ -C ₆ alkenyl-O-, substituted phenyl, substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl or substituted 5-6-membered heteroaryl, the number of substituents is independently 1, 2, 3 or 4 and preferably 1 or 2.

In a preferred embodiment of the present invention, when R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 , or R ^1-11 and R ^1-12 , independently together with the N atom to which they directly bond, form an unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl, C ₃ -C ₅ heterocycloalkyl does not contain additional heteroatoms or contains one heteroatom selected from O , S and N, in addition to the existing N atom.

In a preferred embodiment of the present invention, when R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 , or R ^1-11 and R ^1-12 independently, together with the N atom with which they directly bind, form an unsubstituted or substituted C ₃ -C ₅ heterocycloalkenyl, C ₃ -C ₅ heterocycloalkenyl does not contain additional heteroatoms or contains one heteroatom selected from O, S and N, in addition to the existing N atom.

In a preferred embodiment of the present invention, when R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 , or R ^1-11 and R ^1-12 independently, together with the N atom to which they directly bond, form an unsubstituted or substituted 5-6-membered heteroaryl, an unsubstituted or substituted 5-6-membered heteroaryl does not contain additional heteroatoms or contains one heteroatom selected from one of O, S and N, in addition to the existing N atom.

In a preferred embodiment of the present invention, when R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 , or R ^1-11 and R ^1-12 independently together with the N atom to which they are directly bonded form a substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl or substituted 5-6 membered heteroaryl, and the substituent is halogen , a halogen is independently fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the present invention, when R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 , or R ^1-11 and R ^1-12 , independently together with the N atom to which they directly bind, form a substituted C ₃ -C ₅ heterocycloalkyl, a substituted C ₃ -C ₅ heterocycloalkenyl or a substituted 5-6-membered heteroaryl, and the substituent is A C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl-O- substituted with one or more R ^b , a C ₁ -C ₆ alkyl substituent (for example, methyl, ethyl, propyl, butyl, pentyl or hexyl) is independently C ₁ -C ₄ alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

In a preferred embodiment of the present invention, when R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 , or R ^1-11 and R ^1-12 , independently together with the N atom to which they directly bind, form a substituted C ₃ -C ₅ heterocycloalkyl, a substituted C ₃ -C ₅ heterocycloalkenyl or a substituted 5-6-membered heteroaryl, and the substituent is C ₃ -C ₆ cycloalkyl substituted with one or more R ^b , C ₃ -C ₆ cycloalkyl in the substituent is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In a preferred embodiment of the present invention, when R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 , or R ^1-11 and R ^1-12 , independently together with the N atom to which they directly bind, form a substituted C ₃ -C ₅ heterocycloalkyl, a substituted C ₃ -C ₅ heterocycloalkenyl or a substituted 5-6-membered heteroaryl, the substituent being C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-O- or C ₃ -C ₆ cycloalkyl substituted with one or more R ^b where, when R ^b is halogen, the halogen is independently fluorine, chlorine, bromine or iodine .

In a preferred embodiment of the present invention, when R ^1-3 and R ^1-4 , R ^1-5 and R ^1-6 , R ^1-7 and R ^1-8 , R ^1-9 and R ^1-10 or R ^{1 -11} and R ^1-12 independently, together with the N atom with which they directly bond, form a substituted C ₃ -C ₅ heterocycloalkyl, substituted C ₃ -C ₅ heterocycloalkenyl or substituted 5-6-membered heteroaryl, the number of substituents is 1, 2 , 3 or 4 independently and is preferably 1 or 2.

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 or R ^1-13 is substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl is or .

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 or R ^1-13 is substituted C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl may be .

In a preferred embodiment of the present invention, when R ^1-1 , R ^1-2 , R ^1-3 , R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^{1 -9} , R ^1-10 , R ^1-11 , R ^1-12 or R ^1-13 is substituted C ₃ -C ₆ cycloalkyl, substituted C ₃ -C ₆ cycloalkyl is coon

In a preferred embodiment of the present invention, when Q is a substituted C ₃ -C ₅ heterocycloalkyl, the substituted C ₃ -C ₅ heterocycloalkyl is

In a preferred embodiment of the present invention, when Q is a substituted C ₃ -C ₅ heterocycloalkenyl, the substituted C ₃ -C ₅ heterocycloalkenyl may be

In a preferred embodiment of the present invention, when Q is a substituted 5-6 membered heteroaryl, the substituted 5-6 membered heteroaryl is

In a preferred embodiment of the present invention, if Q is -NH-C(=O)-R ^1-1 , then -NH-C(=O)-R ^1-1 is -NH-C(=O)- CH ₃ , -NH-C(=O)-O-CH ₃ ,

In a preferred embodiment of the present invention, if Q is -S(=O) ₂ -N(R ^1-9 R ^1-10 ), then -S(=O) ₂ -N(R ^1-9 R ^1-10 ) is -S(=O) ₂ -NH-CH ₃ .

In a preferred embodiment of the present invention, Q is H, -OH, -CF ₃ , -CN, -NH-C(=O)-CH ₃ , -NH-C(=O)-O-CH ₃ , , , C(=O)CH ₃ , -C(=O)-C ₂ H ₅ , -C(=O)-O-CH ₃ , -OC(=O)-NH-CH ₃ , -C(=O )-NH-CH ₃ , -C(=NH)-NH-CH ₃ , -S(=O) ₂ -NH-CH ₃ , ,

In a preferred embodiment of the present invention, when R ² represents , one of X and Y represents , and the other is a single bond, methylene or -O- (e.g. , where X represents a single bond, methylene or -O-); preferably X is -O-, that is, R ² is (For example, (For example, or )); and more preferably R ² is (For example, (For example, or )) or (For example, (For example,

In a preferred embodiment of the present invention, the heterocyclic compound of formula I has formula I-C'', as follows:

where Q represents H, halogen, -OH, -CF ₃ , -CN, -NH ₂ , -NH-C(=O)-R ^1-1 , -C(=O)-R ^1-2 , -OC (=O)-N(R ^1-3 R ^1-4 ), -C(=NH)-N(R ^1-7 R ^1-8 ), -S(=O) ₂ -N(R ^1-9 R ^1-10 ), -S(=O)-N(R ^1-11 R ^1-12 ), -OC(=O)-R ^1-13 , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl-O-, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkenyl-O-, unsubstituted or substituted C ₆ -C ₁₀ aryl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkenyl, or unsubstituted or substituted 5-6 membered heteroaryl;

Preferably, the heterocyclic compound of formula I has formula I-C'-1, as follows: where Q represents H, halogen, -OH, -CF ₃ , -CN, -NH ₂ , -NH-C(=O)-R ^1-1 , -C(=O)-R ^1-2 , -OC (=O)-N(R ^1-3 R ^1-4 ), -C(=NH)-N(R ^1-7 R ^1-8 ), -S(=O) ₂ -N(R ^1-9 R ^1-10 ), -S(=O)-N(R ^1-11 R ^1-12 ), -OC(=O)-R ^1-13 , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl-O-, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkenyl-O-, unsubstituted or substituted C ₆ -C ₁₀ aryl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkenyl, or unsubstituted or substituted 5-6-membered heteroaryl; And

More preferably, the heterocyclic compound of formula I is a compound of formula I-C''-2, as follows:

where R ^1' has the definition given for R ¹ , R ^1' is the same or different from R ¹ , and X represents a single bond, methylene or -O-; Q represents H, halogen, -OH, -CF ₃ , -CN, -NH ₂ , -NH-C(=O)-R ^1-1 , -C(=O)-R ^1-2 , -OC( =O)-N(R ^1-3 R ^1-4 ), -C(=NH)-N(R ^1-7 R ^1-8 ), -S(=O) ₂ -N(R ^1-9 R ^1-10 ), -S(=O)-N(R ^1-11 R ^1-12 ), -OC(=O)-R ^1-13 , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl-O-, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkenyl-O-, unsubstituted or substituted C ₆ -C ₁₀ aryl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkenyl, or unsubstituted or substituted 5-6 membered heteroaryl.

In a preferred embodiment of the present invention, the heterocyclic compound of formula I is preferably any of the following compounds:

In a preferred embodiment of the present invention, the pharmaceutically acceptable salt of the heterocyclic compound of Formula I is preferably the following compound:

Thus, throughout the present specification, the groups and their substituents in a heterocyclic compound of formula I or its stereoisomer, geometric isomer, tautomer, nitric oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug may be selected by those skilled in the art to provide a stable heterocyclic compound of formula I or a stereoisomer, geometric isomer, tautomer, nitric oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, including, but not limited to, the compounds described in the examples of the present invention.

The present invention further includes an isotopically labeled heterocyclic compound of formula I or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug disclosed herein, wherein one or more atoms are replaced by one or more atoms having a given atomic mass or mass number. Examples of isotopes that may be included in the compound described herein include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur and chlorine (for example, ^2H , ^3H , ^13C , ^14C , ¹⁵ N, ¹⁸ O, ¹⁷ O, ¹⁸ F, ³⁵ S and ³⁶ Cl). The isotopically labeled compound described herein is useful for analyzing the tissue distribution of the compound, the prodrug, and its metabolite; and preferred isotopes for such assays include ^3H and ^14C . Additionally, in some cases, substitution with heavier isotopes such as deuterium ( ^2H or D) may result in increased metabolic stability, which provides therapeutic benefits such as increased period in vivo half-life or reduced dosage requirements.

An isotopically labeled compound described herein can generally be prepared by replacing an isotopically unlabeled reagent with an isotopically labeled reagent in accordance with the methods described herein.

The heterocyclic compound of formula I or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug described herein can be synthesized by methods similar to those known in the field of chemistry, with steps and conditions , which may be referred to as similar reactions in the art, particularly as described herein. Starting materials are typically obtained from commercial sources (eg, Aldrich) or can be easily obtained using methods well known to those skilled in the art (obtained from the SciFinder and Reaxys online databases).

Other heterocyclic compounds of formula I can also be prepared by peripheral modification of the heterocyclic compound of formula I described herein using the resulting compounds by conventional methods known in the art.

In general, the compound disclosed herein can be prepared by the methods described herein, wherein substituents are defined as in Formula I unless otherwise indicated. The following diagrams and examples serve to further illustrate the context of the present invention.

The present invention provides a method for preparing a heterocyclic compound of formula I, comprising the following schemes.

Scheme I involves the following step: performing a Still compound reaction as shown below on a compound of formula II-1 and an organic tin reagent of formula III-1 in an organic solvent in the presence of a catalyst to produce a heterocyclic compound of formula I:

where X ¹ represents Br or Cl.

The methods and conditions for the Still coupling reaction are generally accepted in the art for such reactions. For example:

The organic solvent is preferably a cyclic ether solvent (eg tetrahydrofuran and/or dioxane) and/or an aromatic hydrocarbon solvent (eg toluene). The amount of the organic solvent is not limited to a specific value as long as the reaction proceeds.

The catalyst is preferably Pd(PPh ₃ ) ₄ . The molar ratio of catalyst to compound of formula II-1 may be 1:5-1:20 (eg 1:10).

The molar ratio of the compound of formula II-1 to the organic tin reactant of formula III-1 may be a conventional molar ratio in the art, and the molar ratio of the compound of formula II-1 to the organic tin reactant of formula III-1 is preferably 1:3 to 1:4 .

The Stille reaction temperature may be 85-110°C (eg 95-100°C).

The progress of the reaction can be monitored by detection methods conventional in the art (eg, TLC, GC, NMR or HPLC) and preferably by detecting the disappearance of the compound of formula 11-1 as the end point of the reaction.

In a preferred embodiment of the present invention in the diagram, IQ is unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₆ -C ₁₀ aryl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl , unsubstituted or substituted C ₃ -C ₅ heterocycloalkenyl or unsubstituted or substituted 5-6-membered heteroaryl.

Scheme II involves the following step: performing a Suzuki coupling reaction as shown below on a compound of formula II-2 and a compound of formula II1-2 in a solvent in the presence of a catalyst and a basic reagent to produce a heterocyclic compound of formula I:

where X ² represents Br or Cl.

Suzuki coupling reaction methods and conditions are generally accepted in the art for such reactions. For example:

The solvent may be water and an organic solvent, and the organic solvent is preferably a cyclic ether solvent (eg, tetrahydrofuran and/or dioxane). The amount of the organic solvent is not limited to a specific value as long as the reaction proceeds.

The catalyst is preferably Pd(PPh ₃ ) ₄ . The molar ratio of catalyst to compound of formula II-2 may be 1:5-1:20 (eg 1:20).

The main reactant may be Na ₂ CO ₃ , and the molar ratio of the main reactant to the compound of Formula II-2 may be 1:1 to 5:1 (eg, 3:1).

The molar ratio of the compound of formula II-2 to the compound of formula III-2 may be a conventional molar ratio in the art, and the molar ratio of the compound of formula II-2 to the compound of formula III-2 is preferably 1:1 to 1:1.2.

The Suzuki coupling reaction temperature can be 90-100°C.

The progress of the reaction can be monitored by detection methods conventional in the art (eg TLC, GC, NMR or HPLC) and preferably by detecting the disappearance of the compound of formula II-2 as the end point of the reaction.

In a preferred embodiment of the present invention in Scheme II, Q is unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₆ -C ₁₀ aryl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl, unsubstituted or substituted C ₃ -C ₅ heterocycloalkenyl or unsubstituted or substituted 5-6-membered heteroaryl.

Scheme III involves the following step: reacting as shown below with a compound of formula II-3, a compound of formula III-3 and formaldehyde in an organic solvent to obtain a heterocyclic compound of formula I:

The reaction methods and conditions are generally accepted in the art for such reactions. For example:

The organic solvent is preferably a carboxylic acid solvent (eg acetic acid). The amount of the organic solvent is not limited to a specific value as long as the reaction proceeds.

The formaldehyde may be an aqueous solution of formaldehyde, and preferably an aqueous solution of formaldehyde at 37 wt. %; and the molar ratio of formaldehyde to the compound of formula II-2 may be 1:1.

The molar ratio of the compound of formula II-2 to the compound of formula III-2 may be a conventional molar ratio in the art, and the molar ratio of the compound of formula II-2 to the compound of formula III-2 is preferably 1.2:1 to 1:1. 2.

The reaction temperature can be 40-60°C.

The progress of the reaction can be monitored by detection methods conventional in the art (eg TLC, GC, NMR or HPLC) and preferably by detecting the disappearance of the compound of formula II-3 as the end point of the reaction.

In a preferred embodiment of the present invention in Scheme III, Z ³ represents a carbon atom; R ² represents preferably .

Scheme IV involves the following step: reacting as shown below with a compound of formula II-3 and a compound of formula III-4 in an organic solvent to obtain a heterocyclic compound of formula I:

where X ³ represents a leaving group (eg -OM, Br or Cl).

The reaction methods and conditions are generally accepted in the art for such reactions. For example:

The organic solvent is preferably an amide solvent (eg N,N-dimethylformamide). The amount of the organic solvent is not limited to a specific value as long as the reaction proceeds.

The main reactant may be potassium tert-butoxide, and the molar ratio of the main reactant to the compound of Formula II-3 may be 2:1-3:1 (eg, 2.2:1).

The molar ratio of the compound of formula II-3 to the compound of formula III-4 may be a conventional molar ratio in the art, and the molar ratio of the compound of formula II-3 to the compound of formula III-4 is preferably 1.2:1 to 1:1. 2.

The reaction temperature can be 100-120°C.

The progress of the reaction can be monitored by detection methods conventional in the art (eg TLC, GC, NMR or HPLC) and preferably by detecting the disappearance of the compound of formula II-3 as the end point of the reaction. In the preferred embodiment of the present invention in Scheme IV, R ² represents and preferably

Scheme V includes the following step: performing an amidation reaction as shown below on a compound of formula I (where R ² is is and Y is -NH-) and a compound of formula III-5 in an organic solvent in the presence of a basic reagent to give a heterocyclic compound of formula I (where Y is

where X ⁴ represents a halogen (eg Br or Cl).

The amidation reaction methods and conditions are generally accepted in the art for such reactions. For example:

The organic solvent is preferably a halogenated alkane solvent (eg dichloromethane). The amount of the organic solvent is not limited to a specific value as long as the reaction proceeds.

The basic reactant may be N,N-diisopropylethylamine, and the molar ratio of the basic reactant to the compound of Formula II-4 may be 2:1 to 4:1 (eg, 3:1).

The molar ratio of the compound of formula II-4 to the compound of formula III-5 may be a conventional molar ratio in the art, and the molar ratio of the compound of formula II-4 to the compound of formula III-5 is preferably 1.2:1 to 1:1. 2.

The temperature of the amidation reaction can be -10-20°C.

The progress of the amidation reaction can be monitored using detection methods known in the art (eg TLC, GC, NMR or HPLC), and preferably by detecting the disappearance of the compound of formula II-4 as the end point of the reaction.

Scheme VI includes the following step: carrying out a deprotection reaction as shown below on a compound of formula II-4 and a compound of formula III-5 in an organic solvent in the presence of an acid to obtain a heterocyclic compound of formula I:

where Y represents -NH-.

The deprotection reaction methods and conditions are generally accepted in the art for such reactions. For example:

The organic solvent is preferably an alcohol solvent (eg ethanol). The amount of the organic solvent is not limited to a specific value as long as the reaction proceeds.

The acid may be hydrochloric acid, and the molar ratio of acid to compound of Formula II-4 may be 1:1 to 4:1 (eg, 1.5:1).

The deprotection reaction temperature can be -10-20°C.

The progress of the amidation reaction can be monitored using detection methods known in the art (eg TLC, GC, NMR or HPLC), and preferably by detecting the disappearance of the compound of formula II-4 as the end point of the reaction.

Scheme VII includes the following step: carrying out a displacement reaction as shown below on a compound of formula II-5 and NH(R ^1-9 R ^1-10 ) in an organic solvent to obtain a heterocyclic compound of formula I (wherein Q is -S( =O) ₂ -N(R ^1-9 R ^1-10 )):

where X ⁵ represents Br or Cl.

The reaction methods and conditions are generally accepted in the art for such reactions. For example:

The organic solvent is preferably a nitrile solvent (eg acetonitrile). The amount of the organic solvent is not limited to a specific value as long as the reaction proceeds.

The molar ratio of the compound of formula II-5 to NH(R ^1-9 R ^1-10 ) may be 1:1-1:5.

NH(R ^1-9 R ^1-10 ) may be in a form conventional in the art, for example, in the form of aqueous ammonia when it is NH ₃ .

The reaction temperature may be -10-20°C (eg 0°C).

The progress of the reaction can be monitored by detection methods conventional in the art (eg TLC, GC, NMR or HPLC) and preferably by detecting the disappearance of the compound of formula II-3 as the end point of the reaction.

Scheme VIII includes the following step: carrying out a deprotection reaction as shown below on a compound of Formula II-6 or Formula II-61 in an organic solvent in the presence of an acid to obtain a heterocyclic compound of Formula I

where X ⁶ , X ^6' and X ^6'' represent N protecting groups.

In a preferred embodiment, when X ⁶ , X ^6' and X ^6'' are N protecting groups, the N protecting group may be 4-methoxybenzyl (PMB).

The reaction methods and conditions are generally accepted in the art for such reactions. For example:

The organic solvent is preferably a halogenated alkane solvent (eg dichloromethane). The amount of the organic solvent is not limited to a specific value as long as the reaction proceeds.

The acid may be trifluoromethanesulfonic acid, and the volume/weight ratio of the acid to the compound of Formula II-6 or Formula II-6' may be 1-5 ml/g (eg, 3-4 ml/g).

The reaction temperature may be 0-100°C (eg 30-50°C).

The progress of the reaction can be monitored by conventional detection methods in the art (eg TLC, GC, NMR or HPLC) and preferably by detecting the disappearance of the compound of formula II-6 or formula II-6' as the end point of the reaction.

In the present invention, after completion of the reaction, conventional treatment methods can be used for treatment. In the present invention, after workup, if the crude product of the heterocyclic compound of formula I is obtained, conventional means such as preparative HPLC, preparative TLC or recrystallization can be used for separation and purification.

The present invention also relates to a compound of formula II-1, II-2, II-3, II-4, II-5, II-6 or II-6':

R ³ , R ² , R ¹ , W, X, Y, R ^2-1 , R ^2-2 , n, m, X ⁵ , X ⁶ , X ^6' , X ^6'' and X ¹ have definitions like described above.

The present invention also provides the following compounds:

The present invention also provides a pharmaceutical composition for the prevention, treatment or amelioration of diseases in an animal that are mediated at least in part by P2X3 or associated with P2X3 activity, comprising a heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical composition may also contain one or more additional active ingredients. For example, such a pharmaceutical composition may contain one or more additional heterocyclic compounds of Formula I or pharmaceutically acceptable salts, hydrates, solvates, metabolites, stereoisomers, tautomers or prodrugs thereof. Alternatively or in addition, the pharmaceutical composition may, for example, contain one or more active ingredients other than a heterocyclic compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug thereof.

The pharmaceutical composition contains a therapeutically effective amount of a heterocyclic compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug thereof.

An effective amount of a compound, pharmaceutical composition or drug disclosed herein can be readily determined through routine experimentation, and the most effective and convenient route of administration and the most suitable method of preparation can also be determined through routine experimentation.

Pharmaceutically acceptable excipients may be those commonly used in the pharmaceutical industry. Excipients are generally used to provide a safe, stable and functional pharmaceutical composition, and may also provide methods for dissolving active ingredients at a desired rate or for promoting efficient absorption of active ingredients after administration of the composition to a subject. Pharmaceutically acceptable excipients may be excipients or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. Pharmaceutically acceptable excipients may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, release agents, glidants, wetting agents, gelling agents, absorption retarding agents, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, dyes, flavorings and sweeteners.

Substances that can serve as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; whey proteins, such as human serum protein; buffering agents such as phosphate; glycine; sorbic acid; potassium sorbate; a partial mixture of saturated vegetable fatty acid glycerides; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salt; colloidal silicon dioxide; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate; waxes; polyethylene-polyoxypropylene blocking polymer; lanolin (wool fat); sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffered saline and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colors, releasing agents, coating agents, sweeteners, flavors and fragrances, preservatives and antioxidants.

The pharmaceutical composition described herein may be prepared as described by any method known to those skilled in the art, for example, by conventional methods of mixing, dissolving, granulating, emulsifying, levigating, encapsulating, embedding, or lyophilizing.

The compound described herein may be provided in pharmaceutical dosage forms, including immediate release, controlled release, sustained release, or targeted drug release systems. For example, typical dosage forms include solutions and suspensions, (micro)emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft- or hard-shell capsules, suppositories, vaginal suppositories (ovules), implants, amorphous or crystalline powders, aerosols and lyophilized preparations. Depending on the route of administration, special devices for drug administration or delivery may be required, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks. Pharmaceutical dosage forms often include drugs, excipients and packaging/closure systems. One or more excipients (also known as inactive ingredients) may be added to a compound described herein to improve or facilitate drug production, stability, administration, and safety, and may provide a means of achieving a desired drug release profile . Thus, the types of excipients added to a drug may depend on various factors, such as the physical and chemical properties of the drug, route of administration, and methods of preparation. Pharmaceutical excipients may be used in the art, including those listed in various pharmacopoeias. (See United States Pharmacopoeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP) and British Pharmacopoeia (BP); publications of the Center for Drug Evaluation and Research (CEDR) of the US Food and Drug Administration (www.fda .gov), e.g., Inactive ingredient Guide, 1996; and Handbook of Pharmaceutical Additives, 2002, edited by Ash & Ash, Synapse Information Resources, Inc., Endicott NY; etc.)

Pharmaceutical dosage forms of the compound disclosed herein can be prepared by any method well known in the art, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tableting, suspending, extruding, spray drying, grinding , emulsification, (nano/micro)encapsulation, embedding or lyophilization. As described above, the composition described herein may contain one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecules into preparations for pharmaceutical use.

Appropriate drugs will be determined according to the desired route of administration. For example, for intravenous injection, the composition can be prepared in an aqueous solution and, if necessary, physiologically compatible buffers, including, for example, phosphate, histidine or citrate to adjust the pH of the drug and tonic agents such as sodium chloride or dextrose. For transmucosal or nasal administration, a semi-solid liquid preparation or patch, possibly containing a penetration enhancer, may be preferred; and a penetration enhancer is generally known in the art. For oral administration, the compound can be prepared in liquid or solid dosage forms and used as immediate release or controlled/sustained release formulations. Suitable dosage forms for oral administration by an individual include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, ointments, suspensions and emulsions. The compound may also be formulated in rectal compositions such as suppositories or retention enemas, for example containing conventional suppository matrices such as cocoa butter or other glycerides.

Oral solid dosage forms can be prepared using excipients including fillers, disintegrants, binders (dry and wet), dissolution inhibitors, lubricants, lubricants, release agents, cationic ion exchange resins, wetting agents, antioxidants, preservatives, colors and flavors. . These excipients may be synthetic or natural sources. Examples of such excipients include cellulose derivatives, citric acid, calcium hydrogen phosphate, gelatin, magnesium carbonate, magnesium/sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicates, silicon dioxide, sodium benzoate, sorbitol, starches, stearic acid or salts thereof, sugars ( i.e. dextrose, sucrose, lactose, etc.), talc, mucilage of tragacanth, vegetable oils (hydrogenated) and waxes. Ethanol and water can be used as adjuvants for granulation. In some cases, it is desirable to coat the tablets with, for example, a taste masking film, a stomach acid resistant film, or a sustained release film. Natural and synthetic polymers are often used to coat tablets in combination with dyes, sugars and organic solvents or water to form pills. When capsules are superior to tablets, pharmaceutical powders, suspensions or solutions can be delivered in the form of compatible hard or soft shell capsules.

In some embodiments, a compound described herein can be administered topically, for example, through a skin patch, semi-solid or liquid formulation such as gels, (micro)emulsions, ointments, solutions, (nano/micro)suspensions or foams. The penetration of drugs into the skin and underlying tissues can be modulated by: for example, the use of penetration enhancers; using appropriate selection and combination of lipophilic, hydrophilic and amphiphilic excipients, including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants and emulsifiers; by adjusting the pH value; and the use of complexing agents. Other techniques, such as iontophoresis, can also be used to modulate the skin penetration of a compound disclosed herein. Transdermal or topical administration will be preferred, for example, in situations where local administration with minimal systemic exposure is desired.

For inhalation or nasal administration, the compound used herein is conveniently administered in the form of solutions, suspensions, emulsions or semi-solid aerosols from pressurized packs or nebulizers, typically with propellants such as halohydrocarbons derived from methane and ethane, carbon dioxide or any other suitable gas. Hydrocarbons such as butane, isobutene and pentane are suitable for topical aerosols. In the case of a pressurized aerosol, the appropriate dosage unit can be determined by providing a valve flow measurement. Capsules and cartridges containing, for example, gelatin, can be prepared for use in an inhaler or insufflator.

They typically contain powder mixtures of compounds with suitable powder matrices such as lactose or starch.

Compositions prepared for parenteral administration by injection are generally sterile and may be presented in unit dosage form, for example, in ampoules, syringes, pens or multiple dose containers, the latter usually containing preservatives. The compositions may take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain agents such as buffers, tonic agents, viscosity enhancers, surfactants, suspending and dispersing agents, antioxidants, biocompatible polymers, chelating agents and preservatives. Depending on the injection site, the carrier may contain water, synthetic or vegetable oils and/or organic co-solvents. In some cases, such as lyophilized products or concentrates, parenteral drugs will be reconstituted or diluted prior to administration. Depot formulations that provide controlled or sustained release of a compound disclosed herein may include injectable suspensions of nano/microparticles or nano/micro or non-micronized crystals. Other matrices well known in the art, polymers such as poly(lactic acid), poly(glycolic acid), or copolymers thereof, can be used as controlled/sustained release matrices. Other depot delivery systems may come in the form of implants and pumps that require incisions.

Suitable carriers for intravenous administration of the compound described herein are well known in the art and include aqueous solutions containing a base (eg, sodium hydroxide) to form the ionic compound, sucrose or sodium chloride as a tonic agent, and buffers, for example, containing phosphate or histidine. A co-solvent such as polyethylene glycol may be added. These aqueous-based systems can effectively dissolve the compound described herein and provide low toxicity after systemic administration. The proportion of solution system components can vary significantly without affecting the solubility and toxicity characteristics. Additionally, component properties may change. For example, low toxicity surfactants such as polysorbate or poloxamer may be used, polyethylene glycol or other cosolvents may be used, biocompatible polymers such as polyvinylbenzidine may be added, and other sugars and polyols may be used in place of dextrose.

The therapeutically effective dose may first be assessed using various methods well known in the art. Initial dosing for animal studies may be based on established effective concentrations in cell culture assays. Dosage ranges suitable for human individuals can be determined, for example, using data obtained from animal studies and cell culture assays. In some embodiments, a compound described herein can be formulated into a dosage form for oral administration.

An effective or therapeutically effective amount or dosage of a drug (eg, a compound described herein) refers to the amount of the drug or compound that causes an improvement in symptoms or an increase in survival in an individual. The toxicity and therapeutic efficacy of a molecule can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, for example by measuring the LD ₅₀ (lethal dose for 50% of the population) and ED ₅₀ (therapeutically effective dose for 50% of the population). The dose ratio of toxic and therapeutic effects represents the therapeutic index and can be expressed as LD ₅₀ /ED ₅₀ . Preferred are drugs that demonstrate high therapeutic performance.

An effective or therapeutically effective amount is an amount of a compound or pharmaceutical composition that will produce a biological or medical response in a tissue, system, animal, or human being sought by a researcher, veterinarian, physician, or other clinician. The dosage is preferably within a range of circulating concentrations that include the ED ₅₀ with minimal or no toxicity. The dosage may vary within this range depending on the dosage form used and/or the route of administration used. The correct drug, route of administration, dose and time interval between administrations must be selected based on methods known in the art, taking into account the specificity of the individual condition.

The dosage and timing may be adjusted individually to provide plasma levels of the active moiety sufficient to achieve the desired effect; those. minimum effective concentration (MEC). The MEC for each compound will vary but can be estimated, for example, from in vitro data and animal experiments. The dosage required to obtain MEC will depend on individual characteristics and route of administration. When administered topically or selectively absorbed, the effective local drug concentration may be unrelated to plasma concentration.

The amount of drug or composition administered may depend on various factors, including the sex, age and weight of the subject being treated, the severity of the lesion, the route of administration and the judgment of the prescribing physician.

If desired, the composition disclosed herein may be presented in a package or dispensing device containing one or more unit dosage forms containing the active ingredients. For example, the package or device may comprise metal or plastic foil (such as a foam pouch) or glass and a rubber stopper, such as in a bottle. The package or dosing device may be accompanied by instructions for administration. A composition containing a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, packaged in an appropriate container, and labeled for the treatment of a specific condition.

The present invention also relates to the use of a heterocyclic compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug or pharmaceutical composition thereof for the preparation of a P2X3 inhibitor.

The present invention also provides the use of a heterocyclic compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug or pharmaceutical composition for the preparation of a drug. The drug is used for the prevention, treatment or amelioration of diseases in an animal that are mediated at least in part by P2X3 or associated with P2X3 activity; alternatively, the drug is used to treat pain, urinary tract disease or respiratory disease.

In some embodiments, the medicament can be used to treat a urinary tract disorder in an animal (eg, a human), including, but not limited to: urinary incontinence, overactive bladder, dysuria, or cystitis.

In some embodiments, the medicament can be used to treat respiratory diseases in an animal (eg, a human), including, but not limited to: respiratory disorders including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or chronic cough.

In some embodiments, the medicament may be used to treat pain in an animal (eg, human), including, but not limited to: inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, burn pain, migraine. , cluster headache or chronic pain.

The present invention also relates to the use of a heterocyclic compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug or pharmaceutical composition for the treatment and prevention of diseases.

The present invention also relates to the use of a heterocyclic compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug or pharmaceutical composition thereof for the prevention, treatment, treatment or amelioration of diseases in an animal (eg, human) mediated by at least partially P2X3 or related to P2X3 activity. Conditions include, but are not limited to: respiratory diseases, cough, chronic cough, idiopathic pulmonary fibrosis, chronic pulmonary obstruction, asthma, pain, urinary incontinence, autoimmune diseases, overactive bladder, dysuria, inflammation, dementia, Parkinson's disease, sleep disorders , epilepsy, psychiatric diseases, arthritis, neurogene generation, traumatic brain injury, myocardial infarction, rheumatoid arthritis, cerebral stroke, thrombosis, atherosclerosis, colon syndrome, inflammatory bowel diseases, diseases of the digestive tract, gastrointestinal dysfunction, respiratory failure, sexual dysfunction, cardiovascular diseases, heart failure, arterial hypertension, urinary incontinence, cystitis, arthritis, endometriosis, hematopathy, developmental disorders of the musculoskeletal system and connective tissue or systemic diseases.

In some embodiments, the diseases include pain, including, but not limited to: inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain caused by burns, migraines, or cluster headaches.

In some embodiments, the diseases include urinary tract diseases.

In some embodiments, the diseases include respiratory diseases, including, but not limited to: respiratory disorders, including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or chronic cough.

The present invention further provides a method of treating or preventing diseases, comprising administering to a patient an effective dose of a heterocyclic compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug or pharmaceutical composition thereof.

Definitions and general terms

Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention relates. All patents and publications mentioned herein are incorporated herein by reference in their entirety.

Unless otherwise noted, the following definitions as used herein apply. For the purposes of the present invention, the chemical elements correspond to the Periodic Table of the Elements (CAS version) and "Handbook of Chemistry and Physics", 75th edition, 1994. In addition, general principles of organic chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books , Sausalito:1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, which are incorporated herein by reference in their entirety.

The term “include,” “includes,” or “including” is open-ended, that is, it includes what is intended by the present invention, but not to the exclusion of other aspects.

The term "stereoisomer" refers to compounds that have the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers and the like.

The term "enantiomer" refers to two isomers of a compound that do overlap but are mirror images of each other.

The term "diastereoisomer" refers to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography (eg HPLC).

Stereochemical definitions and rules used in this document generally conform to S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Any asymmetric atom (eg, carbon, etc.) of a compound described herein may exist in a racemate or enantiomeric form enriched, for example, in an (R)-, (S)-, or R,S-configuration. In some embodiments, each asymmetric atom has at least 0% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least at least 95% enantiomeric excess or at least 99% enantiomeric excess of the (R)- or (S)-configuration.

Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers and diastereomers depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible at a low energy barrier. If a tautomer is possible (for example, in solution), chemical equilibrium of the tautomer can be achieved. For example, a protic tautomer, also known as a prototropic tautomer, involves proton transfer interconversions such as keto-enol isomerization and imine-dynamin isomerization. The valence tautomer involves interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerization is the interversion of the tautomers of pentan-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interversion of the tautomers of pyridin-4-ol and pyridin-4(1H)-one. Unless otherwise indicated, all tautomeric forms of the compound described herein are included within the scope of the present invention.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a particular substituent. In addition, when a group is substituted with one or more substituents described above, the substituents are independent of each other, that is, one or more substituents may be different from each other or the same. Unless otherwise indicated, substitution of a substituent may occur at various substitutable positions of a substituted group. When more than one position in a given structure can be replaced by one or more substituents selected from particular groups, the substitution of the substituents can occur at different positions in the same or different ways.

As will be appreciated by those skilled in the art, , as used in a structural formula describing groups herein, means that the corresponding groups are connected to other moieties and groups in connection through that region in accordance with the conventions used in the art.

In each part of the present specification, substituents of the disclosed compound are described according to types or ranges of groups. In particular, it should be noted that each individual sub-combination of the various members of these types and ranges of groups is covered by the present invention. For example, the term "C ₁ -C ₆ alkyl" or "C _1-6 alkyl" may be linear or branched and particularly refers to the independently described methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl; "C _1-4 alkyl" specifically refers to the independently described methyl, ethyl, C ₃ alkyl (i.e., propyl, including n-propyl and isopropyl), and C ₄ alkyl (i.e., butyl, including n-butyl, isobutyl , etor-butyl and tert-butyl).

In each part of the present invention, connecting substituents are described. If a structure explicitly requires a join group, the Markush variables listed for that group should be treated as join groups. For example, if a linking group is required in the structure, and “alkyl” or “aryl” is listed to define the Markush group associated with the variable, then “alkyl” or “aryl” is understood to represent a connected alkylene group or arylene group, respectively.

The term "alkyl" as used herein refers to a linear or branched saturated monovalent hydrocarbon radical containing 1-20 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-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, n-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, n-heptyl, n-octyl and the like.

In some specific structures, when an alkyl group is explicitly designated as a connecting group, the alkyl group is a linked alkylene group, for example, C ₁ -C ₆ alkyl in the group "halogenated C ₁ -C _b alkyl" should be considered C ₁ -C ₆ alkylene .

The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a linear or branched saturated hydrocarbon radical. Examples of alkylene groups include methylene (-CH ₂ -), ethylidene (including -CH ₂ CH ₂ - or -CH(CH ₃ )-), isopropylene (including -CH(CH ₃ )CH ₂ - or -C(CH ₃ ) ₂ -) and the like.

The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical containing 2-12 carbon atoms where there is at least one unsaturated site, that is, an sp2 carbon-carbon double bond, which includes the positioning "cis" and "tane", or positioning "E" and "Z". Examples of alkenyl groups include, but are not limited to, ethenyl (-CH= _CH2 ), allyl ( _-CH2CH = _CH2 ) and the like.

The term "alkoxy" or "alkyl-O" means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group is described herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy and the like.

The term "haloalkyl", "haloalkoxy" or "haloalkyl-O" means that the alkyl or alkoxy group is substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy and the like.

The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic or bicyclic system containing 3-12 ring carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like; where C ₃ -C ₆ cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "cycloalkenyl" refers to an unsaturated monocyclic carbocycloalkenyl group containing 3-6 ring carbon atoms ("C ₃ -C ₆ cycloalkenyl"). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cyclohexadienyl and the like.

The term “heterocycloalkyl” refers to a saturated monocyclic or bicyclic system containing 3-10 ring atoms, which may include fused, bridged or spiro ring systems (eg, bicyclic systems (“bicyclic heterocycloalkyl”)); wherein the monocyclic or bicyclic system contains 3-9 ring carbon atoms and at least one ring heteroatom selected from nitrogen, sulfur and oxygen (“C ₃ -C ₉ heterocycloalkyl”). A bicyclic heterocycloalkyl system may contain one or more heteroatoms in one or two rings and is saturated. Unless otherwise specified, heterocycloalkyl may be carbon or nitrogen based, and the -CH ₂ group may be optionally substituted with -C(=O)-. The sulfur atom in the ring may optionally be oxidized to an S-oxide. The ring nitrogen atom may optionally be oxidized to an N-oxide. In some embodiments, the heterocycloalkyl is a C ₃ -C ₅ heterocycloalkyl, which means that the heterocycloalkyl contains 3-5 ring carbon atoms and at least one ring heteroatom selected from O, S, and N. Examples of heterocycloalkyl include, but are not limited to are limited to: oxiranyl, thietanyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, tetrahydropyrimidinyl, oxazinanyl, thiomorpholinyl, piperazinyl and the like. Examples of substitution of -CH ₂ -group by -C(=O)- in heterocycloalkyl include, but are not limited to, 2-oxopyrrolidinyl, 2-piperidonyl, 3-morpholinonyl, 3-thiomorpholinonyl and oxotetrahydropyrimidinyl and the like or isomers and stereoisomers thereof. In some embodiments, typical C ₃ -C ₉ heterocycloalkyl groups include, but are not limited to, the C ₃ -C ₅ heterocycloalkyl groups described above in combination with azepanil, oxepanil, tiepanil, diazepanil, azocanil, oxecanil, thiocanil, quinuclidinyl, octahydroinolinyl, octahydroisoindolyl, decahydroquinolinyl, decahydroisoquinolinyl or isomers and stereoisomers thereof.

The term "heterocycloalkenyl" refers to a monocyclic or bicyclic system containing partially unsaturated alkenyl groups, which contains 3-9 ring carbon atoms and at least one ring atom selected from nitrogen, sulfur and oxygen atoms ("C ₃ -C ₉ heterocycloalkenyl"); where heterocycloalkenyl is non-aromatic and does not contain any aromatic ring. Unless otherwise specified, heterocycloalkenyl may be carbon or nitrogen based, and the -CH ₂ group may be optionally substituted with -C(=O)-. The sulfur atom in the ring may optionally be oxidized to an S-oxide. The ring nitrogen atom may optionally be oxidized to an N-oxide. In some embodiments, the heterocycloalkenyl is preferably C ₃ -C ₅ heterocycloalkenyl; examples of C ₃ -C ₅ heterocycloalkenyl include, but are not limited to, dihydrofuranyl, dihydrothienyl, dihydropyrrolyl, dioxolyl, dihydroimidazolyl, dihydropyrazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridinyl, 3,4- dihydro-2H-pyran, pyranyl, thiopyranyl, dihydropyridinyl, dihydropyrazinyl, dihydropyrimidinyl, oxazinyl and dihydrotetrazolyl or their isomers and stereoisomers. In some embodiments, typical C ₃ -C ₉ heterocycloalkenyl groups include, but are not limited to, C ₃ -C ₅ heterocycloalkenyl groups described above in combination with octahydroisoquinolinyl, 3H-indolyl, dihydroisoquinolinyl, dihydroquinolyl, or 4H-quinolisinyl, or isomers thereof and stereoisomers.

The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "aryl" refers to monocyclic, bicyclic and tricyclic carbon ring systems containing 6-14 ring atoms or 6-10 ring atoms. Examples of aryl groups may include phenyl, naphthyl and anthryl. Unless otherwise specified, the group "C ₆ -C ₁₀ aryl" refers to a caryl group containing 6-10 ring carbon atoms.

The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic systems containing 5-6 ring atoms or 5-10 ring atoms or 5-12 ring atoms, where at least one ring contains one or more heteroatoms in the ring selected from nitrogen, oxygen and sulfur. Unless otherwise specified, the heteroaryl group can be attached to the rest of the molecule (eg, the host structure in the formula) through any reasonable site (which may be a C in CH or an N in NH). Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl and the like; and include, but are not limited to, the following bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl, oxoindolyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl and the like.

In addition, it should be noted that, unless expressly stated otherwise, the description "...independently" as used herein is to be taken broadly to mean that each distinct group described is independent of the others and may be independently the same or different specific group. In more detail, the description "...independent" could mean that specific options expressed by the same symbols in different groups do not affect each other; it can also mean that specific options expressed by the same symbols in the same group do not affect each other.

The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically cause an allergic or similar adverse reaction, such as gastrointestinal distress and dizziness, when administered to a human.

The term "carrier" refers to the diluent, adjuvant, excipient or matrix with which the compound is administered. Such pharmaceutical carriers may be sterile liquids such as water and oil, including those derived from petroleum, animals, plants, or synthetically, such as peanut oil, soybean oil, mineral oil, and sesame oil. Preferably, water or aqueous physiological solutions and aqueous solutions of dextrose and glycerol, in particular injection solutions, are used as carriers. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E.W. Martin.

As used herein, the term “prodrug” is a compound that is converted in vivo to a compound of Formula I. Such conversion is accomplished by hydrolysis of the prodrug in the blood or enzymatic conversion of the prodrug to its parent structure in the blood or tissue. The prodrugs described herein may be esters, and in the prior art, esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a hydroxyl-containing compound described herein can be acylated to form a prodrug. Other prodrugs include phosphate esters, and these phosphate esters are produced by phosphorylation through a hydroxyl on the parent structure. For a complete discussion of prodrugs, reference may be made to the following: T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the ACS, Symposium Series; Edward B. Roche, ed., Bioreversible Carriers Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautioetai.; Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and S. J. Heckeretal., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

The term "metabolite" as used herein refers to the product obtained by metabolism of a particular compound or salt thereof in vivo. Metabolites of a compound can be identified by methods well known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic digestion and the like of the input compound. Accordingly, the present invention includes metabolites of a compound, including metabolites obtained by contacting a compound disclosed herein with a mammal for a sufficient period of time.

The term "pharmaceutically acceptable salt" as used herein refers to both organic and inorganic salts of the compound described herein. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. pharmaceutically acceptable salts are described in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.

Pharmaceutically acceptable salts formed with non-toxic acids include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate; organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate; or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate , hexanoate, hydrate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate , thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Salts formed with suitable bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternary ammonium salts formed by any compound containing an N group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal that can form salts include sodium, lithium, potassium, calcium, magnesium and the like. Pharmaceutically acceptable salts further include suitable and non-toxic ammonium salts, quaternary ammonium salts and amine cations formed by counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8 sulfonates and aromatic sulfonates.

"Solvate" as described herein refers to the association of one or more solvent molecules with a compound described herein. Solvents that form the solvate include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" refers to the association of solvent molecules with water.

"Ester" as described herein refers to an ester that is hydrolyzed in vivo and formed by a hydroxyl or carboxyl containing compound. Such esters are, for example, pharmaceutically acceptable esters that are hydrolyzed in the human or animal body to produce the parent alcohol or acid. The compound of Formula I disclosed herein contains a carboxyl which can form an ester when hydrolyzed in vivo with appropriate groups including, but not limited to, alkyl, arylalkyl and the like.

"Nitroxide" as disclosed herein refers to an N-oxide formed by the oxidation of one or more nitrogen atoms when the compound contains multiple amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. Appropriate amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (eg, peroxycarboxylic acid) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the L.W. process. Deady (Syn. Comm. 1977, 7, 509-514), in which the amine compound reacts with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

In some embodiments, the term “treating,” “treating,” or “treating,” as used herein, refers to alleviating diseases or disorders (i.e., slowing, stopping, or reducing the progression of diseases or at least one clinical symptom). In other embodiments, “treat,” “treat,” or “provide a treatment” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treating,” “treating,” or “providing a treatment” refers to modulating a disease or disorder either physically (eg, stabilizing a tangible symptom), physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, “treating,” “treating,” or “treating” refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

Unless otherwise indicated, abbreviations for any of the protecting groups, amino acids and other compounds used herein are presented on the basis of their commonly used and accepted abbreviations or by reference to the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem.1972, 11 :942-944).

The biological activity of the compound described herein can be assessed using any generally known method. Suitable detection methods are well known in the art. For example, a compound described herein may be tested for P2X3 inhibitory activity, pharmacokinetic activity and/or liver microsomal stability, etc. in the appropriate normal manner. The detection methods proposed by the present invention are presented as examples only and do not limit the present invention. A compound disclosed herein is active in at least one of the detection methods provided by the present invention.

As used herein, terms such as “certain embodiments,” “examples,” or “preferred embodiment” mean that the particular feature, structure, material, or characteristic described with reference to the embodiment or example is included in at least one an embodiment or example of the present invention. In the present description, the schematic descriptions of the terms used above do not necessarily refer to the same embodiment or example. In addition, a particular feature, structure, material or characteristic described herein may be combined in any one or more embodiments or examples as appropriate. In addition, various embodiments or examples and features of various embodiments or examples described herein may be combined by one skilled in the art to the extent that they do not contradict each other.

The above preferred conditions may be combined arbitrarily to obtain preferred embodiments of the present invention without departing from the general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

Advantages of the present invention: The heterocyclic compound has high P2X3 antagonistic activity, good selectivity, low toxicity, good metabolic stability and little effect on taste, showing good prospects for drug development.

BRIEF DESCRIPTION OF THE DRAWINGS

In fig. 1 shows the number of coughs caused by citric acid for the compounds of the present invention compared to the vehicle;

In fig. 2 shows the latency of citric acid-induced cough for compounds of the present invention compared to vehicle;

In fig. 3 shows the number of coughs induced by citric acid for the compounds of the present invention compared to their baseline level;

In fig. 4 shows the number of coughs, cough suppression rate and cough latency obtained in vivo for a portion of the compounds of the present invention;

In fig. 5 shows the number of coughs for the compounds of the present invention in the ATP-citric acid model;

In fig. 6 shows cough latency for compounds of the present invention in the ATP-citric acid model;

In fig. 7 shows the ratio of quinine/tap water consumed by rats after administration of the compounds of the present invention; And

In fig. 8 illustrates the ratio of quinine/tap water consumed by rats after administration of compounds of the present invention at varying concentrations.

DETAILED DESCRIPTION

The present invention is further illustrated by the following examples, which are not intended to limit the invention. The unspecified experimental procedures in the following examples are carried out in accordance with traditional procedures and conditions or in accordance with commercial instructions.

In the present invention, the following abbreviations are used: TEMPO (2,2,6,6-tetramethyl-1-piperidone), LDA (lithium diisopropylamide), DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), DCM ( dichloromethane), DME (dimethoxyethane), PE (petroleum ether), EA (ethyl acetate), DIPEA (N,N-diisopropylethylamine), THF (tetrahydrofuran), Ac (acetyl), MeOH (methanol), Boc (tert-butoxycarbonyl), B2Pin2 (bis(pinacolato) diboron), rt (room temperature), HATU (2-(7-azabenzotriazol-1-yl) - N,N,N,N-tetramethyluronium hexafluorophosphate), arr. cold (conditions with reflux), eq. (equivalent), Rf (retention factor), g (gram), mg (milligram), mol (mol), mmol (millimole), h (hour), min (minute), ml (milliliter), µl (microliter).

The term "overnight" refers to 8-15 hours, for example 12 hours; the term "room temperature" refers to 10-30°C; the ratio of solvents such as PE/EA refers to the volume ratio.

Unless otherwise noted, all temperatures in the examples described below are in degrees Celsius. Unless otherwise specified, reagents are purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company and used without further purification. General reagents are purchased from Shantou Xilong Chemical Plant Co. Ltd., Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Co., Ltd.

Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are prepared by refluxing and drying with sodium metal. Anhydrous dichloromethane and chloroform are prepared by refluxing and drying with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide are pre-dried over anhydrous sodium sulfate.

The following reactions are usually carried out under positive pressure of nitrogen or argon, or by placing a drying tube over an anhydrous solvent (unless otherwise stated), sealing the reaction flask with a suitable rubber stopper, and injecting the substrate with a syringe. Each piece of glassware is dried.

The chromatography column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Haiyang Chemical Co., Ltd. NMR spectral data are obtained on a Bruker Avance 400 NMR spectrometer or a Bruker Avance IIIHD 600 NMR spectrometer using CDCl ₃ , DMSO-d6, CD3OD or acetone-c/6 as solvents (data reported in ppm) and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. If there are multiple peaks, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), br (extended), dd (doublet of doublets), dt (doublet of triplets), ddd (doublet of doublets) ), ddt (doublet of doublets of triplets), dddd (doublet of doublets of doublets of doublets). Coupling constants are expressed in hertz (Hz).

Low resolution mass spectrometry (MS) data are determined on an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and aG1316ATCC (column temperature maintained at 30°C), with a G1329An autosampler and a G1315BDAD detector used for analysis, and the ESI source supplied with the LC-MS spectrometer.

These two spectrometers are equipped with an Agilent ZorbaxSB-C18 column (2.1 x 30 mm, 5 µm). The injection volume is determined by the sample concentration; flow rate is 0.6 ml/min; HPLC peak values were recorded at wavelengths from the UV-visible range of 210 nm and 254 nm.

Example 1:

Step (1) Preparation of tert-butyl-(R)-2-formylmorpholine-4-carboxylate

A mixture of compound 1-1 (10 g, 460 mmol), TEMPO (0.073 g, 0.44 mmol), aqueous sodium bromide (0.5 M, 10 mL, 41 mmol) and dichloromethane (100 mL) was cooled to 0- 5°C. Sodium bicarbonate (2.3 g, 23 mmol) was added to the sodium hypochlorite solution (1.5 M, 34 mL, 58 mmol) and the solution was adjusted to pH 9.3 and added dropwise to the reaction system over 30 min. After the dropwise addition was completed, the reaction system was stirred for 0.5 h, heated to 20° C. and water (50 ml) was added. The aqueous phase was subjected to extraction with dichloromethane several times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 1-2 (6 g, 60% yield) as an orange-yellow oily liquid. LC-MS: [M+H] ⁺ =216.4.

Step (2) Preparation of tert-butyl-(S)-2-ethynylmorpholine-4-carboxylate

Dimethyl (1-diazo-2-oxopropyl) phosphonate (6 g, 31.3 mmol) was dissolved in a mixture of acetonitrile and methanol (5:1) and K ₂ CO ₃ (59 mmol) was added. The reaction system was stirred at 20°C for 15 min and a dissolved solution of compound 1-2 (6 g, 28 mmol) in a mixed solvent (10 ml) of acetonitrile and methanol (5:1) was slowly added dropwise. After the dropwise addition was completed, the reaction system was incubated at this temperature overnight. The suspension was filtered and the filtrate was concentrated under reduced pressure to give an oil, which was then added to water (about 100 ml) to precipitate a solid. The mixture was filtered and the filter cake was washed with water. The residue was purified by silica gel column chromatography to give compound 1-4 (3.4 g, 56.7% yield) as a solid. LC-MS: [M+H] ⁺ =212.1.

Stage 3.

To a solution of compound 1-4 (300 mg, 1.4 mmol), compound 1-5 (145 mg, 1.4 mmol) and compound 1-6 (145 mg, 1.4 mmol) in toluene (3 ml) was added CuCl (42 mg, 0.4 mmol) and Cu(CF ₃ SO ₃ ) ₂ (154 mg, 0.4 mmol) at room temperature. Under a nitrogen atmosphere, the reaction system was heated to 85°C, DME (0.1 ml) was added and reacted at this temperature for 5 hours. After completion of the reaction, water (15 ml) was added to the reaction system to quench the reaction, and extraction was carried out with dichloromethane ( 10 ml × 3), washed with saturated sodium chloride solution (10 ml × 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 1/1) to give intermediate 1-7 (500 mg) as a yellow oily liquid. LC-MS: [M+H] ⁺ =404.2.

Stage 4.

To a solution of intermediate 1-7 (3 g, 7.44 mmol) in THF (20 mL) was added LiOH (936 mg, 22.3 mmol) at 0°C. The reaction system was stirred at room temperature for 2 hours. After completion of the reaction, the reaction system was adjusted to pH 6 with HCl (1 M) at 0°C, extracted with DCM (10 mL x 3), washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate 1-8 (2 g) as a yellow oily liquid. LC-MS: [M+H] ⁺ =376.1.

Stage 5.

Intermediate 1-8 (375 mg) was dissolved in DCM (10 ml) and HATU (2 mmol) and DIPEA (4 mmol) were added. The reaction system was stirred at room temperature for 15 minutes, N,O-dimethylhydroxylamine hydrochloride (1.2 mmol) was added and stirred at room temperature for another 6-8 hours. After completion of the reaction, as monitored by TLC, the residue was purified with using column chromatography to obtain intermediate 1-10 (275 mg, 65.8% yield), LC-MS: [M+H] ⁺ =419.3.

Stage 6.

Intermediate 1-10 (418 mg, 1 mmol) was dissolved in anhydrous THF (10 ml) and methyl Grignard reagent was added dropwise at 0°C. After the dropwise addition was completed, the reaction system was stirred overnight. After completion of the reaction, the reaction system was quenched and the reaction system was extracted with ethyl acetate, washed, dried and purified by column chromatography to provide intermediate 1-11 (236 mg, 63.3% yield). LC-MS: [M+H] ⁺ =374.1.

Stage 7.

Intermediate 1-11 (373 mg) was dissolved in DCM (5 ml) and a solution of HCl in EtOH (1 N, 1.5 ml) was added dropwise at 0°C. Once the dropwise addition was complete, the reaction system was stirred for 2 h and poured into a NaHCO ₃ solution to adjust the pH to 8. The aqueous phase was extracted with DCM. The organic phase was washed with NaCl solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 1-12 (160 mg, 58.6% yield). LC-MS: [M+H] ⁺ =274.6.

Stage 8.

Intermediate 1-12 (273 mg, 1 mmol) and DIPEA (258 mg, 2 mmol) were dissolved in DCM (5 ml) and methyl chloroformate (compound 1-13) (282 mg, 3 mmol) was added. The reaction system was stirred at 0°C for 3 hours, poured into H ₂ O and extracted with DCM. The organic phase was washed with NaCl solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 1-14 (300 mg, 91% yield) as a yellow oil. LC-MS: [M+H] ⁺ =332.2.

Stage 9.

Intermediate 1-14 (331 mg, 1 mmol) was dissolved in tetrahydrofuran (5 ml) and water (2 ml) and N-bromosuccinimide (214 mg, 1.2 mmol) was added. The reaction system was reacted at room temperature for 1 hour under a nitrogen atmosphere. The reaction system was then concentrated to half volume, diluted with water (10 ml) and extracted with ethyl acetate (10 ml x 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate and concentrated to give intermediate 1-15 (300 mg, 73.3% yield) as a solid. LC-MS: [M+H] ⁺ =410.2.

Stage 10.

Intermediate 1-15 (0.82 g, 2 mmol) was dissolved in absolute ethanol (10 ml) and 1-acetylguanidine (242 mg, 2.4 mmol) and triethylamine (404 mg, 4 mmol) were added. The reaction system was heated to reflux. After completion of the reaction as determined by TLC, the reaction system was concentrated under reduced pressure, extracted with EA and washed. The residue was purified by column chromatography to give compound 1 (531 mg, 64.4% yield).

LC-MS: [M+H] ⁺ =413.2.

Example 2:

Step (1) Preparation of 2,6-difluoro-4-bromobenzaldehyde

3,5-difluorobromobenzene (10 g, 51.8 mmol) was dissolved in anhydrous THF (80 ml) and LDA (31 ml, 62.5 mmol) was added dropwise at -78°C under N ₂ atmosphere. After the dropwise addition was complete, the reaction system was stirred for 1 hour, DMF (4 mL, 51.9 mmol) was added and stirred for an additional 30 minutes. The reaction system was poured into NH4CI solution and subjected to extraction with ethyl acetate. The organic phase was washed with NaCl solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 2-2 (8 g, 70% yield) as a yellow solid.

Step (2) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-bromophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)-methyl) morpholine-4-carboxylate

Compound 2-2 (200 mg, 0.9 mmol), 2-amino-4-methylpyridine (100 mg, 0.9 mmol), Compound 1-4 (191 mg, 0.9 mmol), CuCl (27 mg, 0.27 mmol) and Cu(CF ₃ SO ₃ ) ₂ (100 mg, 0.27 mmol) were dissolved in toluene (3 ml). Under N ₂ atmosphere, the reaction system was heated to 85°C, DMA (0.05 ml) was added and stirred for 5 hours. The reaction system was then cooled to room temperature and incubated overnight. The resulting reaction system was poured into water (5 ml) and extracted with DCM (5 ml x 3). The organic phase was washed with saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA=1:1) to give intermediate 2-4 (100 mg, 21% yield) as a yellow oil. LC-MS: [M+H] ⁺ =522.3.

Step (3) Preparation of (S)-2-((2-(2,6-difluoro-4-bromophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)-methyl)morpholine

Intermediate 2-4 (100 mg) was dissolved in DCM (1 ml) and a solution of HCl in EtOH (0.5 ml) was added dropwise at 0°C. After the dropwise addition was completed, the reaction system was stirred for 2 hours and poured into NaHCO ₃ solution to adjust the pH to 8. The aqueous phase was extracted with DCM. The organic phase was washed with NaCl solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 2-5 (60 mg, 75% yield) as a yellow oil. LC-MS: [M+H] ⁺ =422.6.

Step (4) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-bromophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

Intermediate 2-5 (320 mg, 0.76 mmol) and DIPEA (86 mg, 0.91 mmol) were dissolved in DCM (5 mL) and methyl chloroformate (2-6) (86 mg, 0.91 mmol) was added. . The reaction system was stirred at 0°C for 3 hours, poured into H ₂ O and extracted with DCM. The organic phase was washed with NaCl solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 2-7 (330 mg, 91% yield) as a yellow oil. LC-MS: [M+H] ⁺ =480.6.

Step (5) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-acetamidophenyl)-7-methylimidazo[1,2-a]

pyridin-3-yl)-methyl)morpholine-4-carboxylate

CS ₂ CO ₃ (51 mg, 0.16 mmol), xanthos (1.2 mg, 0.002 mmol) and Pd ₂ (dba) ₃ (2 mg, 0.002 mmol) at room temperature. Under a nitrogen atmosphere, the reaction system was heated to 80°C and reacted overnight. After completion of the reaction, the reaction system was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 2 (18 mg, 38% yield) as a white solid.

LC-MS: [M+H] ⁺ =459.7. ^1H NMR (400 MHz, MeOD): δ 8.41 (d, J=7.1 Hz, 1H), 7.43 (d, J=9.7 Hz, 2H), 7.35 (s, 1H ), 6.88 (dd, J=7.1, 1.5 Hz, 1H), 3.80 (d, J=12.3 Hz, 3H), 3.67 (s, 3H), 3.59 (m, 1H), 3.43-3.34 (m, 1H), 3.15-3.01 (m, 2H), 2.91 (m, 1H), 2.63 (m, 1H), 2.47(s, 3H),2.19(s, 3H).

Example 3:

Step (1) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-aminophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)-methyl)morpholine- 4-carboxylate

To a solution of compound 2 (145 mg, 0.32 mmol) in ethanol (3 ml) was added hydrochloric acid (1.5 ml) at room temperature. The reaction system was reacted at 100°C for 1 hour. After completion of the reaction, the reaction system was cooled to room temperature, NaHCO ₃ solution (1 N) was added to quench the reaction, extracted with DCM (5 ml × 3), washed with saturated chloride solution sodium (5 ml×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a yellow oily liquid (90 mg). LC-MS: [M+H] ⁺ =417.3.

Step (2) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(methoxycarbonylamino)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)-methyl )morpholine-4-carboxylate

To a solution of intermediate 3-1 (70 mg, 0.17 mmol) and DIPEA (65 mg, 0.5 mmol) in DCM (5 ml) was added methyl chloroformate (20 mg, 0.21 mmol) at 0°C. The reaction system was reacted at this temperature for 3 hours. After completion of the reaction, water (3 ml) was added to the reaction system, extracted with DCM (3 ml x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH, 40/1) to give compound 3 (20 mg, 25% yield) as a white solid.

LC-MS: [M+H] ⁺ =475.6. ^1H NMR (400 MHz, MeOD): δ 8.42 (d, J=7.1 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J=9.9 Hz, 2H ), 6.90 (d, J=7.1 Hz, 1H), 3.88-3.81 (m, 2H), 3.80 (s, 3H), 3.79-3.76 (m, 1H), 3.67 (s, 3H), 3.63-3.55 (m, 1H), 3.38 (t, J=10.8 Hz, 1H), 3.15-3.00 (m , 2H), 2.90 (dt, J=20.6, 7.7 Hz, 1H), 2.64 (t, J=11.5 Hz, 1H), 2.47 (s, 3H).

Example 4:

Step (1) Preparation of methyl-(S)-2-((2-(4-(1-tert-butoxycarbonylpyrrol-2-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine -3-yl)-methyl)morpholine-4-carboxylate

To a solution of intermediate 2-7 (50 mg, 0.1 mmol), N-tert-butoxycarbonylpyrrolidine-2-boronic acid (compound 4-1) (26 mg, 0.12 mmol) and K ₂ CO ₃ (36 mg , 0.26 mmol) in H ₂ O (0.3 ml) and 1,4-dioxane (2 ml) was added Pd (dppf) Cl ₂ (2 mg, 0.016 mmol) at room temperature. Under a nitrogen atmosphere, the mixture was heated to 80°C and reacted for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, water (3 ml) was added, extracted with ethyl acetate (5 ml x 3), washed with saturated sodium chloride solution (3 ml x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. . The residue was purified by silica gel column chromatography (PE/EA, 5/1) to obtain a yellow oily liquid (50 mg, 93% yield). LC-MS: [M+H] ⁺ =567.4.

Step (2) Preparation of methyl-(S)-2-(2-(2,6-difluoro-4-(1H-pyrrol-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridin-3 -yl)methyl)morpholine-4-carboxylate

To a solution of intermediate 4-2 (20 mg, 0.035 mmol) in methanol (1 ml) was added 1 M NaOH (4 mg, 0.1 mmol). The reaction mixture was reacted at 60°C for 2 hours. After completion of the reaction, the reaction mixture was added to water (1 ml), extracted with DCM (1 ml × 3), washed with saturated sodium chloride solution (1 ml × 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 4 (17.3 mg, 92.9% yield) as a white solid.

LC-MS: [M+H] ⁺ =467.6. ^1H NMR (400 MHz, MeOD): δ 8.41 (d, J=7.1 Hz, 1H), 7.34 (d, J=9.2 Hz, 3H), 6.91 (dd, J =2.6, 1.4 Hz, 1H), 6.88 (dd, J=7.1, 1.5 Hz, 1H), 6.69 (dd, J=3.6, 1.4 Hz, 1H), 6.24 (dd, J=3.5, 2.7 Hz, 1H), 3.81 (d, J=12.4 Hz, 3H), 3.66 (s, 3H), 3, 63-3.56 (m, 1H), 3.39 (t, J=10.6 Hz, 1H), 3.17-3.04 (m, 2H), 2.96-2.85 (m, 1H), 2.71-2.59 (m, 1H), 2.47 (s, 3H).

Example 5:

Preparation of methyl-(S)-2-(2-(2,6-difluoro-4-(1H-imidazol-1-yl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

Intermediate 2-7 (50 mg, 0.1 mmol) was dissolved in toluene (2 ml) and imidazole (21 mg, 0.31 mmol), (1R,2R)-N1,N ₂ -dimethylcyclohexyl-1,2 was added -diamine (1.5 mg, 0.01 mmol) and K ₂ CO ₃ (15 mg, 0.11 mmol). Under N ₂ atmosphere, the reaction system was added with CuI (2 mg, 0.01 mmol) and heated to 110°C overnight. The reaction system was then filtered and the filtrate purified to give compound 5 (8.4 mg, 17.2% yield) as a yellow solid.

LC-MS: [M+H] ⁺ =468.6. ^1H NMR (400 MHz, MeOD): δ 8.44(d, 1H), 8.42(s, 1H), 7.78(s, 1H), 7.56 (d, 2H), 7.36 (s, 1H), 7.22 (s, 1H), 6.91 (dd, 1H), 3.82 (m, 3H), 3.67 (s, 3H), 3.60 (m, 1H) , 3.38 (m, 1H), 3.12 (m, 2H), 2.90 (m, 2H), 2.64 (s, 3H).

Example 6:

Step (1) Preparation of 2,6-difluoro-4-cyanobenzaldehyde

To a solution of compound 6-1 (2 g, 14 mmol) in THF (20 ml) was added LDA (8.6 ml, 17.2 mmol) dropwise at -78°C under a nitrogen atmosphere. The reaction system was then stirred at -78°C for 1 hour under a nitrogen atmosphere and DMF (1.26 g, 17.2 mmol) was added dropwise over 30 minutes. After completion of the reaction, the reaction system was added with AcOH (10%) to quench the reaction, extracted with ethyl acetate (50 ml × 3), washed with saturated sodium chloride solution (50 ml × 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 8/1) to give compound 6-2 (1.5 g, 60% yield) as a yellow solid.

Step (2) Preparation of tert-butyl-(S)-2-((2-(4-cyano-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine -4-carboxylate

To a solution of compound 6-2 (500 mg, 3 mmol), compound 1-5 (330 mg, 3 mmol) and compound 1-4 (630 mg, 3 mmol) in toluene (15 ml) was added CuCl (90 mg, 0 .9 mmol) and Cu(CF ₃ SO ₃ ) ₂ (330 mg, 0.9 mmol) at room temperature. Under a nitrogen atmosphere, the reaction system was heated to 85°C, DME (0.1 ml) was added and reacted at this temperature for 5 hours. After completion of the reaction, water (15 ml) was added to the reaction system to quench the reaction, and extraction was carried out with dichloromethane ( 10 ml × 3), washed with saturated sodium chloride solution (10 ml × 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 1/1) to give intermediate 6-3 (450 mg, 32% yield) as a yellow oil.

Step (3) Preparation of (S)-3,5-difluoro-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-a]pyridin-2-yl)benzonitrile

To a solution of intermediate 6-3 (400 mg, 1.1 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise at 0°C. The reaction system was reacted at room temperature for 1 hour. After completion of the reaction, saturated NaHCO ₃ was added to the reaction system to quench the reaction at 0°C, extraction was carried out with dichloromethane (3 ml × 3), washed with saturated sodium chloride solution (3 ml × 2 ), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH, 40/1) to give intermediate 6 (280 mg, 79% yield) as a brown solid.

Step (4) Preparation of methyl-(S)-2-((2-(4-cyano-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

To a solution of intermediate 6-4 (230 mg, 0.6 mmol) and DIPEA (230 mg, 1.8 mmol) in DCM (2 ml) was added methyl chloroformate (66 mg, 0.72 mmol) at 0°C. Reaction the system was reacted for 1 hour. After completion of the reaction, water (3 ml) was added to the reaction system, extraction was carried out with dichloromethane (3 ml × 3), washed with saturated sodium chloride solution (3 ml × 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 2/1) to give compound 6 (230 mg, 83% yield) as a yellow solid.

LC-MS: [M+H] ⁺ =427.7. ^1H NMR (400 MHz, CDCl ₃ ): 68.19 (d, J=7.1 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J=6.2 Hz, 2H ), 6.72 (d, J=7.0 Hz, 1H), 4.03-3.74 (m, 3H), 3.71 (s, 3H), 3.61 -3.51 (m, 1H), 3.38 (t, J=11.8 Hz, 1H), 3.09 - 2.82 (m, 3H), 2.68-2.53 (m, 1H), 2.44 (s , 3H).

Example 7:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(1H-imidazol-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl) methyl)morpholine-4-carboxylate

A solution of compound 6 (120 mg, 0.3 mmol) and NaOMe (3 mg, 0.05 mmol) in MeOH (2 ml) was stirred at room temperature for 15 min and aminoacetaldehyde diethyl acetal (49 mg, 0.4 mmol) was added. and AcOH (34 mg, 0.6 mmol). The reaction system was reacted at 50°C for 1 hour, then cooled to room temperature, HCl (0.5 ml) and MeOH (2 ml) were added and reacted at 65°C for 18 hours. After completion of the reaction, the reaction system concentrated under reduced pressure. The crude product was purified by preparative HPLC, added 1 M hydrochloric acid and lyophilized to give compound 7 (32 mg, 24% yield) as a white solid.

LC-MS: [M+H] ⁺ =468.1. ^1H NMR (400 MHz, CDCl ₃ ): 616.00 (s, 2H), 15.16 (s, 1H), 8.68 (s, 3H), 8.00 (s, 1H), 7.49 (s, 2H), 7.22 (s, 1H), 3.94 (s, 3H), 3.70 (m, 3H), 3.61 (m, 1H), 3.34 (m, 1H) , 2.97 (m, 4H), 2.62 (s, 3H).

Example 8:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(N-methylcarbamidoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine- 4-carboxylate

A solution of compound 6 (50 mg, 0.12 mmol) and NaOMe (2 mg, 0.03 mmol) in MeOH (2 ml) was stirred at room temperature for 30 min, then a solution of MeNH ₂ /THF (2 M, 0) was added .1 ml, 0.15 mmol) and AcOH (14 mg, 0.24 mmol) at 50°C. The reaction system was reacted for 1 hour. After completion of the reaction, the reaction system was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 8 (17 mg, 31% yield) as a white solid.

LC-MS: [M+H] ⁺ =458.1. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.54 (s, 1H), 8.25 (s, 1H), 7.57 (d, J=6.8 Hz, 2H), 7.39 ( s, 1H), 6.74 (d, J=6.8 Hz, 1H), 3.82 (m, 3H), 3.68 (s, 3H), 3.56 (m, 1H), 3, 36 (m, 1H), 3.22 (s, 2H), 3.07 - 2.75 (m, 4H), 2.61 (m, 1H), 2.45 (s, 3H).

Example 9:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(1-methyl-1H-imidazol-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridin- 3-yl)methyl)morpholine-4-carboxylate

Intermediate 2-7 (50 mg, 0.1 mmol) was dissolved in toluene (3 ml) and Pd(PPh ₃ ) ₄ (12 mg, 0.01 mmol) and 1-methyl-2-(tri -n-butylstannyl)imidazole (78 mg, 0.2 mmol). Under _N2 atmosphere, the reaction system was heated to 85°C and incubated at this temperature for 5 hours. The reaction system was then filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 9 (24 mg, 49% yield) as a white solid.

LC-MS: [M+H] ⁺ =482.2. ^1H NMR (400 MHz, MeOD): δ 8.69 (s, 1H), 8.55 (s, 1H), 7.99 (s, 1H), 7.55 (s, 1H), 7.22 (d, 2H), 7.15 (d, 1H), 4.06 (s, 1H), 3.96 (s, 3H), 3.86 (m, 2H), 3.73 (s, 3H) , 3.68 (s, 1H), 3.43 (m, 1H), 3.09 (d, 2H), 2.99 (m, 1H), 2.73 (m, 1H), 2.61 ( s, 3H).

Example 10:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(oxazol-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl) morpholine-4-carboxylate

To a solution of intermediate 2-7 (50 mg, 0.1 mmol) in 1,4-dioxane (2 ml) was added Pd(Ph ₃ P) ₄ (12 mg, 0.01 mmol) and 2-(tri-n -butylstannyl)oxazole (119 mg, 0.33 mmol) at room temperature. Under a nitrogen atmosphere, the reaction system was heated to 95°C and reacted for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 10 (12 mg, 25% yield) as a white solid.

LC-MS: [M+H] ⁺ =469.7. ^1H NMR (400 MHz, MeOD): δ 8.43 (d, J=7.1 Hz, 1H), 8.10 (d, J=0.8 Hz, 1H), 7.80 (d, J =8.0 Hz, 2H), 7.42 (d, J=0.8 Hz, 1H), 7.36 (s, 1H), 6.89 (dd, J=7.2, 1.6 Hz , 1H), 3.93-3.74 (m, 3H), 3.66 (s, 3H), 3.64-3.56 (m, 1H), 3.42-3.34 (m, 1H ), 3.13 (d, J=6.3 Hz, 2H), 2.97-2.85 (m, 1H), 2.73-2.60 (m, 1H), 2.48 (s, 3H).

Example 11:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(furan-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl) morpholine-4-carboxylate

Intermediate 2-7 (50 mg, 0.1 mmol) was dissolved in toluene (3 ml) and Pd(PPh ₃ ) ₄ (12 mg, 0.01 mmol) and 2-(tri-n-butylstannyl) were added to the reaction system. furan (37 mg, 0.1 mmol). Under _N2 atmosphere, the reaction system was heated to 110°C and incubated at this temperature for 18 hours. The reaction system was then filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 11 (12 mg, 24% yield) as a white solid.

LC-MS: [M+H] ⁺ =468.1. ^1H NMR (400 MHz, CDCl ₃ ): δ 8.55 (d, 1H), 8.08 (s, 1H), 7.58 (d, 1H), 7.14 (d, 1H), 6. 86 (d, 1H), 6.58 (s, 1H), 3.82 (m, 3H), 3.73 (s, 3H), 3.68 (m, 1H), 3.43 (m, 1H ), 3.05 (m, 2H), 2.96 (m, 1H), 2.71 (m, 1H), 2.61 (s, 3H).

Example 12:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(thiophen-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl) morpholine-4-carboxylate

Intermediate 2-7 (50 mg, 0.1 mmol) was dissolved in dioxane (3 ml) and Pd(PPh ₃ ) ₄ (12 mg, 0.01 mmol) and 2-{trino-butylstannyl)thiophene ( 117 mg, 0.31 mmol). Under _N2 atmosphere, the reaction system was heated to 100°C and incubated at this temperature for 8 hours. The reaction system was then filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 12 (18 mg, 35% yield) as a white solid.

LC-MS: [M+H] ⁺ =484.6. ^1H NMR (400 MHz, CDCl ₃ ): δ 8.22 (d, 1H), 7.41 (m, 3H), 7.31 (m, 2H), 7.14 (dd, 1H), 6. 71 (d, 1H), 3.82 (m, 3H), 3.68 (s, 3H), 3.62 (m, 1H), 3.41 (m, 1H), 3.03 (m, 2H ), 2.92 (m, 1H), 2.64 (m, 1H), 2.46 (s, 3H).

Example 13:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(1-methyl-1H-pyrrol-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridin- 3-yl)methyl)morpholine-4-carboxylate

Intermediate 2-7 (50 mg, 0.1 mmol) was dissolved in dioxane (3 ml) and Pd(PPh ₃ ) ₄ (12 mg, 0.01 mmol) and 2-(tri-n-butylstannyl) were added to the reaction system. methylpyrrole (115 mg, 0.31 mmol). Under _N2 atmosphere, the reaction system was heated to 100°C and incubated at this temperature for 8 hours. The reaction system was then filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 13 (28 mg, 54% yield) as a white solid.

LC-MS: [M+H] ⁺ =481.4. ^1H NMR (400 MHz, CD ₃ OD): δ 8.86 (d, 1H), 7.72 (S, 1H), 7.42 (dd, 1H), 7.39 (d, 2H), 6 .91 (t, 1H), 6.49 (dd, 1H), 6.20 (dd, 1H), 4.02 (d, 1H), 3.84 (s, 3H) 3.75 (m, 3H ), 3.69 (s, 3H), 3.38 (m, 1H), 3.27 (m, 2H), 2.96 (m, 1H), 2.79 (m, 1H), 2.66 (s, 3H).

Example 14:

Step (1) Preparation of methyl-(S)-2-(2-(4-(1-ethoxyethyl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl) morpholine-4-carboxylate

Intermediate 2-7 (300 mg, 0.62 mmol) was dissolved in toluene (3 ml) and PdCl ₂ (PPh ₃ ) ₂ (44 mg, 0.062 mmol), tri-tert-butyl(1- ethoxyethyl)tin (680 mg, 1.88 mmol). Under _N2 atmosphere, the reaction system was heated to 95°C and incubated at this temperature for 3 hours. The reaction system was then filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to give intermediate 14-2 (215 mg, 73% yield) as a yellow oil. LC-MS: [M+H] ⁺ =472.7.

Step (2) Preparation of methyl-(S)-2-((2-(4-acetyl-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

Intermediate 14-2 (250 mg, 0.53 mmol) was dissolved in EtOH (3 mL) and HCl (2 N, 1.7 mL) was added. The reaction system was stirred at room temperature for 2 hours. After completion of the reaction, the reaction system was poured into NaHCO ₃ solution to adjust the pH to 8. The aqueous phase was subjected to extraction with DCM. The organic phase was washed with NaCl solution 2-3 times, followed by separation of the liquid. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified to give compound 14 (25 mg, 38% yield) as a white solid.

LC-MS: [M+H] ⁺ =444.7. ^1H NMR (400 MHz, MeOD): δ 8.43 (d, 1H), 7.76 (d, 2H), 7.36 (s, 1H), 6.90 (dd, 1H), 3.79 (m, 3H), 3.67 (s, 3H), 3.59 (m, 1H), 3.36 (m, 1H), 3.11 (m, 2H), 2.86 (m, 1H) , 2.68(s, 3H), 2.63(m, 1H), 2.47(s, 3H).

Example 15:

Step (1) Preparation of methyl-(S,E)-2-((2-(4-(3-(dimethylamino)acryloyl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin- 3-yl)-methyl)morpholine-4-carboxylate

Compound 14 (180 mg, 0.41 mmol) was dissolved in DMF-DMA (2 ml). Under N ₂ atmosphere, the reaction system was heated to 95°C and reacted overnight. The reaction system was then cooled to room temperature and concentrated under reduced pressure. The residue was purified to give intermediate 15-1 (120 mg, 59.4% yield). LC-MS: [M+H] ⁺ =499.7.

Step (2) Preparation of methyl-(S)-2-(2-(2,6-difluoro-4-(1H-pyrazol-3-yl)phenyl)-7-methylimidazo[1,2-a]pyridin-3 -yl)methyl)morpholine-4-carboxylate

Intermediate 15-1 (80 mg, 0.12 mmol) was dissolved in ethanol (2 ml). N ₂ H ₄ -H ₂ O (16 mg, 0.32 mg) was added dropwise to the reaction system, heated to 100°C and incubated at this temperature for 2 hours. The reaction system was then concentrated under reduced pressure. The residue was purified to give compound 15 (49.8 mg, 66.4% yield) as a white solid.

LC-MS: [M+H] ⁺ =468.6. ^1H NMR (400 MHz, MeOD): δ 8.86 (d, 1H), 7.81 (d, 1H), 7.76 (d, 2H), 7.73 (s, 1H), 7.43 (dd, 1H), 6.91 (d, 1H), 4.02 (m, 1H), 3.79 (m, 3H), 3.69 (s, 3H), 3.37 (m, 1H) , 3.27 (m, 2H), 2.94 (m, 1H), 2.73 (m, 1H), 2.66 (s, 3H).

Example 16:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(isoxazol-3-yl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl) morpholine-4-carboxylate

Intermediate 15-1 (80 mg, 0.12 mmol) was dissolved in methanol (2 ml). N ₂ OH-HCl (21 mg, 0.30 mg) was added dropwise to the reaction system, heated to 100° C. and incubated at this temperature for 2 hours. The reaction system was then concentrated under reduced pressure. The residue was purified to give compound 16 (34.2 mg, 45.4% yield) as a white solid.

LC-MS: [M+H] ⁺ =469.4. ^1H NMR (400 MHz, CDCl ₃ ): δ 8.27 (d, 1H), 7.66 (m, 2H), 7.35 (s, 1H), 6.82 (dd, 1H), 3 .78 (m, 3H), 3.61 (s, 3H), 3.54 (m, 1H), 3.3.30 (m, 1H), 3.10 (m, 2H), 2.88 (m, 1H), 2.63 (m, 1H), 2.47 (s, 3H).

Example 17:

Step (1) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl )-7-methylimidazo[1,2-a]pyridin-3-yl)-methyl)morpholine-4-carboxylate

Intermediate 2-7 (100 mg, 0.21 mmol), boronate (64 mg, 0.25 mmol), Pd(dppf)Cl ₂ (8 mg, 0.01 mmol) and AcOK (6.2 mg, 0.625 mmol) was dissolved in dioxane (3 ml). Under N ₂ atmosphere, the reaction system was heated to 90° C. and reacted overnight. The reaction system was then cooled to room temperature to provide intermediate 17-2. LC-MS: [M+H] ⁺ =528.2.

Step (2) Preparation of methyl-(S)-2-(2-(2,6-difluoro-4-(pyridin-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl )methyl)morpholine-4-carboxylate

Intermediate 17-2 (55 mg, 0.1 mmol), 2-bromopyridine (18 mg, 0.11 mmol), Na ₂ CO ₃ (33 mg, 0.31 mmol), Pd(PPh ₃ ) ₄ (6 mg, 0.005 mmol) was dissolved in dioxane (3 ml) and a small amount of water. In an N ₂ atmosphere, the reaction system was heated to 100°C. After completion of the reaction, the reaction system was filtered and the filtrate was diluted with water and extracted with EA. The organic phase was washed with NaCl, dried, filtered and concentrated under reduced pressure. The residue was purified to give compound 17 (25 mg, 50% yield) as a white solid.

LC-MS: [M+H] ⁺ =479.7. ^1H NMR (400 MHz, CDCl ₃ ): δ 8.75 (d, 1H), 8.27 (d, 1H), 7.85 (t, 1H), 7.76 (dd, 3H), 7. 56 (m, 1H), 7.35 (m, 1H), 6.76 (d, 1H), 3.82 (s, 3H), 3.68 (s, 3H), 3.62(s, 1H ), 3.41 (s, 1 H), 3.03 (dd, 2H), 2.92 (s, 1 H), 2.64 (dd, 1 H), 2.47 (s, 3H).

Example 18:

Preparation of methyl-(S)-2-((2-(3-fluoro-4-(methylcarbamoyl)-1H-pyrrol-2-yl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

Intermediate 17-2 (55 mg, 0.1 mmol), 2-bromopyrimidine (19 mg, 0.11 mmol), Na ₂ CO ₃ (27 mg, 0.31 mmol), Pd(PPh ₃ ) ₄ (4 mg, 0.005 mmol) was dissolved in dioxane (3 ml) and a small amount of water. Under N ₂ atmosphere, the reaction system was heated to 90°C. After completion of the reaction, the reaction system was filtered and the filtrate was diluted with water and extracted with EA. The organic phase was washed with NaCl, dried, filtered and concentrated under reduced pressure. The residue was purified to give compound 18 (25 mg, 50% yield) as a white solid.

LC-MS: [M+H] ⁺ =480.2. ^1H NMR (400 MHz, CDCl ₃ ): δ 8.87 (d, 2H), 8.24 (t, 1H), 8.18 (d, 2H), 7.54 (s, 1H), 7. 30 (m, 1H), 6.76 (d, 1H), 3.82 (s, 3H), 3.72-3.77 (m, 3H), 3.68 (s, 3H), 3.62 (s, 1H), 3.41 (s, 1H), 3.03 (t, 2H), 2.92 (s, 1H), 2.64 (dd, 1H), 2.46 (s, 3H ).

Example 19:

Step (1) Preparation of methyl 2-(2-((2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl) acetate

3,5-difluoro-4-formyl-N-methylbenzamide (200 mg, 1 mmol), 2-amino-4-methylpyridine (108 mg, 1 mmol), methyl propiolate (84 mg, 1 mmol), CuCl (30 mg, 0.3 mmol) and Cu(CF ₃ CO ₃ ) ₂ (109 mg, 0.3 mmol) were dissolved in toluene (3 ml). Under N ₂ atmosphere, the reaction system was heated to 85°C, DMA (0.05 ml) was added and stirred for 5 hours. The reaction system was then cooled to room temperature and incubated overnight. The resulting reaction system was poured into H ₂ O (5 ml) and extracted with DCM (5 ml x 3). The organic phase was washed with saturated NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA=1:1) to give intermediate 19-3 (172 mg, 25% yield) as a yellow oil. LC-MS: [M+H] ⁺ =374.4.

Step (2) Preparation of 4-(3-(2-amino-2-oxoethyl)-7-methylimidazo[1,2-a]pyridine)-3,5-difluorobenzoylmethylamine

Intermediate 19-3 (82 mg, 0.22 mmol) was dissolved in methanol (2 ml). NH ₃ ⋅H ₂ O (1 ml) was added to the reaction system and stirred overnight. The reaction system was then concentrated under reduced pressure. The crude product was purified to give compound 19 (25 mg, 32% yield) as a white solid.

LC-MS: [M+H] ⁺ =359.8. ^1H NMR (400 MHz, CD ₃ OD): δ 8.36 (d, 1H), 7.63 (d, 2H), 7.46 (s, 1H), 7.02 (d, 1H), 3 .93 (s, 2H), 2.97 (s, 3H), 2.52 (s, 3H).

Example 20:

Step (1) Preparation of tert-butyl-(S)-2-((2-(3,5-difluorophenyl)carbamoyl)-7-methylimidazo[1,2-a]pyridin-3-yl)-methyl)morpholine- 4-carboxylate

A solution of intermediate 1-8 (400 mg, 1.07 mmol) and HATU (608 mg, 1.6 mmol) in DMF (5 ml) was stirred at room temperature for 10 min and DIPEA (418 mg, 3.24 mmol) and compound 20-1 (168 mg, 1.3 mmol) at room temperature. The reaction system was reacted for 1 hour. After completion of the reaction, water (15 ml) was added to the reaction system to quench the reaction, extracted with dichloromethane (10 ml × 3), washed with saturated sodium chloride solution (10 ml × 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH, 10/1) to give intermediate 20-2 (450 mg) as a yellow oily liquid.

Step (2) Preparation of (S)-N-(3,5-difluorophenyl)-7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-a]pyridine-2-carboxamide

To a solution of intermediate 20-2 (330 mg, 0.7 mmol) in DCM (4 mL), a solution of HCl in ethanol (1 mL) was added dropwise at 0°C. The reaction system was reacted at room temperature for 1 hour. After completion of the reaction, saturated NaHCO ₃ was added to the reaction system to quench the reaction at O°C, extraction was carried out with dichloromethane (3 ml × 3), washed with saturated sodium chloride solution (3 ml × 2 ), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH, 10/1) to give intermediate 20-3 (80 mg, 31% yield) as a brown solid.

Step (3) Preparation of ethyl-(S)-2-((2-(3,5-difluorophenyl)carbamoyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-acetate

To a solution of intermediate 20-3 (80 mg, 0.2 mmol) and DIPEA (25 mg, 0.6 mmol) in DCM (2 ml) was added methyl chloroformate (1 ml) at 0°C. The reaction system was reacted for 1 hour. After completion of the reaction, water (3 ml) was added to the reaction system, extraction was carried out with dichloromethane (3 ml × 3), washed with saturated sodium chloride solution (3 ml × 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 20 (15 mg, 16% yield) as a white solid.

LC-MS: [M+H] ⁺ =459.7. ^1H NMR (400 MHz, CDCl ₃ ): 68.30 (s, 1H), 7.52 (s, 3H), 6.90 (s, 1H), 6.59 (t, J=8.7 Hz , 1H), 4.23 (d, J=9.8 Hz, 1H), 4.16 (dd, J=14.1, 7.1 Hz, 2H), 3.96-3.79 (m, 3H), 3.75 (d, J=12.2 Hz, 1H), 3.41 (dd, J=11.9, 9.2 Hz, 1H), 3.35-3.19 (m, 1H ), 2.99-2.85 (m, 1H), 2.84-2.73 (m, 1H), 2.50 (s, 3H), 1.35-1.18 (m, 3H).

Example 21:

Step (1) Preparation of 5-formyl-N-methylthiophene-2-carboxamide

Oxalyl chloride (447 mg, 1.1 mmol) was added to a solution of 5-formylthiophene-2-carboxylic acid (500 mg, 3.2 mmol) and DMF (12 mg) at 0°C. The reaction system was reacted at this temperature for 2 hours and aqueous methylamine (40%, 746 mg, 9.6 mmol) was added over 10 minutes. After completion of the reaction, water (3 mL) was added to the reaction system to quench the reaction, extraction was performed with dichloromethane (5 mL x 3), washed with saturated sodium chloride solution (5 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 1/1) to give compound 21-2 as a white solid (300 mg, 56% yield), LC-MS: [M+H] ⁺ =170, 9.

Step (2) Preparation of tert-butyl-(S)-2-((7-methyl-2-(5-(methylcarbamoyl)thiophen-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

To a solution of compound 21-2 (500 mg, 2.96 mmol), 4-methylpyridin-2-amine (320 mg, 2.96 mmol) and compound 1-4 (625 mg, 2.96 mmol) in toluene (5 ml) copper(I) chloride (88 mg, 0.89 mmol) and copper(II) trifluoromethanesulfonate (321 mg, 0.89 mmol) were added at room temperature. Under nitrogen atmosphere, the reaction system was heated to 85°C, DMA (0.05 ml) was added and reacted at this temperature for 5 hours. After completion of the reaction, the reaction system was added with water (5 ml) to quench the reaction, extracted with dichloromethane (5 ml × 3), washed with saturated sodium chloride solution (5 ml × 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH, 40/1) to give intermediate 21-3 (300 mg, 56% yield) as a yellow oil, LC-MS: [M+H] ⁺ =471 ,7.

Step (3) Preparation of (S)-5-(7-methyl-3-(morpholin-2-yl-methyl)imidazo[1,2-a]pyridin-2-yl)thiophene-2-carboxamide

To a solution of intermediate 21-3 (400 mg, 0.85 mmol) in DCM (4 mL), a solution of HCl in ethanol (0.5 mL, 33%) was added dropwise at 0°C. The reaction system was reacted at room temperature for 1 hour. After completion of the reaction, saturated NaHCO ₃ was added to the reaction system to quench the reaction at 0°C, extraction was carried out with dichloromethane (5 ml × 3), washed with saturated sodium chloride solution (5 ml × 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give intermediate 21-4 (300 mg) as a yellow oil, LC-MS: [M+H] ⁺ =371.8.

Step (4) Preparation of methyl-(S)-2-((7-methyl-2-(5-(methylcarbamoyl)thiophen-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine -4-carboxylate

To a solution of intermediate 21-4 (100 mg, 0.27 mmol) and DIPEA (105 mg, 0.81 mmol) in DCM (2 ml) was added methyl chloroformate (31 mg, 0.33 mol) at 0°C. Reaction the system was reacted for 3 hours. After completion of the reaction, water (3 ml) was added to the reaction system, extraction was performed with dichloromethane (3 ml × 2), washed with saturated sodium chloride solution (3 ml × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 21 (28.5 mg, 28% yield) as a yellow solid.

LC-MS: [M+H] ⁺ =429.7. ^1H NMR (400 MHz, MeOD): δ 8.32 (d, J=7.0 Hz, 1H), 7.67 (d, J=3.9 Hz, 1H), 7.52 (d, J =3.8 Hz, 1H), 7.31 (s, 1H), 6.88- 6.80 (m, 1H), 4.13 (d, J=12.8 Hz, 1H), 3.92 -3.75 (m, 3H), 3.72 (s, 3H), 3.46-3.28 (m, 3H), 3.01 (m, 1H), 2.94 (s, 3H), 2.91 (m, 1H), 2.44 (s, 3H).

Examples 22-24

The compounds were prepared using appropriate starting materials in accordance with the method described in Example 21.

Example 25:

Step (1) Preparation of benzyl (3,5-difluoro-4-formylphenyl)-carbamate

To a solution of compound 2-2 (1 g, 4.5 mmol) in toluene (20 ml) was added cesium carbonate (2 g, 6.3 mmol), benzyl carbamate (0.8 g, 5.4 mmol), (±) -2,2'-bis-(diphenylphosphino)-1,1'-binaphthalene (0.28 g, 0.45 mmol) and tris(dibenzylideneacetone) dipalladium (0.2 g, 0.2 mmol) at room temperature. After addition, the reaction system was purged with nitrogen three times, heated to 100°C and stirred overnight (16 h) under a nitrogen atmosphere. The reaction system was then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA/PE=1/10) to give intermediate 25-1 (0.72 g, 55.2% yield) as a yellow solid, LC-MS: [M+H ] ⁺ =292.1.

Step (2) Preparation of tert-butyl-(S)-2-((2-(4-(((benzyloxy)-carbonyl)amino)-2,6-difluorophenyl)-7-methylimidazo[1,2-a] pyridin-3-yl)methyl)morpholine-4-carboxylate

To a 20 ml microwave tube (Biotage) was added compound 25-1 (0.2 g, 0.68 mmol), compound 1-4 (0.22 g, 1.03 mmol) and compound 1-5 (74 mg, 0 .68 mmol), copper (I) chloride (20 mg, 0.2 mmol), copper (II) trifluoromethanesulfonate (74 mg, 0.2 mmol) and toluene (6 ml). After addition, the reaction system was purged with nitrogen for 2 min and reacted at 120°C overnight (16 h) after sealing the tube. A new spot was obtained by developing a TLC plate (PE/EA=1/1) with an Rf value of about 0.3 and was identified as the target product using liquid chromatography. The reaction system was then cooled to room temperature and concentrated under reduced pressure. The residue was mixed with silica gel and purified by silica gel column chromatography (EA/PE=1/1) to give intermediate 25-2 (184 mg, 45.5% yield) as a yellow solid. LC-MS: [M+H] ⁺ =593.6.

Step (3) Preparation of methyl-(S)-2-((2-(4-((benzyloxy)-carbonyl)amino)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine-3 -yl)methyl)morpholine-4-carboxylate

To intermediate 25-2 (0.8 g, 1.35 mmol) was added a solution of HCl in ethyl acetate (about 4 M, 5 ml) at room temperature. After addition, the reaction system was stirred at room temperature for 2 hours. After completion of the reaction, as monitored by liquid chromatography, the reaction system was concentrated under reduced pressure to obtain the crude product, to which were added dichloromethane (5 ml), triethylamine (0.4 g, 4 mmol) and methyl chloroformate (0.19 g, 2 mmol). After addition, the reaction system was stirred at room temperature for 3 hours. After completion of the reaction as determined by liquid chromatography, the reaction system was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA) to give intermediate 25-3 (675 mg, 90.8% yield) as a brown oil. LC-MS: [M+H] ⁺ =551.2.

Step (4) Preparation of methyl-(S)-2-((2-(4-amino-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

To a solution of intermediate 25-3 (200 mg, 0.363 mmol) in methanol (10 ml) was added palladium hydroxide (about 40 mg, 20% w/w) at room temperature. After addition, the reaction system was purged with a hydrogen balloon 3 times and stirred at room temperature for 4 hours under a hydrogen atmosphere. After completion of the reaction, as determined by liquid chromatography, the reaction system was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA) to give intermediate 25-4 (111 mg, 74% yield) as a yellow solid. LC-MS: [M+H] ⁺ =417.2.

Step (5) Preparation of (S)-4-(((3,5-difluoro-4-(3-((4-(methoxycarbonyl)morpholin-2-yl)methyl)-7-methylimidazo[1,2-a ]pyridin-2-yl)-phenyl)-amino)-4-oxobutanoic acid

To a solution of intermediate 25-4 (100 mg, 0.24 mmol) in toluene (5 ml) was added triethylamine (24 mg, 0.24 mmol) and succinic anhydride (28.8 mg, 0.288 mmol) at room temperature. After addition, the reaction system was heated to 80° C. and reacted for 4 hours. After completion of the reaction as determined by liquid chromatography, the reaction system was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give compound 25 (90 mg, 72.5% yield) as a white solid.

LC-MS: [M+H] ⁺ =517.1, ^1H NMR (400 MHz, CD3OD):6 8.39 (d, J=7.2 Hz, 1H), 7.46-7.38 ( m, 2H), 7.33 (s, 1H), 6.87-6.85 (m, 1H), 3.85-3.58 (m, 3H), 3.67 (s, 3H), 3 ,60-3.56 (m, 1H), 3.39-3.33 (m, 1H), 3.13-3.02 (m, 2H), 2.93-2.87 (m, 1H) , 2.74-2.65 (m, 4H), 2.64-2.60 (m, 1H), 2.46 (s, 3H).

Example 26:

Preparation of methyl-(S)-2-((2-(4-(2,5-dioxopyrrolidin-1-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl )methyl)morpholine-4-carboxylate

To a solution of compound 25 (77.6 mg, 0.15 mmol) in acetic anhydride (2 ml) was added sodium acetate (9.2 mg, 0.11 mmol) at room temperature. The reaction system was stirred at room temperature for 4 hours. The reaction system was then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (trifluoroacetic acid method) and lyophilized to give compound 26 (30 mg, 40% yield) as a white solid.

LC-MS: [M+H] ⁺ =499.1, ^1H NMR (400 MHz, CD3OD): δ 8.84 (d, J=6.8 Hz, 1H), 7.72 (s, 1H) , 7.44-7.40 (m, 3H), 4.02-3.99 (m, 1H), 3.82-3.69 (m, 2H), 3.67 (s, 3H), 3 .35-3.24 (m, 5H), 2.92-2.88 (m, 4H), 2.76-2.71 (m, 1H), 2.64 (s, 3H).

Example 27:

(S,E)-4-((3,5-difluoro-4-(3-(4-(methoxycarbonyl)-morpholin-2-yl)-methyl)-7-methylimidazo[1,2-a]pyridin- 2-yl)-phenyl)-amino)-4-oxobutyl-2-enoic acid

To a solution of intermediate 25-4 (20 mg, 0.048 mmol) in tetrahydrofuran (5 ml) was added maleic anhydride (7 mg, 0.071 mmol) at room temperature. After addition, the reaction system was heated to 60°C and reacted overnight (16 hours). After completion of the reaction as determined by liquid chromatography, the reaction system was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (trifluoroacetic acid method) and lyophilized to give compound 27 (16 mg, 65% yield) as a white solid.

LC-MS: [M+H] ⁺ =515.9. ^1H NMR (400 MHz, DMSO- _d6 ): δ 12.9 (br, 1H), 10.88 (s, 1H), 8.78 (d, J=2.8 Hz, 1H), 7, 68 (s, 1H), 7.56 (d, J=10.4 Hz, 2H), 7.31-7.30 (m, 1H), 6.53 (d, J=12 Hz, 1H), 6.37 (d, J=12 Hz, 1H), 3.90-3.87 (m, 1H), 3.76-3.62 (m, 3H), 3.57-3.54 (m, 3H), 3.25-3.07 (m, 4H), 2.85-2.80 (m, 1H), 2.52 (overlap, 3H).

Example 28:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(2,5-dioxo-2,5-dihydropyrrol-1-yl)phenyl)-7-methylimidazo[1,2- a]pyridin-3-yl)methyl)morpholine-4-carboxylate

To a solution of compound 27 (100 mg, 0.25 mmol) in acetic anhydride (3 ml) was added sodium acetate (32.7 mg, 0.4 mmol) at room temperature. The reaction system was stirred at room temperature for 4 hours. The reaction system was then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (trifluoroacetic acid method) and lyophilized to give compound 28 (40 mg, 30% yield) as a white solid.

LC-MS: [M+H] ⁺ =497.1, ^1H NMR (400 MHz, CD ₃ OD): δ 8.83 (d, J=7.2 Hz, 1H), 7.71 (s, 1H), 7.56-7.52 (m, 2H), 7.43-7.39 (m, 1H), 7.68 (s, 2H), 4.02-3.99 (m, 1H) , 3.83-3.69 (m, 3H), 3.67 (s, 3H), 3.36-3.33 (m, 1H), 3.30-3.22 (m, 2H), 2 .92-2.90 (m, 1H), 2.87-2.73 (m, 1H), 2.64 (s, 3H).

Example 29:

Preparation of methyl-(S,E)-2-(2-(2,6-difluoro-4-(4-amino-4-oxobutyl-2-enamido)phenyl)-7-methylimidazo[1,2-a]pyridine -3-yl)methyl)morpholine-4-carboxylate

To a solution of compound 28 (20 mg, 0.04 mmol) in acetonitrile (3 ml) was added an aqueous solution of ammonium bicarbonate (5%, 2 ml) at room temperature. The reaction system was reacted at room temperature for 2 hours. The reaction system was then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give compound 29 (10 mg, 40% yield) as a white solid.

LC-MS: [M+H] ⁺ =514.1. ^1H NMR (400 MHz, DMSO-sub): 5 11.36 (s, 1H), 8.38 (d, J=7.2 Hz, 1H), 7.93 (s, 1H), 7.45 -7.42 (m, 3H), 7.33 (s, 1H), 6.82-6.80 (m, 1H), 6.35-6.28 (m, 2H), 3.73-3 .62 (m, 3H), 3.55 (s, 3H), 3.51-3.46 (m, 1H), 3.25-3.22 (m, 2H), 3.02-3.00 (m, 2H), 2.83-2.79 (m, 1H), 2.37 (s, 3H).

Example 30:

Step (1) Preparation of (1-acetylpiperidin-4-yl)methyl acetate

4-hydroxymethylpiperidine (5.2 g, 45.15 mmol) was dissolved in dichloromethane (60 ml) and triethylamine (13.5 g, 133.61 mmol) was added. The reaction system was cooled to 0°C, acetic anhydride (13.8 g, 135.4 mmol) was added and reacted at room temperature for 15 hours. The reaction system was then washed with dilute hydrochloric acid (1 N, 40 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 30-3 (6.2 g) as a yellow oily liquid.

Step (2) Preparation of 1-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one

Compound 30-3 (6.2 g) was dissolved in methanol (50 ml) and an aqueous solution of lithium hydroxide (3.75 N, 25 ml) was added. The reaction system was stirred at room temperature for 12 hours. The reaction system was then concentrated. The residue was separated by column chromatography (EA/MeOH=50/1) to obtain compound 30-4 (7.5 g) as a colorless oily liquid. LC-MS: [M+H] ⁺ =158.0.

Step (3) Preparation of 1-acetylpiperidine-4-carbaldehyde

Compound 30-4 (3.2 g, 20.35 mmol) was dissolved in dichloromethane (40 ml) and Dess-Martin periodinane (12.9 g, 30.52 mmol) was added. The reaction system was reacted at room temperature for 1.5 hours. Saturated sodium thiosulfate solution (20 ml) was then added to the reaction system, diluted with water (40 ml) and extracted with dichloromethane (40 ml x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (EA-EA/MeOH=50/1) to give compound 30-5 (1.0 g, 31% yield) as a white solid. LC-MS: [M+H] ⁺ =156.1.

Step (4) Preparation of tert-butyl-(S)-2-((2-(1-acetylpiperidin-4-yl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

Compound 30-5 (200 mg, 1.29 mmol) was dissolved in anhydrous toluene (40 ml) and 4-methyl-2-aminopyridine (140 mg, 1.29 mmol), tert-butyl-(S)-2- ethynylmorpholine-4-carboxylate (272 mg, 1.29 mmol), copper(I) chloride (40 mg, 0.4 mmol) and copper(II) trifluoromethanesulfonate (140 mg, 0.39 mmol). Under a nitrogen atmosphere, the reaction system was heated to 85°C, two drops of N,N-dimethylacetamide were added, heated and stirred for 6 hours. The reaction system was then cooled to room temperature and stirred overnight. The resulting reaction system was filtered and the filtrate was concentrated. The residue was separated by column chromatography (DCM/MeOH=20/1) to give intermediate 30-6 (227 mg, 38% yield) as a yellow solid. LC-MS: [M+H] ⁺ =456.8.

Step (5) Preparation of (S)-1-(4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-a]pyridin-2-yl)piperidin-1-yl)acetamide

Intermediate 30-6 (227 mg, 0.49 mmol) was dissolved in ethanol (2 ml) and a solution of HCl in ethanol (1 ml, 33%) was added. The reaction system was stirred at room temperature for 1.5 hours. The reaction system was then concentrated to give intermediate 30-7 (250 mg, crude) which was used directly in the next step. LC-MS [M+H] ⁺ =357.8.

Step (6) Preparation of methyl (S)-2-(2-(1-acetylpiperidin-4-yl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 30-7 (356 mg) was dissolved in dichloromethane (5 ml) and pyridine (244 mg, 3.09 mmol) was added followed by methyl chloroformate (62 mg, 0.65 mmol). The reaction system was stirred at room temperature for 1.5 hours. The reaction system was then concentrated to give compound 30 (360 mg, 87% yield).

LC-MS: [M+H] ⁺ =415.6. 1HNMR (400 MHz, MeOD): δ 8.42 (s, 1H), 7.56 (d, 1H), 6.91 (d, 1H), 3.82 (m, 3H), 3.67 (s , 3H), 3.60 (m, 1H), 3.54 (t, 4H) 3.38 (dd, 1H), 3.12 (m, 2H), 2.90 (m, 2H), 2, 83 (m, 2H), 2.64 (m, 2H), 2.10 (s, 3H), 1.69 (m, 4H).

To a solution of compound 28 (20 mg, 0.04 mmol) in acetonitrile (3 ml) was added an aqueous solution of ammonium bicarbonate (5%, 2 ml) at room temperature. The reaction system was reacted at room temperature for 2 hours. The reaction system was then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give compound 29 (10 mg, 40% yield) as a white solid.

LC-MS: [M+H] ⁺ =514.1. ^1H NMR (400 MHz, DMSO- _d6 ): δ 11.36 (s, 1H), 8.38 (d, J=7.2 Hz, 1H), 7.93 (s, 1H), 7. 45-7.42 (m, 3H), 7.33 (s, 1H), 6.82-6.80 (m, 1H), 6.35-6.28 (m, 2H), 3.73- 3.62 (m, 3H), 3.55 (s, 3H), 3.51-3.46 (m, 1H), 3.25-3.22 (m, 2H), 3.02-3, 00 (m, 2H), 2.83-2.79 (m, 1H), 2.37 (s, 3H).

Example 30:

Step (1) Preparation of (1-acetylpiperidin-4-yl)methyl acetate

4-hydroxymethylpiperidine (5.2 g, 45.15 mmol) was dissolved in dichloromethane (60 ml) and triethylamine (13.5 g, 133.61 mmol) was added. The reaction system was cooled to 0°C, acetic anhydride (13.8 g, 135.4 mmol) was added and reacted at room temperature for 15 hours. The reaction system was then washed with dilute hydrochloric acid (1 N, 40 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 30-3 (6.2 g) as a yellow oily liquid.

Step (2) Preparation of 1-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one

Compound 30-3 (6.2 g) was dissolved in methanol (50 ml) and an aqueous solution of lithium hydroxide (3.75 N, 25 ml) was added. The reaction system was stirred at room temperature for 12 hours. The reaction system was then concentrated. The residue was separated by column chromatography (EA/MeOH=50/1) to obtain compound 30-4 (7.5 g) as a colorless oily liquid. LC-MS: [M+H] ⁺ =158.0.

Step (3) Preparation of 1-acetylpiperidine-4-carbaldehyde

Compound 30-4 (3.2 g, 20.35 mmol) was dissolved in dichloromethane (40 ml) and Dess-Martin periodinane (12.9 g, 30.52 mmol) was added. The reaction system was reacted at room temperature for 1.5 hours. Saturated sodium thiosulfate solution (20 ml) was then added to the reaction system, diluted with water (40 ml) and extracted with dichloromethane (40 ml x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (EA-EA/MeOH=50/1) to give compound 30-5 (1.0 g, 31% yield) as a white solid. LC-MS: [M+H] ⁺ =156.1.

Step (4) Preparation of tert-butyl-(S)-2-((2-(1-acetylpiperidin-4-yl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

Compound 30-5 (200 mg, 1.29 mmol) was dissolved in anhydrous toluene (40 ml) and 4-methyl-2-aminopyridine (140 mg, 1.29 mmol), tert-butyl-(S)-2- ethynylmorpholine-4-carboxylate (272 mg, 1.29 mmol), copper(I) chloride (40 mg, 0.4 mmol) and copper(II) trifluoromethanesulfonate (140 mg, 0.39 mmol). Under a nitrogen atmosphere, the reaction system was heated to 85°C, two drops of N,N-dimethylacetamide were added, heated and stirred for 6 hours. The reaction system was then cooled to room temperature and stirred overnight. The resulting reaction system was filtered and the filtrate was concentrated. The residue was separated by column chromatography (DCM/MeOH=20/1) to give intermediate 30-6 (227 mg, 38% yield) as a yellow solid. LC-MS: [M+H] ⁺ =456.8.

Step (5) Preparation of (S)-1-(4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-a]pyridin-2-yl)piperidin-1-yl)acetamide

Intermediate 30-6 (227 mg, 0.49 mmol) was dissolved in ethanol (2 ml) and a solution of HCl in ethanol (1 ml, 33%) was added. The reaction system was stirred at room temperature for 1.5 hours. The reaction system was then concentrated to give intermediate 30-7 (250 mg, crude) which was used directly in the next step. LC-MS [M+H] ⁺ =357.8.

Step (6) Preparation of methyl (S)-2-(2-(1-acetylpiperidin-4-yl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 30-7 (356 mg) was dissolved in dichloromethane (5 ml) and pyridine (244 mg, 3.09 mmol) was added followed by methyl chloroformate (62 mg, 0.65 mmol). The reaction system was stirred at room temperature for 1.5 hours. The reaction system was then concentrated to give compound 30 (360 mg, 87% yield).

LC-MS: [M+H] ⁺ =415.6. ^1H NMR (400 MHz, MeOD): δ 8.42(s, 1H), 7.56(d, 1H), 6.91 (d, 1H), 3.82 (m, 3H), 3.67 (s, 3H), 3.60 (m, 1H), 3.54 (t, 4H) 3.38 (dd, 1H), 3.12 (m, 2H), 2.90 (m, 2H), 2.83 (m, 2H), 2.64 (m, 2H), 2.10 (s, 3H), 1.69 (m, 4H).

Example 31:

Step (1) Preparation of methyl 4-bromo-3,5-difluorobenzoate

4-bromo-3,5-difluorobenzoic acid (11.5 g, 48.5 mmol) was dissolved in methanol (100 ml) and concentrated sulfuric acid (1.0 ml) was added. The reaction system was refluxed for 15 hours. The reaction system was then concentrated, diluted with water (50 ml) and extracted with ethyl acetate (50 ml x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (PE) to give compound 31-2 (10 g, 82% yield) as a colorless oily liquid.

Step (2) Preparation of methyl 4-(1-ethoxyethyl)-3,5-difluorobenzoate

Compound 31-2 (10.0 g, 39.83 mmol) was dissolved in anhydrous toluene (90 ml) and palladium acetate (449 mg, 2 mmol), triphenylphosphine (2.0 g, 8.0 mmol) and tributyl- (1-ethoxyethyl)stannane (15.9 g, 44 mmol). The reaction system was refluxed overnight under a nitrogen atmosphere. The reaction system was then concentrated, diluted with water (100 ml) and extracted with ethyl acetate (50 ml x 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (PE) to give compound 31-4 (7.4 g, 76% yield) as a colorless liquid. LC-MS: [M+H] ⁺ =214.8/242.8.

Step (3) Preparation of methyl 4-(2-bromoacetyl)-3,5-difluorobenzoate

Compound 31-4 (7.4 g, 30.46 mmol) was dissolved in tetrahydrofuran (60 ml) and water (20 ml) and N-bromosuccinimide (5.4 g, 30.46 mmol) was added. The reaction system was reacted at room temperature for 1 hour under a nitrogen atmosphere. The reaction system was then concentrated to half volume, diluted with water (60 ml) and extracted with ethyl acetate (30 ml x 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate and concentrated to give intermediate 31-5 (9.0 g) as a yellow solid. LC-MS: [M+H] ⁺ =292.5.

Step (4) Preparation of methyl 3,5-difluoro-4-(7-methylimidazo[1,2-a]pyridin-2-yl)benzoate

Intermediate 31-5 (9.0 g) was dissolved in ethanol (90 ml) and 4-methyl-2-aminopyridine (3.3 g, 30.47 mmol) was added. The reaction system was refluxed for 12 hours under a nitrogen atmosphere. The reaction system was then concentrated, diluted with water (60 ml), adjusted to pH 7-8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (40 ml x 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (PE/EA=1/1) to give intermediate 31-6 (4.2 g, 56% yield) as a yellow solid. LC-MS: [M+H] ⁺ =303.8.

Step (5) Preparation of 3,5-difluoro-G\1-methyl-4-(7-methylimidazo[1,2-a]pyridin-2-yl)benzamide

Intermediate 31-6 (1.5 g, 4.96 mmol) was dissolved in ethanol (15 ml) and aqueous methylamine (6 ml, 25-30%) was added. The reaction system was stirred at room temperature for 12 hours. The reaction system was then concentrated. The residue was separated by column chromatography (EA-EA/MeOH=50/1) to give intermediate 31-7 (1.1 g, 73% yield) as a yellow solid. LC-MS: [M+H] ⁺ =302.8.

Step (6) Preparation of 3,5-difluoro-4-(7-methyl-3-((3-oxopiperazin-1-yl)methyl)imidazo[1,2-a]pyridin-2-yl)benzamide

Intermediate 31-7 (150 mg, 0.49 mmol) and piperazin-2-one (50 mg, 0.49 mmol) were dissolved in acetic acid (1 ml) and aqueous formaldehyde (40 mg, 37%) was added. The reaction system was heated to 50°C and reacted for 3 hours. The reaction system was then cooled to room temperature and stirred for 12 hours. The resulting reaction system was diluted with dichloromethane (10 ml) and adjusted to pH 8 with aqueous sodium hydroxide (2 N). The aqueous phase was extracted with dichloromethane (10 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (DCM/MeOH=20/1) to give compound 31 (39.2 mg, 19% yield) as a white solid.

LC-MS: [M+H] ⁺ =414.8. ^1H NMR (400 MHz, MeOD): 58.52 (d, J=7.1 Hz, 1H), 7.62 (d, J=8.0 Hz, 2H), 7.40 (s, 1H) , 6.94 (dd, J=7.1, 1.5 Hz, 1H), 3.90 (s, 2H), 3.21 (t, J=5.4 Hz, 2H), 3.05 ( s, 2H), 2.97 (s, 3H), 2.66 - 2.54 (m, 2H), 2.48 (s, 3H).

Example 32:

Step (1) Preparation of methylpiperazine-1-carboxylate

Piperazine (3 g, 34.8 mmol) was dissolved in dichloromethane (50 ml) and methyl chloroformate (658 mg, 6.96 mmol) was added portionwise. The reaction system was reacted at room temperature for 30 minutes. Then, an aqueous solution of potassium hydroxide (50 ml, 1 N) was added to the reaction system to quench the reaction, and extraction was carried out with dichloromethane (50 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give a white solid (1.8 g, 36% yield). LC-MS: [M+H] ⁺ =145.7.

Step (2) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl) piperazine-4-carboxylate

Intermediate 31-7 (150 mg, 0.49 mmol) and compound 32-2 (180 mg) were dissolved in acetic acid (1 ml) and aqueous formaldehyde (40 mg, 37%) was added. The reaction system was heated to 50°C and reacted for 3 hours. The reaction system was then cooled to room temperature and stirred for 12 hours. The resulting reaction system was diluted with dichloromethane (10 ml) and adjusted to pH 8 with aqueous sodium hydroxide (2 N). The aqueous phase was subjected to extraction with dichloromethane (15 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was separated by HPLC to give compound 32 (98.2 mg, 43% yield) as a white solid.

LC-MS: [M+H] ⁺ =458.7. ^1H NMR: ^1H NMR (400 MHz, MeOD): δ 8.55 (d, J=7.0 Hz, 1H), 7.60 (d, J=7.9 Hz, 2H), 7.39 (s, 1H), 6.94 (d, J=7.1 Hz, 1H), 3.80 (s, 2H), 3.66 (s, 3H), 3.47-3.36 (m, 4H), 2.97 (s, 3H), 2.49 (s, 3H), 2.37-2.29 (m, 4H).

Example 33:

Preparation of 3,5-difluoro-4-(7-methyl-3-morpholinomethylimidazo[1,2-a]pyridin-2-yl)benzamide

Intermediate 31-7 (100 mg, 0.33 mmol) and morpholine (29 mg, 0.33 mmol) were dissolved in acetic acid (0.5 ml) and aqueous formaldehyde (28 mg, 37%) was added. The reaction system was heated to 50°C and reacted for 3 hours. The reaction system was then cooled to room temperature and stirred for 12 hours. The resulting reaction system was diluted with dichloromethane (15 ml) and adjusted to pH 8 with aqueous sodium hydroxide (2 N). The aqueous phase was extracted with dichloromethane (10 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by HPLC to provide compound 33 (50.2 mg, 38% yield) as a white solid.

LC-MS: [M+H] ⁺ =401.7. ¹ NMR(400 MHz, CDCl ₃ ): 68.44 (d, J=7.0 Hz, 1H), 7.58-7.37 (m, 4H), 6.80 (d, J=6.9 Hz, 1H), 3.71 (s, 2H), 3.67 - 3.60 (m, 4H), 3.03 (d, J=4.6 Hz, 3H), 2.48 (s, 3H ), 2.39-2.31 (m, 4H).

Example 34:

Step (1) Preparation of tert-butyl-3,5-difluorobenzoate

3,5-difluorobenzoic acid (10.0 g, 63.25 mmol) was dissolved in tert-butanol (100 ml) and DMAP (2.3 g, 18.98 mmol) and di-tert-butyl dicarbonate (27.6 g, 126.50 mmol). The reaction system was reacted at room temperature for 15 hours. The reaction system was then concentrated, diluted with water (80 ml) and extracted with ethyl acetate (50 ml x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (PE/EA=20/1) to give compound 34-2 (12.0 g, 88% yield) as a colorless oily liquid.

Step (2) Preparation of tert-butyl-3,5-difluoro-4-formyl benzoate

LDA (2N, 8.4 ml) was dissolved in tetrahydrofuran (10 ml). The reaction system was cooled to -78°C under a nitrogen atmosphere. Compound 34-2 (3.0 g, 14.0 mmol) was dissolved in tetrahydrofuran (20 ml) and the resulting solution was added to the reaction system. The reaction system was stirred at -78°C for 1.5 hours, DMF (1.2 g, 16.8 mmol) was added and stirred for an additional 1 hour at a temperature maintained at -70°C. Then, saturated ammonium chloride solution (60 ml) was added to the reaction system to quench the reaction, and extraction was carried out with ethyl acetate (30 ml × 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (PE/EA=10/1) to give compound 34-3 (1.5 g, 44% yield) as a yellow solid.

Step (3) Preparation of tert-butyl-(S)-2-(((2-(4-(tert-butoxycarbonyl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3- yl)methyl)morpholine carboxylate

Compound 34-3 (480 mg, 1.98 mmol) was dissolved in anhydrous toluene (4 ml) and 4-methyl-2-aminopyridine (215 mg, 1.98 mmol), tert-butyl-(S)-2- ethynylmorpholine-4-carboxylate (419 mg, 1.98 mmol), copper (I) chloride (62 mg, 0.63 mmol) and copper (II) trifluoromethanesulfonate (216 mg, 0.60 mmol). Under a nitrogen atmosphere, the reaction system was heated to 85°C, two drops of N,N-dimethylacetamide were added, heated and stirred for 6 hours. The reaction system was then cooled to room temperature and stirred overnight. The resulting reaction system was filtered and the filtrate was concentrated. The residue was separated by column chromatography (PE/EA=2/1) to give intermediate 34-4 (340 mg, 31% yield) as a brown solid. LC-MS: [M+H] ⁺ =544.7.

Step (4) Preparation of (S)-3,5-difluoro-4-(7-methyl-3-(morpholinyl-2-methyl)imidazo[1,2-a]pyridin-2-yl)benzoic acid

Intermediate 34-4 (340 mg, 0.62 mmol) was dissolved in ethanol (3 ml) and a solution of HCl in ethanol (1 ml, 33%) was added. The reaction system was stirred at room temperature for 1.5 hours. The reaction system was then concentrated to give intermediate 34-5 (400 mg) as a yellow oily liquid. LC-MS: [M+H] ⁺ =388.7.

Step (5) Preparation of (S)-3,5-difluoro-4-(3-(4-(methoxycarbonyl)morpholin-2-yl)methyl)-7-methylimidazo[1,2-a]pyridin-2-yl )benzoic acid

Intermediate 34-5 (400 mg) was dissolved in dichloromethane (5 ml) and pyridine (244 mg, 3.09 mmol) was added followed by methyl chloroformate (62 mg, 0.65 mmol). The reaction system was stirred at room temperature for 1.5 hours and concentrated to give intermediate 34-6 (190 mg). LC-MS: [M+H] ⁺ =446.6.

Step (6) Preparation of methyl-(S)-2-((2-(4-((cyanomethyl)carbamoyl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl) methyl)morpholine-4-carboxylate

Intermediate 34-6 (445 mg, 1 mmol) was dissolved in CH ₃ CN (10 ml) and triethylamine (1.2 mmol), DMAP (1.2 mmol) and EDCl (1.2 mmol) were added. The reaction system was stirred at room temperature overnight. After completion of the reaction, the reaction system was purified by column chromatography to obtain intermediate 34-7 (362 mg, 75% yield). LC-MS: [M+H] ⁺ =484.6.

Step (7) Preparation of methyl-(S)-2-((2-(4-(4-chloro-1H-imidazol-2-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a ]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 34-7 (483 mg, 1 mmol) was dissolved in THF (10 ml) and amounts of CCl ₄ and PPh ₃ were added. The reaction system was heated to 50°C and analyzed by LC-MS to determine whether the reaction was complete. After completion of the reaction, the reaction system was purified by column chromatography to obtain compound 34 (50 mg, 10% yield). LC-MS: [M+H] ⁺ =502.1.

Example 35:

Step (1) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-hydroxyphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine -4-carboxylate

2,6-difluoro-4-hydroxybenzaldehyde (2.0 g, 9.05 mmol), 4-methylpyridin-2-amine (0.97 g, 9.05 mmol), compound 1-4 (1.9 g, 9.05 mmol), copper(I) chloride (0.27 g, 2.70 mmol) and copper(II) trifluoromethanesulfonate (0.98 g, 2.70 mmol) were dissolved in toluene solution (20 ml) under nitrogen atmosphere . The reaction system was reacted at 85°C for 10 minutes, N,N-dimethylacetamide (0.5 ml) was added and reacted at 85°C for another 5 hours. The reaction system was then reacted at room temperature overnight. After completion of the reaction, water (40 ml) was added to the reaction system and extraction was carried out with dichloromethane (50 ml × 3). The organic phases were combined, washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography (40 g silica gel, petroleum ether:ethyl acetate=1:1) to give intermediate 35-2 (1.2 g, 29% yield) as a yellow oil. LC-MS: [M+H] ⁺ =460.1.

Step (2) Preparation of (S)-3,5-difluoro-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-a]pyridin-2-yl)phenol

Intermediate 35-2 (1.0 g, 1.91 mmol) was dissolved in dichloromethane (10 ml) and a solution of HCl in ethanol (2 ml, 33%) was added dropwise. After the dropwise addition was completed, the reaction system was reacted at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added dropwise to the reaction system to adjust the pH to 8, water (30 mL) was added, and extracted with dichloromethane (40 mL x 3 ). The organic phases were combined, washed with brine (40 mL), dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to give intermediate 35-3 (800 mg) as a yellow oil. LC-MS [M+H] ⁺ =360.7.

Step (3) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-hydroxyphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

Intermediate 35-3 (350 mg, 0.97 mmol) and N,N-diisopropylethylamine (378 mg, 2.92 mmol) were dissolved in dichloromethane (10 ml) and methyl chloroformate (110 mg, 1.16 mmol) was added dropwise with temperature support 0°C. After the dropwise addition was completed, the reaction system was reacted at 0°C for 3 hours. After completion of the reaction, the reaction system was added to lithium hydroxide solution (1.0 ml, 3 N) and reacted at room temperature for 2 hours. After completion of the reaction, the pH of the reaction system was adjusted to 5 with dilute hydrochloric acid, diluted with water (10 ml) and extraction was carried out with dichloromethane (15 ml × 3). The organic phases were combined, washed with brine (20 ml), dried over magnesium sulfate and dried. The organic phase was filtered and concentrated on a rotary evaporator. The residue was separated by HPLC to give compound 35 (150 mg, 37% yield) as a yellow solid.

LC-MS: [M+H] ⁺ =418.7. ^1H NMR (400 MHz, MeOD): δ 8.57 (d, J=6.9 Hz, 1H), 7.47 (s, 1H), 7.08 (d, J=6.9 Hz, 1H), 6.60 (d, J=9.6 Hz, 2H), 3.92 - 3.76 (m, 3H), 3.68 (s, 3H), 3.69 -3.57 ( m, 1H), 3.39 (dd, J=11.9, 2.7 Hz, 1H) 3.16 - 3.10 (m, 2H), 2.98 - 2.86 (m, 1H) , 2.74 - 2.63 (m, 1H), 2.53 (s, 3H).

Example 36:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(methylcarbamoyloxy)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4- carboxylate

Compound 35 (359 mg, 1 mmol) was dissolved in CH ₂ Cl ₂ (10 ml) and triethylamine (2 mmol) was added. Methylaminoformyl chloride (186 mg, 2 mmol) was dissolved in anhydrous CH ₂ Cl ₂ (2 ml), and the resulting solution was added dropwise to the reaction system. After completion of the reaction, the reaction system was neutralized and washed, dried, filtered and purified by column chromatography to provide compound 36 (62 mg, 13% yield). LC-MS [M+H] ⁺ =475.1.

Example 37:

Step (1) Preparation of 2-(3,5-difluorophenyl)-1,3-dioxolane

3,5-difluorobenzaldehyde (5.68 g, 40 mmol), p-toluenesulfonic acid (0.69 g, 4 mmol) and ethylene glycol (7.45 g, 120 mmol) were dissolved in toluene (80 ml). The reaction system was refluxed to separate the water overnight. The reaction system was then cooled to room temperature, diluted with ethyl acetate (40 ml) and washed with NaHCO ₃ solution (40 ml x 2). The organic phase was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography (PE:EA=20:1) to give compound 37-3 (7.0 g, 94% yield) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ): δ 7.03-7.00 (m, 2H), 6.82-6.76 (m, 1H), 5.79 (s, 1H), 4 .09-4.05 (m, 2H), 4.07-3.99 (m, 2H).

Step (2) Preparation of 4-(1,3-dioxolan-2-yl)-2,6-difluorobenzaldehyde

Compound 37-3 (7.0 g, 37.8 mmol) was dissolved in tetrahydrofuran (50 ml). The reaction system was cooled to -78°C under nitrogen and LDA (22.4 mL, 44.8 mmol) was added dropwise. After the dropwise addition was completed, the reaction system was reacted at this temperature for 30 min, then anhydrous DMF (3.3 g, 44.3 mmol) was added. After the dropwise addition was completed, the reaction system was reacted at this temperature for 2.5 hours. Saturated NH ₄ Cl (20 mL) was then added to the reaction system to quench the reaction mixture, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated on a rotary evaporator. The resulting crude product was purified by silica gel column chromatography (PE:EA=10:1) to give intermediate 37-4 (0.90 g, 12% yield) as a white solid.

^1H NMR (300 MHz, DMSO): δ 10.18 (s, 1H), 7.28 (d, J=9.8 Hz, 2H), 5.82 (s, 1H), 4.06-4 .00 (m, 2H), 4.01-3.93 (m, 2H).

Step (3) Preparation of tert-butyl-(S)-2-((2-(4-(1,3-dioxolan-2-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a ]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 37-4 (100 mg, 0.47 mmol), Compound 1-4 (100 mg, 0.47 mmol), 4-methylpyridin-2-amine (51 mg, 0.47 mmol), copper(I) chloride ) (25 mg, 0.14 mmol) and copper(II) trifluoromethanesulfonate (51 mg, 0.14 mmol) were dissolved in toluene (3 ml) in a one-neck flask. The reaction system was heated to 85°C under a nitrogen atmosphere, added dropwise with two drops of DMA, and reacted at this temperature for 5 hours. The reaction system was then cooled to room temperature and stirred overnight. The resulting reaction system was diluted with water (20 ml) and extracted with ethyl acetate (20 ml x 3). The organic phases were combined, washed with brine (20 ml), dried over Na ₂ SO ₄ and filtered, and the filtrate was concentrated on a rotary evaporator. The resulting crude product was purified by silica gel column chromatography (PE:EA=5:1) to give intermediate 37-5 (150 mg, 62% yield). LC-MS: [M+H] ⁺ =516.7.

Step (4) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-formylphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine -4-carboxylate

Intermediate 37-5 (150 mg, 0.29 mmol) was dissolved in acetone (10 mL) and water (1 mL) and TsOH (90 mg, 0.3 mmol) was added. The reaction system was heated to 50°C and reacted overnight. The reaction system was then diluted with water (50 ml), Na ₂ CO ₃ (92 mg, 0.87 mmol) and (Boc) ₂ O (75 mg, 0.35 mmol) were added, stirred for 1.5 h and extracted with ethyl acetate (15 ml × 2). The organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated on a rotary evaporator. The resulting crude product was purified by silica gel column chromatography (PE:EA=5:1) to give intermediate 37-6 (60 mg, 44.8% yield) as a white solid. LC-MS: [M+H] ⁺ =472.7.

Step (5) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-(4-trifluoromethyl-1H-imidazol-2-yl)phenyl)-7-methylimidazo[1, 2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

3,3-dibromo-1,1,1-trifluoropropan-2-one (35 mg, 0.13 mmol) was dissolved in sodium acetate solution (2 ml, 15 wt%). The reaction system was stirred at 90°C for 30 minutes and cooled to room temperature. Intermediate 37-6 (50 mg, 0.11 mmol) was dissolved in methanol (3 mL) and strong ammonia (0.6 mL) and the solution was added to the reaction system and stirred at room temperature overnight. The reaction system was then concentrated on a rotary evaporator. The residual liquid was extracted with ethyl acetate (5 mL x 3) and washed with brine (10 mL). The organic phase was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated on a rotary evaporator. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=50:1) to give intermediate 37-8 (45 mg, 72.2% yield) as a white solid. LC-MS: [M+H] ⁺ =578.6.

Step (6) Preparation of (S)-2-(((2-(2,6-difluoro-4-(4-trifluoromethyl-1H-imidazole)phenyl)-7-methylimidazo[1,2-a]pyridine-3 -yl)methyl)morpholine

Intermediate 37-8 (45 mg, 0.08 mmol) was dissolved in dichloromethane (3 ml) and a solution of HCl in ethanol (0.5 ml) was added. The reaction system was stirred at room temperature for 3 hours. The reaction system was then concentrated by rotary evaporation to give intermediate 37-9 (80 mg, crude product). LC-MS: [M+H] ⁺ =478.7.

Step (7) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(4-trifluoromethyl-1H-imidazol-2-yl)phenyl)-7-methylimidazo[1,2- a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 37-9 (80 mg, crude product) and DIPEA (30 mg, 0.23 mmol) were dissolved in dichloromethane (3 ml). The reaction system was cooled to 0°C and stirred for 10 minutes. A solution of methyl chloroformate in dichloromethane (0.1 N, 0.8 ml) was then added dropwise to the reaction system, stirred for 3 hours, water (10 ml) was added to quench the reaction mixture, and extracted with ethyl acetate (10 ml × 3). The organic phase was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated on a rotary evaporator. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=20:1) prepared and lyophilized to give compound 37 (7.0 mg, 16.3% yield) as a white solid.

LC-MS: [M+H] ⁺ =536.7. ^1H NMR (400 MHz, CDCl ₃ ): δ 13.18 (s, 1H), 8.58 (brs, 1H), 7.97 - 7.93 (m, 3H), 7.53 (s, 1 H), 7.16 (d, J=6.0 Hz, 1 H), 4.05 - 3.70 (m, 3H), 3.71 (s, 3H), 3.64 -3.56 ( m, 1H), 3.45 - 3.30 (m, 1H), 3.09 - 2.85 (m, 3H), 2.74 - 2.64 (m, 1H), 2.60 (s, 3H).

Example 38:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(4-cyano-1H-imidazol-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridin- 3-yl)methyl)morpholine-4-carboxylate

Compound 37 (30 mg, 0.05 mmol) was dissolved in methanol (2 ml) and strong ammonia (0.8 ml) and water (0.8 ml) were added. The reaction system was stirred at room temperature for 36 hours. The reaction system was then diluted with water (10 ml) and extracted with ethyl acetate (10 ml x 3). The organic phase was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated on a rotary evaporator. The crude product was purified by preparative thin layer chromatography (dichloromethane:methanol=20:1) and lyophilized to give compound 38 (11 mg, 44.6% yield) as a white solid.

LC-MS: [M+H] ⁺ =493.6. ¹ H NMR (400 MHz, CDCl ₃ ): δ 15.61 (brs, 1 H), 8.31 (d, J=7.0 Hz, 1 H), 7.74 (s, 1 H), 7 .47 (s, 1H), 7.33 (d, J=7.2 Hz, 2H), 6.85 (d, J=7.0 Hz, 1H), 3.97 - 3.72 (m, 3H), 3.66 (s, 3H), 3.62 - 3.52 (m, 1H), 3.42 - 3.30 (m, 1H), 3.03 - 2.85 (m, 3H ), 2.65 - 2.55 (m, 1H), 2.54(s, 3H).

Example 39:

Step (1) Preparation of N-(2-bromo-5-methylphenyl)-2,2,2-trifluoroacetamide

2-bromo-5-methylbenzenamine (2.5 g, 13.44 mmol) and pyridine (3.3 mL, 40.32 mmol) were dissolved in dichloromethane (30 mL). Trifluoroacetic anhydride (3.4 g, 16.12 mmol) was added dropwise to the reaction system at 0° C. and reacted at room temperature overnight. The reaction mixture was washed successively with water (10 mL x 2) and diluted with hydrochloric acid (30 mL, 1 mol/L), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give compound 39-3 (3.4 g, yield 90%) as a gray solid, LC-MS: [M+H] ⁺ =281.7.

Step (2) Preparation of R-(morpholin-2-yl)methanol

(R)-N-Boc-2-hydroxymethylmorpholine (3.5 g, 16.13 mmol) was dissolved in dichloromethane (20 ml) and a solution of HCl in ethanol (3.5 ml, 33%) was added dropwise at 0°C . The reaction system was stirred at room temperature overnight and concentrated under reduced pressure to give 39-5 (1.8 g, 95% yield, crude product) as a yellow oil. LC-MS: [M+H] ⁺ =118.1.

Step (3) Preparation of methyl (R)-2-(hydroxymethyl)morpholine-4-carboxylate

Compound 39-5 (4.0 g, 16.13 mmol) was dissolved in dichloromethane (40 ml) and DIPEA (12.5 g, 96.78 mmol) was added dropwise at 0°C. Methyl chloroformate (1.97 g, 20.97 mmol) was then dissolved in dichloromethane (10 ml) and added dropwise to the reaction system at 0°C. The reaction system was stirred at room temperature overnight, dichloromethane (100 ml) was added, washed with brine (35 ml x 2) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g silica gel, ethyl acetate:petroleum ether=1:2) to give intermediate 39-6 (1.0 g, 35% yield) as a colorless oil. LC-MS: [M+H] ⁺ =176.9.

Step (4) Preparation of methyl (R)-2-formylmorpholine-4-carboxylate

Intermediate 39-6 (600 mg, 3.43 mmol) was dissolved in dichloromethane (10 mL) and Dess-Martin periodinane (1.74 g, 4.11 mmol) was added. The reaction system was allowed to react at room temperature for 2 hours, saturated sodium thiosulfate (2 ml) was added and stirred for 30 minutes. The reaction system was then extracted with dichloromethane (30 ml x 2), washed with brine (15 ml) and purified by silica gel column chromatography (12 g silica gel, ethyl acetate:petroleum ether=1:1) to give intermediate 39-A (180 mg, yield 30%) as a yellow oil. LC-MS: [M+H] ⁺ =174.5.

Step (5) Preparation of 4-ethynyl-3,5-difluoro-N-methylbenzamide

Dimethyl (1-diazo-2-oxopropyl) phosphonate (2.2 g, 11.3 mmol) was dissolved in acetonitrile (15 ml) and methanol (3 ml), then potassium carbonate (2.3 g, 16.56 mmol). The reaction system was stirred at room temperature for 30 min, 3,5-difluoro-4-formyl-N-methylbenzamide (1.5 g, 7.53 mmol) was added and stirred at room temperature overnight. The reaction system was then filtered and concentrated. The residue was purified by silica gel column chromatography (20 g silica gel, ethyl acetate:petroleum ether=1:5) to give intermediate 39-8 (1.2 g, 81% yield) as a yellow solid. LC-MS: [M+H] ⁺ =196.1.

Step (6) Preparation of 3,5-difluoro-4-(6-methyl-1H-indol-2-yl)benzamide

To N,N-dimethylformamide (20 ml) was added intermediate 39-8 (1.4 g, 7.18 mmol), intermediate 39-3 (2.43 g, 8.61 mmol), potassium carbonate (1, 97 g, 15.09 mmol), copper(I) iodide (0.14 g, 1.43 mmol) and L-proline (0.25 g, 2.87 mmol). The reaction system was reacted at 80°C overnight under nitrogen atmosphere. The reaction system was then cooled, poured into water (60 ml), extracted with ethyl acetate (50 ml x 2), washed with brine (30 ml x 3) and purified by silica gel column chromatography (20 g silica gel, developer: ethyl acetate: petroleum ether=1:2) to give intermediate 39-9 (800 mg, 44% yield) as a yellow solid. LC-MS: [M+H] ⁺ =301.8.

Step (7) Preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylindol-3-yl)methyl)morpholine-4-carboxylate

Trifluoroacetic acid (304 mg, 2.66 mmol) and triethylsilane (617 mg, 5.32 mmol) were dissolved in dichloromethane (3 ml) in a round bottom flask (25 ml). Intermediate 39-9 (160 mg, 0.53 mmol) and intermediate 39-A (110 mg, 0.64 mmol) were then dissolved in dichloromethane (3 ml) and the solution was added dropwise to the reaction system at 0°C. The reaction system was stirred at room temperature overnight. The reaction system was then added with water (20 mL), extracted with dichloromethane (20 mL x 2) and separated by preparative reverse phase chromatography to give compound 39 (18 mg, 7.4% yield) as a white solid.

LC-MS: [M+H] ⁺ =458.2. ^1H NMR (400 MHz, CDCl ₃ ): δ 8.18 (brs, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.43 (d, J=7.5 Hz , 2H), 7.21 (s, 1 N), 7.02 (d, J=8.1 Hz, 1 N), 6.29 (brs, 1 N), 3.88 - 3.75 (m , 3H), 3.64 (s, 3H), 3.60 - 3.55 (m, 1H), 3.45-3.39 (m, 1H), 3.07 (d, J=3.6 Hz, 3H), 3.04 -2.98 (m, 1H), 2.90-2.88 (m, 1H), 2.78 (dd, J=14.9, 6.6 Hz, 1 H), 2.50 (s, 3H), 2.49 - 2.41 (m, 1H).

Example 40:

Step (1) Preparation of methyl (R)-2-((((methylsulfonyl)oxo)methyl)morpholine-4-carboxylate

Intermediate 39-6 (400 mg, 2.28 mmol) and N,N-diisopropylethylamine (737 mg, 5.71 mmol) were dissolved in dichloromethane (10 ml) and methyl sulfonyl chloride (313 mg, 2.74 mmol) was added dropwise at 0°C. After the dropwise addition was completed, the reaction system was reacted at room temperature overnight. The reaction system was then added with dichloromethane (20 mL), washed with brine (15 mL x 2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give intermediate 40-1 (600 mg, crude product) as a brown oils LC-MS: [M+H] ⁺ =254.9.

Step (2) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1H-indol-1-yl)methyl)morpholine-4- carboxylate

Intermediate 39-9 (250 mg, 0.83 mmol) was dissolved in N,N-dimethylformamide (5 ml) and intermediate 40-1 (421 mg, 1.67 mmol) and potassium tert-butoxide (205 mg, 1 .83 mmol) was added at room temperature. The reaction system was stirred at 120°C overnight under a nitrogen atmosphere. The reaction system was then cooled to room temperature, water (20 ml) was added and extracted with ethyl acetate (30 ml x 2). The organic phases were combined, washed with brine (15 ml), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by preparative reverse phase chromatography to give compound 40 (35 mg, 9.2% yield) as a white solid.

LC-MS: [M+H] ⁺ =458.8. ^1H NMR (400 MHz, CDCl ₃ ): δ 7.57 (d, J=8.1 Hz, 1H), 7.43 (d, J=7.7 Hz, 1H), 7.22 (s , 1H), 7.03 (d, J=8.1 Hz, 1H), 6.61 (s, 1H), 6.22 (brs, 1H), 4.15-3.99 (m, 2H) , 3.85 - 3.60 (m, 3H), 3.67 (s, 3H), 3.60 - 3.50 (m, 1H), 3.32 (t, 1H), 3.08 (d , J=4.7 Hz, 3H), 2.81 (t, J=11.6 Hz, 1H), 2.54 (s, 3H), 2.39 (dd, J=13.0, 10, 8 Hz, 1H).

Example 41:

The compound was prepared in accordance with the preparation method described in Example

LC-MS: [M+H] ⁺ =461.2.

Example 42:

Step (1) Preparation of ethyl 2-(4-phenylmethylmorpholin-2-yl) acetate

2-(phenylmethylamino)ethanol (45.0 g, 298 mmol) and triethylamine (30.0 g, 298 mmol) were dissolved in water (450 ml). The reaction system was heated to 100°C, (£)-ethyl-4-bromobut-2-enoate (57.5 g, 298 mmol) was added, reacted overnight and extracted with ethyl acetate (200 ml x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (PE/EA=10/1) to give compound 42-3 (27.0 g, 35% yield) as a yellow oily liquid. LC-MS: [M+H] ⁺ =264.2.

Step (2) Preparation of 2-(4-phenylmethylmorpholin-2-yl)ethanol

Compound 42-3 (27.0 g, 103 mmol) was dissolved in tetrahydrofuran (300 ml). The reaction system was cooled to 0°C under nitrogen, lithium aluminum hydride (3.9 g, 103 mmol) was added in portions and warmed to room temperature and stirred for 3 hours. The reaction system was then added with sodium sulfate decahydrate to quench the reaction, filtered and washed with ethyl acetate, and the filtrate was concentrated. The residue was separated by column chromatography (PE/EA=2/1) to give compound 42-4 (17.4 g, 76% yield) as a colorless oily liquid. LC-MS: [M+H] ⁺ =222.1.

Step (3) Preparation of tert-butyl 2-(2-hydroxyethyl)morpholine-4-carboxylate

Compound 42-4 (17.6 g, 78.4 mmol) and di-tert-butyl dicarbonate (51.3 g, 235 mmol) were dissolved in absolute methanol (180 ml) and palladium-carbon (1.74 g, 10 %). The reaction system was purged with hydrogen and stirred at room temperature overnight. The reaction system was then filtered and the filtrate was concentrated. The residue was separated by column chromatography (PE/EA=3/1) to give compound 42-5 (12.5 g, 68% yield) as a colorless oily liquid. LC-MS: [M+H] ⁺ =232.3.

Step (4) Preparation of tert-butyl 2-(2-carbonylethyl)morpholine-4-carboxylate

Compound 42-5 (2.0 g, 1.44 mmol) was dissolved in dichloromethane (40 ml) and Dess-Martin periodinane (5.5 g, 2.15 mmol) was added. The reaction system was stirred at room temperature for 2 hours. The reaction system was then added with sodium thiosulfate to quench the reaction and extracted with dichloromethane (40 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (PE/EA=2/1) to give compound 42-6 (1.1 g, 67% yield) as a colorless oily liquid. LC-MS: [M+H] ⁺ =230.1.

Step (5) Preparation of tert-butyl-2-(prop-2-yn-1-yl)morpholine-4-carboxylate

Dimethyl (1-diazo-2-oxopropyl) phosphonate (4.0 g, 20.9 mmol) was dissolved in dichloromethane (40 ml) and acetonitrile (8 ml). The reaction system was stirred at room temperature for 15 minutes, compound 42-6 (4.0 g, 17.5 mmol) and potassium carbonate (2.4 g, 17.5 mmol) were added and stirred at room temperature overnight. The reaction system was then filtered and the filtrate was concentrated. The residue was separated by column chromatography (PE/EA=10/1) to give compound 42-7 (2.1 g, 53% yield) as a colorless oily liquid. LC-MS: [M-55] ⁺ =226.2.

Step (6) Preparation of tert-butyl 2-(3-bromoprop-2-yn-1-yl)morpholine-4-carboxylate

Compound 42-7 (2.1 g, 9.3 mmol) and silver nitrate (1.9 g, 11.1 mmol) were dissolved in acetone (20 ml) and N-bromosuccinimide (1.8 g, 10.2 mmol). The reaction system was stirred at room temperature for 4 hours and extracted with ethyl acetate (60 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (PE/EA=20/1) to give intermediate 42-8 (2.0 g, 71% yield) as a colorless oil. LC-MS: [M+H] ⁺ =304.2.

Step (7) Preparation of tert-butyl-2-((2-bromo-7-methylimidazo[1,2-c]pyrimidin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 42-8 (2.0 g, 6.5 mmol), 6-methylpyrimidin-4-amine (0.85 g, 7.9 mmol) and copper(II) trifluoromethanesulfonate (0.24 g, 0.65 mmol) was dissolved in acetonitrile (20 ml). The reaction system was stirred at room temperature overnight under oxygen, diluted with water (50 ml) and extracted with ethyl acetate (30 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (PE/EA=2/1) to give intermediate 42-10 (400 mg, 15% yield) as a colorless oily liquid. LC-MS: [M+H] ⁺ =411.1.

Step (8) Preparation of tert-butyl-2-(((7-methyl-2-(tributylstannyl)imidazo[1,2-c]pyrimidin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 42-10 (40 mg, 0.1 mmol), 1,1,1,2,2,2-hexabutyldistannan (170 mg, 0.3 mmol) and tetrakis(triphenylphosphine)palladium (11 mg, 0.01 mmol) was dissolved in 1,4-dioxane (2 ml). The reaction system was stirred at 100°C overnight under nitrogen and detected by LC-MS to complete yield of intermediate 42-11 (5% yield). LC-MS: [M+H] ⁺ =623.5.

Step (9) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-c]pyrimidin-3-yl) methyl)morpholine-4-carboxylate

The compound was prepared according to the method for preparing compound 37-9.

Step (10) Preparation of (S)-2-(((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-c]pyrimidin-3-yl)methyl)morpholine

The compound was prepared in accordance with the production method as described in step (6) of Example 37.

Step (11) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-c]pyrimidin-3-yl)methyl) morpholine-4-carboxylate

The compound was prepared in accordance with the production method as described in step (7) of Example 37.

LC-MS: [M+H] ⁺ =460.2.

Example 43:

Step (1) Preparation of 4-bromo-3,5-difluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide

1-(4-methoxyphenyl)-N-methylmethylamine (1.30 g, 8.24 mmol) and triethylamine (2.10 g, 20.61 mmol) were dissolved in dichloromethane (16 ml) and solution 4 was added dropwise -bromo-3,5-difluorobenzenesulfonyl chloride (2.00 g, 6.87 mmol) in dichloromethane (4 ml) at 0°C. The reaction system was warmed to room temperature and reacted for 4 hours. The reaction system was then added with water (50 mL) to quench the reaction, extracted with dichloromethane (50 mL x 2), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 43-3 (2.30 g, 78% yield) as a white solid. MS [M+Na]=427.6, 429.6.

Step (2) Preparation of 3,5-difluoro-4-formyl-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide

Intermediate 43-3 (1.70 g, 4.19 mmol) was dissolved in anhydrous tetrahydrofuran (17 ml) under nitrogen and n-butyllithium (2.4 mol/L, 1.75 ml) was added dropwise at 78° WITH. After the dropwise addition was completed, the reaction system was stirred at this temperature for 0.5 h, N,N-dimethylformamide (367 mg, 5.03 mmol) was added dropwise and reacted for 3 h. Dilute hydrochloric acid was then added to the reaction system. acid (0.5 mol/l, 10 ml) to quench the reaction mixture, diluted with water (50 ml) and extraction with ethyl acetate (30 ml × 2). The organic phases were combined, washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 43-4 (600 mg, 32% yield) as a white solid. MS [M+Na]=377.8.

Step (3) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-(N-(4-methoxybenzyl)-N-methylsulfamoyl)phenyl)-7-methylimidazo[1, 2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 43-4 (600 mg, 1.69 mmol), 4-methylpyridin-2-amine (183 mg, 1.69 mmol) and tert-butyl (S)-2-ethynylmorpholine-4-carboxylate (359 mg , 1.69 mmol) was dissolved in toluene (6 ml) under a nitrogen atmosphere and copper (I) chloride (50 mg, 0.51 mmol) and copper (II) trifluoromethanesulfonate (183 mg, 0.51 mmol) were added. The reaction system was reacted at 85°C for 10 minutes, dimethylacetamide (0.1 ml) was added and reacted at 85°C for another 5 hours. The reaction system was then stirred at room temperature overnight. The resulting reaction system was filtered and the filtrate was added with water (30 ml) and extracted with dichloromethane (30 ml x 3). The organic phases were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to provide intermediate 43-5 (298 mg, 27% yield) as a light yellow solid. MS [M+H] ⁺ =656.7.

Step (4) Preparation of (S)-3,5-difluoro-N-(4-methoxybenzyl)-N-methyl-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2- a]pyridin-2-yl)benzenesulfonamide

Intermediate 43-5 (298 mg, 0.45 mmol) was dissolved in dichloromethane (5 ml) and a solution of HCl in ethanol (33%, 0.45 ml) was added dropwise. The reaction system was reacted at room temperature for 16 hours. The reaction system was then concentrated under reduced pressure to obtain intermediate 43-6 (300 mg, crude hydrochloride product) as a light yellow solid. MS [M+H] ⁺ =556.8.

Step (5) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(N-(4-methoxybenzyl)-N-methylsulfamoyl)phenyl)-7-methylimidazo[1,2- a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 43-6 (300 mg, 0.50 mmol) was dissolved in dichloromethane (5 ml) under nitrogen and triethylamine (202 mg, 2.00 mmol) was added at 0° C., followed by dropwise addition of methyl chloroformate solution (57 mg , 0.60 mmol) in dichloromethane (1 ml). The reaction system was reacted at 0° C. for 4 hours. Then, water (20 ml) was added to the reaction system to quench the reaction, and extraction was carried out with dichloromethane (20 ml × 2). The organic phases were combined, washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to provide intermediate 43-7 (200 mg, 88% purity, 64.5% yield) as a brown solid. MS [M+H] ⁺ =615.2.

Step (6) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(N-methylsulfamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl) methyl)morpholine-4-carboxylate

Intermediate 43-7 (200 mg, 0.32 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) was added at 0°C. The reaction system was reacted at room temperature for 16 hours. The reaction system was then concentrated under reduced pressure. The residue was dissolved in dichloromethane (40 ml), washed with aqueous sodium bicarbonate (10%, 15 ml x 2) and brine (15 ml) successively, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative chromatography to provide compound 43 (80.2 mg, 49.8% yield) as a white solid.

MS [M+N] ⁺ =494.7. 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=5.2 Hz, 1H), 7.93 (s, 1H), 7.61 (d, J=6.7 Hz, 2H), 7.20 (d, J=7.1 Hz, 1H), 5.11 - 4.95 (m, 1H), 4.22 - 4.06 (m, 1H), 3.96 - 3.90 (m, 1H), 3.86 - 3.77 (m, 1H), 3.74 (s, 3H), 3.69 - 3.63 (m, 1H), 3.45 - 3.39 (m , 1H), 3.13 -3.02 (m, 2H), 3.01 - 2.92 (m, 1H), 2.79 (s, 3H), 2.75 - 2.70 (m, 1H), 2.63 (s, 3H).

Example 44:

Step (1) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(4-methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl) methyl)morpholine-4-carboxylate

The compound was prepared in accordance with patent literature CN105246888A.

Step (2) Preparation of methyl-(2S)-2-(2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridin-3-yl)methyl)morpholine-4-carboxylate

Positive control compound 1 (120 mg, 0.3 mmol) and concentrated hydrochloric acid (0.1 ml) were dissolved in absolute methanol (3 ml). The reaction system was purged with hydrogen and stirred at room temperature for 6 hours. The reaction system was then filtered and concentrated. The residue was diluted successively with ethyl acetate (50 ml), washed with saturated sodium bicarbonate (15 ml) and brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH=40/1) to give compound 44 (61 mg, 50% yield) as a white solid.

LC-MS: [M+H] ⁺ =463.2. ^1H NMR (400 MHz, CDCl ₃ ): δ 7.48 (brs, 2H), 4.30 - 4.23 (m, 1H), 4.12-4.04 (m, 1H), 3.99 -3.69 (m, 4H), 3.68 (s, 3H), 3.40-3.30 (s, 2H), 3.20-3.10 (m, 1H), 3.03 (d , J=3.5 Hz, 3H), 2.92 - 2.80 (m, 1 N), 2.74 - 2.62 (m, 2H), 2.18 - 2.06 (m, 2H) , 1.80 -1.68 (m, 1H), 1.20 (d, J=5.8 Hz, 3H).

Example 45:

Step (1) Preparation of methyl-(S)-2-((2-(4-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)-2,6-difluorophenyl)-7-methylimidazo[1 ,2-a]pyridin-3-yl)-methyl)morpholine-4-carboxylate

Intermediate 2-7 (250 mg, 0.52 mmol) was dissolved in anhydrous toluene (3 ml) and tert-butyl-3-carbonylpiperazine-1-carboxylate (125 mg, 0.62 mmol), potassium carbonate was added under nitrogen (216 mg, 1.56 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (7.4 mg, 0.052 mmol) and copper(I) iodide (10 mg, 0.052 mmol). The reaction system was reacted at 110°C overnight. After completion of the reaction, the reaction system was cooled to room temperature, filtered, water (10 ml) was added to the filtrate, and extraction was carried out with dichloromethane (30 ml × 3). The organic phases were combined, washed with brine (30 mL x 1), dried over magnesium sulfate, filtered and concentrated by rotary evaporation to give the crude product. The crude product was purified by column chromatography (4 g silica gel column, petroleum ether:ethyl acetate=1:1) to give intermediate 45-2 as a yellow oil (200 mg, 64% yield), LC-MS: [M+ H] ⁺ =600.9.

Step (2) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(2-oxopiperazin-1-yl)phenyl)-7-methylimidazo[1,2-a]pyridin- 3-yl)methyl)morpholine-4-carboxylate

Intermediate 45-2 (200 mg, 0.33 mmol) was dissolved in dichloromethane (5 ml) and a solution of HCl in ethanol (33%, 0.5 ml) was added dropwise while the temperature was maintained at 0°C. After the dropwise addition was completed, the reaction system was reacted at room temperature for 2 hours. After completion of the reaction, saturated sodium bicarbonate solution was added dropwise to the reaction system to adjust the pH to 8 at a temperature maintained at 0°C, water (10 ml) was added and extracted with dichloromethane (20 ml × 3). The organic phases were combined, washed with brine (20 mL x 1), dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to give intermediate 45-3 (175 mg) as a yellow oil, LC-MS: [M+H ] ⁺ =500.9.

Step (3) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(4-methyl-2-oxopiperazin-1-yl)phenyl)-7-methylimidazo[1,2- a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 45-3 (175 mg, 0.35 mmol) and aqueous formaldehyde (37%, 30 mg, 0.364 mmol) were dissolved in dichloromethane (3 mL) and sodium triacetoxyborohydride (287 mg, 1.36 mmol) was added slowly. The reaction system was reacted at room temperature for 3 hours. After completion of the reaction, water (10 ml) was added to the reaction system and extracted with dichloromethane (15 ml x 3). The organic phases were combined, washed with brine (20 mL x 1), dried over magnesium sulfate, filtered and concentrated by rotary evaporation to give the crude product. The crude product was purified by column chromatography to provide compound 45 (74 mg, 41% yield) as a yellow solid.

LC-MS: [M+H] ⁺ =514.7. ^1H NMR (400 MHz, MeOD): δ 8.86 (d, J=7.1 Hz, 1H), 7.73 (s, 1H), 7.51 (d, J=9.0 Hz, 2H ), 7.43 (dd, J=7.1, 1.4 Hz, 1H), 4.18 (m, 3H), 4.18-4.11 (m, 1H), 4.01 (d, J=13.0 Hz, 1H), 3.88-3.74 (m, 4H), 3.70 (s, 3H), 3.69 - 3.65 (m, 1H), 3.40-3 .32 (m, 1 H), 3.26 (d, J=5.7 Hz, 2H), 3.10 (s, 3H), 2.00 - 2.86 (m, 1 H), 2, 82 - 2.70 (m, 1 H), 2.65 (s, 3 H).

Example 46:

Step (1) Preparation of 1-tert-butyl-4-methyl-(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate

Tert-butyl-(R)-2-(hydroxymethyl)piperazine-1-carboxylate (2.0 g, 9.0 mmol) and N,N-diisopropylethylamine (3.6 g, 27.0 mmol) were dissolved in dichloromethane ( 20 ml). Under a nitrogen atmosphere, the reaction system was cooled to 0°C, methyl chloroformate (1.0 g, 11.0 mmol) was added and warmed to room temperature and reacted for 1 hour. The reaction system was then extracted with ethyl acetate (25 ml x 3). The organic phase was washed with brine (30 ml x 2), dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (PE/EA=2/1) to give intermediate 46-2 (1.7 g, 68% yield) as a colorless oil. LC-MS: [M+H] ⁺ =275.2.

Step (2) Preparation of 1-tert-butyl-4-methyl-(R)-2-formylpiperazine-1,4-dicarboxylate

Intermediate 46-2 (1.7 g, 6.0 mmol) was dissolved in dichloromethane (30 ml). Under a nitrogen atmosphere, the reaction system was cooled to 0°C, Dess-Martin periodinane (3.9 g, 9.0 mmol) was added and warmed to room temperature and stirred for 2 hours. The reaction system was then extracted with dichloromethane (30 ml x 3) . The organic phase was washed with brine (50 ml x 2), dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (PE/EA=2/1) to give intermediate 46-3 (360 mg, 21% yield) as a colorless oil. LC-MS: [M-55] ⁺ =217.1.

Step (3) Preparation of 1-tert-butyl-4-methyl-(S)-2-ethynylpiperazine-1,4-dicarboxylate

Compound 1-3 (305 mg, 1.6 mmol) and potassium carbonate (365 mg, 2.6 mmol) were dissolved in acetonitrile (2.5 ml) and absolute methanol (0.5 ml). The reaction system was stirred at room temperature for 15 min, a dissolved solution of intermediate 46-3 (360 mg, 1.3 mmol) in acetonitrile (2.5 mL) and absolute methanol (0.5 mL) was added and stirred at room temperature during the night. The reaction system was then filtered and concentrated. The residue was separated by column chromatography (PE/EA=10/1) to give intermediate 46-4 (165 mg, 46% yield) as a white oil. LC-MS: [M-55] ⁺ =213.7.

Step (4) Preparation of methyl-(S)-2-((2-(2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl )methyl)-1-tert-butylcarboxylate-piperazine-4-carboxylate

Intermediate 46-4 (165 mg, 0.6 mmol), 4-methylpyridin-2-amine (66 mg, 0.6 mmol), 3,5-difluoro-4-formyl-N-methylbenzamide (123 mg, 0 .6 mmol), copper (I) chloride (18 mg, 0.2 mmol) and copper (II) trifluoromethanesulfonate (67 g, 0.2 mmol) were dissolved in anhydrous toluene (3 ml). The reaction system was heated to 85°C, N,N-dimethylacetamide (0.2 ml) was added and the reaction was carried out at 85°C for 5 hours. The reaction system was then cooled to room temperature, reacted overnight and extracted with dichloromethane (15 ml x 3). The organic phase was washed with brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (DCM/MeOH=40/1) to give intermediate 46-6 (105 mg) as a brown solid. LC-MS: [M+H] ⁺ =558.2.

Stage (5). Preparation of methyl-(S)-2-((2-(2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)piperazine -4-carboxylate

Intermediate 46-6 (105 mg, 0.2 mmol) was dissolved in anhydrous dichloromethane (2 ml). The reaction system was cooled to 0°C, a solution of HCl in ethanol (0.5 ml) was added dropwise and warmed to room temperature and stirred for 1 hour. The reaction system was then concentrated. The residue was separated by preparative reverse phase chromatography to give compound 46 (3.5 mg) as a white solid.

LC-MS: [M+H] ⁺ =458.5. ^1H NMR (400 MHz, MeOD): δ 8.75 (brs, 1H), 7.84 (m, 3H), 7.42 (brs, 1H), 4.10 - 4.02 (m, 2H ), 3.70 - 3.66 (m, 1H), 3.66 (s, 3H), 3.57 - 3.37 (m, 3H), 3.20 -3.10 (m, 2H) , 2.98(s, 3H), 2.95 -2.85(m, 1H), 2.64(s, 3H).

Example 47:

Step (1) Preparation of methyl 3,5-difluoro-4-(3-(hydroxymethyl)-7-methylimidazo[1,2-a]pyridin-2-yl)benzoate

Intermediate 47-1 (synthesized by the preparation of intermediate 31-7, LC-MS [M+H] ⁺ : 303.18) (1.2 g, 4.0 mmol) was dissolved in acetonitrile (8 ml) and added acetic acid (8 ml), aqueous formaldehyde (0.25 ml, 24 mmol) and sodium acetate (1.31 g, 16 mmol). The reaction system was heated to 50°C and reacted for 16 hours. The reaction system was then concentrated on a rotary evaporator to remove the solvent. The residue was diluted with dichloromethane (50 ml) and washed with saturated aqueous sodium bicarbonate (20 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (DCM/MeOH=50/1) to give intermediate 47-2 (945 mg, 71% yield) as a yellow solid. LC-MS: [M+H] ⁺ =333.2.

Step (2) Preparation of methyl 4-(3-(chloromethyl)-7-methylimidazo[1,2-a]pyridin-2-yl)-3,5-difluorobenzoate

Intermediate 47-2 (1.2 g, 4.0 mmol) was dissolved in dichloromethane (15 ml) and thionyl chloride (4 ml) was added at 0°C. The reaction system was reacted at 0°C for 3 hours. The reaction system was then concentrated on a rotary evaporator to remove the solvent to obtain intermediate 47-2 (900 mg) as a yellow solid. LC-MS: [M+H] ⁺ =336.1.

Step (3) Preparation of methyl 3,5-difluoro-4-(7-methyl-3-((3-oxo-4-morpholinyl)methyl)imidazo[1,2-a]pyridin-2-yl)benzoate

Morpholin-3-one (101 mg, 1.0 mmol) was dissolved in DMF (5 ml) and sodium hydride (80 mg, 2 mol) was added in an ice bath. The reaction system was reacted for 0.5 hours, methyl intermediate 47-4 (351 mg, 1 mmol) was added and reacted at room temperature for 16 hours. The reaction system was then poured into ice water (10 mL), extracted with dichloromethane (10 mL x 2), washed with brine (10 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated on a rotary evaporator to obtain intermediate 47 -5 (120 mg) as a yellow solid. LC-MS: [M+H] ⁺ =416.4.

Step (4) Preparation of 3,5-difluoro-4-(7-methyl-3-(((3-oxo-4-morpholinyl)methyl)imidazo[1,2-a]pyridin-2-yl)benzoic acid

Intermediate 47-5 (120 mg, 0.29 mmol) was dissolved in THF (9 ml) and MeOH (3 ml), H ₂ O (3 ml) and lithium hydroxide (61 mg, 1.45 mmol) were added sequentially. The reaction system was stirred at room temperature overnight, then diluted with water (10 ml) and concentrated on a rotary evaporator under reduced pressure to remove the organic solvent. The aqueous phase was adjusted to pH 5-6 with hydrochloric acid (1 N) and extracted with dichloromethane (10 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography (DCM/MeOH=15:1) to give intermediate 47-6 (85 mg, 72.4% yield) as a white solid. LC-MS: [M+H] ⁺ =402.3.

Step (S) Preparation of 3,5-difluoro-N-methyl-4-(7-methyl-3-(((3-oxo-4-morpholinyl)methyl)imidazo[1,2-a]pyridin-2-yl )benzamide

Intermediate 47-6 (80 mg, 0.2 mmol) was dissolved in DMF (5 ml) and methylamine hydrochloride (20 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-N, was added sequentially. N,N',N'-tetramethyluronium hexafluorophosphate (114 mg, 0.3 mmol) and triethylamine (44 mg, 0.4 mmol). The reaction system was stirred at room temperature overnight. The reaction system was then diluted with water (15 ml), extracted with ethyl acetate (10 ml x 2), washed with brine (10 ml), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography (DCM/MeOH=30:1) to give compound 47 (21 mg, 20% yield) as a white solid.

LC-MS: [M+H] ⁺ =415.1. ^1H NMR (400 MHz, MeOD): δ 8.44 (d, J=6.9 Hz, 1H), 7.64 (d, J=7.8 Hz, 2H), 7.43 (s, 1H ), 6.96 (d, J=6.9 Hz, 1 H), 5.00 (s, 2H), 4.14-4.12 (m, 2H), 3.75-3.71 (m , 2H), 3.04-3.01 (m, 2H), 2.98 (s, 3H), 2.47 (s, 3H).

Example 48:

Step (1) Preparation of 4-(3-((4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)methyl)-7-methylimidazo[1,2-a]pyridin-2-yl)-3, 5-difluorobenzoic acid

Tert-butyl-3-carbonylpiperazine carboxylate (400 mg, 2.0 mmol) was dissolved in N,N-dimethylformamide (10 ml). The reaction system was cooled in an ice water bath for 5 min, sodium hydride (120 mg, 3.0 mmol) was added slowly and reacted for 30 min. Intermediate 47-3 (350 mg, 1.0 mmol) (60% purity indicated by LC-MS) was then added to the reaction system and stirred overnight. After the reaction mixture was quenched with saturated ammonium chloride solution (5 ml), hydrochloric acid (1 N) was added dropwise to the reaction system to adjust the pH to 3-4, diluted with water (20 ml) and extracted with dichloromethane (45 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (DCM/CH ₃ OH=10/1) to give intermediate 48-1 (300 mg, 50% purity by LC-MS) as a light yellow solid. LC-MS: [M+H] ⁺ =501.2.

Step (2) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-carbomethoxyphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)- 2-carbonylpiperazinecarboxylate

Intermediate 48-1 (300 mg, 0.69 mmol) was dissolved in methanol (5 ml). Acetyl chloride (0.5 ml) was added dropwise to the reaction system and stirred overnight. The reaction system was then concentrated, diluted with dichloromethane (25 ml) and washed with saturated sodium bicarbonate solution (15 ml). The aqueous phase was subjected to extraction with dichloromethane (20 ml x 2). The organic phases were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (PE/EA=1/1) to give intermediate 48-2 (70 mg, 60% purity as shown by LC-MS) as a colorless oil, LC-MS: [M+H ] ⁺ =515.1.

Step (3) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl) methyl)-2-carbonylpiperazinecarboxylate

Intermediate 48-2 (70 mg, 0.13 mmol) was dissolved in ethanol (5 ml) and aqueous methylamine (2 ml, 25-30% w/w) was added. The reaction system was stirred at room temperature overnight. The reaction system was then added with H ₂ O (15 ml) to quench the reaction mixture and extracted with ethyl acetate (15 ml x 2). The organic phases were combined, washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 48-3 (60 mg, 60% purity as shown by LC-MS) as a colorless oily liquid. LC-MS: [M+H] ⁺ =514.1.

Step (4) Preparation of (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)-2 -carbonyl-piperazine

Intermediate 48-3 (60 mg, 0.12 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (3 ml) was added. The reaction system was stirred overnight at room temperature, concentrated by rotary evaporation, diluted with dichloromethane (40 ml), washed with saturated sodium bicarbonate (10 ml), washed with saturated brine (10 ml) and dried over anhydrous sodium sulfate. The residue was purified by preparative chromatography and lyophilized to give compound 48 (3 mg) as a white solid.

LC-MS: [M+H] ⁺ =414.1. ^1H NMR (400 MHz, MeOD): δ 8.47 (d, J=7.2 Hz, 1H), 7.64 (d, J=7.8 Hz, 2H), 7.42 (s, 1H ), 6.95 (d, J=7.2 Hz, 2H), 4.99 (s, 2H), 3.42 (s, 2H), 3.00 - 2.95 (m, 5H), 2 .87 (t, J=5.2 Hz, 2H), 2.49 (s, 3H).

Example 49:

Step (1) Preparation of tert-butyl-3,5-difluorobenzoate

3,5-difluorobenzoic acid (10 g, 63.25 mmol) was dissolved in tert-butanol (100 ml) and DMAP (12.3 g, 18.975 mmol) and Boc anhydride (27.6 g, 126.5 mmol) were added ). The reaction system was reacted at room temperature for 15 hours. The reaction system was then concentrated, diluted with water (150 ml) and extracted with ethyl acetate (50 ml x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (PE/EA=20/1) to give compound 49-2 (12 g, 88% yield) as a colorless oily liquid.

Step (2) Preparation of tert-butyl-3,5-difluoro-4-formyl benzoate

LDA (2 M, 8.4 ml) was dissolved in tetrahydrofuran (10 ml). The reaction system was cooled to -78°C under a nitrogen atmosphere. Compound 49-2 (3 g, 14 mmol) was dissolved in tetrahydrofuran (20 ml) and the resulting solution was added to the reaction system. The reaction system was stirred at -78°C for 1.5 hours, DMF (1.228 g, 16.8 mmol) was added and stirred for an additional 1 hour at a temperature maintained at -70°C. Then, saturated aqueous ammonium chloride (60 ml) was added to the reaction system to quench the reaction, and extraction was carried out with ethyl acetate (30 ml × 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography (PE/EA=10/1) to give compound 49-3 (1.5 g, 44% yield) as a yellow solid.

Step (3) Preparation of tert-butyl-(S)-2-((2-(4-(tert-butoxycarbonyl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl )methyl)morpholine-4-carboxylate

Compound 49-3 (480 mg, 1.98 mmol) was dissolved in anhydrous toluene (4 ml) and compound 1-4 (419 mg, 1.98 mmol), compound 1-5 (215 mg, 1.98 mmol) was added , copper (I) chloride (62 mg, 0.63 mmol) and copper (II) trifluoromethanesulfonate (216 mg, 0.60 mmol). Under a nitrogen atmosphere, the reaction system was heated to 85°C, two drops of N,N-dimethylacetamide were added, heated and stirred for 6 hours. The reaction system was then cooled to room temperature and stirred overnight. The reaction system was then filtered and the filtrate was concentrated. The residue was separated by column chromatography (PE/EA=2/1) to give intermediate 49-4 (340 mg, 31% yield) as a brown solid. LC-MS: [M+H] ⁺ =544.7.

Step (4) Preparation of (S)-3,5-difluoro-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-a]pyridin-2-yl)benzoic acid

Intermediate 49-4 (340 mg, 0.62 mmol) was dissolved in ethanol (3 mL) and a solution of HCl in ethanol (1 mL, 33%) was added. The reaction system was stirred at room temperature for 1.5 hours. The reaction system was then concentrated to give intermediate 49-5 (400 mg) as a yellow oily liquid. LC-MS: [M+H] ⁺ =388.7.

Step (5) Preparation of (S)-3,5-difluoro-4-(3-(4-(methoxycarbonyl)morpholin-2-yl)methyl)-7-methylimidazo[1,2-a]pyridin-2-yl )benzoic acid

Intermediate 49-5 (400 mg) was dissolved in dichloromethane (5 ml) and pyridine (244 mg, 3.09 mmol) was added followed by methyl chloroformate (62 mg, 0.65 mmol). The reaction system was stirred at room temperature for 1.5 hours and concentrated to give intermediate 49-6 (190 mg). LC-MS: [M+H] ⁺ =446.6.

Step (6) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-carbomethoxyphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)-methyl)morpholine- 4-carboxylate

Intermediate 49-6 (50 mg, 0.1124 mmol) was dissolved in absolute methanol (5 mL) and concentrated sulfuric acid (0.1 mL) was added. The reaction system was stirred under reflux overnight. The reaction system was then concentrated, diluted with water (10 ml) and extracted with ethyl acetate (10 ml x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was separated by thin layer chromatography (PE/EA=3/1) to give compound 49 (20.8 mg, 40% yield) as a white solid.

LC-MS: [M+H] ⁺ =460.7. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.27 (brs, 1H), 7.73 (d, J=7.1 Hz, 2H), 7.54 (brs, 1H), 6.80 ( brs, 1H), 4.00 (s, 3H), 3.99 -3.75 (m, 3H), 3.70 (s, 3H), 3.65 - 3.56 (m, 1H), 3 .45 - 3.35 (m, 1H), 3.10 - 3.85 (m, 3H), 2.67 - 2.57 (m, 1H), 2.48 (s, 3H).

Example 50:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(1H-parazole)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine- 4-carboxylate

Intermediate 2-7 (120 mg, 0.25 mmol) was dissolved in anhydrous toluene (3 ml) and potassium carbonate (104 mg, 0.75 mmol), copper(I) iodide (4.8 mg, 0.025 mmol) was added , 1H-pyrazole (34 mg, 0.50 mmol) and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (3.6 mg, 0.025 mmol) under nitrogen. The reaction system was reacted at 110°C overnight. After completion of the reaction, the reaction system was cooled to room temperature, filtered, water (10 ml) was added to the filtrate, and extraction was carried out with dichloromethane (20 ml × 3). The organic phases were combined, washed with brine (20 mL x 1), dried over magnesium sulfate, filtered and concentrated by rotary evaporation to give the crude product. The crude product was purified by high performance liquid chromatography to provide compound 50 (18.7 mg, 16% yield) as a yellow solid.

LC-MS: [M+H] ⁺ =468.7. ^1H NMR (400 MHz, MeOD): δ 8.44 - 8.40 (m, 2H), 7.80 (s, 1H), 7.67 (d, J=8.1 Hz, 2H), 7 .35 (s, 1H), 6.88 (d, J=7.0 Hz, 1H), 6.61 (s, 1H), 3.89 - 3.76 (m, 3H), 3.66 (s, 3H), 3.65 - 3.56 (m, 1H), 3.42 - 3.36 (m, 1H), 3.15 - 3.06 (m, 2H), 2.96 - 2 .80 (m, 1H), 2.72 - 2.60(m, 1H), 2.47 (s, 3H).

Example 51:

Step (1) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-formylaminophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

Intermediate 3-1 (360 mg, 0.86 mmol) was dissolved in formic acid (5 ml). The reaction system was reacted at 90°C for 2 hours. After completion of the reaction as determined by TLC, the reaction system was concentrated under reduced pressure, added brine (10 ml), adjusted to pH 7-8 with saturated sodium bicarbonate solution and extracted DXM (10 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 51-1 (220 mg, 52% yield) as a yellow solid. MS [M+H] ⁺ =445.1.

Step (2) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-isocyanophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

Intermediate 51-1 (220 mg, 0.49 mmol) and triethylamine (149 mg, 1.5 mmol) were dissolved in dichloromethane (25 ml) and phosphorus oxychloride (115 mg, 0.75 mmol) was added slowly dropwise at 0 °C. After the dropwise addition was completed, the reaction system was reacted at 0°C for 2 hours. After completion of the reaction, as monitored by LCMS, the reaction system was added with water at 0°C to quench the reaction at a temperature maintained 25°C below. The reaction system was then adjusted to pH 7-8 with saturated sodium bicarbonate solution and washed with brine (10 mL). The organic phase was dried and concentrated to give intermediate 51-2 (210 mg, 84% yield, crude product) as a yellow oil, which was used directly in the next step without purification. MS [M+N] ⁺ =427.0.

Step (3) Preparation of methyl-(S)-2-((2-(4-(4-(carbethoxy<ethoxycarbonyl>)-1H-imidazol-1 -yl)-2,6-difluorophenyl)-7-methyl imidazo [1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 51-2 (170 mg, 0.4 mmol), ethyl isocyanoacetate (45 mg, 0.4 mmol), copper(I) chloride (8.6 mg, 0.06 mmol) and 1,10-phenanthroline (22 mg, 0.12 mmol) was dissolved in tetrahydrofuran (15 ml). The reaction system was reacted at 60°C for 3 hours under a nitrogen atmosphere and reacted at room temperature overnight. Then, brine (20 mL) was added to the reaction system and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to obtain the crude product. The crude product was purified by FCC to give compound 51 (160 mg, 70% yield) as a white solid. MS [M+N] ⁺ =540.1.

1H NMR (400 MHz, d6-DMSO) δ 8.70 (d, J=1.3 Hz, 1H), 8.60 (d, J=1.3 Hz, 1H), 8.44 (d, J =7.1 Hz, 1H), 7.89 (d, J=8.6 Hz, 2H), 7.37 (s, 1H), 6.85 (dd, J=7.1, 1.5 Hz , 1 N), 4.30 (q, J=7.1 Hz, 2H), 3.77 (d, J=12.2 Hz, 1 N), 3.66 (t, J=12.1 Hz , 2H), 3.56 (s, 3H), 3.53 - 3.47 (m, 1 H), 3.29 - 3.21 (m, 1 H), 3.10 - 3.00 (m , 2H), 2.90 - 2.74 (m, 1H), 2.60 - 2.45 (m, 1H), 2.40 (s, 3H), 1.32 (t, J=7, 1 Hz, 3H).

Example 52:

Stage 1.

Compound 52-1 was prepared by replacing methyl chloroformate with acetyl chloride according to the method for preparing compound 6 in Example 6.

Stage 2.

Compound 52 was prepared using Compound 52-1 as a starting material according to the preparation method described in Example 7.

LC-MS: [M+H] ⁺ =466.1

Example 53:

Step (1) Preparation of 1-bromo-2-(methoxymethoxy)-4-methylbenzene

2-bromo-5-methylphenol (1.6 g, 8.55 mmol) was dissolved in tetrahydrofuran (20 ml) and sodium hydride (855 mg, 21.37 mmol) was added portionwise under a nitrogen atmosphere in an ice-water bath. The reaction system was reacted at 0°C for 30 min, bromomethyl methyl ether (1.4 g, 11.12 mmol) was added dropwise and stirred at room temperature overnight. The reaction system was then poured into ice water (20 ml) and extracted with ethyl acetate (20 ml x 2). The organic phases were combined, washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to give intermediate 53-2 (1.7 g, 68% yield) as a colorless oil.

Step (2) Preparation of 1-iodo-2-(methoxymethoxy)-4-methylbenzene

Intermediate 53-2 (528 mg, 2.29 mmol) was dissolved in tetrahydrofuran (10 ml) under nitrogen and n-butyllithium (1.2 ml, 2.75 mmol) was added dropwise at -78°C. The reaction system was reacted at this temperature for 20 minutes, a solution of iodine (874 mg, 3.44 mmol) in tetrahydrofuran (5 ml) was added dropwise and reacted for 2 hours. Ice water (20 mL) was then added to the reaction system to quench the reaction, saturated sodium thiosulfate solution (2 mL) was added, stirred at room temperature for 5 min, and extracted with ethyl acetate (25 mL x 2). The organic phases were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 53-3 (570 mg, 80% purity, 72% yield, crude product) as a brown oil.

Step (3) Preparation of 2-iodo-5-methylphenol

Intermediate 53-3 (570 mg, 2.05 mmol) was dissolved in tetrahydrofuran (8 ml) and a solution of HCl in ethanol (1.03 ml, 4.1 mmol) was added dropwise at 0°C. The reaction system was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give intermediate 53-4 (400 mg, 70% purity, 58% yield) as a colorless oil.

Step (4) Preparation of tert-butyl 3,5-difluoro-4-((2-iodo-5-methylphenoxy)methyl)benzoate

Intermediate 53-4 (400 mg, 1.71 mmol), triphenylphosphine (673 mg, 2.57 mmol) and tert-butyl 3,5-difluoro-4-(hydroxymethyl)benzoate (418 mg, 1.71 mmol ) was dissolved in tetrahydrofuran (6 ml) under nitrogen and di-tert-butyl azodicarboxylate (591 mg, 2.57 mmol) was added. The reaction system was reacted at room temperature overnight. The reaction system was then concentrated under reduced pressure, ethyl acetate (30 ml) was added, washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 53-6 (375 mg, 75% purity, 37% yield) as a yellow oil. ESI-MS [M+Na] ⁺ : 462.5

Step (5) Preparation of tert-butyl-(S)-2-((2-((4-(tert-butoxycarbonyl)-2,6-difluorobenzyl)oxo)-4-methylphenyl)ethynyl)morpholine-4-carboxylate

Intermediate 53-6 (290 mg, 0.63 mmol) and tert-butyl-(S)-2-ethynylmorpholine-4-carboxylate (146 mg, 0.69 mmol) were dissolved in N,N-dimethylformamide (1.5 ml) under nitrogen atmosphere and copper(I) iodide (12 mg, 0.063 mmol), bis(triphenylphosphine)palladium(II) chloride (91 mg, 0.13 mmol) and triethylamine (4 ml) were added. The reaction system was reacted at 80°C for 8 hours, cooled to room temperature, water (40 ml) was added and extracted with ethyl acetate (30 ml x 2). The organic phases were combined, washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to give intermediate 53-7 (132 mg, 75% purity, 29% yield) as a brown solid. ESI-MS [M+Na] ⁺ : 565.6

Step (6) Preparation of (S)-4-(3-((4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-6-methylbenzofuran-2-yl)-3,5-difluorobenzoic acid

Intermediate 53-7 (132 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (3 mL) under nitrogen and potassium tert-butoxide (96 mg, 0.72 mmol) was added. The reaction system was reacted at 80°C for 3 hours. The reaction system was then cooled to room temperature, poured into water (10 ml), adjusted to pH 4 with dilute hydrochloric acid (1 N) and extracted with ethyl acetate (20 ml x 2) . The organic phases were combined, washed with brine (15 ml x 2), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 53-8 (100 mg, 70% purity, 55% yield) as a brown solid. ESI-MS [M+Na] ⁺ : 510.1.

Step (7) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-6-methylbenzofuran-3-yl)methyl)morpholine-4-carboxylate

Intermediate 53-8 (100 mg, 0.20 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (114 mg, 0.30 mmol) were dissolved in N,N-dimethylformamide (3 ml) under nitrogen atmosphere. The reaction system was stirred at room temperature for 10 min, N,N'-diisopropylethylamine (1.79 mL, 1.40 mmol) and methylamine hydrochloride (68 mg, 1.00 mmol) were added and stirred at room temperature for another 4 h. The reaction system was then added with water (20 ml) and extracted with ethyl acetate (20 ml x 2). The organic phases were combined and washed with brine (15 mL x 2). The crude product was purified by silica gel column chromatography to give intermediate 53-9 (65 mg, 63% yield) as a light yellow solid. ESI-MS [M+Na] ⁺ : 522.7.

Step (8) Preparation of (S)-3,5-difluoro-N-methyl-4-(6-methyl-3-(morpholin-2-ylmethyl)benzofuran-2-yl)benzamide hydrochloride

Intermediate 53-9 (65 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL) and a solution of HCl in ethanol (0.5 mL, 0.52 mmol) was added dropwise. The reaction system was stirred at room temperature for 4 hours and concentrated under reduced pressure to give intermediate 53-10 as a light yellow solid (70 mg, crude), ESI-MS [M+H] ⁺ : 400.7 .

Step (9) Preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-6-methylbenzofuran-3-yl)methyl)morpholine-4-carboxylate

Intermediate 53-10 (70 mg, 0.18 mmol) and triethylamine (0.99 mL, 0.72 mmol) were dissolved in dichloromethane (2 mL) and methyl chloroformate (21 mg, 0.22 mmol) was added dropwise at 0 °C. The reaction system was reacted at this temperature for 4 hours. The reaction system was then poured into ice water (10 ml) and extracted with dichloromethane (15 ml x 2). The organic phases were combined, washed with brine (10 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative high performance liquid chromatography to provide compound 53 (22 mg, 22% yield) as a white solid.

ESI-MS [M+H] ⁺ : 458.8. 1H NMR (400 MHz, MeOD) δ 7.63 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.35 (s, 1H) , 7.17 (d, J=8.0 Hz, 1 H), 3.81-3.78 (m, 3H), 3.65 (s, 3H), 3.63 - 3.58 (m, 1H), 3.39 -3.38 (m, 1H), 2.97 (s, 3H), 2.95-2.86 (m, 2H), 2.83 - 2.76 (m, 1H) , 2.62-2.58 (m, 1H), 2.51 (s, 3H).

Example 54:

Step (1) Preparation of 2-iodo-5-methylpyridin-3-ol

Iodine (2.56 g, 10.08 mmol) was added to a solution of 5-methylpyridin-3-ol (1.10 g, 10.08 mmol) and potassium carbonate (4.18 g, 30.24 mmol) in water ( 100 ml) with stirring at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction system was then adjusted to pH 6 with dilute hydrochloric acid and extracted with DCM (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by silica gel column chromatography to provide intermediate 54-2 (1.9 g, 79.4% yield) as a white solid. LC-MS: [M+H] ⁺ = 235.9.

Step (2) Preparation of tert-butyl-3,5-difluoro-4-((((((2-iodo-5-methylpyridin-3-yl)oxy)methyl)benzoate

Intermediate 54-2 (773 mg, 3.29 mmol), tert-butyl 3,5-difluoro-4-(hydroxymethyl) benzoate (884 mg, 3.62 mmol) and triphenylphosphine (949 mg, 3.62 mmol ) was dissolved in THF (15 ml) at 0°C under a nitrogen atmosphere, and a solution of DTAD (833 mg, 3.619 mmol) in THF (5 ml) was added dropwise. After the dropwise addition was completed, the reaction system was slowly warmed to room temperature and stirred for 4 hours. Then, water (50 ml) was added to the reaction system to quench the reaction, and extraction was carried out with dichloromethane (30 ml × 3). The organic phases were combined, washed with brine (40 ml), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography to provide intermediate 54-4 (1.5 g, 97.9% yield) as a white solid. LC-MS: [M+H] ⁺ = 462.0.

Step (3) Preparation of tert-butyl-(S)-2-((3-((4-(tert-butoxycarbonyl)-2,6-difluorobenzyl)oxy)-5-methylpyridin-2-yl)ethynyl)morpholine- 4-carboxylate

Copper iodide was added to a solution of intermediate 54-4 (500 mg, 1.08 mmol) and tert-butyl-(25)-2-ethynylmorpholin-4-yl formate (344 mg, 1.62 mmol) in tea (30 mL). (I) (21 mg, 0.11 mmol) and bis(triphenylphosphine)palladium (II) chloride (38 mg, 0.054 mmol) under nitrogen atmosphere. The reaction system was stirred at 90°C overnight. The reaction system was then evaporated to dryness to remove the solvent. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give intermediate 54-6 (452 mg, 73.2% yield) as a yellow oil. LC-MS: [M+H] ⁺ = 545.2.

Step (4) Preparation of (S)-4-(3-((4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-6-methylfurano[3,2-b]pyridin-2-yl)-3 ,5-difluorobenzoic acid

To a solution of intermediate 54-6 (453 mg, 0.83 mmol) in THF (20 mL) was added t-BuOK (232 mg, 2.08 mmol) at room temperature. The reaction system was reacted at 60°C for 2 hours. The reaction system was then cooled to room temperature, water (50 ml) was added, adjusted to pH 6 with formic acid and extracted with EA (30 ml x 3). The organic phases were combined, washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography to give intermediate 54-7 (230 mg, 56.7% yield) as a yellow solid. LC-MS: [M+H] ⁺ = 489.2.

Step (5) Preparation of tert-butyl-(S)-2-(2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-6-methylfurano[3,2-b]pyridin-3-yl)methyl )morpholine-4-carboxylate

To a solution of intermediate 54-7 (230 mg, 0.47 mmol) and HATU (268 mg, 0.71 mmol) in DMF (10 mL) was added DIEA (243 mg, 1.88 mmol) at room temperature under nitrogen. . The reaction system was stirred for 10 min, methylamine hydrochloride (63 mg, 0.94 mmol) was added and stirred at room temperature overnight. The reaction system was then added to water (50 mL) to quench the reaction and extracted with EA (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by silica gel column chromatography to give intermediate 54-8 (162 mg, 68.1% yield) as a yellow solid. LC-MS: [M+H] ⁺ = 502.2.

Step (6) Preparation of (S)-3,5-diflutro-N-methyl-4-(6-methyl-3-(morpholin-2-ylmethyl)furano[3,2-b]pyridin-2-yl)benzamide

A solution of HCl in EA (3 M, 2 mL) was added dropwise to a solution of intermediate 54-8 (162 mg, 0.32 mmol) in EA (1 mL). The reaction system was stirred at room temperature for 2 hours and concentrated on a rotary evaporator to obtain (S)-3,5-difluoro-N-methyl-4-(6-methyl-3-(morpholin-2-ylmethyl)furano[ 3,2-b]pyridin-2-yl)benzamide as a yellow solid (130 mg, crude), LC-MS: [M+H] ⁺ = 402.1.

Step (7) Preparation of methyl-(S)-2-(2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-6-methylfurano[3,2-b]pyridin-3-yl)methyl)morpholine -4-carboxylate

To a solution of intermediate 54-8 (130 mg, 0.32 mmol) and THA (100 mg, 0.96 mmol) in DCM (10 mL), methyl chloroformate (61 mg, 0.64 mmol) was added dropwise with stirring at room temperature. temperature. After the dropwise addition was completed, the reaction system was reacted at room temperature for 2 hours and concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography and lyophilized to give compound 54 (110 mg, 74.3% yield over two steps) as a white solid.

LC-MS: [M+H] ⁺ = 460.1. ^1H NMR (400 MHz, MeOD): δ 8.45 (s, 1H), 7.84 (s, 1H), 7.64 (d, J=8.3 Hz, 2H), 3.93 (d, J=13.6 Hz, 1H), 3.77 (d, J=13.2 Hz, 2H), 3.71-3.63 (m, 4H), 3.38 - 3.29 (m, 1H), 3.03-2.92 (m, 5H), 2.90-2.80 (m, 1H), 2.67-2.56 (m, 1H), 2.55 (s, 3H).

Example 55:

Step (1) Preparation of 5-iodo-2-methylpyridin-4-ol

Iodine (7.8 g, 31 mmol) was added to a solution of 6-methylpyridin-2-ol (3.0 g, 28 mmol) and potassium hydroxide (6.3 g, 112 mmol) in methanol (200 ml) in portions with stirring at room temperature. The reaction system was stirred at room temperature overnight. The reaction system was then adjusted to pH 6 with concentrated hydrochloric acid and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to provide intermediate 55-2 (1.2 g, 18.6% yield) as an off-white solid. LC-MS: [M+H] ⁺ = 235.8.

Step (2) Preparation of tert-butyl-3,5-difluoro-4-((((((5-iodo-2-methylpyridin-4-yl)oxy)methyl)benzoate

Intermediate 55-2 (470 mg, 2.0 mmol), tert-butyl 3,5-difluoro-4-(hydroxymethyl) benzoate (733 mg, 3.0 mmol) and triphenylphosphine (1049 mg, 4.0 mmol ) was added to THF (25 ml) at 0°C under nitrogen, and a solution of DTAD (1382 mg, 6.0 mmol) in THF (5 ml) was added dropwise. After the dropwise addition was completed, the reaction system was slowly warmed to room temperature and stirred for 2 hours. Then, water (50 ml) was added to the reaction system to quench the reaction, and extraction was carried out with dichloromethane (30 ml × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by silica gel column chromatography to give intermediate 55-4 (620 mg, 66.5% yield) as a white solid. LC-MS [M+H] ⁺ = 461.6.

Step (3) Preparation of tert-butyl-(S)-2-((4-((4-(tert-butoxycarbonyl)-2,6-difluorobenzyl)oxy)-6-methylpyridin-3-yl)ethynyl)morpholine- 4-carboxylate

Iodide was added to a solution of intermediate 55-4 (620 mg, 1.35 mmol) and /tert-butyl-(25)-2-ethynylmorpholin-4-yl formate (436 mg, 2.06 mmol) in tea (20 ml). copper(I) (26 mg, 0.14 mmol) and bis(triphenylphosphine)palladium(II) chloride (48 mg, 0.07 mmol) under nitrogen atmosphere. The reaction system was heated to 90°C and reacted overnight. The reaction system was then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give intermediate 55-5 (520 mg, 68.6% yield) as a yellow solid. LC-MS: [M+H] ⁺ = 544.8.

Step (4) Preparation of (S)-4-(3-((4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-6-methylfurano[3,2-c]pyridin-2-yl)-3 ,5-difluorobenzoic acid

To a solution of intermediate 55-5 (500 mg, 0.92 mmol) in THF (15 mL) was added t-BuOK (258 mg, 2.30 mmol) under nitrogen. The reaction system was stirred at 70°C for 2 hours. The reaction system was then cooled to room temperature, adjusted to pH 6 with formic acid and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give intermediate 55-6 (250 mg, 53.3% yield) as a yellow solid. LC-MS: [M+H] ⁺ = 488.7.

Step (5) Preparation of /tert-butyl-(S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-6-methylfurano[3,2-c]pyridin-3-yl )methyl)morpholine-4-carboxylate

To a solution of intermediate 55-6 (250 mg, 0.51 mmol) and HATU (233 mg, 0.61 mmol) in DMF (4 mL) was added DIEA (264 mg, 2.04 mmol) under nitrogen. The reaction system was stirred at room temperature for 10 min, methylamine hydrochloride (52 mg, 0.77 mmol) was added and stirred at room temperature overnight. The reaction system was then added with water (30 ml) and extracted with ethyl acetate (10 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 55-7 (250 mg, 94.12% yield) as a yellow oil. LC-MS: [M+H] ⁺ = 502.2.

Step (6) Preparation of (S)-3,5-difluoro-N-methyl-4-(6-methyl-3-(morpholin-2-ylmethyl)furano[3,2-c]pyridin-2-yl)benzamide

To a solution of intermediate 55-7 (250 mg, 0.50 mmol) in EA (5 ml) was added a solution of HCl (g) in EA (3 M, 10 ml) at room temperature. The reaction system was stirred at room temperature for 2 hours and concentrated under reduced pressure to give intermediate 55-8 (250 mg, crude product). LC-MS: [M+H] ⁺ = 402.1.

Step (7) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-6-methylfurano[3,2-c]pyridin-3-yl)methyl) morpholine-4-carboxylate

To a solution of intermediate 55-8 (300 mg, 0.75 mmol) and TEA (228 mg, 2.25 mmol) in DCM (10 mL), methyl chloroformate (142 mg, 1.50 mmol) was added dropwise under nitrogen for ice water bath. After the dropwise addition was completed, the reaction system was warmed to room temperature and stirred for 2 hours. The reaction system was then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 55 (70 mg, 20.0% yield) as a white solid. LC-MS: [M+H] ⁺ = 460.2.

^1H NMR (400 MHz, MeOD) δ 8.93 (s, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.48 (s, 1H), 3.90 (d, J=13.0 Hz, 1H), 3.83 - 3.77 (m, 2H), 3.65 (s, 3H), 3.64 - 3.58 (m, 1H), 3.39 (dt , J=11.8, 2.8 Hz, 1H), 2.95 (s, 3H), 2.94 - 2.81 (m, 3H), 2.70 - 2.63 (m, 1H), 2.69(s, 3H).

Example 56:

Step (1) Preparation of 3-iodo-6-methylpyridin-2-ol

6-methylpyridin-2-ol (5 g, 46 mmol) and sodium hydrogen carbonate (7.73 g, 92 mmol) were added to a mixture of water and dichloromethane (500 ml, 3/2) with stirring at room temperature and iodine (11) was added .68 g, 46 mmol). The reaction mixture was stirred at room temperature overnight. The reaction system was then extracted with dichloromethane (200 ml x 2). The organic phases were combined, washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 56-2 (2.5 g, 21.74% yield) as an off-white solid. LC-MS: [M+H] ⁺ = 235.0.

Step (2) Preparation of tert-butyl-3,5-difluoro-4-((((((3-iodo-6-methylpyridin-2-yl)oxy)methyl)benzoate

Intermediate 56-2 (510 mg, 2.17 mmol), tert-butyl 3,5-difluoro-4-(hydroxymethyl) benzoate (583 mg, 2.39 mmol) and triphenylphosphine (626 mg, 2.39 mmol ) was dissolved in THF (15 ml) at 0°C under nitrogen, and a solution of DTAD (550 mg, 2.39 mmol) in THF (5 ml) was added dropwise. After the dropwise addition was completed, the reaction system was reacted at room temperature for 2 hours. Then, the reaction system was added with water (50 ml) and extracted with dichloromethane (30 ml x 3). The organic phases were combined, washed with brine (30 ml), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated on a rotary evaporator to obtain the crude product. The crude product was purified by silica gel column chromatography to provide intermediate 56-3 (860 mg, 94.84% yield) as a white solid. LC-MS: [M+H] ⁺ = 462.1.

Step (3) Preparation of tert-butyl-(S)-2-((2-((4-(tert-butoxycarbonyl)-2,6-difluorobenzyl)oxy)-6-methylpyridin-3-yl)ethynyl)morpholine- 4-carboxylate

Iodide was added to a solution of intermediate 56-3 (500 mg, 1.08 mmol) and /tert-butyl-(25)-2-ethynylmorpholin-4-yl formate (344 mg, 1.62 mmol) in triethylamine (20 mL). copper(I) (21 mg, 0.11 mmol) and bis(triphenylphosphine)palladium(II) chloride (38 mg, 0.05 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 90°C for 12 hours. The reaction system was then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give intermediate 56-4 (570 mg, 91.67% yield) as a brownish-yellow solid. LC-MS: [M+H] ⁺ = 567.1.

Step (4) Preparation of (S)-4-(3-((4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-6-methylfurano[2,3-b]pyridin-2-yl)-3 ,5-difluorobenzoic acid

To a solution of intermediate 56-4 (502 mg, 0.92 mmol) in DMF (20 mL) was added potassium tert-butoxide (310 mg, 2.76 mmol) under nitrogen. The reaction system was stirred at 90°C for 2 hours. After completion of the reaction, the reaction system was cooled to room temperature, adjusted to pH 6 with formic acid and concentrated on a rotary evaporator (oil pump) to remove the solvent. The crude product was purified by silica gel column chromatography to give intermediate 56-5 (108 mg, 39.13% yield) as a yellow solid. LC-MS: [M+H] ⁺ = 489.8.

Step (5) Preparation of tert-butyl-(S)-2-(2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-6-methylfurano[2,3-b]pyridin-3-yl)methyl )morpholine-4-carboxylate

To a solution of intermediate 56-5 (180 mg, 0.37 mmol) in DMF (5 mL) was added HATU (211.06 mg, 0.56 mmol) and DIEA (143 mg, 1.11 mmol) under nitrogen. The reaction system was stirred at room temperature for 10 min, methylamine hydrochloride (50 mg, 0.74 mmol) was added and stirred at room temperature overnight. The reaction system was then added with water (20 ml) and extracted with ethyl acetate (10 ml x 3). The organic phases were combined, washed with brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 56-6 (90 mg, 48.65% yield) as a yellow solid. LC-MS: [M+H] ⁺ = 502.8.

Step (6) Preparation of (S)-3,5-difluoro-N-methyl-4-(6-methyl-3-(morpholin-2-ylmethyl)furano[2,3-b]pyridin-2-yl)benzamide

To a solution of intermediate 56-6 (100 mg, 0.20 mmol) in EA (1 ml) was added a solution of HCl (g) in EA (3 M, 2 ml) at room temperature. The reaction system was stirred at room temperature for 2 hours. The reaction system was then concentrated to give intermediate 56-7 hydrochloride (100 mg, crude), LC-MS: [M+H] ⁺ = 401.9.

Step (7) Preparation of methyl-(S)-2-(2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-6-methylfurano[2,3-b]pyridin-3-yl)methyl)morpholine -4-carboxylate

To a solution of intermediate 56-7 hydrochloride (100 mg, 0.20 mmol) and TEA (101 mg, 1.0 mmol) in DCM (10 mL), a solution of methyl chloroformate (47.25 mg, 0.50 mmol) was added dropwise. in dichloromethane (1 ml) in an ice water bath. The reaction system was stirred at room temperature for 2 hours. Then, water (10 ml) was added to the reaction system to quench the reaction mixture, and extraction was carried out with dichloromethane (10 ml × 2). The organic phases were combined, washed with brine (10 ml), filtered and concentrated. The crude product was purified by silica gel column chromatography and lyophilized to give 56 (45 mg, 49.01% yield) as an off-white solid.

LC-MS: [M+H] ⁺ = 460.8. ^1H NMR (400 MHz, MeOD): δ 8.19 (d, J=7.9 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.31 (d, J =7.9 Hz, 1H), 3.89 (d, J=12.9 Hz, 1H), 3.85 - 3.75 (m, 2H), 3.67 (s, 3H), 3.66 - 3.58 (m, 1H), 3.44 - 3.35 (m, 1H), 2.97 (s, 3H), 2.92 - 2.82 (m, 3H), 2.73 - 2 .58 (m, 1H), 2.65 (s, 3H).

Example 57:

The compound was prepared according to the preparation method described in Example 39. LC-MS: [M+H] ⁺ = 459.4.

Example 58:

Intermediate 3-1 (400 mg, 0.96 mmol), triethyl orthoformate (456 mg, 3.07 mmol), sodium azide (78 mg, 1.20 mmol) and acetic acid (923 mg, 15.37 mmol) were added sequentially ). The reaction system was stirred at room temperature for 10 minutes and then stirred at 70°C for 3 days. The reaction system was then adjusted to pH 9 and extracted with ethyl acetate three times. The organic phases were combined, dried and concentrated on a rotary evaporator. The crude product was purified by column chromatography to give product (270 mg) as a white solid, which was then purified by preparative HPLC to give compound 58 (109 mg, 99% purity, 24% yield) as a white solid.

LC/MS [M+H] ⁺ = 470. ¹ H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.39 (dd, J=24.5, 7.3 Hz, 1H), 8.01 - 7.83 (m, 2H), 7.41 - 7.28 (m, 1H), 6.82 (dd, J=7.1, 1.6 Hz, 1H), 3 .79 - 3.71 (m, 1H), 3.61 (t, J=9.8 Hz, 2H), 3.52 (s, 3H), 3.46 (dd, J=7.5, 2 .8 Hz, 1H), 3.20 (m, 2.8 Hz, 1H), 3.10-2.93 (m, 2H), 2.77 (s, 1H), 2.51 (s, 1H ), 2.35 (s, 3H).

Example 59:

Step (1) Preparation of methyl-(S)-2-((2-(4-urea-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

Compound 6 (800 mg, 1.88 mmol) and sodium methoxide (51 mg, 0.94 mmol) were dissolved in methanol (8 ml) under nitrogen atmosphere. The reaction system was stirred at room temperature overnight, solid NH ₄ Cl (152 mg, 2.80 mmol) was added and stirred at room temperature overnight. The reaction system was then adjusted to pH 8 with saturated sodium bicarbonate solution (10 ml), concentrated under reduced pressure to 1/2 volume and extracted with dichloromethane (20 ml x 3). The organic phases were combined, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 59-1 (760 mg, crude) as a brown solid. LC-MS [M+H]+: 444

Step (2) Preparation of methyl-(S)-2-((2-(4-(1-(ethoxycarbonyl)cyclopropyl)-1H-imidazol-2-yl)-2,6-difluorophenyl)-7-methylimidazo[1 ,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 59-1 (800 mg, 1.80 mmol) and ethyl 1-(2-bromoacetyl)cyclopropane-1-carboxylate (329 mg, 1.4 mmol) were dissolved in N,N-dimethylformamide (8 ml) in nitrogen atmosphere and potassium bicarbonate (360 mg, 3.6 mmol) was added. The reaction system was stirred at 70°C overnight. The reaction system was then added with water (30 mL) to quench the reaction, and extraction was carried out with dichloromethane (20 mL x 3). The organic phases were combined, washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to give intermediate 59-3 (600 mg, 57% yield) as a brown solid. LC-MS [M+H] ⁺ : 580

Step (3) Preparation of (S)-1-(2-(3,5-difluoro-4-(3-((4-(methoxycarbonyl)morpholin-2-yl)methyl)-7-methylimidazo[1,2- a]pyridin-2-yl)phenyl)-1H-imidazol-4-yl)cyclopropane-1-carboxylic acid

Intermediate 59-3 (600 mg, 1.1 mmol) was dissolved in tetrahydrofuran (4 ml) and absolute methanol (2 ml), and lithium hydroxide solution (1.5 ml, 3 M) was added dropwise at 0°C. The reaction system was warmed to room temperature and stirred for 3 hours. The reaction system was then adjusted to pH 4 with dilute hydrochloric acid (1N) and concentrated to give the crude product (450 mg) as a yellow solid. The crude product (50 mg) was purified by preparative chromatography to give compound 59 (4.6 mg) as a white solid.

LC-MS [M+H]+: 552. ¹ H NMR (400 MHz, CDCl3) δ 8.28 (d, J=8.0 Hz, 1H), 7.47 (s, 1H), 7.30 (d, J=8.3 Hz, 2H), 6.81 (d, J=7.7 Hz, 1H), 6.75 (s, 1H)., 4.00 - 3.81 (m, 3H ), 3.67 (s, 3H), 3.63 - 3.57 (m, 1H), 3.45 - 3.35 (m, 1H), 3.05 - 2.85 (m, 3H), 2.66 - 2.57 (m, 1H), 2.52 (s, 3H), 1.92-1.86 (m, 2H), 1.25-1.19 (m, 2H).

Example 60:

Step (1) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(1-(methoxycarbonyl)cyclopropane-1-carboxamido)phenyl)-7-methylimidazo[1,2-a ]pyridin-3-yl)methyl)morpholine-4-carboxylate

1-(methoxycarbonyl)cyclopropane-1-carboxylic acid (104 mg, 0.72 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (275 mg, 0 .72 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 ml) under nitrogen atmosphere. The reaction system was reacted at room temperature for 10 min, N,N-diisopropylethylamine (252 mg, 1.95 mmol) and intermediate 3-1 (200 mg, 0.48 mmol) were added and reacted at room temperature for nights. The reaction system was then added to water (20 ml) and extracted with ethyl acetate (20 ml x 3). The organic phases were combined, washed with brine (30 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by high performance liquid chromatography to provide intermediate 60-2 (100 mg, 51.3% yield) as a white solid. LC-MS: [M+H] ⁺ = 543.7.

Step (2) Preparation of (S)-2-((2-(2,6-difluoro-4-(1-(methoxycarbonyl)cyclopropane-1-carboxamido)phenyl)-7-methylimidazo[1,2-a]pyridine -3-yl)methyl)morpholine-4-carboxylic acid

Intermediate 60-2 (100 mg, 0.18 mmol) was dissolved in tetrahydrofuran (1.5 mL) and lithium hydroxide solution (0.18 mL, 3 M) was added dropwise. The reaction system was reacted at room temperature for 1 hour. After completion of the reaction, dilute hydrochloric acid (1 M) was added dropwise to the reaction system to adjust the pH to 6, water (10 ml) was added and extraction was carried out with dichloromethane (20 ml × 3) . The organic phases were combined, washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporation to give the crude product. The crude product was purified by high performance liquid chromatography to provide compound 60 (65.9 mg, 67.6% yield) as a white solid.

LC-MS: [M+H] ⁺ = 529.6. ^1H NMR (400 MHz, MeOD): δ 8.84 (d, J=7.1 Hz, 1H), 7.70 (s, 1H), 7.64 (d, J=7.4 Hz, 2H ), 7.41 (dd, J=7.1, 1.5 Hz, 1H), 4.01-3.97(m, 1H), 3.86-3.74 (m, 2H), 3, 70 (s, 3H), 3.69-3.65 (m, 1H), 3.39-3.36 (m, 1H), 3.25-3.24 (m, J=5.2 Hz, 2H), 2.99-2.85 (m, 1H), 2.81-2.67 (m, 1H), 2.65 (s, 3H), 1.75-1.72 (m, 2H) , 1.71-1.68 (m, 2H).

Example 61:

Step (1) Preparation of 1-(2,4-dimethoxybenzyl)-4-methyl-2-methylene succinate

Monomethyltaconate (3.00 g, 21.10 mmol), (2,4-dimethoxy)benzyl alcohol (3.90 g, 23.21 mmol) and triphenylphosphine (6.65 g, 25.33 mmol) were dissolved in THF ( 50 ml) at 0°C under nitrogen atmosphere and a solution of DIAD (5.12 g, 25.33 mmol) in THF (10 ml) was added dropwise. After the dropwise addition was completed, the reaction system was warmed to room temperature and stirred overnight. Then, water (60 ml) was added to the reaction system to quench the reaction mixture, and extraction was carried out with ethyl acetate (40 ml × 3). The organic phases were combined, washed with brine (40 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give intermediate 61-3 (4.5 g, 72.2% yield) as a white solid. MS [M+Na] ⁺ = 316.8.

Step (2) Preparation of 2,4-dimethoxybenzyl-1-(2-methoxy-2-carbonylethyl)cyclopropanecarboxylate

To a mixture of potassium hydroxide (30 ml, 40% aq.) and diethyl ether (20 ml) was added 1-methyl-3-nitro-1-nitrosoguanidine (4.0 g, 13.6 mmol, 50% water) at 0 °C in a nitrogen atmosphere. The reaction system was stirred at 0°C for 15 min and left to separate the liquid. The upper organic phase was collected and dried over anhydrous sodium sulfate. Intermediate 61-3 (600 mg, 2.04 mmol) and palladium acetate (92 mg, 0.41 mmol) were dissolved in diethyl ether (15 ml) at 0°C under nitrogen and a fresh solution of diazomethane in diethyl was added dropwise. air. After the dropwise addition was completed, the reaction system was slowly warmed to room temperature and stirred for 16 hours. The reaction system was added with absolute methanol (10 ml) to quench the reaction mixture and filtered, and the filtrate was concentrated on a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography to give intermediate 61-4 (520 mg, 82.7% yield) as a colorless oil. MS [M+Na]+ = 330.8.

Step (3) Preparation of 2-(1-((2,4-dimethoxybenzyl)oxo)carbonyl)cyclopropyl)acetic acid

To a mixture of intermediate 61-4 (500 mg, 1.62 mmol) in tetrahydrofuran (40 ml) and water (10 ml) was added lithium hydroxide monohydrate (11.9 ml, 11.9 mmol) at 0°C. The reaction mixture was stirred at 0°C for 8 hours. The reaction system was then warmed to room temperature, adjusted to pH 4 with dilute hydrochloric acid and extracted with DCM (20 mL x 3). The organic phases were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give intermediate 61-5 (320 mg, 73.2% yield, crude product) as a yellow oil. MS [M-N] ^- = 292.4.

Step (4) Preparation of methyl-(S)-2-((2-(4-(2-(1-(((2,4-dimethoxybenzyl)oxo)carbonyl)cyclopropyl)acetamido)-2,6-difluorophenyl) -7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

To a solution of intermediate 61-5 (300 mg, 1.02 mmol) in DMF (5 mL) was added DIEA (527 mg, 4.08 mmol) and HATU (466 mg, 1.22 mmol) at room temperature under nitrogen. . The reaction system was stirred at 45°C for 0.5 h, intermediate 3-1 (213 mg, 0.51 mmol) was added and stirred at 45°C for an additional 18 h. The reaction system was then cooled to room temperature, added water (10 ml) and extracted with EA (10 ml × 3). The organic phases were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography to give intermediate 61-6 (160 mg, 22.6% yield) as a yellow solid. MS [M+H] ⁺ = 692.7.

Step (5) Preparation of (S)-1-(2-((3,5-difluoro-4-(3-((4-(carbomethoxymethoxy<methoxycarbonyl>)morpholin-2-yl)methyl)-7-methylimidazo[ 1,2-a]pyridin-2-yl)phenyl)amino)-2-carbonylethyl)cyclopropanecarboxylic acid

To a solution of intermediate 61-6 (100 mg, 0.14 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (1 ml) at room temperature. The reaction system was stirred at room temperature for 3 hours and concentrated. The residue was separated by preparative high performance liquid chromatography and lyophilized to give compound 61 (29 mg, 36.9% yield) as a white solid. MS [M+H] ⁺ = 542.7.

^1H NMR (400 MHz, CDCl3) δ 10.44 (brs, 1H), 8.51 (d, J=7.0 Hz, 1H), 7.96 (s, 1H), 7.43 (d, J=11.1 Hz, 2H), 7.09 (d, J=6.7 Hz, 1H). 4.10-3.75 (m, 3H), 3.69 (s, 3H), 3.65-3.61 (m, 1H), 3.45 - 3.35 (m, 1H), 3, 05 - 2.85 (m, 3H), 2.76-2.68 (m, 1H), 2.58 (s, 3H), 1.39 (s, 2H), 0.94 (s, 2H) .

Example 62:

The compound was prepared according to the preparation method described in Example 44. LC-MS: [M+H] ⁺ = 464.2.

Example 63:

Step (1) Preparation of methyl-(S)-2-((2-(4-(diethylmalonate)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine -4-carboxylate

Intermediate 2-7 (300 mg, 0.62 mmol), 1,3-diethylmalonate (200 mg, 1.24 mmol) and bromidenonone (180 mg, 1.24 mmol) were dissolved in 1,4-dioxane (3 ml ) and sodium hydride (60%, 55 mg, 1.36 mmol) was added portionwise under nitrogen. The reaction system was reacted at 100°C for 10 hours. After completion of the reaction, the reaction system was cooled to room temperature, water (20 ml) was added to quench the reaction, and extraction was carried out with dichloromethane (20 ml × 3). The organic phases were combined, washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified by column chromatography to give intermediate 63-2 (230 mg, 66% yield) as a yellow oil. LC-MS: [M+H] ⁺ = 560.2.

Step (2) (S)-2-(3,5-difluoro-4-(3-((4-(methoxycarbonyl)morpholin-2-yl)methyl)-7-methylimidazo[1,2-a]pyridin- 2-yl)phenyl)acetic acid

Intermediate 63-2 (210 mg, 0.38 mmol) was dissolved in absolute ethanol (1.5 mL) and sodium hydroxide solution (3 M, 45 mg, 1.14 mmol) was added. The reaction system was reacted at room temperature for 1 hour. After completion of the reaction, the reaction system was adjusted to pH 6 with hydrochloric acid (1 M), water (5 ml) was added and extracted with dichloromethane (20 ml x 3). The organic phases were combined, washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by column chromatography to give intermediate 63-3 (140 mg, 77% yield) as a yellow oil. LC-MS: [M+H] ⁺ = 460.2.

Step (3) Preparation of methyl-(S)-2-((2-(4-(2-amino-2-carbonylethyl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine-3 -yl)methyl)morpholine-4-carboxylate

Intermediate 63-3 (70 mg, 0.15 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (87 mg, 0.23 mmol) were dissolved in N,N- dimethylformamide (2 ml) under nitrogen atmosphere. The reaction system was reacted at room temperature for 10 min, N,N-diisopropylethylamine (60 mg, 0.46 mmol) and ammonium chloride (10 mg, 0.19 mmol) were added and reacted at room temperature for another 2 h After completion of the reaction, water (20 ml) was added to the reaction system and extraction was carried out with ethyl acetate (30 ml × 3). The organic phases were combined, washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified by preparative chromatography to give compound 63 (10.5 mg, 15% yield) as a white solid.

LC-MS: [M+H] ⁺ = 459.2. ^1H NMR (400 MHz, CDCl3): δ 8.60 (brs, 1H), 7.97 (brs, 1H), 7.67-7.62 (brs, 1H), 7.27-7.08 ( m, 3H), 6.50 (brs, 1H), 4.08-3.78 (m, 4H), 3.73 (s, 3H), 3.71-3.58 (m, 2H), 3 .45-3.37 (m, 1H), 3.07-3.03 (m, 2H), 3.00-2.92 (m, 1H), 2.77-2.69 (m, 1H) , 2.62 (s, 3H).

Example 64:

Step (1) Preparation of methyl-(S)-2-(2-(4-(2-ethoxy-2-oxoethyl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3- yl)methyl)morpholine-4-carboxylate

Compound 63-3 (459 mg, 1 mmol) was dissolved in absolute ethanol (10 ml) and H ₂ SO ₄ (0.1 mmol) was added. The reaction system was heated to reflux. After completion of the reaction, as determined by TLC, the reaction system was diluted with water adjusted to neutral pH and concentrated under reduced pressure. The aqueous phase was subjected to EA extraction. The organic phase was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to give intermediate 64-1 (0.36 g, 74% yield), LC-MS: [M+H] ⁺ = 488.2.

Step (2) Preparation of methyl-(S)-2-((2-(4-(2-(methylamino)-2-oxoethyl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine -3-yl)methyl)morpholine-4-carboxylate

Intermediate 64-1 (70 mg, 0.15 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (87 mg, 0.23 mmol) were dissolved in N,N- dimethylformamide (2 ml) under nitrogen atmosphere. The reaction system was reacted at room temperature for 10 min, N,N-diisopropylethylamine (60 mg, 0.46 mmol) and a tetrahydrofuran solution of methylamine (1 M, 0.1 mL, 0.15 mmol) were added and reacted at room temperature for another 2 hours. After completion of the reaction, water (20 ml) was added to the reaction system and extraction was carried out with ethyl acetate (30 ml × 3). The organic phases were combined, washed with brine (30 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by high performance liquid chromatography to provide compound 64 (17.2 mg, 24% yield) as a white solid.

LC-MS: [M+H] ⁺ = 473.2. ^1H NMR (400 MHz, CDCl3): δ 8.59 (brs, 1H), 7.92 (s, 1H), 7.55 (brs, 1H), 7.19 (d, J=7.4 Hz 1H), 7.08 (d, J=8.1 Hz, 2H), 4.10-3.90 (m, 3H), 3.86-3.78 (m, 1H), 3.73 (s , 3H), 3.73-3.65 (m, 2H), 3.46 -3.35 (m, 1H), 3.08-3.02 (m, 2H), 3.00-2.90 (m, 1H), 2.85 (s, 3H), 2.76-2.70 (m, 1H), 2.62 (s, 3H).

Example 65:

The compound was prepared in accordance with the preparation method described in Example 63. LC-MS: [M+H] ⁺ = 485.2.

Example 66:

The compound was prepared according to the preparation method described in Example 63. LC-MS: [M+H] ⁺ = 499.3.

Example 67:

Step (1) Preparation of 1-(3,5-difluorophenyl)cyclopropan-1-amine

3,5-difluorobenzonitrile (10.0 g, 71.89 mmol) and tetraisopropyl titanate (27.0 g, 95.00 mmol) were dissolved in methyl tert-butyl ether (120 ml) and ethyl magnesium bromide (3 M in diethyl ether , 55 ml, 165.35 mmol) was added at -20°C under nitrogen atmosphere. The reaction system was allowed to react at this temperature for 30 minutes, boron trifluoride diethyl ether (46.5%, 44 g, 143.78 mmol) was added and stirred at room temperature for an additional 3 hours. The reaction system was then added with sodium hydroxide solution ( 3 M, 72 ml, 215.67 mmol) and filtered, and the filtrate was added with water (100 ml) and extracted with dichloromethane (150 ml x 3). The organic phases were combined, washed with brine (100 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography to give intermediate 67-2 (2 g, 16.6% yield) as a yellow oil, MS [M+H] ⁺ = 170.0.

Step (2) Preparation of tert-butyl-(1-(3,5-difluorophenyl)cyclopropyl)carbamate

Intermediate 67-2 (2.0 g, 11.83 mmol) was dissolved in anhydrous dichloromethane (20 ml) and di-tert-butyl dicarbonate (3.9 g, 17.75 mmol) and triethylamine (2.4 g, 23 .67 mmol) was added under nitrogen atmosphere. The reaction system was reacted at room temperature overnight. The reaction system was then added with water (50 ml) and extracted with dichloromethane (50 ml). The organic phase was washed with brine (50 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography to give intermediate 67-3 (640 mg, 18.08% yield) as a white solid. MS [M+H] ⁺ = 269.9.

Step (3) Preparation of tert-butyl-(1-(3,5-difluorophenyl)cyclopropyl)(methyl)carbamate

Intermediate 67-3 (620 mg, 2.30 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL) under nitrogen and sodium hydride (60%, 138 mg, 3.45 mmol) was added. The reaction system was reacted at room temperature for 30 min, methyl iodide (720 mg, 5.07 mmol) was added and reacted at 40°C for 1 h. Ice water (20 mL) was then added to the reaction system to quench the reaction mixture and extraction was carried out with ethyl acetate (20 ml × 2). The organic phases were combined, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography to give intermediate 67-4 (260 mg, 40% yield) as a white solid. MS [M+H] ⁺ = 283.9.

Step (4) Preparation of tert-butyl (1-(3,5-difluoro-4-formylphenyl)cyclopropyl)(methyl)carbamate

Intermediate 67-4 (260 mg, 0.92 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml) under nitrogen and lithium diisopropylamide (2Mb tetrahydrofuran, 0.6 ml, 1.10 mmol) was added dropwise at -78°C . After the dropwise addition was completed, the reaction system was reacted at -78°C for 1 hour, anhydrous N,N-dimethylformamide (67 mg, 0.92 mmol) was added and reacted for another 30 minutes. After completion of the reaction, saturated ammonium chloride solution was added to the reaction system to quench the reaction, diluted with water (20 ml) and extracted with ethyl acetate (20 ml × 2). The organic phases were combined, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography to give intermediate 67-5 (250 mg, 85% yield) as a white solid. MS [M+H] ⁺ = 311.9.

Step (5) Preparation of (S)-2-ethynylmorpholine

Intermediate 1-4 (200 mg, 0.95 mmol) was dissolved in anhydrous dichloromethane (3 ml) and a solution of HCl in ethanol (33%, 0.5 ml) was added at 0°C. The reaction system was reacted at room temperature in for 1 hour. After completion of the reaction, the reaction system was concentrated on a rotary evaporator to obtain intermediate 67-6 (230 mg, crude product) as a yellow oil, MS [M+H] ⁺ = 120.0.

Step (6) Preparation of methyl (S)-2-ethynylmorpholine-4-carboxylate

Intermediate 67-6 (230 mg, crude product, 0.95 mmol) and N,N-diisopropylethylamine (1.1 g, 8.51 mmol) were dissolved in anhydrous dichloromethane (3 mL) and methyl chloroformate (180 mg, 1.90 mmol) in an ice water bath. After the dropwise addition was completed, the reaction system was reacted at 0° C. for 1 hour. After the reaction was completed, water (15 ml) was added to the reaction system and extraction was carried out with dichloromethane (20 ml × 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give intermediate 67-7 (160 mg, crude) as a yellow oil. MS [M+H] ⁺ = 169.7.

Step (7) Preparation of methyl-(S)-2-((2-(4-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropyl)-2,6-difluorophenyl)-7-methylimidazo[1, 2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 67-5 (250 mg, 0.80 mmol), 4-methylpyridin-2-amine (87 mg, 0.80 mmol), methyl (S)-2-ethynylmorpholine-4-carboxylate (136 mg, 0 .80 mmol), copper (I) chloride (24 mg, 0.24 mmol) and copper (II) trifluoromethanesulfonate (87 mg, 0.24 mmol) were dissolved in a toluene solution (3 ml) under a nitrogen atmosphere. The reaction system was reacted at 85°C for 10 minutes, N,N-dimethylacetamide (0.1 ml) was added and stirred at 85°C for another 5 hours. The reaction system was then reacted at room temperature overnight. The resulting reaction system was filtered and the filtrate was added with water (20 ml) and extracted with dichloromethane (30 ml x 3). The organic phases were combined, washed with brine (30 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography to give intermediate 67-8 (150 mg, 32.6% yield) as a yellow oil. MS [M+H] ⁺ = 570.8.

Step (8) Preparation of methyl-(S)-2-(((2-(2,6-difluoro-4-(1-(methylamino)cyclopropyl)phenyl)-7-methylimidazo[1,2-a]pyridin- 3-yl)methyl)morpholine-4-carboxylate

Intermediate 67-8 (150 mg, 0.26 mmol) was dissolved in anhydrous dichloromethane (3 ml) and a solution of HCl in ethanol (33%, 0.5 ml) was added at 0°C. The reaction system was reacted at room temperature in for 1 hour. After completion of the reaction, the reaction system was concentrated on a rotary evaporator, diluted with dichloromethane (30 ml), dissolved with saturated sodium bicarbonate solution (10 ml) and stirred for 5 minutes. The reaction system was then subjected to extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by high performance liquid chromatography to provide compound 67 (55.4 mg, 43.5% yield) as a white solid. MS [M+H] ⁺ = 470.8.

^1H NMR (400 MHz, MeOD) δ 8.85 (d, J=7.1 Hz, 1H), 7.73 (s, 1H), 7.59 (d, J=8.4 Hz, 2H) , 7.41 (d, J=7.0 Hz, 1H), 4.02 - 3.93(m, 1H), 3.87 - 3.73 (m, 2H), 3.70 (s, 3H ), 3.69 - 3.62 (m, 1H), 3.39 - 3.35 (m, 1H), 3.28 - 3.23(m, 2H), 2.99 - 2.85 (m , 1H), 2.75 (s, 3H), 2.74 - 2.66 (m, 1H), 2.65 (s, 3H), 1.61 - 1.54 (m, 2H), 1, 52 - 1.46 (m, 2H).

Example 68:

Step (1) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-formylphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

7ret-butyl-(R)-2-(2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate (2.0 g, 4.0 mmol) was dissolved in acetone (15 ml). The reaction system was cooled to 0°C, dilute hydrochloric acid (1 N, 5 ml) was added dropwise and warmed to room temperature and stirred for 4 hours. The reaction system was then adjusted to pH 8 with saturated sodium carbonate solution (8 mL), methyl chloroformate (0.45 g, 4.8 mmol) was added dropwise at 0°C and stirred at 0°C for 1 hour. The resulting reaction system was added water (50 ml) and extracted with dichloromethane (60 ml x 3). The organic phases were combined, washed with brine (100 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to give intermediate 68-1 (770 mg, 46% yield) as a yellow solid. LC-MS [M+H] ⁺ = 430.

Step (2) Preparation of methyl-(S)-2-(2-(2,6-difluoro-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-7-methylimidazo[1,2-a ]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 68-1 (100 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2 ml) under nitrogen and potassium carbonate (16 mg, 0.11 mmol) was added followed by dropwise addition of trifluoromethyltrimethylsilane (50 mg , 0.30 mmol). The reaction system was stirred at room temperature for 4 hours, HCl (2 ml, 2N) was added and stirred at room temperature overnight. The reaction system was then added with water (20 ml) and extracted with dichloromethane (15 ml x 3). The organic phases were combined, washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to give intermediate 68-2 (80 mg, 69% yield) as a yellow solid. LC-MS: [M+H] ⁺ = 500.

Step (3) Preparation of methyl (S)-2-(2-(2,6-difluoro-4-(2,2,2-trifluoro-1-(trifluoromethyl)sulfonyl)oxy)ethyl))-7-methylimidazo [1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 68-2 (80 mg, 0.16 mmol) and 2,6-dimethylpyridine (34 mg, 0.32 mmol) were dissolved in dichloromethane (3 ml) under nitrogen. The reaction system was cooled to 0°C, trifluoromethanesulfonic anhydride (81 mg, 0.29 mmol) was added dropwise and stirred for 1 hour. The reaction system was then concentrated to give intermediate 68-3 (100 mg) as a brown solid, which was directly used in the next step. LC-MS: [M+H] ⁺ = 632.

Step (4) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(2,2,2-trifluoro-1-(methylamino)ethyl)phenyl)-7-methylimidazo[1 ,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 68-3 (100 mg, 0.16 mmol) and N,N-diisopropylethylamine (62 mg, 0.48 mmol) were dissolved in tetrahydrofuran (2 ml) and methylamine in tetrahydrofuran (1 ml, 2 N) was added. The reaction system was stirred at room temperature for 2 hours under a nitrogen atmosphere. Water (20 ml) was then added to the reaction system to quench the reaction mixture, and extraction was carried out with dichloromethane (10 ml × 3). The organic phases were combined, washed with brine (10 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative chromatography to provide compound 68 (trifluoroacetate salt, 18.3 mg, 22% yield) as a white solid. LC-MS: [M+H] ⁺ = 513.

^1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=6.9 Hz, 1H), 7.95 (s, 1H), 7.37 (d, J=8.1 Hz, 2H) , 7.16 (d, J=7.0 Hz, 1H), 6.56 (brs, 2H), 4.62-4.52 (m, 1H), 4.14-3.77 (m, 3H ), 3.72(s, 3H), 3.71 - 3.65 (m, 1H), 3.46 - 3.36 (m, 1H), 3.12 - 3.11 (m, 2H) , 2.01 - 2.88 (m, 1H), 2.78 - 2.68 (m, 1H), 2.61 (s, 6H).

Example 69:

Step (1) Preparation of methyl-(2S)-2-((2-(4-(3-((tert-butylsulfinyl)amino)oxetan-3-yl)-2,6-difluorophenyl)-7-methylimidazo[1 ,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 2-7 (300 mg, 0.63 mmol) was dissolved in tetrahydrofuran (5 ml) under nitrogen and n-butyllithium (0.32 ml, 0.76 mmol) was added dropwise at -78°C in a dry bath ice-acetone. After the dropwise addition was completed, the reaction system was allowed to react for 15 min, a solution of 2-methyl-N-(oxetan-3-ylidene)propan-2-sulfinamide (121 mg, 0.69 mmol) in tetrahydrofuran (1 mL) was added dropwise ) and reacted at -78°C for 3 hours. Then, saturated aqueous ammonium chloride (2 ml) was added to the reaction system to quench the reaction mixture, diluted with water (20 ml) and extracted with ethyl acetate (20 ml × 2). The organic phases were combined, washed with brine (15 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 69-2 (60 mg, 70% purity, 12% yield) as a brown solid. ESI-MS [M+H] ⁺ : 576.7.

Step (2) Preparation of methyl-(2S)-2-((2-(4-(3-(tert-butylsulfinyl)(methyl)amino)oxetan-3-yl)-2,6-difluorophenyl)-7-methylimidazo [1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 69-2 (60 mg, 0.10 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL) under nitrogen and sodium hydride (10 mg, 0.25 mmol) was added in an ice-water bath. The reaction system was stirred for 0.5 h, a solution of iodomethane (21 mg, 0.15 mmol) in N,N-dimethylformamide (0.5 ml) was added dropwise and stirred at 0°C for 3 h. Then the reaction system poured into ice water (15 ml) and extracted with ethyl acetate (15 ml × 2). The organic phases were combined, washed with brine (10 ml x 3), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to give intermediate 69-3 (50 mg, 70% purity, 57% yield) as a brown solid. ESI-MS [M+H]+: 590.8

Step (3) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(3-(methylamino)oxetan-3-yl)phenyl)-7-methylimidazo[1,2-a ]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 69-3 (50 mg, 0.085 mmol) was dissolved in dichloromethane (1.5 mL) and a solution of HCl in ethanol (0.1 mL, 0.40 mmol) was added dropwise at 0°C. The reaction system was stirred for 15 min, poured into ice water (10 ml), adjusted to pH 8 with saturated sodium bicarbonate solution and extracted with dichloromethane (10 ml x 2). The organic phases were combined, washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative high performance liquid chromatography to provide compound 69 (6.4 mg, 15.6% yield) as a white solid. ESI-MS [M+H] ⁺ : 486.8

^1H NMR (400 MHz, CDCl3) 5 8.26 (d, J=7.0 Hz, 1H), 7.50 (s, 1H), 5 7.20 (d, J=8.5 Hz, 2H ), 6.74 (d, J=6.2 Hz, 1H), 4.93 (d, J=6.7 Hz, 2H), 4.82 (d, J=6.7 Hz, 2H), 3.98 -3.80 (m, 3H), 3.70 (s, 3H), 3.64 - 3.60 (m, 1H), 3.47 - 3.36 (m, 1H), 3, 10 - 2.97 (m, 2H), 2.97 - 2.86 (m, 1H), 2.65 (dd, J=13.1, 10.7 Hz, 1H), 2.47 (s, 3H), 2.35 (s, 3H).

Example 70:

The compound was prepared in accordance with the preparation method described in Example 63. LC-MS: [M+H] ⁺ = 473.3. Example 71:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(oxetan-3-ylamino)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl) morpholine-4-carboxylate

Intermediate 2-7 (40 mg, 0.08 mmol), 3-oxetane (7 mg, 0.096 mmol), cesium carbonate (78 mg, 0.24 mmol), tris(dibenzylideneacetone) dipalladium (7 mg, 0.008 mmol) and (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthalene (10 mg, 0.016 mmol) was dissolved in anhydrous toluene (5 ml). The reaction system was reacted at 80°C for 16 hours under nitrogen, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography to provide compound 71 (25 mg, 62.5% yield) as a white solid. MS [M+H] ⁺ = 473.1.

¹ H NMR (400 MHz, d6-DMSO) δ 8.35 (d, J=7.0 Hz, 1H), 7.30 (s, 1H), 7.15 (d, J=6.5 Hz, 1H), 6.78 (dd, J=7.1, 1.6 Hz, 1H), 6.27 (d, J=10.6 Hz, 2H), 4.88 (t, J=6.5 Hz, 2H), 4.61 (dt, J=13.1, 6.7 Hz, 1H), 4.44 (td, J=6.1, 2.1 Hz, 2H), 373 - 3.64 (m, 3H), 3.56 (s, 3H), 3.51 - 3.45 (m, 1 H), 3.25 (dt, J=11.7, 2.6 Hz, 1 H), 3.04 - 2.92 (m, 2H), 2.90 - 2.77 (m, 1H), 2.60 - 2.46 (m, 1H), 2.36(s, 3H).

Example 72:

The compound was prepared according to the preparation method described in Example 25. LC-MS: [M+H] ⁺ = 517.1.

Example 73:

The compound was prepared according to the preparation method described in Example 25. LC-MS: [M+H] ⁺ = 501.2.

Example 74:

The compound was prepared in accordance with the preparation method described in Example 25. LC-MS: [M+H] ⁺ = 483.3.

Example 75:

Preparation of methyl 2-((2-(2,6-difluoro-4-(tetrahydrofuran-3-yl)amino)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholin- 4-carboxylate

Intermediate 2-7 (50 mg, 0.10 mmol) was dissolved in toluene (5 ml) under nitrogen and oxolan-3-amine (11 mg, 0.12 mmol), cesium carbonate (98 mg, 0.30 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol) and (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (13 mg, 0.02 mmol). The reaction system was stirred at 80°C overnight. The reaction system was then filtered and concentrated. The residue was separated by preparative high performance liquid chromatography to give compound 75 (14.7 mg, 30.0%) as a white solid. LC-MS: [M+H] ⁺ = 487.1.

^1H NMR (400 MHz, MeOD) δ 8.47 (d, J=6.8 Hz, 1H), 7.38 (s, 1H), 6.95 (d, J=6.5 Hz, 1H) , 6.37 (d, J=10.9 Hz, 2H). 4.19-4.08 (m, 1H), 4.99-3.95 (m, 2H), 3.90-3.78 (m, 4H), 3.77-3.73 (m, 1H ), 3.68 (s, 3H), 3.62-3.57 (m, 1H), 3.43-3.36 (m, 1H), 3.14-3.03 (m, 2H), 2.97 - 2.85 (m, 1H), 2.72 - 2.62 (m, 1H), 2.49 (s, 3H), 2.38 - 2.28 (m, 1H), 1, 98 - 1.88 (m, 1H).

Example 76:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)amino)phenyl)-7-methylimidazo[1,2-a]pyridin- 3-yl)methyl)morpholine-4-carboxylate

Intermediate 2-7 (80 mg, 0.17 mmol) was dissolved in toluene (5 ml) under nitrogen and tetrahydro-2H-pyran-4-amine (21 mg, 0.20 mmol), cesium carbonate (166 mg, 0.51 mmol), tris(dibenzylideneacetone)dipalladium (16 mg, 0.017 mmol) and (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (21 mg, 0.034 mmol). The reaction system was stirred at 80°C overnight. The reaction system was then filtered and concentrated. The residue was separated by preparative high performance liquid chromatography to give compound 76 (51.9 mg, 58.8% yield) as a white solid. LC-MS: [M+H] ⁺ = 501.2.

^1H NMR (400 MHz, DMSO) δ 8.36 (d, J=7.0 Hz, 1H), 7.31 (s, 1H), 6.80 (d, J=6.6 Hz, 1H) , 6.41 - 6.34 (m, 1H), 6.38 (d, J=11.0 Hz, 2H), 3.91 - 3.85 (m, 2H), 3.75 - 3.63 (m, 3H), 3.56 (s, 3H), 3.55 - 3.41 (m, 4H), 3.32 - 3.22 (m, 1H), 3.05 - 2.92 (m , 2H), 2.90 - 2.76 (m, 1H), 2.62 -2.50 m, 1H), 2.38 (s, 3H), 1.94 - 1.86 (m, 2H) , 1.45 - 1.34 (m, 2H).

Example 77:

The compound was prepared in accordance with the preparation method described in Example 25. LC-MS: [M+H] ⁺ = 502.2.

Example 78:

The compound was prepared according to the preparation method described in Example 25. LC-MS: [M+H] ⁺ = 485.2.

Example 79:

Preparation of methyl-(25)-2-((2-(2,6-difluoro-4-(3-carbonylcyclopentyl)amino)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl) morpholine-4-carboxylate

Intermediate 3-1 (60.0 mg, 0.14 mmol) was dissolved in cyclopent-2-enone (3 mL) under nitrogen and anhydrous aluminum trichloride (117.5 mg, 1.15 mmol) was added. The reaction system was reacted at room temperature for 18 hours. The reaction system was then filtered and concentrated. The crude product was separated by preparative high performance liquid chromatography and lyophilized to give compound 79 (29.7 mg, 42% yield) as a white solid. LC-MS: [M+H] ⁺ = 499.3.

¹ H NMR (400 MHz, CDCl3) δ 8.21 (brs, 1H), 7.46 (brs, 1H), 6.70 (brs, 1H), 6.27 (d, J=9.9 Hz, 2H), 4.17 - 4.08 (m, 1H), 4.00 - 3.76 (m, 3H), 3.70 (s, 3H), 3.64 - 3.56 (m, 1H) , 3.47 - 3.36 (m, 1H), 3.02 - 2.97 (m, 2H), 2.94 - 2.85 (m, 1H), 2.75 (dd, J=18, 2, 6.5 Hz, 1H), 2.64 (dd, J=13.1, 10.7 Hz, 1H), 2.56-2.48 (m, 1H), 2.44 (s, 3H ), 2.39-2.32 (m, 1H), 2.30-2.22 (m, 1H), 2.12-2.00 (m, 2H).

Example 80:

Step (1) Preparation of methyl-(S)-2-(2-(2,6-difluoro-4-(4-hydroxycyclopohexyl)amino)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl )methyl)morpholine-4-carboxylate

Intermediate 2-7 (200 mg, 0.42 mmol) was dissolved in anhydrous toluene (3 ml) under nitrogen and 4-aminocyclohexanol (58 mg, 0.50 mmol), cesium carbonate (407 mg, 1.25 mmol) was added ), (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthalene (52 mg, 0.084 mmol) and tris(dibenzylideneacetone) dipalladium (40 mg, 0.043 mmol). The reaction system was reacted at 80°C overnight. After completion of the reaction, the reaction system was cooled to room temperature, filtered, water (20 ml) was added to the filtrate, and extraction was carried out with dichloromethane (30 ml × 3). The organic phases were combined, washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to obtain the crude product. The crude product was purified by silica gel column chromatography to give intermediate 80-2 (150 mg, 70% yield) as a yellow oil. LC-MS: [M+H] ⁺ = 514.8.

Step (2) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(4-carbonylcyclohexyl)amino)phenyl)-7-methylimidazo[1,2-a]pyridin-3- yl)methyl)morpholine-4-carboxylate

Intermediate 80-2 (150 mg, 0.29 mmol) was dissolved in anhydrous dichloromethane (2 mL) under nitrogen and Dess-Martin periodinane (185 mg, 0.44 mmol) was added. The reaction system was reacted at room temperature for 1 hour. Then, the reaction system was added with water (20 ml) and extracted with dichloromethane (20 ml x 3). The organic phases were combined, washed with brine (20 ml), dried over sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product. The crude product was purified by preparative high performance liquid chromatography to provide compound 80 (20.2 mg, 20.3% yield) as a white solid. LC-MS: [M+H] ⁺ = 512.8.

^1H NMR (400 MHz, MeOD) δ 8.82 - 8.78 (m, 1H), 7.65 -7.64 (m, 1H), 7.38 - 7.36 (m, 1H), 6 .53 (d, J=11.7 Hz, 1H), 6.46 - 6.41 (m, 1H), 3.98 - 3.95 (m, 1H), 3.92 - 3.75 (m , 3H), 3.70 (s, 3H), 3.39 - 3.35 (m, 1H), 3.25 - 3.18 (m, 2H), 2.99 - 2.90 (m, 1H ), 2.80 - 2.72 (m, 1H), 2.63 (s, 3H), 2.59 -2.55 (m, 1H), 2.48 -2.44 (m, 1H), 2.34 - 2.29 (m, 1H), 1.97 - 1.97 (m, 2H), 1.86 -1.49 (m, 4H).

Example 81:

Preparation of methyl-(2S)-2-((2-(4-(1,1-dihydroxytetrahydrothiophen-3-yl)amino)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3 -yl)methyl)morpholine-4-carboxylate

Intermediate 2-7 (80 mg, 0.16 mmol), 3-Aminotetrahydrothiophene 1,1-disulfone hydrochloride (43 mg, 0.24 mmol), cesium carbonate (217 mg, 0.64 mmol), (±)- 2,2'-bis-(diphenylphosphino)-1,1'-binaphthalene (21 mg, 0.03 mmol) and tris(dibenzylideneacetone)dipalladium (15 mg, 0.02 mmol) were dissolved in toluene (3 ml) under atmosphere nitrogen. The reaction system was heated to 80°C and reacted overnight. The reaction system was then cooled to room temperature, water (20 mL) was added to quench the reaction, and extracted with dichloromethane (15 mL x 3). The organic phases were combined, washed with brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by preparative high performance liquid chromatography to give compound 81 (32.4 mg, 36% yield) as a yellow solid, LC-MS: [M+H] ⁺ = 535.1.

^1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.55 (d, J=7.4 Hz, 1H), 6.77 (d, J=6.9 Hz, 1H) , 6.27 (d, J=9.8 Hz, 2H), 4.37 - 4.30 (m, 1H), 4.01 - 3.79 (m, 3H), 3.70 (s, 3H ), 3.63 - 3.56 (m, 1H), 3.55-3.48 (m, 1H), 3.45 - 3.32 (m, 2H), 3.25-3.16 (m , 1H), 3.13 - 3.05 (m, 1H), 3.03-2.86 (m, 3H), 2.67 - 2.62 (m, 2H), 2.46 (s, 3H ), 2.45 - 2.36 (m, 1H).

Example 82:

The compound was prepared according to the preparation method described in Example 25. LC-MS: [M+H] ⁺ = 571.2.

Example 83:

The compound was prepared in accordance with the preparation method described in Example 25. LC-MS: [M+H] ⁺ = 541.3.

Example 84:

The compound was prepared in accordance with the preparation method described in Example 25. LC-MS: [M+H] ⁺ = 521.2.

Example 85:

Step (1) Preparation of methyl-(S)-2-((2-(4-amino-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

Intermediate 3-1 (80 mg, 0.19 mmol) and diisopropylethylamine (74 mg, 0.57 mmol) were dissolved in dichloromethane (10 ml). The reaction system was cooled to 0°C, a solution of methyl 4-(chloroformyl)benzoate (75 mg, 0.38 mmol) in dichloromethane (0.2 ml) was added dropwise and stirred at room temperature for 12 hours. Then the reaction system diluted with dichloromethane (10 ml) and washed with saturated saline (10 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give intermediate 85-2 (100 mg, 49% yield) as a white solid. MS [M+H] ⁺ = 579.2.

Step (2) Preparation of (S)-4-((3,5-difluoro-4-(3-((4-(carbomethoxy<methoxycarbonyl>)morpholin-2-yl)methyl)-7-methylimidazo[1,2 -a]pyridin-2-yl)phenyl)carbamoyl)benzoic acid

Intermediate 85-2 (50 mg, 0.09 mmol) was dissolved in tetrahydrofuran (5 ml) and water (1 ml) and lithium hydroxide monohydrate (22 mg, 0.55 mmol) was added. The reaction system was stirred at room temperature for 1 hour. After completion of the reaction, the reaction system was adjusted to pH 4-5 with dilute hydrochloric acid (1 N) and concentrated on a rotary evaporator to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography to provide compound 85 (35 mg, 59% yield) as a white solid. MS [M+H] ⁺ = 565.2.

¹ H NMR(400 MHz, d6-DMSO) δ 13.24 (s, 1H), 10.84 (s, 1H), 8.42 (d, J=6.9 Hz, 1H), 8.10 ( q, J=7.0 Hz, 4H), 7.69 (d, J=9.9 Hz, 2H), 7.35 (s, 1H), 6.83 (d, J=7.1 Hz, 1H), 3.77 - 3.59 (m, 3H), 3.56 (s, 3H), 3.52 - 3.46 (m, 1H), 3.30 - 3.22 (m, 1H ), 3.08 - 3.00 (m, 2H), 2.90 - 7.74 (m, 1H), 2.60 - 2.48 (m, 1H), 2.39 (s, 3H).

Example 86:

The compound was prepared according to the preparation method described in Example 25. LC-MS: [M+H] ⁺ = 522.2.

Example 87:

The compound was prepared according to the preparation method described in Example 25. LC-MS: [M+H] ⁺ = 471.2.

Example 88:

The compound was prepared in accordance with the preparation method described in Example 25. LC-MS: [M+H] ⁺ = 513.3.

Example 89:

Preparation of methyl-(S)-2-((2-(4-(1-cyanocyclopropane-1-carboxamido<oxalilamino>)-2,6-difluorophenyl)-7-methylimidazo[1,2- a]pyridine-3- yl)methyl)morpholine-4-carboxylate

1-cyanocyclopropane-1-carboxylic acid (52 mg, 0.47 mmol) and 2-(7-azabenzotriazol-1 -yl)-N,N,N',N-tetramethyluronium hexafluorophosphate (180 mg, 0.47 mmol) dissolved in anhydrous N,N-dimethylformamide (2 ml) under nitrogen atmosphere. The reaction system was reacted at room temperature for 10 min, N,N-diisopropylethylamine (162 mg, 1.25 mmol) and intermediate 3-1 (130 mg, 0.31 mmol) were added and reacted at room temperature for nights. Then water (20 ml) was added to the reaction system and extraction was carried out with ethyl acetate (30 ml × 3). The organic phases were combined, washed with brine (30 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by high performance liquid chromatography to provide compound 89 (35.8 mg, 23% yield) as a white solid.

LC-MS: [M+H] ⁺ = 510.6. ^1H NMR (400 MHz, MeOD): δ 8.83 (d, J=7.1 Hz, 1H), 7.69 (s, 1H), 7.67 (d, J=10.1 Hz, 2H ), 7.40 (dd, J=7.1, 1.5 Hz, 1H), 3.98 (d, J=12.8 Hz, 1H), 3.83 (d, J=13.6 Hz , 1H), 3.76 (d, J=9.2 Hz, 1H), 3.70 (s, 3H), 3.70 - 3.65 (m, 1H), 3.37 - 3.34 ( m, 1H), 3.24 (d, J=5.3 Hz, 2H), 3.00 - 2.85 (m, 1H), 280 - 2.67 (m, 1H), 2.64 (s , 3H), 1.81 - 1.76 (m, 2H), 1.75-1.70 (m, 2H).

Example 90:

The compound was prepared according to the preparation method described in Example 25. LC-MS: [M+H] ⁺ = 517.2.

Example 91:

The compound was prepared according to the preparation method described in Example 25. LC-MS: [M+H] ⁺ = 545.4.

Example 92:

The compound was prepared in accordance with the preparation method described in Example 25. LC-MS: [M+H] ⁺ = 531.2.

Example 93:

The compound was prepared according to the preparation method described in Example 25. LC-MS: [M+H] ⁺ = 531.4.

Example 94:

Step (1) Preparation of tert-butyl-(R)-2-(azidomethyl)morpholine-4-carboxylate

Tert-butyl-(R)-2-(bromomethyl)morpholine-4-carboxylate (1.0 g, 3.58 mmol) was dissolved in N,N-dimethylformamide (8 ml) and sodium azide (700 mg, 10. 75 mmol). The reaction system was heated to 90°C for 8 hours. The reaction system was then cooled to room temperature, water (40 mL) was added to quench the reaction, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with brine (15 ml x 2), dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography to give intermediate 94-2 (738 mg, 92% yield) as a white solid. LC-MS: [M+H] ⁺ = 243.2.

Step (2) Preparation of tert-butyl-(S)-2-(aminomethyl)morpholine-4-carboxylate

Intermediate 94-2 (738 mg, 3.05 mmol) was dissolved in methanol (10 ml) and a catalyst of wet palladium on carbon (200 mg, 10% w/w) was added. The reaction system was purged with hydrogen and reacted at room temperature for 2.5 hours. The reaction system was then filtered and concentrated to give intermediate 94-3 (580 mg, 82% yield) as a light yellow oil. LC-MS: [M+H] ⁺ = 217.2.

Step (3) Preparation of tert-butyl-(S)-2-(((5-methyl-3-nitropyridin-2-yl)amino)methyl)morpholine-4-carboxylate

Intermediate 94-3 (580 mg, 2.68 mmol) was dissolved in ethanol (10 ml) and 2-chloro-5-methyl-3-nitropyridine (509 mg, 2.95 mmol) and triethylamine (895 mg, 8 .84 mmol). The reaction system was heated to boiling for 24 hours. The reaction system was then concentrated on a rotary evaporator. The residue was separated by column chromatography (PE/EA = 4/1) to give intermediate 94-5 (710 mg, 75% yield) as a yellow solid. LC-MS: [M+H] ⁺ = 353.1.

Step (4) Preparation of tert-butyl-(S)-2-(((((3-amino-5-methylpyridin-2-yl)amino)methyl)morpholine-4-carboxylate

Intermediate 94-5 (326 mg, 0.96 mmol) was dissolved in ethyl acetate (20 ml) and wet palladium carbon catalyst (50 mg, 10% w/w) was added. The reaction system was purged with hydrogen and stirred at room temperature for 2.5 hours. The reaction system was then filtered and concentrated to give intermediate 94-6 (266 mg, 81% yield) as a yellow solid. LC-MS: [M+H] ⁺ = 323.2.

Step (5) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-6-methyl-3H-imidazo[4,5-b]pyridin- 3-yl)methyl)morpholine-4-carboxylate

Intermediate 94-6 (266 mg, 0.82 mmol), sodium bisulfite (512 mg, 4.92 mmol) and 3,5-difluoro-4-formyl-N-methylbenzamide (213 mg, 1.07 mmol) were dissolved in N,N-dimethylformamide (8 ml). The reaction system was heated to 100°C and reacted for 15 hours. After completion of the reaction, the reaction system was added with water (30 ml) to quench the reaction and extracted with dichloromethane (20 ml x 3). The organic phases were combined, washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The reaction system was separated by column chromatography (EA) to obtain intermediate 94-8 (210 mg, 46% yield) as a yellow solid. LC-MS: [M+H] ⁺ = 502.1.

Step (6) Preparation of (R)-3,5-difluoro-N-methyl-4-(6-methyl-3-(morpholin-2-yl-methyl)-3H-imidazo[4,5-b]pyridin- 2-yl)benzamide

Intermediate 94-8 (210 mg, 0.52 mmol) was dissolved in ethyl acetate (4 mL) and a solution of HCl in ethyl acetate (1 mL, 4 N) was added dropwise. The reaction system was stirred at room temperature for 2.5 hours. The reaction system was then concentrated to give intermediate 94-9 (hydrochloride, 222 mg, crude) as a yellow solid, which was used directly in the next step. LC-MS: [M+H] ⁺ =402.1.

Step (7) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-6-methyl-3H-imidazo[4,5-b]pyridine-3- yl)methyl)morpholine-4-carboxylate

Intermediate 94-9 (222 mg, 0.52 mmol) was dissolved in anhydrous dichloromethane (10 mL) and triethylamine (157 mg, 1.56 mmol) was added. Under a nitrogen atmosphere, the reaction system was cooled to 0°C, methyl chloroformate (59 mg, 0.62 mmol) was added dropwise and reacted for 3 hours. The reaction system was then diluted with dichloromethane (20 ml) and washed with water (20 ml). The aqueous phase was subjected to extraction with dichloromethane (15 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative high performance liquid chromatography to provide compound 94 (64 mg, 27% yield) as a white solid. LC-MS: [M+H] ⁺ =460.8.

^1H NMR (400 MHz, CDCl ₃ ): δ 8.39 (s, 1H), 8.03 (s, 1H), 7.56 (brs, 2H), 7.02 (brs, 1H), 4 .50-4.41 (m, 1H), 4.25-4.15 (m, 1H), 4.12-3.96 (m, 1H), 3.85-3.65 (m, 5H) , 3.65-3.55 (m, 1H), 3.30-3.20 (m, 1H), 3.07 (s, 3H), 2.85-2.70 (m, 1H), 2 .57 (s, 3H), 2.56-2.46 (m, 1H).

Example 95:

The compound was prepared in accordance with the preparation method described in Example 25. LC-MS: [M+H] ⁺ =543.3.

Example 96:

The compound was prepared in accordance with the preparation method described in Example 25. LC-MS: [M+H] ⁺ =524.3.

Example 97:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(methoxycarbonyl)cyclopropane-1-carboxamido)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl) methyl)morpholine-4-carboxylate

Intermediate 97-1 (31 mg, 0.22 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (82 mg, 0.22 mmol) were dissolved in anhydrous N,N-dimethylformamide (1.0 ml) under nitrogen atmosphere. The reaction system was reacted at room temperature for 10 min, N,N-diisopropylethylamine (75 mg, 0.58 mmol) and intermediate 3-1 (60 mg, 0.14 mmol) were added and reacted at room temperature for nights. Then, water (20 ml) was added to the reaction system to quench the reaction mixture, and extraction was carried out with ethyl acetate (20 ml × 3). The organic phases were combined, washed with brine (30 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by high performance liquid chromatography to provide compound 97 (11.7 mg, 15% yield) as a yellow solid. LC-MS: [M+H] ⁺ =543.7.

^1H NMR (400 MHz, MeOD) δ 8.84 (d, J=7.1 Hz, 1H), 7.70 (s, 1H), 7.64 (d, J=10.1 Hz, 2H) , 7.41 (dd, J=7.1, 1.4 Hz, 1H), 4.01-3.97 (m, 1H), 3.85-3.82(m, 1H), 3, 80 (s, 3H), 3.78-3.71 (m, 2H), 3.70 (s, 3H), 3.39-3.35 (m, 1H), 3.28-3.21 ( m, 2H), 2.98-2.90 (m, 1H), 2.80-2.70 (m, 1H), 2.65 (s, 3H), 1.71-1.64 (m, 4H).

Example 98:

The compound was prepared in accordance with the preparation method described in Example 5. LC-MS: [M+H] ⁺ =484.2.

Example99:

The compound was prepared in accordance with the preparation method described in Example 5. LC-MS: [M+H] ⁺ =485.3.

Example 100:

The compound was prepared in accordance with the preparation method described in Example 5. LC-MS: [M+H] ⁺ =483.4.

Example 101:

The compound was prepared in accordance with the preparation method described in Example 5. LC-MS: [M+H] ⁺ =485.2.

Example 102:

The compound was prepared in accordance with the preparation method described in Example 4. LC-MS: [M+H] ⁺ =518.2.

Example 103:

The compound was prepared in accordance with the preparation method described in Example 15. LC-MS: [M+H] ⁺ =472.5.

Example 104:

Compound 6 (540 mg, 1.27 mmol) was dissolved in DMF (15 ml) and a magnetic stirrer was added, followed by the addition of NaN ₃ (247.7 mg, 3.81 mmol) and NH ₄ Cl (271 mg, 5.08 mmol ). The reaction system was slowly heated to 100°C and reacted overnight. Once the reaction was complete, as determined by LCMS, the reaction system was dissolved with water and extracted with EA, followed by separation of the liquid. The organic phase was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to obtain the crude product (200 mg). The crude product was separated by pre-HPLC and lyophilized to give compound 104 (54.1 mg, 95.03% purity) as an off-white solid.

LC/MS [M+H]+=470.10. 1H NMR (400 MHz, CD3OD) δ 8.81 (d, J=7.2 Hz, 1H), 7.96 (m, 2H), 7.69 (s, 1H), 7.36 (dd, J =1.2 Hz,7.2 Hz, 1H), 4.01 (m, 1H), 3.85 (m, 1H), 3.73 (m, 2H), 3.68 (s, 3H), 3.37 (m, 1H), 3.26 (m, 2H), 2.92 (br, 1H), 2.75 (m, 1H), 2.64 (s, 3H).

Example 105:

The compound was prepared in accordance with the preparation method described in Example 7. LC-MS: [M+H] ⁺ =547.2.

Example 106:

The compound was prepared in accordance with the preparation method described in Example 38. LC-MS: [M+H] ⁺ =497.4.

Example 107:

Preparation of (S)-1-(3,5-difluoro-4-(3-(((4-(carbomethoxy<methoxycarbonyl>)morpholin-2-yl)methyl)-7-methylimidazo[1,2-a]pyridine -2-yl)phenyl)-1H-imidazole-4-carboxylic acid

Compound 51 (30 mg, 0.06 mmol) and sodium hydroxide (7 mg, 0.30 mmol) were dissolved in methanol (2 ml) and water (1 ml). The reaction system was stirred at room temperature for 1 hour. The reaction system was then adjusted to pH 4-5 with dilute hydrochloric acid (1N) and concentrated on a rotary evaporator to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography to provide compound 107 (10 mg, 33% yield) as a white solid. MS [M+H] ⁺ =512.1.

1H NMR (400 MHz, d6-DMSO) δ 8.56 (brs, 1H), 8.44 (d, J=5.0 Hz, 1H), 7.89 (brs, 1H), 7.37 (brs , 1H), 6.84 (d, J=6.3 Hz, 1H), 3.74-3.60 (m, 3H), 3.56 (s, 3H), 3.51-3.45 ( m, 1H), 3.26-3.21 (m, 1H), 3.10-2.98 (m, 2H), 2.88-2.75 (m, 1H), 2.60-2, 48 (m, 1H), 2.38 (s, 3H).

Example 108:

The compound was prepared in accordance with the preparation method described in Example 50. LC-MS: [M+H] ⁺ =526.2.

Example 109:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(4-trifluoromethyl-1H-imidazol-1-yl)phenyl)-7-methylimidazo[1,2-a]pyridin- 3-yl)methyl)morpholine-4-carboxylate

Intermediate 17-2 (130 mg, 0.25 mmol), 4-(trifluoromethyl)-1H-imidazole (40 mg, 0.3 mmol), copper(II) acetate (67 mg, 0.37 mmol) and pyridine (39 mg, 0.5 mmol) was dissolved in acetonitrile (2 ml). The reaction system was heated to 60°C and the reaction was carried out overnight. The reaction system was then cooled to room temperature, diluted with water (10 ml) and extracted with dichloromethane (10 ml x 3). The organic phases were combined, washed with brine (10 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative high performance liquid chromatography to provide compound 109 (13 mg, 9% yield) as a white solid.

LC-MS: [M+H] ⁺ =536.4. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.29 (d, J=7.3 Hz, 1H), 7.99 (s, 1H), 7.70 (s, 1H), 7.61 ( s, 1H), 7.19 (d, J=7.2 Hz, 1H), 6.83 (d, J=7.0 Hz, 1H), 4.10-3.80 (m, 3H), 3.71 (s, 3H), 3.65-3.57 (m, 1H), 3.46-3.35 (m, 1H), 3.09-2.95 (m, 3H), 2, 70-2.62 (m,1H), 2.49 (s,3H).

Example 110:

Preparation of methyl-(S)-2-((2-(4-(4-carbamoyl-1H-imidazol-1-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3 -yl)methyl)morpholine-4-carboxylate

Compound 107 (30 mg, 0.06 mmol), HATU (34 mg, 0.09 mmol) and N,N-diisopropylethylamine (23 mg, 0.18 mmol) were dissolved in N,N-dimethylformamide (2 ml). The reaction system was stirred at room temperature for 5 minutes, anhydrous ammonium chloride (10 mg, 0.18 mmol) was added and stirred at room temperature for an additional 1 hour. Saturated brine (15 mL) was then added to the reaction system to quench the reaction. mixture and extracted with ethyl acetate (10 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to provide compound 110 (28 mg, 83% yield) as a white solid. LC-MS: [M+H] ⁺ =511.1.

1H NMR (400 MHz, MEOD) δ 8.43 (d, J=7.2 Hz, 1H), 8.36 (d, J=1.3 Hz, 1H), 8.27 (d, J=1 ,3 Hz, 1H), 7.62 (d, J=8.1 Hz, 2H), 7.37 (s, 1H), 6.90 (dd, J=7.1, 1.6 Hz, 1H ), 3.89-3.76 (m, 3H), 3.67 (s, 3H), 3.63-3.58 (m, 1H), 3.41-3.35 (m, 1H) , 3.16-3.10 (m, 2H), 2.98-2.82 (m, 1H), 2.72-2.58 (m, 1H), 2.48 (s, 3H).

Example 111:

The compound was obtained in accordance with the method for preparing compound 5. MS [M+H] ⁺ =483.3.

Example 112:

The compound was obtained in accordance with the method for preparing compound 5. MS [M+H] ⁺ =498.2.

Example 113:

The compound was obtained in accordance with the method for preparing compound 5. MS [M+H] ⁺ =552.2.

Example 114:

Preparation of (S)-2-(3,5-difluoro-4-(3-((4-(methoxycarbonyl)morpholin-2-yl)methyl)-7-methylimidazo[1,2-a]pyridin-2-yl )phenyl)oxazole-4-carboxylic acid

Step (1) Preparation of methyl-(R)-2-((2-(4-(1,3-dioxolan-2-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine -3-yl)methyl)morpholine-4-carboxylate

4-(1,3-Dioxolan-2-yl)-2,6-difluorobenzaldehyde (600 mg, 2.8 mmol), 4-methylpyridin-2-amine (302.8 mg, 2.8 mmol), tert. butyl (S)-2-ethynylmorpholine-4-carboxylate (595 mg, 2.8 mmol), copper(I) chloride (84 mg, 0.84 mmol) and copper(II) trifluoromethanesulfonate (304 mg, 0.84 mmol) was dissolved in toluene (10 ml). The reaction system was stirred at 85°C for 30 min, N,N-dimethylacetamide (0.1 ml) was added dropwise and stirred at 85°C overnight. The reaction system was then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give intermediate 114-2 (1.2 g, 55.36% yield) as a yellow solid. MS [M+H] ⁺ =516.2.

Step (2) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-formylphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine -4-carboxylate

Intermediate 114-2 (1.2 g, 2.33 mmol) was dissolved in acetone (10 ml) at room temperature and dilute hydrochloric acid (10 ml, 1 N) was added. The reaction system was stirred overnight. After completion of the reaction, the pH of the reaction system was adjusted to 8-9 with saturated sodium carbonate solution, BOC anhydride (766 mg, 3.5 mmol) was added and stirred at room temperature for 5 hours. The reaction system was then extracted with ethyl acetate (20 ml x 3 ). The organic phases were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 114-3 (563 mg, 51.3% yield) as a yellow solid. MS [M+H] ⁺ =471.2.

Step (3) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-(4-(carbomethoxymethoxy<methoxycarbonyl>)oxazol-2-yl)phenyl)-7-methylimidazo[ 1,2-a]iridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 114-3 (495 mg, 1.05 mmol) was dissolved in N,N-dimethylacetamide (4 ml) under nitrogen and methyl (2S)-2-amino-3-hydroxypropionate acid (163 mg, 1.05 mmol) was added. 05 mmol) and potassium carbonate (290 mg, 2.10 mmol). The reaction system was stirred at room temperature for 18 hours. The reaction system was then cooled to 0°C, bromotrichloromethane (625 mg, 3.15 mmol) and 1,8-diaza-cyclo[5.4.0]undec-7-ene (480 mg, 3.15 mmol) were added and stirred at 0°C for 2 h and stirred at room temperature for 24 h. The resulting reaction system was added with water (20 ml) to quench the reaction and extracted with diethyl ether (20 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by silica gel column chromatography to give intermediate 114-4 (231 mg, 37.2% yield) as a yellow solid. MS [M+H] ⁺ =569.2.

Step (4) Preparation of methyl-(S)-2-(3,5-difluoro-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-a]pyridin-2-yl) phenyl)oxazole-4-carboxylate

Intermediate 114-4 (231, 0.41 mmol) was dissolved in dichloromethane (4 ml) and trifluoroacetic acid (1 ml) was added. The reaction system was stirred at room temperature for 2 hours. The reaction system was then concentrated on a rotary evaporator under reduced pressure, diluted with dichloromethane (30 ml) and saturated sodium bicarbonate solution (20 ml) was slowly added with stirring, followed by separation of the liquid. The aqueous phase was subjected to extraction with dichloromethane (20 ml). The organic phases were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give intermediate 114-5 (195 mg, 97.6% yield) as a brown solid. MS [M+H]+=469.1.

Step (5) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(4-(<carbomethoxymethoxycarbonyl>)oxazol-2-yl)phenyl)-7-methylimidazo[1,2 -a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 114-5 (150 mg, 0.30 mmol) and diisopropylethylamine (160 mg, 1.20 mmol) were dissolved in DCM (10 ml) at 0°C under nitrogen. The reaction system was stirred for 10 min and methyl chloroformate (34 mg, 0.36 mmol) was added dropwise. After the dropwise addition was completed, the reaction mixture was reacted for 2 hours. The reaction system was then concentrated on a rotary evaporator. The crude product was purified by silica gel column chromatography to provide intermediate 114-6 (110 mg, 66.7% yield) as a white solid. MS [M+H] ⁺ =527.1.

Step (6) Preparation of 2-[3,5-difluoro-4-(3-{[(2S)-4-(carbomethoxy<methoxycarbonyl>)morpholin-2-yl]methyl}-7-methylimidazo[1,2- a]pyridin-2-yl)phenyl]-1,3-oxazole-4-carboxylic acid

Intermediate 114-6 (80 mg, 0.15 mmol) was dissolved in methanol (2 mL) and sodium hydroxide solution (1.5 mL, 1 N) was added. The reaction system was allowed to react at room temperature for 2 hours. The reaction system was then adjusted to pH 5 with dilute hydrochloric acid and concentrated. The residue was separated by preparative high performance liquid chromatography to give compound 114 (33 mg, 40% yield) as a white solid. LC-MS [M+H] ⁺ =513.1.

1H NMR (400 MHz, DMSO) δ 13.24 (brs,1H), 8.99 (s, 1H), 8.47 (d, J=7.1 Hz, 1H), 7.81 (d, J =7.5 Hz, 2H), 7.39 (s, 1H), 6.88 (d, J=7.0 Hz, 1H), 3.82-3.73 (m, 1H), 3, 69-3.60 (m, 2H), 3.56 (s, 3H), 3.49 (s, 1H), 3.27-3.18 (m, 1H), 3.14-3.00 ( m, 2H), 2.87-2.75 (m, 1H), 2.55-2.45 (m, 1H), 2.40 (s, 3H).

Example 115:

The compound was prepared in accordance with the preparation method described in Example 114. LC-MS: [M+H] ⁺ =493.2.

Example 116:

The compound was prepared in accordance with the preparation method described in Example 114. LC-MS: [M+H] ⁺ =493.2.

Example 117:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(4-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)phenyl)-7-methylimidazo[ 1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Compound 51 (30 mg, 0.06 mmol) was dissolved in tetrahydrofuran (2 mL) and a solution of methylmagnesium bromide in n-hexane (3 M, 0.06 mL, 0.18 mmol) was added dropwise under nitrogen in an ice-water bath . After the dropwise addition was completed, the reaction system was stirred at room temperature for 1 hour. The reaction system was then added with saturated ammonium chloride solution to quench the reaction and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography to provide compound 117 (5 mg, 17% yield) as a white solid. MS [M+N] ⁺ =526.1.

1H NMR (400 MHz, d6-DMSO) δ 8.43 (d, J=7.0 Hz, 1H), 8.38 (d, J=1.2 Hz, 1H), 7.73 (d, J =8.8 Hz, 2H), 7.71 (d, J=1.4 Hz, 1H), 7.36 (s, 1H), 6.85 (dd, J=7.1, 1.5 Hz , 1H), 4.84 (s, 1H), 3.78-3.60 (m, 3H), 3.56 (s, 3H), 3.52-3.46 (m, 1H), 3, 29-3.21 (m, 1H), 3.08-3.02 (m, 2H), 2.90-2.75 (m, 1H), 2.60-2.46 (m, 1H), 2.39 (s, 3H), 1.45 (s, 6H).

Example 118:

The compound was prepared in accordance with the preparation method described in Example 114. MS [M+H] ⁺ =525.2.

Example 119:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(4-(2-hydroxypropyl-2-yl)oxazol-2-yl)phenyl)-7-methylimidazo[1,2 -a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 114-6 (150 mg, 0.29 mmol) was dissolved in tetrahydrofuran (8 ml) and methylmagnesium chloride (0.3 ml, 3.0 M) was added dropwise while maintaining the temperature at -20°C. The reaction system was stirred at this temperature for 4 hours. The reaction system was then added with a small amount of water to quench the reaction and concentrated. The residue was separated by preparative chromatography to give compound 119 (10.8 mg, 7.1% yield) as a white solid. LC-MS [M+H] ⁺ : 527.0

1H NMR(400 MHz, CDCl ₃ ) δ 8.43 (d, J=7.2 Hz, 1H), 7.89 (s, 1H), 7.80 (d, J=7.9 Hz, 1H) , 7.36 (s, 1H), 6.89 (dd, J=7.1, 1.5 Hz, 1H), 3.89-3.74 (m, 3H), 3.70 (s, 3H ), 3.64-3.57 (m, 1H), 3.41-3.33 (m, 1H), 3.16-3.09 (m, 2H), 2.96-2.80 (m , 1H), 2.70-2.55 (m, 1H), 2.49 (s, 3H), 1.61 (s, 6H).

Example 120:

The compound was prepared in accordance with the preparation method described in Example 10. LC-MS: [M+H] ⁺ =494.3.

Example 121:

The compound was prepared in accordance with the preparation method described in Example 10. LC-MS: [M+H] ⁺ =492.4.

Example 122:

The compound was prepared in accordance with the preparation method described in Example 10. LC-MS: [M+H] ⁺ =473.5.

Example 123:

The compound was prepared according to the preparation method described in Example 10. LC-MS: [M+H]+=487.1.

Example 124:

Intermediate 17-2 (190 mg, 0.36 mmol), 1H-pyrazole-3-carbonitrile (40 mg, 0.43 mmol), anhydrous copper(II) acetate (98 mg, 0.54 mmol) and pyridine ( 57 mg, 0.72 mmol) was dissolved in acetonitrile (3 ml). The reaction system was heated to 60°C and the reaction was carried out overnight. The reaction system was then cooled to room temperature, diluted with water (20 ml) and extracted with dichloromethane (20 ml x 3). The organic phases were combined, washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative high performance liquid chromatography to provide compound 124 (70 mg, white solid) and compound 124-2 (5 mg, 42% yield) as a white solid. LC-MS: [M+H] ⁺ =493.3.

Compound 124: ^1H NMR (400 MHz, CDCl ₃ ) δ 8.33 (d, J=6.0 Hz, 1H), 8.08 (d, J=2.4 Hz, 1H), 7.70 ( brs, 1H), 7.52 (d, J=8.0 Hz, 2H), 6.95 (d, J=2.5 Hz, 1H), 6.88 (d, J=6.0 Hz, 1H), 4.05-3.76 (m, 3H), 3.71 (s, 3H), 3.66-3.58 (m, 1H), 3.10-2.83 (m, 3H) , 2.70-2.62 (m,1H), 2.51 (s,3H).

Compound 124-2: ^1H NMR (400 MHz, CDCl ₃ ) δ 8.29 (brs, 1H), 7.88 (s, 1H), 7.70-7.50 (m, 3H), 7.14 (s, 1H), 6.83 (brs, 1H), 4.08-3.75 (m, 3H), 3.70 (s, 3H), 3.66-3.58 (m, 1H), 3.46-3.36 (m, 1H), 3.10-2.85 (m, 3H), 2.72-2.62 (m, 1H), 2.49 (s, 3H).

Example 125

Step (1) Preparation of (S)-3,5-difluoro-4-(7-methyl-3-(morpholinyl-2-methyl)imidazo[1,2-a]pyridin-2-yl)-1H-pyrazol- 3-carboxylic acid

Compound 124 (40 mg, 0.08 mmol) was dissolved in ethanol (2 ml) and water (1 ml) and potassium hydroxide (13 mg, 0.24 mmol) was added. The reaction system was reacted at 100°C for 12 hours under a nitrogen atmosphere. The reaction system was cooled to room temperature and concentrated to give intermediate 125-1 (40 mg, crude), which was used directly in the next step. LC-MS: [M+H] ⁺ =454.2.

Step (2) Preparation of (S)-1-(3,5-difluoro-4-(3-((4-(methoxycarbonyl)morpholin-2-yl)methyl)-7-methylimidazo[1,2-a]pyridine -2-yl)phenyl)-1H-pyrazole-3-carboxylic acid

Intermediate 125-1 (40 mg, 0.08 mmol, crude product) was dissolved in tetrahydrofuran/water (2 mL, 1/1) and methyl chloroformate (10 mg, 0.108 mmol) was added dropwise in an ice-water bath. The reaction system was reacted at this temperature for 1 hour. The reaction system was then adjusted to pH 4 with dilute hydrochloric acid and concentrated. The residual aqueous phase was lyophilized. The crude product was purified by preparative high performance liquid chromatography to give compound 125 (7.6 mg, 18% yield), LC-MS: [M+H] ⁺ =512.3.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J=7.0 Hz, 1H), 7.98 (d, J=2.1 Hz, 1H), 7.70 (s, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.07 (d, J=2.4 Hz, 1H), 6.81 (d, J=7.0 Hz, 1H) , 4.06-3.78 (m, 3H), 3.70 (s, 3H), 3.66-3.58 (m, 1H), 3.46-3.35 (m, 1H), 3 .05-2.85 (m, 3H), 2.70-2.62 (m, 1H), 2.49 (s, 3H).

Example 126:

Step (1) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(3-(carbomethoxy<methoxycarbonyl>)1H-pyrazol-1-yl)phenyl)-7-methylimidazo[ 1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Methyl (S)-2-((7-methyl-2-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (700 mg, 1.67 mmol), methyl 3-pyrazole carboxylate (210 mg, 1.67 mmol) and anhydrous potassium carbonate (692 mg, 5.00 mmol) were dissolved in N,N-dimethylformamide (15 ml) under nitrogen atmosphere. The reaction system was stirred at 130°C for 4 hours. The reaction system was then cooled, ice water (15 ml) was added to quench the reaction mixture, and extracted with ethyl acetate (10 ml x 3). The organic phases were combined, washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 126-2 (300 mg, 80% purity, 27% yield) as a yellow solid. MS [M+H] ⁺ =526.2.

Step (2) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)phenyl)- 7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 126-2 (150 mg, 0.28 mmol) was dissolved in tetrahydrofuran (5 ml) under nitrogen. The reaction system was cooled to 0°C in an ice water bath, a solution of methylmagnesium bromide (3 M, 0.3 mL, 0.9 mmol) was added dropwise with the temperature maintained at 0°C, and stirred for 1 hour. The reaction system was then added with saturated ammonium chloride solution (10 mL) at 0° C. to quench the reaction mixture and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative high performance liquid chromatography to provide compound 126 (30 mg, 17% yield) as a white solid. MS [M+H] ⁺ =525.8.

^1H NMR (400 MHz, MEOD): δ 8.45 (d, J=7.0 Hz, 1H), 8.31 (d, J=2.6 Hz, 1H), 7.67 (d, J =8.9 Hz, 2H), 7.39 (s, 1H), 6.93 (d, J=7.1 Hz, 1H), 6.60 (d, J=2.6 Hz, 1H), 3.89-3.76 (m, 3H), 3.66 (s, 3H), 3.64-3.60 (m, 1H), 3.16-3.11 (m, 2H), 3. 00-2.85 (m, 1H), 2.71-2.60 (m, 1H), 2.49 (s, 3H), 1.64 (s, 6H).

Example 127:

Step (1) Preparation of 2,6-difluoro-4-(4-nitro-1H-pyrazol-1-yl)benzaldehyde

2,4,6-trifluorobenzaldehyde (2.0 g, 12.5 mmol), 4-nitro-1H-pyrazole (1.4 g, 12.5 mmol) and triethylamine (3.8 g, 37.5 mmol) dissolved in acetonitrile (20 ml) under nitrogen atmosphere. The reaction system was heated to reflux for 3 hours. The reaction system was then cooled to room temperature, water (50 mL) was added to quench the reaction, and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with brine (30 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 127-3 (450 mg, 14% yield) as a yellow solid. LC-MS [M+H] ⁺ =254.

Step (2) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-(4-nitro-1H-pyrazol-1-yl)phenyl)-7-methylimidazo[1, 2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 127-3 (450 mg, 1.78 mmol), 4-methylpyridin-2-amine (192 mg, 1.78 mmol), tert-butyl (S)-2-ethynylmorpholine-4-carboxylate (375 mg , 1.78 mmol), copper (I) chloride (53 mg, 0.53 mmol) and copper (II) trifluoromethanesulfonate (193 mg, 0.53 mmol) were dissolved in toluene (5 ml) under a nitrogen atmosphere. The reaction system was heated to 85°C and stirred for 20 minutes, N,N-dimethylacetamide (0.15 ml) was added and reacted at 85°C for 5 hours. The reaction system was then cooled to room temperature and reacted for nights. The reaction system was then added with water (30 mL) to quench the reaction, and extraction was carried out with dichloromethane (15 mL x 3). The organic phases were combined, washed with brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to give intermediate 127-4 (260 mg, 26% yield) as a brown oil. LC-MS [M+H] ⁺ =555.2.

Step (3) Preparation of (S)-2-(((2-(2,6-difluoro-4-(4-nitro-1H-pyrazol-1-yl)phenyl)-7-methylimidazo[1,2-a ]pyridin-3-yl)methyl)morpholine

Intermediate 127-4 (260 mg, 0.5 mmol) was dissolved in dichloromethane (3 ml). The reaction system was cooled to 0°C in an ice water bath, a solution of HCl in ethanol (33%, 1 ml) was added dropwise and stirred at room temperature for 1 hour. The reaction system was then concentrated by rotary evaporation to obtain intermediate 127- 5 (280 mg, crude product), which was used directly in the next step. LC-MS [M+H] ⁺ =455.2.

Step (4) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(4-nitro-1H-pyrazol-1-yl)phenyl)-7-methylimidazo[1,2- a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 127-5 (200 mg, 0.44 mmol) and N,N-diisopropylethylamine (284 mg, 2.20 mmol) were dissolved in dichloromethane (3 ml) under nitrogen. Methyl chloroformate (50 mg, 0.52 mmol) was added dropwise to the reaction system at 0°C in an ice water bath. After the dropwise addition was completed, the reaction system was reacted for 1 hour. Then, water (20 ml) was added to the reaction system to quench the reaction mixture, and extraction was carried out with dichloromethane (15 ml × 3). The organic phases were combined, washed with brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to give intermediate 127-6 (110 mg, 48% yield) as a brown solid. LC-MS [M+H] ⁺ =513.3.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 8.34 (s, 1H), 8.25 (d, J=7.1 Hz, 1H), 7.52-7 .48 (m, 3H), 6.78 (s, 1H), 4.00-3.75 (m, 3H), 3.70 (s, 3H), 3.67-3.56 (m, 1H ), 3.45-3.35 (m, 1H), 3.10-2.85 (m, 3H), 2.68-2.60 (m, 1H), 2.47 (s, 3H).

Step (5) Preparation of methyl-(S)-2-((2-(4-(4-amino-1H-pyrazol-1-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a ]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 127-6 (80 mg, 0.15 mmol) and saturated ammonium chloride (0.5 ml) were dissolved in ethanol (2 ml) under nitrogen. The reaction system was heated to 80°C, iron powder (44 mg, 0.75 mmol) was added and stirred for 15 minutes. The reaction system was then cooled to room temperature, filtered and concentrated. The crude product was purified by preparative high performance liquid chromatography to provide compound 127 (9 mg, 12% yield) as a white solid. LC-MS [M+H] ⁺ =483.2.

1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=7.1 Hz, 1H), 7.53 (s, 1H), 7.52 (s, 1H), 7.46 (s, 1H ), 7.34 (d, J=8.7 Hz, 2H), 6.76 (d, J=7.0 Hz, 1H), 4.00-3.75 (m, 3H), 3.69 (s, ZN), 3.66 -3.56 (m, 1H), 3.45-3.35 (m, 1H), 3.08-2.85 (m, 3H), 2.67-2 .61 (m, 1H), 2.46 (s, 3H).

Example 128:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(4-hydroxy-1H-pyrazol-1-yl)phenyl)-7-methylimidazo[1,2-a]pyridin- 3-yl)methyl)morpholine-4-carboxylate

Step (1) Preparation of 4-(4-bromo-1H-pyrazol-1-yl)-2,6-difluorobenzaldehyde

2,4,6-trifluorobenzaldehyde (2.0 g, 12.49 mmol) was dissolved in anhydrous acetonitrile (20 ml) and 4-bromopyrazole (1.8 g, 12.49 mmol) and triethylamine (3.8 g, 37 .47 mmol) was added under nitrogen atmosphere. The reaction system was reacted at 80°C for 1 hour. The reaction system was then cooled to room temperature, water (60 ml) was added, and extracted with ethyl acetate (80 ml x 3). The organic phases were combined, washed with brine (50 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 128-3 (800 mg, 22.2% yield) as a white solid. MS [M+H] ⁺ =287.7.

Step (2) Preparation of tert-butyl-(S)-2-((2-(4-(4-bromo-1H-pyrazol-1-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2 -a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 128-3 (600 mg, 2.09 mmol), 4-methylpyridin-2-amine (226 mg, 2.09 mmol), tert-butyl (S)-2-ethynylmorpholine-4-carboxylate (442 mg , 2.09 mmol), copper(I) chloride (62 mg, 0.63 mmol) and copper(II) trifluoromethanesulfonate (227 mg, 0.63 mmol) were dissolved in toluene solution (6 ml) under nitrogen atmosphere. The reaction system was reacted at 85°C for 10 minutes, N,N-dimethylacetamide (0.2 ml) was added and reacted at 85°C for another 5 hours. The reaction system was then reacted at room temperature overnight. After completion of the reaction, the reaction system was filtered, water (30 ml) was added to the filtrate, and extraction was carried out with dichloromethane (30 ml × 3). The organic phases were combined, washed with brine (40 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 128-4 (200 mg, 17% yield) as a yellow oil. MS [M+N] ⁺ =588.8.

Step (3) Preparation of (S)-2-((2-(4-(4-bromo-1H-pyrazol-1-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridine -3-yl)methyl)morpholine

Intermediate 128-4 (200 mg, 0.34 mmol) was dissolved in dichloromethane (2 mL) and a solution of HCl in ethanol (33%, 0.5 mL) was added dropwise while the temperature was maintained at 0°C. After the dropwise addition was completed, the reaction system was reacted at room temperature for 2 hours. The reaction system was then added dropwise with saturated sodium bicarbonate solution to adjust the pH to 8 while the temperature was maintained at 0°C, water (10 ml) was added and extracted with dichloromethane (20 ml x 3). The organic phases were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 128-5 (180 mg, crude) as a yellow oil. MS [M+H] ⁺ =488.7.

Step (4) Preparation of methyl-(S)-2-((2-(4-(4-bromo-1H-pyrazol-1-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a ]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 128-5 (180 mg, 0.34 mmol) and N,N-diisopropylethylamine (143 mg, 1.11 mmol) were dissolved in dichloromethane (2 ml) and methyl chloroformate (42 mg, 0.44 mmol) was added dropwise. under a nitrogen atmosphere at a temperature maintained at 0°C. After completion of the dropwise addition, the reaction system was reacted at 0°C for 1 hour. The reaction system was then added with water (10 ml) and extracted with dichloromethane (15 ml x 3). The organic phases were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 128-6 (150 mg, 81% yield) as a yellow solid. MS [M+H] ⁺ =546.7.

Step (5) Preparation of methyl-(S)-2-(2-(2,6-difluoro-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) )-1H-pyrazol-1-yl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 128-6 (150 mg, 0.27 mmol) was dissolved in anhydrous 1,4-dioxane (2 ml) under nitrogen and 4,4,4',4',5,5,5',5' was added -octamethyl-2,2'-bis(1,3,2-dioxaborolane) (87 mg, 0.34 mmol), potassium acetate (54 mg, 0.55 mmol) and [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium (10 mg, 0.014 mmol). The reaction system was reacted at 90°C for 2 hours. After completion of the reaction, the reaction system was cooled to room temperature, filtered and concentrated on a rotary evaporator to give intermediate 128-7 (180 mg, crude product) in yellow oil, MS [M +H] ⁺ =593.7.

Step (6) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(4-hydroxy-1H-pyrazol-1-yl)phenyl)-7-methylimidazo[1,2- a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 128-7 (180 mg, 0.27 mmol) was dissolved in tetrahydrofuran (2 ml) and hydrogen peroxide (0.5 ml) was added dropwise. The reaction system was reacted at room temperature for 1 hour. After completion of the reaction, the reaction system was added dropwise with saturated sodium thiosulfate solution (2 mL) to quench the reaction, water (10 mL) was added, and extracted with dichloromethane (15 mL x 3). The organic phases were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by high performance liquid chromatography to provide compound 128 (22.9 mg, 17.3% yield) as a white solid. MS [M+H] ⁺ =483.8.

^1H NMR (400 MHz, MeOD) δ 8.86 (d, J=7.1 Hz, 1H), 7.93 (s, 1H), 7.72 (s, 1H), 7.70 (d, J=9.6 Hz, 2H), 7.50 (s, 1H), 7.42 (dd, J=7.1, 1.5 Hz, 1H), 4.03-4.00 (m, 1H ), 3.85-3.76 (m, 3H), 3.69 (s, 3H), 3.40-3.36 (m, 1H), 3.28-3.26 (m, 2H), 2.99-2.90 (m, 1H), 2.80-2.72 (m, 1H), 2.66 (s, 3H).

Example 129:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(4-methoxy-1H-pyrazol-1-yl)phenyl)-7-methylimidazo[1,2-a]pyridin- 3-yl)methyl)morpholine-4-carboxylate

Compound 128 (45 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (1 ml) under nitrogen, and cesium carbonate (36 mg, 0.11 mmol) and iodomethane (20 mg, 0.14 mmol) were added sequentially ). The reaction system was reacted at room temperature for 1 hour. After completion of the reaction, water (10 mL) was added to the reaction system to quench the reaction mixture and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified by high performance liquid chromatography to provide compound 129 (5.3 mg, 11.4% yield) as a white solid. MS [M+N] ⁺ =497.8.

^1H NMR (400 MHz, MeOD) δ 8.42 (d, J=7.0 Hz, 1H), 8.15 (s, 1H), 7.59 (d, J=9.0 Hz, 2H) , 7.56 (s, 1H), 7.35 (s, 1H), 6.88 (dd, J=7.2 Hz, 1.2 Hz, 1H), 3.86 (s, 3H), 3 .86-3.76 (m, 3H), 3.66 (s, 3H), 3.63-3.58 (m, 1H), 3.42-3.36 (m, 1H), 3.12 -3.11 (m, 2H), 2.93-2.88 (m, 1H), 2.68-2.61 (m, 1H), 2.47 (s, 3H).

Example 130:

Step (1) Preparation of 2-(1H-pyrazol-3-yl)acetylhydrazide

5-nitropyridin-2-ol (10.0 g, 71.38 mmol) was dissolved in hydrazine hydrate (50 ml). The reaction system was stirred at 100°C for 3 hours. After completion of the reaction, the reaction system was concentrated by rotary evaporation to obtain intermediate 130-2 (10.0 g, crude product) as a red oil. LC-MS [M+H]=140.7.

Step (2) Preparation of 2-(1H-pyrazol-3-yl)acetic acid

Intermediate 130-2 (10 g) was added to concentrated hydrochloric acid (100 ml) under nitrogen. The reaction system was heated to 100°C and stirred for 3 hours. After completion of the reaction, the reaction system was concentrated on a rotary evaporator to obtain intermediate 130-3 (10 g, crude product) as a colorless, clear oil, MS [M+H]+ =127.0.

Step (3) Preparation of ethyl 2-(1H-pyrazol-3-yl)acetate

Intermediate 130-3 (10.0 g, crude product) was dissolved in ethanol (15 ml) and a solution of HCl in ethanol (33%, 12.5 ml) was added. The reaction system was stirred at room temperature for 3 hours. After completion of the reaction, the reaction system was concentrated on a rotary evaporator to give intermediate 130-4 (12 g, crude) as a brown oil, MS [M+H] ⁺ =155.0.

Step (4) Preparation of ethyl 2-(1-trityl-1H-pyrazol-3-yl)acetate

Intermediate 130-4 (12.0 g, crude product) was dissolved in anhydrous DMF (100 ml) and triphenylmethyl chloride (20.0 g, 77.42 mmol) and triethylamine (28.8 g, 285.5 mmol) were added. The reaction system was stirred at room temperature overnight. After completion of the reaction, water (300 ml) was added to the reaction system and extraction was carried out with ethyl acetate (100 ml × 3). The organic phases were combined, washed with brine (150 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography to give intermediate 130-5 (2.3 g, 7.5% yield) as a white solid. MS [M+N] ⁺ =418.8.

Step (5) Preparation of ethyl 1-(1-trityl-1H-pyrazol-3-yl)cyclopropane-1-carboxylate

Intermediate 130-5 (1.0 g, 2.52 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml). The reaction system was cooled to -78°C, lithium diisopropylamide (2.4 ml, 2N, 4.80 mmol) was added dropwise and stirred at -78°C for 20 minutes. Dibromethane (2.8 g, 15.13 mmol) was then added to the reaction system, slowly warmed to room temperature and stirred overnight. After completion of the reaction, saturated ammonium chloride (10 ml) was added to the reaction system, diluted with water (20 ml) and extracted with ethyl acetate (30 ml x 2). The organic phases were combined, washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography to give intermediate 130-6 (550 mg, 51.6% yield) as a yellow oil. MS [M+H] ⁺ =444.8.

Step (6) Preparation of ethyl 1-(1H-pyrazol-3-yl)cyclopropane-1-carboxylate

Intermediate 130-6 (400 mg, 1.01 mmol) was dissolved in dichloromethane (2 ml) and methanol (2 ml) and trifluoroacetic acid (1.2 ml) was added. The reaction system was stirred at room temperature overnight. After completion of the reaction, the reaction system was adjusted to pH 10 with saturated sodium carbonate solution and extracted with dichloromethane (15 ml x 3). The organic phases were combined, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by silica gel column chromatography to provide intermediate 130-7 (65 mg, 35.6% yield) as a white solid, MS [M+H]+=181.0.

Step (7) Preparation of methyl (5)-2-((2-(4-(3-(1-(carbethoxy<ethoxycarbonyl>)cyclopropyl)-1H-pyrazol-1-yl)-2,6-difluorophenyl) -7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 130-7 (35 mg, 0.19 mmol) was dissolved in anhydrous DMSO (1.5 mL) and intermediate 126-1 (87 mg, 0.21 mmol) and potassium carbonate (66 mg, 0.48 mmol) were added mmol). The reaction system was stirred at 130°C overnight. After completion of the reaction, the reaction system was added to water (15 ml) and extracted with ethyl acetate (10 ml x 3). The organic phases were combined, washed with brine (10 ml), dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by silica gel column chromatography to give intermediate 130-8 (25 mg, 22.7% yield) as a white solid. MS [M+N] ⁺ =579.8.

Step (8) Preparation of (S)-1-(1-(3,5-difluoro-4-(3-((4-(carbomethoxy<methoxycarbonyl>)morpholin-2-yl)methyl)-7-methylimidazo[1 ,2-a]pyridin-2-yl)phenyl)-1H-pyrazol-3-yl)cyclopropane-1-carboxylic acid

Intermediate 130-8 (25 mg, 0.044 mmol) was dissolved in tetrahydrofuran (1 mL)/methanol (1 mL) and lithium hydroxide solution (0.5 mL, 1 N) was added. The reaction system was stirred at room temperature overnight. After completion of the reaction mixture, the reaction system was adjusted to pH 4 with dilute hydrochloric acid and extracted with ethyl acetate (5 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated by high performance liquid chromatography and lyophilized to give compound 130 (5.0 mg, 20.6% yield) as a white solid. MS [M+N] ⁺ =551.7.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J=6.6 Hz, 1H), 7.93 (d, J=2.6 Hz, 1H), 7.63 (s, 1H ), 7.38 (d, J=8.2 Hz, 2H), 6.84 ((d, J=6.8 Hz, 1H), 6.33 (s, 1H), 3.05-3, 77 (m, 3H), 3.70 (s, 3H), 3.66-2.59 (m, 1H), 3.46-3.37 (m, 1H), 3.10-2.99 ( m, 2H), 2.99-2.87 (m, 1H), 2.70-2.63 (m, 1H), 2.50 (s, 3H), 1.94 (dd, J=7, 6, 4.0 Hz, 2H), 1.47 (dd, J=7.6, 4.1 Hz, 2H)

Example 131:

The compound was prepared in accordance with the preparation method described in Example 126. LC-MS: [M+H] ⁺ =524.2.

Example 132:

The compound was prepared in accordance with the preparation method described in Example 5. LC-MS: [M+H] ⁺ =472.2.

Example 133:

Preparation of methyl-(S)-2-(((2-(4-(4-(1-carbamylcyclopropyl)-1H-imidazol-2-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2- a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Compound 59 (400 mg, 0.72 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (410 mg, 1.08 mmol) were dissolved in N,N -dimethylformamide (5 ml). The reaction system was stirred at room temperature for 10 min under nitrogen, N,N-diisopropylethylamine (279 mL, 2.16 mmol) and ammonium chloride (58 mg, 1.1 mmol) were added and stirred at room temperature for another 2 h. Then the reaction system was added with water (30 ml) to quench the reaction mixture and subjected to extraction with ethyl acetate (15 ml × 3). The organic phases were combined, washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to give the crude product (200 mg) as a brown solid. The crude product (50 mg) was purified by preparative chromatography to give compound 133 (11.1 mg) as a white solid. LC-MS [M+H] ⁺ : 551

1H NMR (400 MHz, CDCl ₃ ) δ 8.27 (d, J=6.9 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J=8.3 Hz, 2H) , 6.96 (s, 1H), 6.80 (d, J=6.9 Hz, 1H), 5.56 (brs, 1H), 3.90-3.80 (m, 3H), 3, 66 (s, 3H), 3.62-3.54 (m, 1H), 3.43-3.34 (m, 1H), 3.04-2.82 (m, 3H), 2.67- 2.56 (m, 1H), 2.51 (s, 3H), 1.65-1.59 (m, 2H), 1.15-1.09 (m, 2H).

Example 134:

Step (1) Preparation of 1-tosyl-1H-pyrrole-3-sulfonyl chloride

N-p-toluenesulfonylpyrrole (2.00 g, 9.01 mmol) was dissolved in acetonitrile (20 ml) and chlorosulfonic acid (5 ml) was slowly added dropwise at 0°C in an ice water bath. The reaction system was reacted at room temperature overnight. The reaction system was then slowly added dropwise to ice (100 g) and extracted with dichloromethane (80 mL x 2). The organic phases were combined, washed with saturated sodium bicarbonate (30 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to give intermediate 134-3 (600 mg, 21% yield) as a white solid.

Step (2) Preparation of N,N-bis(4-methoxybenzyl)-1-tosyl-1H-pyrrole-3-sulfonamide

Bis-(4-methoxybenzyl)-amine (195 mg, 0.76 mmol) and triethylamine (191 mg, 1.89 mmol) were dissolved in dichloromethane (5 ml) under nitrogen and a solution of intermediate 134-3 was added dropwise ( 200 mg, 0.63 mmol) in dichloromethane (1 ml) at 0°C in an ice water bath. The reaction system was stirred at room temperature overnight. The reaction system was then poured into water (20 ml) and extracted with dichloromethane (30 ml x 2). The organic phases were combined, washed with brine (30 ml), filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 134-5 (300 mg, 88% yield) as a white solid. MS [M+Na] ⁺ =562.

Step (3) Preparation of N,N-bis(4-methoxybenzyl)-1H-pyrrole-3-sulfonamide

Intermediate 134-5 (800 mg, 1.48 mmol) was dissolved in methanol (10 ml) and tetrahydrofuran (10 ml) and aqueous potassium carbonate (3 ml, 7.40 mmol) was added. The reaction system was stirred at 60°C overnight. The reaction system was then concentrated under reduced pressure. The residue was adjusted to pH 4 with acetic acid, diluted with ethyl acetate (50 ml), washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 134-6 (500 mg, 88% yield) as a white solid. MS [M+Na] ⁺ =408.8.

Step (4) Preparation of methyl-(S)-2-((2-(4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrrol-1-yl)-2,6- difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Methyl (S)-2-((7-methyl-2-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (271 mg, 0.65 mmol, intermediate 134-7, prepared according to the method for preparing intermediate 2-7, LC-MS: [M+H] ⁺ =420.2) was dissolved in dimethyl sulfoxide (5 ml), and potassium carbonate (269) was added mg, 1.95 mmol) and N,N-bis(4-methoxybenzyl)-1H-pyrrole-3-sulfonamide (251 mg, 0.65 mmol). The reaction system was reacted at 130°C for 6 hours under a nitrogen atmosphere. The reaction system was then added with water (30 ml) and extracted with ethyl acetate (30 ml x 2). The organic phases were combined, washed with brine (20 ml x 2), filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 134-8 (320 mg, 44% yield) as a brown solid. MS [M+H] ⁺ =786.2.

Step (5) Preparation of methyl-(S)2-((2-(2,6-difluoro-4-(3-sulfamoyl-1H-pyrrol-1-yl)phenyl)-7-methylimidazo[1,2-a ]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 134-8 (280 mg, 0.36 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (3 ml) was added. The reaction system was reacted at room temperature for 16 hours. The reaction system was then concentrated under reduced pressure. The crude product was dissolved in dichloromethane (40 ml), washed with aqueous sodium bicarbonate (10%, 10 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative chromatography to provide compound 134 (22.6 mg, 12% yield) as a white solid. MS [M+H] ⁺ =545.7.

1H NMR(400 MHz, CDCl3) δ 8.23 (d, J=7.0 Hz, 1H), 7.73-7.63 (m, 1H), 7.45 (s, 1H), 7.16 -7.13 (m, 1H), 7.11 (d, J=7.7 Hz, 2H), 6.80-6.69 (m, 2H), 4.96 (s, 2H), 4, 00-3.82 (m, 3H), 3.70 (s, 3H), 3.64-3.58 (m, 1H), 3.45-3.38 (m, 1H), 3.12- 2.99 (m, 2H), 2.98-2.88 (m, 1H), 2.69-2.59 (m, 1H), 2.46 (s, 3H).

Example 135:

The compound was prepared in accordance with the preparation method described in Example 126. LC-MS: [M+H] ⁺ =525.2.

Example 136:

The compound was obtained in accordance with the preparation method of compound 5. LC-MS: [M+H] ⁺ =551.2.

Example 137:

The compound was obtained in accordance with the preparation method of compound 5. LC-MS: [M+H] ⁺ =492.7.

Example 138:

Step (1) Preparation of methyl-(S)-2-((2-(4-(1-(tert-butoxycarbonyl)-5-cyanopyrrol-2-yl)-2,6-difluorophenyl)-7-methylimidazo[1 ,2-a]pyridin-3-yl)-methyl)morpholine-4-carboxylate

Intermediate 4-2 (290 mg, 0.51 mmol) was dissolved in anhydrous dichloromethane (5 ml) under nitrogen and chlorosulfonylisocyanate (58 mg, 0.41 mmol) was added dropwise slowly at -78°C. After the addition was completed dropwise for 2 min, the reaction system was reacted at -78°C for 1 h, N,N-dimethylformamide (0.44 ml) was added dropwise for 1 min, and reacted at room temperature for 1 h. The reaction system was then added with water (20 ml) and extracted with dichloromethane (50 ml x 3). The organic phases were combined, washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporation to give the crude product. The crude product was purified by silica gel column chromatography to give intermediate 138-2 (200 mg, 66% yield) as a yellow solid. LC-MS: [M+H] ⁺ =592.8.

Step (2) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(5-cyano-1H-pyrrol-2-yl)phenyl)-7-methylimidazo[1,2- a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 138-2 (200 mg, 0.41 mmol) was dissolved in absolute methanol (3 mL) and sodium hydroxide solution (3 M, 0.4 mL) was added. The reaction system was reacted at 60°C for 1 hour. After completion of the reaction, dilute hydrochloric acid (1 M) was added dropwise to the reaction system to adjust the pH to 6, water (10 ml) was added and extraction was carried out with dichloromethane (20 ml × 3 ). The organic phases were combined, washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporation to give the crude product. The crude product was purified by high performance liquid chromatography to provide compound 138 (41.2 mg, 25% yield) as a yellow solid. LC-MS: [M+H] ⁺ =492.7.

^1H NMR (400 MHz, MeOD) δ 8.85 (d, J=7.3 Hz, 1H), 7.72 (s, 1H), 7.64 (d, J=9.3 Hz, 2H) , 7.42-7.41 (m, 1H), 6.99 (d, J=4.0 Hz, 1H), 6.91 (d, J=4.0 Hz, 1H), 4.02- 3.99 (m, 1H), 3.85-3.75(m, 3H), 3.69-3.34 (m, 1H), 3.28-3.26 (m, 2H), 3, 00-2.88 (m, 1H), 2.81-2.71 (m, 1H), 2.65 (s, 3H).

Example 139:

Preparation of methyl-(S)-2-((2-(4-(5-cyanothiophen-2-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

Intermediate 2-7 (100 mg, 0.21 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 ml) and (5-cyanothiophen-2-yl)boronic acid (32 mg, 0.21 mmol), potassium phosphate (132 mg, 0.62 mmol), palladium acetate (9.4 mg, 0.042 mmol) and tetrabutylammonium bromide (20 mg, 0.062 mmol) were added under nitrogen atmosphere. The reaction system was reacted at 90°C for 12 hours. After completion of the reaction, the reaction system was cooled to room temperature, filtered, water (20 ml) was added to the filtrate, and extraction was carried out with ethyl acetate (20 ml × 3). The organic phases were combined, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by high performance liquid chromatography to provide compound 139 (3.8% yield) as a yellow solid.

LC-MS: [M+H] ⁺ =509.7. ^1H NMR (400 MHz, MeOD): δ 8.47 (d, J=6.8 Hz, 1H), 7.83 (d, J=4.0 Hz, 1H), 7.71 (d, J =4.0 Hz, 1H), 7.59 (d, J=8.3 Hz, 2H), 7.40 (s, 1H), 6.95 (d, J=7.0 Hz, 1H), 3.79-3.89 (m, 3H), 3.67 (s, 3H), 3.63-3.59 (m, 1H), 3.40-3.37 (m, 1H), 3. 14-3.13 (m, 2H), 2.93-2.88 (m, 1H), 2.70-2.61 (m, 1H), 2.49 (s, 3H).

Example 140:

Step (1) Preparation of (S)-1-(2-((2-(4-bromo-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholino) propan-1-one

Intermediate 2-5 (500 mg, 1.18 mmol) was dissolved in anhydrous dichloromethane (5 ml) and N,N'-diisopropylethylamine (304 mg, 2.36 mmol) was added dropwise, followed by dropwise addition of propionyl chloride (131 mg, 1.42 mmol) at a temperature maintained at 0°C. After completion of the dropwise addition, the reaction system was reacted at 0°C for 2 hours. After completion of the reaction, water (40 ml) was added to the reaction system and extraction was carried out with dichloromethane (30 ml × 3). The organic phases were combined, washed with brine (40 ml), dried over magnesium sulfate, filtered and concentrated by rotary evaporation to give the crude product. The crude product was purified by silica gel column chromatography to give intermediate 140-2 (450 mg, 79% yield) as a brown solid, LC-MS: [M+H]+=478.7.

Step (2) Preparation of (S)-5-(3,5-difluoro-4-(7-methyl-3-(((4-propionylmorpholin-2-yl)methyl)imidazo[1,2-a]pyridin- 2-yl)phenyl)thiophene-2-carbonitrile

Intermediate 140-2 (100 mg, 0.21 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 ml) and (5-cyanothiophen-2-yl)boronic acid (32 mg, 0.21 mmol), potassium phosphate (134 mg, 0.63 mmol), palladium acetate (9.6 mg, 0.043 mmol) and tetrabutylammonium bromide (22 mg, 0.068 mmol) were added under nitrogen atmosphere. The reaction system was reacted at 90°C for 12 hours. After completion of the reaction, the reaction system was cooled to room temperature, filtered, water (20 ml) was added to the filtrate, and extraction was carried out with ethyl acetate (20 ml × 3). The organic phases were combined, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by high performance liquid chromatography to provide compound 140 (14.7 mg, 13.9% yield) as a yellow solid.

LC-MS: [M+H] ⁺ =507.6. ^1H NMR (400 MHz, MeOD): δ 8.45 (brs, 1H), 7.83 (d, J=4.0 Hz, 1H), 7.70 (d, J=3.8 Hz, 1H ), 7.58 (t, 2H), 7.37 (brs, 1H), 6.95-6.87 (m, 1H), 4.32-4.23 (m, 1H), 3.84- 3.81 (m, 1H), 3.77-3.68 (m, 1H), 3.65-3.56 (m, 1H), 3.44-3.36 (m, 1H), 3. 16-3.15 (m, 2H), 2.96-2.85 (m, 1H), 2.76-2.63 (m, 1H), 2.48 (s, 3H), 2.40- 2.27 (m, 2H), 1.09-1.03 (m, 3H).

Example 141:

Step (1) Preparation of 2,6-difluoro-4-(1H-1,2,3-triazol-1-yl)benzaldehyde

2,4,6-trifluorobenzaldehyde (4.0 g, 24.98 mmol) was dissolved in acetonitrile (40 ml) and 1H-1,2,3-triazole (1.7 g, 24.98 mmol) and triethylamine ( 7.6 g, 74.95 mmol). The reaction system was stirred at 80°C overnight. After completion of the reaction, the reaction system was concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography to give intermediate 141-3 as a light yellow oil (530 mg, 10.2% yield). LC-MS: [M+H] ⁺ =209.9.

Step (2) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-(1H-1,2,3-triazol-1-yl)phenyl)-7-methylimidazo[ 1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 141-3 (520 mg, 2.49 mmol), intermediate 1-5 (268 mg, 2.49 mmol), intermediate 1-4 (525 mg, 2.49 mmol), copper(I) chloride (74 mg, 0.75 mmol) and copper trifluoromethanesulfonate (271 mg, 0.75 mmol) were dissolved in anhydrous toluene (5 ml) under nitrogen atmosphere. The reaction system was heated to 85°C, N,N'-dimethylacetamide (0.2 ml) was added and stirred at 85°C overnight. After completion of the reaction, the reaction system was filtered, water (20 ml) was added to the filtrate, and extraction was carried out with dichloromethane (15 ml × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give intermediate 141-4 (80 mg, 6.7% yield) as a colorless oil, LC-MS: [M+H] ⁺ =510.8.

Step (3) Preparation of (S)-2-((2-(2,6-difluoro-4-(1H-1,2,3-triazol-1-yl)phenyl)-7-methylimidazo[1,2- a]pyridin-3-yl)methyl)morpholine

Intermediate 141-4 (80 g, 0.16 mmol) was dissolved in anhydrous dichloromethane (1 ml) and a solution of HCl in ethanol (0.3 ml) was added. The reaction system was stirred at room temperature for 3 hours. After completion of the reaction, the reaction system was concentrated on a rotary evaporator to obtain intermediate 141-5 (128 mg, crude) as a white solid, LC-MS [M+H] ⁺ =410.8.

Step (4) Preparation of methyl-(S)-2-(2-(2,6-difluoro-4-(1H-1,2,3-triazol-1-yl)phenyl)-7-methylimidazo[1,2 -a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 141-5 (128 mg, 0.16 mmol, crude product) was dissolved in anhydrous dichloromethane (5 ml) and N,N'-diisopropylethylamine (200 mg, 1.56 mmol) was added dropwise under nitrogen, followed by dropwise addition a solution of methyl chloroformate in dichloromethane (10 mg/ml, 1.8 ml, 0.19 mmol) at a temperature maintained at 0°C. After the dropwise addition was completed, the reaction system was reacted at 0°C for 2 hours. After completion of the reaction, water (20 ml) was added to the reaction system and extraction was carried out with dichloromethane (10 ml × 3). The organic phases were combined, washed with brine (10 ml), dried over sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give the product. The product was separated preparatively by high performance liquid chromatography to give compound 141 (14 mg, 19.35% yield) as a white solid, LC-MS: [M+H]+=468.8.

1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=7.1 Hz, 1H), 8.08 (d, J=1.0 Hz, 1H), 7.93 (d, J=1 ,0 Hz, 1H), 7.55 (d, J=7.6 Hz, 2H), 7.47 (s, 1H), 6.75 (d, J=6.7 Hz, 1H), 4, 05-3.80 (hl, 3H), 3.70 (s, 3H), 3.65-3.57 (m, 1H), 3.46-3.36 (m, 1H), 3.10- 2.85 (m, 3H), 2.70-2.60 (m, 1H), 2.46 (s, 3H).

Example 142:

Step (1) Preparation of tert-butyl-(S)-2-((7-methyl-2-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine- 4-carboxylate

2,4,6-trifluorobenzaldehyde (3.0 g, 18.74 mmol), 4-methylpyridin-2-amine (2.0 g, 18.74 mmol), tert-butyl-(S)-2-ethynylmorpholine- 4-carboxylate (4 g, 18.74 mmol), copper(I) chloride (562 mg, 5.68 mmol) and copper(II) trifluoromethanesulfonate (2.1 g, 5.68 mmol) were dissolved in toluene solution (30 ml) in a nitrogen atmosphere. The reaction system was reacted at 85°C for 10 minutes, N,N-dimethylacetamide (0.5 ml) was added and reacted at 85°C for another 5 hours. The reaction system was then reacted at room temperature overnight. After completion of the reaction, the reaction system was filtered, water (50 ml) was added to the filtrate, and extraction was carried out with dichloromethane (100 ml × 3). The organic phases were combined, washed with brine (50 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography to give intermediate 142-2 (3.0 g, 34.8% yield) as a yellow oil, MS [M+H] ⁺ =461.8.

Step (2) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-(1H-1,2,4-triazol-1-yl)phenyl)-7-methylimidazo[ 1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 142-2 (300 mg, 0.65 mmol) was dissolved in anhydrous dimethyl sulfoxide (3 ml) and 1,2,4-triazole (40 mg, 0.58 mmol) and potassium carbonate (180 mg, 1.30) were added mmol) in a nitrogen atmosphere. The reaction system was reacted at 85°C for 1 hour. The reaction system was then cooled to room temperature, water (20 ml) was added, and extracted with ethyl acetate (20 ml x 3). The organic phases were combined, washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 142-3 (150 mg, 45.2% yield) as a yellow oil. MS [M+N] ⁺ =510.8.

Step (3) Preparation of (S)-2-((2-(2,6-difluoro-4-(1H-1,2,4-triazol-1-yl)phenyl)-7-methylimidazo[1,2- a]pyridin-3-yl)methyl)morpholine

Intermediate 142-3 (150 mg, 0.29 mmol) was dissolved in dichloromethane (2 ml) and a solution of HCl in ethanol (33%, 0.5 ml) was added dropwise while the temperature was maintained at 0°C. After the dropwise addition was completed, the reaction system was reacted at room temperature for 2 hours. The reaction system was then adjusted to pH 8 with saturated sodium bicarbonate solution, diluted with water (10 ml) and extracted with dichloromethane (20 ml x 3). The organic phases were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 142-4 (130 mg, crude) as a yellow solid, MS [M+H] ⁺ = 410.8.

Step (4) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(1H-1,2,4-triazol-1-yl)phenyl)-7-methylimidazo[1, 2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 142-4 (130 mg, 0.29 mmol) and N,N-diisopropylethylamine (123 mg, 0.95 mmol) were dissolved in dichloromethane (2 ml) and methyl chloroformate (36 mg, 0.38 mmol) was added dropwise. into a nitrogen atmosphere at a temperature maintained at 0°C. After the dropwise addition was completed, the reaction system was reacted at 0° C. for 1 hour. Then, the reaction system was added with water (20 ml) and extracted with dichloromethane (30 ml x 3). The organic phases were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by high performance liquid chromatography to provide compound 142 (30.4 mg, 20.5% yield) as a yellow solid. MS [M+N] ⁺ =468.7.

1H NMR (400 MHz, MeOD) δ 9.35 (s, 1H), 8.88 (d, J=7.1 Hz, 1H), 8.29 (s, 1H), 7.97 (d, J =8.7 Hz, 2H), 7.75 (s, 1H), 7.44 (dd, J=7.1, 1.4 Hz, 1H), 4.05-4.02 (m, 1H) , 3.85-3.74 (m, 3H), 3.69 (s, 3H), 3.39-3.35 (m, 1H), 3.31-3.22 (m, 2H), 2 .98-2.88 (m, 1H), 2.81-2.71 (m, 1H), 2.67 (s, 3H).

Example 143:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(4H-1,2,4-triazol-4-yl)phenyl)-7-methylimidazo[1,2-a] pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 3-1 (75 mg, 0.18 mmol) and diformyl hydrazide (486 mg, 0.54 mmol) were dissolved in anhydrous pyridine (10 ml). The reaction system was cooled to 0°C, triethylamine (128 mg, 1.26 mmol) and trimethylchlorosilane (294 mg, 2.7 mmol) were added dropwise successively under a nitrogen atmosphere, stirred under reflux for 24 hours. The reaction system was then concentrated under reduced pressure, add saturated saline (10 ml), adjust to pH 7-8 with saturated sodium bicarbonate solution and extract with DCM (10 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative thin layer chromatography to give compound 143 (30 mg, 36% yield) as a white solid. MS [M+H] ⁺ =469.2.

1H NMR (400 MHz, d6-DMSO) δ 9.31 (s, 2H), 8.44 (d, J=7.1 Hz, 1H), 7.85 (d, J=8.2 Hz, 2H ), 7.37 (s, 1H), 6.85 (d, J=7.1 Hz, 1H), 3.82-3.84 (m, 1H), 3.70-3.61 (m, 2H), 3.56 (s, 3H), 3.52-3.45 (m, 1H), 3.29-3.21 (m, 1H), 3.12-3.00 (m, 2H) , 2.90-2.71 (m, 1H), 2.59-2.45 (m, 1H), 2.39 (s, 3H).

Example 144:

Preparation of methyl-(S)-2-((2-(4-(4-(1-cyanochloropropyl)-1H-imidazol-2-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a ]pyridin-3-yl)methyl)morpholine-4-carboxylate

Compound 133 (150 mg, 0.27 mmol) and triethylamine (121 mg, 1.20 mmol) were dissolved in dichloromethane (3 ml). Under a nitrogen atmosphere, the reaction system was cooled to 0°C, trifluoroacetic anhydride (125 mg, 0.60 mmol) was added dropwise and stirred at room temperature overnight. Then, water (10 ml) was added to the reaction system to quench the reaction mixture, and extraction was carried out with dichloromethane (10 ml × 3). The organic phases were combined, washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative chromatography to provide compound 144 (23.7 mg, 16% yield) as a white solid. LC-MS [M+H] ⁺ : 533

1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.62 (s, 1H), 7.44 (d, J=8.2 Hz, 2H), 7.23 (s, 1H ), 6.91 (d, J=7.1 Hz, 1H), 4.00-3.75 (hl, 3H), 3.68 (s, 3H), 3.62-3.53 (m, 1H), 3.44-3.33 (m, 1H), 3.03-2.82 (m, 3H), 2.66-2.56 (m, 1H), 2.55 (s, 3H) , 1.68-1.58 (m, 4H).

Example 145:

Step (1) Preparation of methyl-(S)-2-(((2-(2,6-difluoro-4-(methoxycarbonyl)pyridin-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridine -3-yl)methyl)morpholine-4-carboxylate

Intermediate 17-2 (130 mg, 0.25 mmol) was dissolved in anhydrous 1,4-dioxane (5 ml) under nitrogen and methyl 6-bromocotinate (64 mg, 0.30 mmol), potassium carbonate (103 mg, 0.74 mmol) and tetrakis(triphenylphosphine) palladium (30 mg, 0.025 mmol) followed by the addition of water (0.5 ml). The reaction system was reacted at 90°C for 2 hours. The reaction system was then cooled to room temperature, water (20 ml) was added and extracted with dichloromethane (30 ml x 3). The organic phases were combined, washed with brine (30 mL x 2), dried over anhydrous magnesium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography to give intermediate 145-2 (70 mg, 53% yield) as a yellow solid. LC-MS [M+H] ⁺ =553.2.

Step (2) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-nicotinic acid)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)-methyl )morpholine-4-carboxylate

Intermediate 145-2 (70 mg, 0.13 mmol) was dissolved in tetrahydrofuran (1.5 mL) and lithium hydroxide solution (3 M, 0.13 mL) was added dropwise. The reaction system was reacted at room temperature for 1 hour. After completion of the reaction, dilute hydrochloric acid (1 M) was added dropwise to the reaction system to adjust the pH to 6, water (10 ml) was added and extraction was carried out with dichloromethane (20 ml × 3) . The organic phases were combined, washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporation to give the crude product. The crude product was purified by high performance liquid chromatography to provide compound 145 (30.1 mg, 44% yield) as a white solid. LC-MS: [M+H] ⁺ =523.6.

^1H NMR (400 MHz, MeOD) δ 9.30 (d, J=2.1 Hz, 1H), 8.88 (d, J=7.1 Hz, 1H), 8.53 (dd, J= 8.3, 2.1 Hz, 1H), 8.21 (d, J=8.3 Hz, 1H), 8.13 (d, J=9.3 Hz, 2H), 7.75 (s, 1H), 7.44 (dd, J=7.1, 1.5 Hz, 1H), 4.03-4.01 (m, 1H), 3.87-3.70 (m, 3H), 3 .69 (s, 3H), 3.40-3.36 (m, 1H), 3.31-2.23 (m, 2H), 2.98-2.89 (m, 1H), 2.82 -2.71 (m, 1H), 2.67 (s, 3H).

Example 146:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(formamido)pyridinyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine- 4-carboxylate

Intermediate 17-2 (120 mg, 0.23 mmol) was dissolved in 1,4-dioxane (3 ml) under nitrogen and 6-bromycotinamide (55 mg, 0.27 mmol), potassium carbonate (95 mg, 0 .69 mmol) and tetrakis(triphenylphosphine) palladium (27 mg, 0.023 mmol) followed by the addition of water (0.5 ml). The reaction system was reacted at 90°C for 2 hours. The reaction system was then cooled to room temperature, water (20 ml) was added and extracted with dichloromethane (30 ml x 3). The organic phases were combined, washed with brine (30 ml x 2), dried over anhydrous magnesium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by high performance liquid chromatography to provide compound 146 (16.9 mg, 14% yield) as a yellow solid.

LC-MS: [M+H] ⁺ =522.6. ^1H NMR (400 MHz, MeOD): δ 9.21 (d, J=2.1 Hz, 1H), 8.88 (d, J=7.2 Hz, 1H), 8.42 (dd, J =8.3, 2.3 Hz, 1H), 8.20 (d, J=8.3 Hz, 1H), 8.12 (d, J=9.4 Hz, 2H), 7.75 (s , 1H), 7.44 (dd, J=7.1, 1.4 Hz, 1H), 4.04-4.01 (m, 1H), 3.86-3.71 (m, 3H), 3.70 (s, 3H), 3.40-3.36 (m, 1H), 3.31-3.25 (m, 2H), 2.99-2.90 (m, 1H), 2, 83-2.73 (m, 1H), 2.67 (s, 3H).

Example 147:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-hydroxypyridinyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 17-2 (130 mg, 0.25 mmol) was dissolved in 1,4-dioxane (5 ml) under nitrogen and 2-bromo-5-hydroxypyridine (51 mg, 0.30 mmol), potassium carbonate ( 102 mg, 0.74 mmol) and tetrakis(triphenylphosphine) palladium (28 mg, 0.025 mmol) followed by the addition of water (0.5 ml). The reaction system was reacted at 90°C for 2 hours. After completion of the reaction, the reaction system was cooled to room temperature, water (20 ml) was added, and extraction was carried out with dichloromethane (30 ml x 3). The organic phases were combined, washed with brine (30 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by high performance liquid chromatography to provide compound 147 (62.7 mg, 51.4% yield) as a yellow solid.

LC-MS: [M+H] ⁺ =495.2. ¹ H NMR (400 MHz, DMSO): δ 10.49 (s, 1H), 8.91 (d, J=7.1 Hz, 1H), 8.30 (d, J=2.8 Hz, 1H ), 8.08 (d, J=8.7 Hz, 1H), 8.01 (d, J=9.7 Hz, 2H), 7.80 (s, 1H), 7.44 (dd, J =7.1, 1.2 Hz, 1H), 7.34 (dd, J=8.7, 2.9 Hz, 1H), 3.94 (d, J=12.8 Hz, 1H), 3 ,64-3.62 (m, 3H), 3.58 (s, 3H), 3.34-3.12 (m, 3H), 2.88-2.76 (m, 1H), 2.68 -2.62(m, 1H), 2.58(s, 3H).

Examples 148-170

The compounds of Examples 148, 151, 152, 154, 155, 156 and 157 were prepared using the corresponding starting materials in accordance with the method described in Example 2. The compounds of Examples 165-166 were prepared in accordance with the synthesis method as described in example 10; and the compound of Example 170 was prepared in accordance with the synthesis method described in Example 25.

Example 150:

Step (1) Preparation of tert-butyl-(S)-2-((2-(4-bromo-2,6-difluorophenyl)-7-(hydroxymethyl)imidazo[1,2-a]pyridin-3-yl) methyl)morpholine-4-carboxylate

To toluene (60 mL) was added sequentially Intermediate 150-1 (2 g, 16 mmol), Intermediate 1-4 (3.4 g, 16 mmol), Intermediate 2-2 (3.6 g, 16 mmol) , CuCl (0.5 g, 6 mmol) and Cu(CF ₃ SO ₃ ) ₂ (1.75 g, 6 mmol). The reaction system was purged with N ₂ four times and stirred at room temperature for 15 minutes. The reaction system was then heated to 85°C, DMA (1 ml) was added, heated and reacted for 5 hours, and cooled and stirred overnight (16.5 hours) after heating was stopped. After completion of the reaction as determined by LCMS, the reaction system was diluted with DCM (100 ml), water (80 ml) and 25% aqueous ammonia (15 ml) were added, stirred for 30 min and allowed to stand for DCM phase separation. The aqueous phase was subjected to extraction with DCM (100 ml × 2). The DCM phases were combined, washed with saturated aqueous ammonium chloride and brine successively, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give intermediate 150-2 (3.4 g) as a light yellow oil.

Stage (2)

Intermediate 150-2 (1.3 g, 2.42 mmol) was dissolved in DCM (30 ml). The reaction system was purged with N ₂ three times and cooled to -5°C below. DAST (0.40 mL, 3.03 mmol) was then diluted with DCM (5 mL) and added dropwise to the reaction system. The resulting reaction system was warmed to room temperature and reacted for 16 hours. Once the reaction was complete as detected by TLC, the reaction system was cooled to 5°C below, diluted with DCM, slowly poured into a saturated NaHCO ₃ solution at 5°C below, stirred and allowed to stand for DCM phase separation. The aqueous phase was subjected to extraction with DCM (30 ml × 2). The DCM phases were combined, washed with brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography to give intermediate 150-3 (0.32 g) as a yellow oil.

Step (3) Preparation of tert-butyl-(S)-2-((2-(4-acetamido-2,6-difluorophenyl)-7-(fluoromethyl)imidazo[1,2-a]pyridin-3-yl) methyl)morpholine-4-carboxylate

To dioxane (8 ml) was added sequentially intermediate 150-3 (0.32 g, 0.59 mmol), acetamide (0.05 g, 0.71 mmol), Cs ₂ CO ₃ (0.29 g, 0. 71 mmol) and xantphos (0.07 g, 0.12 mmol). The reaction system was purged with N ₂ three times, Pd ₂ (dba) ₃ (0.05 g, 0.06 mmol) was added, purged with N ₂ three times and reacted at 80°C for 19 hours. Once the reaction was complete as detected by TLC, the reaction system was diluted with DCM (15 ml) and water (30 ml), stirred and allowed to stand to separate the DCM phase. The aqueous phase was subjected to extraction with DCM (15 ml × 2). The DCM phases were combined, washed with brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give intermediate 150-4 (0.47 g, crude product) as a red oil, which was used directly in the next step .

Step (4) Preparation of (S)-N-(3,5-difluoro-4-(7-(fluoromethyl)-3-(morpholin-2-ylmethyl)imidazo[1,2-a]pyridin-2-yl) phenyl)acetamide

Intermediate 150-4 (0.47 g, crude product) was dissolved in EA (5 ml) and a solution of HCl in EA (15 ml) was added. The reaction system was reacted at room temperature for 5.5 hours. After completion of the reaction as detected by TLC, the reaction system was diluted with EA (10 ml) and water (10 ml), back-extracted with stirring to obtain an aqueous phase, and the EA phase was back-extracted with water (10 ml x 1). The aqueous phases were combined, DCM (15 ml) was added, the pH was adjusted to 9-10 with solid Na ₂ CO ₃ , stirred and allowed to separate the DCM phase. The aqueous phase was subjected to extraction with DCM (15 ml × 2). The DCM phases were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give intermediate 150-5 (0.2 g) as a red oil.

Step (5) Preparation of methyl-(S)-2-((2-(4-acetamido-2,6-difluorophenyl)-7-(fluoromethyl)imidazo[1,2-a]pyridin-3-yl)methyl) morpholine-4-carboxylate

Intermediate 150-5 (100 mg, 0.227 mmol) was dissolved in DCM (4 mL) and DIPEA (0.4 mL) was added. The reaction system was purged with N ₂ once and cooled to 5°C below. The reaction system was then added dropwise with methyl chloroformate (43 mg, 0.504 mmol), warmed to room temperature, and reacted for 1 hour. Once the reaction was complete as detected by TLC, the reaction system was diluted with DCM (15 ml) and water (20 ml), stirred and allowed to stand to separate the DCM phase. The aqueous phase was subjected to extraction with DCM (15 ml × 2). The DCM phases were combined, washed with brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was separated using prep. HPLC and lyophilized to give compound 150 (20.2 mg, 98.34% purity) as a white solid.

LC-MS: [M+H] ⁺ =477.25. ^1H NMR (400 MHz, CD3OD) δ 8.52 (d, J=7.1 Hz, 1H), 8.52 (d, J=7.1 Hz, 8H), 8.52 (d, J= 7.1 Hz, 1H), 7.54 (s, 7H), 7.46-7.37 (m, 13H), 6.99 (d, J=7.1 Hz, 8H), 5.54 ( s, 7H), 5.42 (s, 7H), 4.98-4.83 (m, 169H), 4.79 (d, J=15.2 Hz, 2H), 4.58 (s, 9H ), 3.80 (t, J=13.0 Hz, 25H), 3.66 (d, J=11.2 Hz, 19H), 3.58 (s, 8H), 3.33 (tt, J =6.6, 3.2 Hz, 27H), 3.21-3.04 (m, 15H), 2.89 (s, 10H), 2.63 (s, 15H), 2.17 (s, 18H).

Example 153:

Step (1) Preparation of tert-butyl-(S)-2-((2-(4-bromo-2,6-difluorophenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl) methyl)morpholine-4-carboxylate

Compound 153-1 (0.77 g, 4.74 mmol), intermediate 1-4 (1.0 g, 4.74 mmol), intermediate 2-2 (1.04 g, 4.74 mmol), CuCl (0.14 g, 1.42 mmol) and Cu(CF ₃ SO ₃ ) ₂ (0.51 g, 1.42 mmol) were successively dissolved in toluene (10 ml). The reaction system was purged with N ₂ four times and stirred at room temperature for 15 minutes. The reaction system was then heated to 85°C, DMA (0.3 ml) was added, heated and reacted for 6 hours, and cooled and stirred overnight (16 hours) after heating was stopped. After completion of the reaction as determined by LCMS, the reaction system was diluted with DCM (100 mL), water (100 mL) and 25% aqueous ammonia (10 mL) were added, stirred for 10 min, and allowed to stand to separate the DCM phase. The aqueous phase was subjected to extraction with DCM (50 ml × 3). The DCM phases were combined, washed with saturated aqueous ammonium chloride and brine successively, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (small amount of methanol) to give intermediate 153-2 (0.8 g, 86.37% purity) as a yellow foamy solid. LC-MS: [M+H] ⁺ =578.03.

Step (2) Preparation of (S)-2-(((2-(4-bromo-2,6-difluorophenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine

Intermediate 153-2 (0.8 mg, 1.4 mmol) was dissolved in EA (10 ml). The reaction system was cooled to below °C. The reaction system was then added with a solution of HCl in EA (3 M, 15 ml) and reacted at room temperature for 1 hour and 50 minutes. Once the reaction was complete as detected by LCMS, the reaction system was diluted with EA (10 mL) and back-extracted with water (20 mL x 2). The aqueous phases were combined, DCM (20 ml) was added, adjusted to pH 8-9 with solid Na ₂ CO ₃ , stirred and left to stand to separate the DCM phase. The aqueous phase was subjected to extraction with DCM (20 ml × 2). The DCM phases were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give intermediate 153-3 (0.65 g, 94.48% purity) as a yellow oil. LC-MS: [M+H] ⁺ =476.0.

Step (3) Preparation of methyl-(S)-2-((2-(4-bromo-2,6-difluorophenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methyl) morpholine-4-carboxylate

Intermediate 153-3 (650 mg, 1.4 mmol) was dissolved in DCM (10 mL) and DIPEA (0.21 mL) was added. The reaction system was purged with N ₂ once and cooled to 5°C below. Methyl chloroformate (150 mg, 1.6 mmol) was then added dropwise to the reaction system and reacted at room temperature for 2 hours. After completion of the reaction as determined by LCMS, the reaction system was diluted with DCM (10 mL) and water (30 mL ), stirred and left to separate the DCM phase. The aqueous phase was subjected to extraction with DCM (15 ml × 2). The DCM phases were combined, dried over anhydrous sodium sulfate and concentrated at 40°C to give intermediate 153-4 (650 mg, 93.67% purity, crude product) as a yellow foamy solid. LC-MS: [M+H] ⁺ =534.05.

Step (4) Preparation of methyl-(S)-2-((2-(4-acetamido-2,6-difluorophenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methyl) morpholine-4-carboxylate

Intermediate 153-4 (300 mg, 0.56 mmol), acetamide (70 mg, 0.84 mmol), CS ₂ CO ₃ (350 mg, 0.84 mmol), xanthos (40 mg, 0.056 mmol) and Pd ₂ (dba) ₃ (60 mg, 0.056 mmol) were successively dissolved in dioxane (10 ml). The reaction system was purged with N ₂ four times and reacted at 80°C for 20 hours. After completion of the reaction as determined by LCMS, the reaction system was diluted with DCM (15 ml) and water (30 ml), stirred and allowed to stand for phase separation DXM. The aqueous phase was subjected to extraction with DCM (15 ml × 2). The DCM phases were combined, washed with brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was separated using prep. HPLC (H ₂ O/CH ₃ CN) and lyophilized to give compound 153 (60 mg, 99.01% purity) as a white solid. LC-MS: [M+H] ⁺ =513.15.

¹ H NMR (400 MHz, d-DMSO) δ 10.45 (s, 1H), 8.74 (d, J=7.3 Hz, 1H), 8.08 (s, 1H), 7.45 ( d, J=9.9 Hz, 2H), 7.24 (dd, J=7.3, 1.8 Hz, 1H), 3.78 (d, J=12.9 Hz, 1 H), 3 .65 (t, J=10.7 Hz, 2H), 3.56 (s, 3H), 3.51 (s, 1H), 3.23 (td, J=11.8, 2.8 Hz, 1H), 3.10 (dd, J=15.4, 7.2 Hz, 2H), 2.81 (s, 1H), 2.54 (s, 1H), 2.11 (s, 3H).

Example 158:

Step (1) Preparation of (S)-1-(2-(((2-(4-bromo-2,6-difluorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholino )ethane-1-one

The compound was prepared according to the method for preparing intermediate 2-7. LC-MS: [M+H] ⁺ =484.0.

Step (2) Preparation of (S)-1-(2-((7-chloro-2-(2,6-difluoro-4-(1H-imidazol-1-yl)phenyl)imidazo[1,2-a] pyridin-3-yl)methyl)morpholino)ethan-1-one

Intermediate 158-1 (120 mg, 0.25 mmol) was dissolved in toluene (2 ml) and imidazole (25 mg, 0.37 mmol), potassium carbonate (103 mg, 0.75 mmol), copper iodide (I) was added ) (4.7 mg, 0.025 mmol) and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (3.5 mg, 0.025 mmol) under nitrogen. The reaction system was reacted at 110°C overnight. After completion of the reaction, the reaction system was cooled to room temperature, filtered, water (20 ml) was added to the filtrate, and extraction was carried out with dichloromethane (50 ml × 3). The organic phases were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by preparative chromatography to provide compound 158 (13.6 mg, 12% yield) as a white solid. MS [M+H] ⁺ =471.7.

^1H NMR (400 MHz, MeOD) δ 8.59 (t, 1H), 8.39 (s, 1H), 7.79 (s, 1H), 7.65-7.63 (m, 1H), 7.61-7.57 (m, 2H), 7.23 (s, 1H), 7.09-7.00 (m, 1H), 4.33-4.24 (m, 1H), 3, 92-3.54 (m, 3H), 3.47-3.36 (m, 1H), 3.23-3.12 (m, 2H), 3.01-2.63 (m, 1H), 2.53-2.45 (m, 1H), 2.06 (d, 3H).

Example 159:

Preparation of (S)-1-(2-((7-chloro-2-(2,6-difluoro-4-(oxazol-2-yl)phenyl)imidazo[1,2-a]pyridin-3-yl) methyl)morpholino)ethan-1-one

Intermediate 158-1 (4.2 g, 8.66 mmol) and tetrakis(triphenylphosphine)palladium (2.0 g, 1.73 mmol) were added to toluene (125 mL) sequentially. The reaction system was stirred under nitrogen atmosphere. The reaction system was then injected with 2-(tributylstannyl)oxazole (4.9 g, 13.00 mmol) via a syringe, heated to 80°C and reacted overnight. TLC showed that a small amount of intermediate 158-1 remained and was immediately worked up. The reaction system was cooled, saturated aqueous potassium fluoride (100 ml) was added and stirred for 30 minutes. The reaction mixture was then extracted with DCM (100 ml) followed by separation of the liquid. The aqueous phase was subjected to extraction with DCM (50 ml × 2). The organic phases were combined, washed with brine (200 ml), dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The crude product was purified by preparative chromatography to give compound 159 (0.49 g, 99% purity) as a white solid. LC-MS: [M+H] ⁺ =473.05.

^1H NMR (400 MHz, dmso) δ 8.66-8.55 (m, 18H), 8.64-8.56 (m, 17H), 8.34 (s, 16H), 8.34 (s , 14H), 7.77 (dd, J=7.6, 2.5 Hz, 45H), 7.77 (dd, J=7.6, 2.5 Hz, 47H), 7.50 (s, 15H), 7.50 (s, 14H), 7.08 (td, J=7.1, 1.9 Hz, 17H), 7.08 (td, J=7.1, 1.9 Hz, 17H ), 4.20 (d, J=12.8 Hz, 13H), 4.20 (d, J=12.8 Hz, 11H), 4.05 (d, J=12.0 Hz, 9H), 4.05 (d, J=12.0 Hz, 13H), 3.74 (d, J=12.8 Hz, 9H), 3.70 (dd, J=30.3, 12.1 Hz, 29H ), 3.67 (d, J=11.5 Hz, 17Н), 3.55 (d, J=13.5 Hz, 19Н), 3.45 (dd, J=7,2,3,2 Hz , 11H), 3.58-3.20 (m, 61H), 3.26 (dd, J=11.6,9.5 Hz, 11H), 3.26 (dd, J=11.6, 9 .5 Hz, 31 N), 3.26 (dd, J=11.6, 9.5 Hz, 29 N), 3.20-2.94 (m, 51 N), 3.23-3.09 (m , 38Н), 2.80 (dd, J=12.7, 10.7 Hz, 9Н), 2.80 (dd, J=12.7, 10.7 Hz, 10Н), 2.55 (d, J=3.1 Hz, 6H), 2.64-2.45 (m, 22H), 2.39-2.22 (m, 12H), 2.36-2.24 (m, 11H), 1 .92 (s, 47H), 1.92 (s, 48H).

Example 160:

Preparation of (S)-1-(2-((7-chloro-2-(2,6-difluoro-4-(1H-pyrazol-1-yl)phenyl)imidazo[1,2-a]pyridin-3- yl)methyl)morpholino)ethan-1-one

Intermediate 158-1 (170 mg, 0.35 mmol) was dissolved in toluene (2 ml) and parazole (36 mg, 0.53 mmol), potassium carbonate (145 mg, 1.05 mmol), copper(I) iodide was added ) (7 mg, 0.037 mmol) and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.035 mmol) under nitrogen. The reaction system was reacted at 110°C overnight. After completion of the reaction, the reaction system was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane. The filtrate was added with water (30 ml) and subjected to extraction with dichloromethane (50 ml x 3). The organic phases were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by preparative chromatography to provide compound 160 (5.8 mg, 3.5% yield) as a white solid. MS [M+H] ⁺ =471.7.

^1H NMR (400 MHz, MeOD) δ 8.93 (dd, J=7.4, 3.2 Hz, 1H), 8.47 (d, J=2.6 Hz, 1H), 8.02- 7.98 (m, 1H), 7.85-7.82 (m, 3H), 7.51 (dd, J=7.4, 2.0 Hz, 1H), 6.65-6.64 ( m, 1H), 4.43-4.40 (m, 0.5H), 4.29-4.26 (m, 0.5H), 3.92-3.89 (m, 1H), 3.86- 3.80 (m, 1H), 3.72-3.69 (m, 1H), 3.46-3.36 (m, 1H), 3.31-3.21 (m, 2H), 3, 08-3.02 (m, 1H), 2.75-2.70 (m, 0.5H), 2.58-2.52 (m, 0.5H), 2.08 (s, 3H).

Example 161:

Preparation of methyl (S)-2-((2-(4-amino-2,6-difluorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Compound 149 (0.3 g) was dissolved in EtOH (4 ml) and concentrated HCl (6 ml) was added. The reaction system was stirred at 100°C for 2 hours. The starting material was consumed and a new spot was obtained, detected by TLC. The reaction system was then concentrated. The crude product was separated by preparative reverse phase chromatography to give compound 161 (0.14 g) as a white solid, MS [M+H] ⁺ =437.2.

¹ H-NMR (1H NMR (400 MHz, DMSO) δ 8.44, 7.56, 6.88, 6.68, 6.68, 4.07, 4.05, 3.96, 3.93, 3.82, 3.78, 3.69, 3.51, 3.46, 2.73, 2.48.) (NB190027-03-02).

Example 162:

Step (1) Preparation of (S)-1-(2-((2-(4-bromo-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholino) ethane-1-one

Intermediate 2-5 (1.20 g, 2.84 mmol) and N,N-diisopropylethylamine (1.10 g, 8.51 mmol) were dissolved in dichloromethane (6 ml) and acetyl chloride (268 mg, 3 .41 mmol) in an ice water bath maintaining the temperature at 0°C. After the dropwise addition was completed, the reaction system was reacted at 0°C for 2 hours. After completion of the reaction, water (30 ml) was added to the reaction system and extraction was carried out with dichloromethane (50 ml × 3). The organic phases were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate 162-1 (700 mg, 53.8% yield) as a yellow oil. MS [M+H] ⁺ =464.9.

Step (2) Preparation of (S)-1-(2-((2-(2,6-difluoro-4-(1H-imidazol-1-yl)phenyl)-7-methylimidazo[1,2-a]pyridine -3-yl)methyl)morpholino)ethan-1-one

Intermediate 162-1 (150 mg, 0.32 mmol) was dissolved in toluene (2 ml) and imidazole (33 mg, 0.48 mmol), potassium carbonate (135 mg, 0.98 mmol), copper iodide (I) was added ) (6 mg, 0.032 mmol) and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclpohexanediamine (4.6 mg, 0.032 mmol) under nitrogen. The reaction system was reacted at 110°C overnight. After completion of the reaction, the reaction system was cooled to room temperature, filtered, water (20 ml) was added to the filtrate, and extraction was carried out with dichloromethane (30 ml × 3). The organic phases were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by preparative chromatography to provide compound 162 (21.3 mg, 14.6% yield) as a white solid. MS [M+N] ⁺ =451.8.

^1H NMR (400 MHz, MeOD) δ 8.48 (t, 1H), 8.42 (s, 1H), 7.80 (s, 1H), 7.59 (t, 2H), 7.39 ( s, 1H), 6.97-6.91 (m, 1H), 4.33-4.23 (m, 1H), 3.84-3.81 (m, 1H), 3.79-3, 68 (m, 1H), 3.67-3.56 (m, 1H), 3.45-3.34 (m, 1H), 3.22-3.21 (m, 0.5H), 3.17 -3.15 (m, 2H), 2.98-2.92 (m, 0.5H), 2.73-2.67 (m, 0.5H), 2.49 (s, 3H), 2.47 -2.44 (m, 0.5H), 2.05 (d, 3H).

Example 163:

Preparation of (S)-1-(2-(2-(2,6-difluoro-4-(oxazol-2-yl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl) morpholino) ethan-1-one

Intermediate 162-1 (150 mg, 0.32 mmol) was dissolved in 1,4-dioxane (2 ml) and 2-(tributylstannyl)oxazole (174 mg, 0.48 mmol) and tetrakis(triphenylphosphine) palladium (37) were added mg, 0.032 mmol) in a nitrogen atmosphere. The reaction system was reacted at 85°C overnight. After completion of the reaction, the reaction system was cooled to room temperature, filtered, water (30 ml) was added to the filtrate, and extraction was carried out with dichloromethane (50 ml × 3). The organic phases were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by preparative chromatography to provide compound 163 (78.8 mg, 54% yield) as a white solid. MS [M+H] ⁺ =452.8.

^1H NMR (400 MHz, MeOD) δ 8.47 (t, 1H), 8.11 (s, 1H), 7.85-7.75 (m, 2H), 7.42 (s, 1H), 7.39 (s, 1H), 6.93 (d, J=6.1 Hz, 1H), 4.32-4.22 (m, 1H), 3.84-3.76 (m, 1H) , 3.69-3.65 (m, 1H),3.61-3.54(m, 1H), 3.45-3.35 (m, 1H), 3.17-3.16 (m, 2H), 2.99-2.88 (m, 1H), 2.74-2.63 (m, 1H), 2.49 (s, 3H), 2.04 (d, 3H).

Example 164:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(3-propionyl-1H-pyrazol-1-yl)phenyl)-7-methylimidazo[1,2-a]pyridin- 3-yl)methyl)morpholine-4-carboxylate

Intermediate 134-7 (50 mg, 0.12 mmol), 1-(1H-pyrazol-3-yl)propan-1-one (30 mg, 0.12 mmol) and potassium carbonate (30 mg, 0.36 mmol) was added to dimethyl sulfoxide (5 ml). The reaction system was stirred at 130°C for 4 hours under a nitrogen atmosphere. The reaction system was cooled to room temperature and filtered, and the filtrate was dispersed in ethyl acetate (15 ml), washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative chromatography to provide compound 164 (5 mg, 7.5% yield) as a yellow solid.

MS [M+H] ⁺ =523.8. 1H NMR (400 MHz, d4-MeOD) δ 8.51 (d, J=2.7 Hz, 1H), 8.43 (d, J=6.9 Hz, 1H), 7.80 (d, J =8.5 Hz, 2H), 7.37 (s, 1H), 7.03 (d, J=2.6 Hz, 1H), 6.89 (dd, J=7.0, 1.5 Hz , 1H), 3.89-3.78 (m, 3H), 3.66 (s, 3H), 3.68-3.58 (m, 1H), 3.42-3.37 (m, 1H ), 3.21-3.12 (m, 4H), 2.94-2.85 (m, 1H), 2.66-2.62 (m, 1H), 2.48 (s, 3H), 1.25 (t, J=7.3 Hz, 3H).

Example 167:

Preparation of (S)-N-(4-(3-((4-acetylmorpholin-2-yl)methyl)-7-methylimidazo[1,2-a]pyridin-2-yl)-3,5-difluorophenyl)acetamide

Intermediate 162-1 (240 mg, 0.518 mmol) and acetamide (45.9 mg, 0.778 mmol), cesium carbonate (150 mg, 0.778 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6 .00 mg, 0.010 mmol) was added to the reaction flask and 1,4-dioxane. The reaction system was purged with N ₂ , tris(dibenzylideneacetone) dipalladium (9.50 mg, 0.010 mmol) was added, purged with N ₂ again and heated to 80°C and reacted for 4 hours. After completion of the reaction, as monitored by LCMS, Water was added to the reaction system and extraction was carried out with dichloromethane (30 ml × 2). The complex phase was dried over anhydrous sodium sulfate and concentrated to remove dichloromethane. The residue was purified by preparative high performance liquid chromatography to provide compound 167 (102 mg, 52.4% yield) as a white solid. LC-MS [M+H] ⁺ =443.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.40 (s, 1H), 8.42-8.35 (m, 1H), 7.41 (dd, J=9.8, 1.7 Hz, 2H), 7.32 (s, 1H), 6.80 (dd, J=9.6, 4.1 Hz, 1H), 4.07 (dd, J=23.0, 13.0 Hz , 1H), 3.73-3.56 (m, 2H), 3.51-3.36 (m, 1H), 3.32-3.22 (m, 1H), 3.15 (td, J =11.7,2.6 Hz, 1H), 3.01 (dd, J=5.8, 2.7 Hz, 2H), 2.77(dd, J=12.9, 10.5 Hz, 1H), 2.59-2.52 (m, 1H), 2.37 (s, 3H), 2.26 (dd, J=12.6, 11.1 Hz, 1H), 2.10 (s , 3H), 1.91 (d, J=12.7 Hz, 3H).

Example 168:

Step (1) Preparation of 6-bromo-4-methylnicotinaldehyde

2,5-dibromo-4-methylpyridine (5.0 g, 17.19 mmol) was dissolved in tetrahydrofuran (60 ml) under nitrogen atmosphere. The reaction system was cooled to -78°C, n-butyllithium (7.5 ml, 2.4 N) was added and stirred at this temperature for 30 minutes. The reaction system was then added with N,N-dimethylformamide (2.5 g, 34.38 mmol) and reacted at -78°C for 3 hours. The resulting reaction system was added with dilute hydrochloric acid (1 N, 20 ml) to quench reaction, diluted with ethyl acetate (100 ml), washed with saturated sodium bicarbonate (80 ml) and saturated brine (80 ml) successively, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to give intermediate 168-2 (2.3 g, 54% yield) as a white solid. LC-MS [M+H] ⁺ : 199.8.

Step (2) Preparation of tert-butyl-(S)-2-((2-(6-bromo-4-methylpyridin-3-yl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

Intermediate 168-2 (320 mg, 1.50 mmol), tert-butyl-(2S)-2-ethynylmorpholin-4-ylcarboxylate (317 mg, 1.50 mmol), 4-methylpyridin-2-amine (162 mg , 1.50 mmol), copper(I) chloride (45 mg, 0.45 mmol) and copper(II) trifluoromethanesulfonate (163 mg, 0.45 mmol) were added to anhydrous toluene (6 ml) under nitrogen atmosphere. The reaction system was heated to 85°C, N,N-dimethylacetamide (0.1 ml) was added dropwise and stirred at 85°C overnight. After completion of the reaction, the reaction system was cooled to room temperature, filtered and concentrated on a rotary evaporator. The crude product was purified by silica gel column chromatography to give intermediate 168-3 (324 mg, 41% yield) as a brown powdery solid. MS [M+N] ⁺ =500.7.

Step (3) Preparation of tert-butyl-(S)-2-((7-methyl-2-(4-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)imidazo[1,2 -a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 168-3 (320 mg, 0.64 mmol), 1H-pyrazole (130 mg, 1.92 mmol), copper(I) iodide (12 mg, 0.06 mmol), (1R,2R)-N ₁ ,N ₂ -dimethylcyclohexane-1,2-diamine (18 mg, 0.13 mmol) and potassium phosphate (408 mg, 1.92 mmol) were added to dioxane (5 ml) under nitrogen atmosphere. The reaction system was reacted at 100°C for 6 hours. The reaction system was then cooled to room temperature, water (15 mL) was added to quench the reaction, filtered, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography to give intermediate 168-4 (170 mg, 55% yield) as a brownish-yellow oil. MS [M+H] ⁺ =488.9.

Step (4) Preparation of (S)-2-((7-methyl-2-(4-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)imidazo[1,2-a]pyridine -3-yl)methyl)morpholine

Intermediate 168-4 (170 g, 0.35 mmol) was dissolved in dichloromethane (5 ml) and a solution of HCl in ethanol (33%, 1.0 ml) was added. The reaction system was stirred at room temperature for 3 hours. After completion of the reaction, the reaction system was concentrated on a rotary evaporator to obtain intermediate 168-5 (145 mg) as a brown solid, MS [M+H] ⁺ =388.9.

Step (5) Preparation of methyl-(S)-2-((7-methyl-2-(4-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)imidazo[1,2-a ]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 168-5 (135 mg, 0.35 mmol) was dissolved in anhydrous dichloromethane (5 ml) under nitrogen and diisopropylethylamine (225 mg, 1.75 mmol) was added at 0°C, followed by dropwise addition of a solution of methyl chloroformate in dichloromethane (10 mg/ml, 3.5 ml). The reaction system was stirred at 0°C for 2 hours. After completion of the reaction, water (20 ml) was added to the reaction system and extraction was carried out with dichloromethane (20 ml × 3). The organic phases were combined, washed with brine (20 ml), dried over sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 2:1) to give the product. The product was purified by preparative high performance liquid chromatography to provide compound 168 (45 mg, 21% yield) as a white solid.

MS [M+H] ⁺ =446.8. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.60 (d, J=2.2 Hz, 1H), 8.33 (s, 1H), 8.09 (d, J=7.1 Hz, 1H ), 7.96 (s, 1H), 7.77 (s, 1H), 7.39 (s, 1H), 6.71 (d, J=7.1 Hz, 1H), 6.51-6 .47 (m, 1H), 4.00-3.75 (m, 3H), 3.67 (s, 3H), 3.62-3.52 (m, 1H), 3.45-3.34 (m, 1H), 3.08-2.98 (m, 2H), 2.96-2.86 (m, 1H), 2.63-2.52 (m, 1H), 2.44 (s , 3H), 2.41 (s, 3H).

Example 169:

Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(2-carbonyl-2,5-dihydro-1H-pyrrol-1-yl)phenyl)-7-methylimidazo[1, 2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 3-1 (100 mg, 0.24 mmol) was dissolved in acetic acid (1 ml) under nitrogen and 2,5-dimethoxy-2,5-dihydrofuran (35 mg, 0.26 mmol) and sodium acetate were added (50 mg, 0.48 mmol). The reaction system was reacted at 90°C for 2 hours. After completion of the reaction, the reaction system was cooled to room temperature, filtered and concentrated on a rotary evaporator. The crude product was separated by preparative high performance liquid chromatography to provide compound 169 (20.2 mg, 17.4% yield) as a white solid. MS [M+H] ⁺ =482.8.

¹ H NMR (400 MHz, MeOD) δ 8.42 (d, J=7.0 Hz, 1H), 7.70 (d, J=10.1 Hz, 2H), 7.50 (dt, J= 6.1, 1.9 Hz, 1H), 7.35 (s, 1H), 6.89 (dd, J=7.1, 1.4 Hz, 1H), 6.29 (dt, J=4 ,3, 1.9 Hz, 1H), 4.66 (t, J=1.8 Hz, 2H), 3.82-3.79 (m, 3H), 3.67 (s, 3H), 3 .63-3.57 (m, 1H), 3.41-3.38 (m, 1H), 3.15-3.08 (m, 2H), 2.95-2.86 (m, 1H) , 2.70-2.59 (m, 1H), 2.47 (s, 3H).

Example 171:

Step (1) Preparation of 4-bromo-3,5-difluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide

Bis(4-methoxybenzyl)amine (36.0 g, 140 mmol, compound 171-2) and Et ₃ N (21.2 g, 210 mmol) were sequentially dissolved in dichloromethane (1000 ml). The reaction system was stirred in an ice bath and 4-bromo-3,5-difluorobenzenesulfonyl chloride (40.5 g, 139 mmol, compound 171-1) was added in portions (exothermic reaction) while maintaining the internal temperature less than 10°C. After addition of compound 171-1, the ice bath was removed and the reaction system was allowed to react at room temperature for 1.0 h. After compound 171-1 was consumed as detected by TLC (PE/EA = 10/1), the DCM phase was washed with aqueous citric acid (400 ml x 2, 10% wt) and brine (400 ml) successively, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give intermediate 171-3 (68.3 g , 96% yield) as a white solid. LC-MS: [M+H] ⁺ =511.1.

Step (2) Preparation of 3,5-difluoro-4-formyl-N,N-bis(4-methoxybenzyl)benzenesulfonamide

Intermediate 171-3 (68.3 g, 133.3 mmol) was dissolved in THF (800 ml). The reaction system was heated to 40°C to dissolve the undissolved solid, purged with N ₂ three times and cooled to -70°C below. n-Butyllithium (2.5 M, 64 mL, 1.2 eq.) was then added dropwise to the reaction system slowly while maintaining the internal temperature below -70°C. After the dropwise addition of n-butyllithium was completed, the reaction mixture was reacted for 45 min, DMF (12.7 g, 1.3 eq.) was added and reacted for another 2.0 h. Hydrochloric acid ( 0.5 M) to quench the reaction and adjusted the pH to 4, followed by separation of the liquid. The organic phase was concentrated on a rotary evaporator. The aqueous phase was subjected to extraction with DCM (300 ml x 2). The residue from the rotary evaporation of THF was dissolved in the combined DCM phases, which were then washed with brine, dried and concentrated by rotary to give the crude product (74 mg). The crude product was purified by column chromatography to provide intermediate 171-4 (55 g, 90% yield, pure product) as a white solid. LC-MS: [M+H] ⁺ =461.2.

Step (3) Preparation of tert-butyl-(S)-2-((2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2,6-difluorophenyl)-7-methylimidazo[1,2 -a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 171-4 (18.2 g, 39.4 mmol, 1.0 eq), 4-methylpyridin-2-amine (4.26 g, 39.4 mmol, 1 .0 eq., compound 1-5), tert-butyl-(S)-2-ethynylmorpholine-4-carboxylate (8.33 g, 39.4 mmol, 1.0 eq., compound 1-4), CuCl (1.17 g, 11.8 mmol, 0.3 eq.), Cu(OTf) ₂ (4.34 g, 11.8 mmol, 0.3 eq.), toluene (200 ml) and DMA (12 ml). The reaction system was purged with nitrogen 3 times and heated in an oil bath at 85°C overnight (12 h). The starting material (compound 1-5) was consumed, and intermediate 171-4 remained as detected by TLC. The reaction system was then cooled to room temperature, aqueous ammonia (100 ml) and water (150 ml) were added and stirred for 5 minutes, followed by separation of the liquid to obtain a toluene phase. The aqueous phase was subjected to extraction with DCM (150 ml x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The residue was purified by column chromatography to give intermediate 171-5 (11.2 g, 96% purity, 37% yield) as a yellow solid. LC-MS:[M+H] ⁺ =761.9.

Step (4) Preparation of (S)-3,5-difluoro-N,N-bis(4-methoxybenzyl)-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-a] pyridin-2-yl)benzenesulfonamide

Intermediate 171-5 (11.2 g, 14.7 mol) was dissolved in DCM (33 ml) and a solution of HCl in dioxane (4 M, 33 ml) was added. The reaction system was stirred at room temperature for 1.0 hour. After completion of the reaction as determined by TLC, water (100 ml) and dichloromethane (200 ml) were added to the reaction system. The aqueous phase was adjusted to pH 9-10 (slight alkalinity) with sodium carbonate, followed by liquid separation to obtain the DCM phase. The aqueous phase was subjected to extraction with DCM (100 ml × 2). The DCM phases were combined, washed with brine, dried and concentrated by rotary evaporation to give intermediate 171-6 (9.7 g) as a white solid, which was used directly in the next step. LC-MS: [M+H] ⁺ =622.2.

Step (5) Preparation of methyl-(S)-2-((2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a ]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 171-6 (9.7 g, 14.7 mmol, 1.0 eq) was dissolved in DCM (40 ml) and Et ₃ N (2.96 g, 29.3 mmol, 2.0 eq) was added with followed by dropwise addition of methyl chloroformate (2.08 g, 22 mmol, 1.5 eq). The reaction system was reacted for 1.0 h. After completion of the reaction as detected by TLC, water (150 mL) and DCM (200 mL) were added to the reaction system and stirred for 10 min, followed by separation of the liquid to obtain the DCM phase. The aqueous phase was subjected to extraction with DCM (50 ml × 2). The DCM phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to give intermediate 171-7 (9.4 g, 89% yield) as a white solid. LC-MS: [M+H] ⁺ =720.9.

Step (6) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-sulfamoylphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

Intermediate 171-7 (9.4 g) was dissolved in DCM (30 ml) and TFA (30 ml) was added. The reaction system was stirred at 35°C overnight. The product was obtained (80% yield), as shown by LCMS. The reaction system was then supplemented with TFA (10 ml) and reacted at 40°C for 4.0 hours. The resulting reaction system was concentrated on a rotary evaporator. The crude product was dissolved with acetonitrile and separated by preparative chromatography to give compound 171 (3.165 g, 50.6% yield) as a white solid. LC-MS: [M+H] ⁺ =481.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (d, J=7.11 Hz, 1H), 7.69 (s, 2H), 7.59 (d, J=6.6, 2H), 7.33 (s,1H), 6.84-6.78 (m, 1H), 3.76 (d, J=12.5 Hz, 1H), 3.60 (d, J=11 .6 Hz, 2H), 3.53 (s, 3H), 3.44 (d, J=3.6 Hz, 1H), 3.31 (s, 1H), 3.24-3.14 (m , 1H), 3.02 (qd, J=15.7.6.1 Hz, 2H), 2.77 (s, 1H), 2.34 (s, 3H).

Example 172:

Step (1) Preparation of tert-butyl-(S)-2-((2-(4-bromo-2,6-difluorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine -4-carboxylate

To a 100 mL round bottom flask, tert-butyl (S)-2-ethynylmorpholine-4-carboxylate (3.1 g, 1.0 eq., intermediate 1-4), 4-bromo-2,6- difluorobenzaldehyde (2.76 g, 1.0 eq., compound 172-1), 4-chloropyridin-2-amine (1.61 g, 1.0 eq., compound 172-2), CuCl (0.37 g , 0.3 eq.), Cu(OTf) ₂ (1.36 g, 0.3 eq.) and isopropanol (50 ml). The reaction system was purged with nitrogen 3 times and reacted in an oil bath at 80°C overnight. The starting material (compound 172-2) was consumed by TLC. The reaction system was concentrated on a rotary evaporator to remove isopropanol and extracted sequentially with EA and aqueous ammonia. The EA phase was washed successively with brine and citric acid, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to give intermediate 172-3 (3.0 g, 78% purity) as a white solid. LC-MS: [M+H] ⁺ =542.2.

Step (4) Preparation of (S)-2-((2-(4-bromo-2,6-difluorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine

Intermediate 172-3 (2.67 g) was dissolved in dichloromethane (24 ml) and a solution of HCl in dioxane (24 ml) was added. The reaction system was stirred at room temperature for 1.0 hour. Once the reaction was complete as determined by TLC, the reaction system was concentrated on a rotary evaporator, water (15 mL) and dichloromethane (15 mL) were added and extracted to obtain an aqueous phase. The aqueous phase was brought to pH 8-9 (slight alkalinity) with an aqueous solution of sodium carbonate, followed by liquid separation to obtain a dichloromethane phase. The aqueous phase was subjected to extraction with dichloromethane (10 ml × 2). The dichloromethane phases were combined, washed with brine and concentrated on a rotary evaporator to give intermediate 172-4 (1.70 g, 88.6% purity) as a white solid. LC-MS: [M+H] ⁺ =442.1.

Step (5) Preparation of methyl-(S)-2-((2-(4-bromo-2,6-difluorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

Intermediate 172-4 (1.4 g, 1.0 eq) was dissolved in dichloromethane (10 ml) and triethylamine (480 mg, 1.5 eq) was added followed by dropwise addition of methyl chloroformate (388 mg, 1.3 eq) . The reaction system was reacted for 1.0 h and the product was obtained as detected by LC-MS. After completion of the reaction, water (10 ml) was added to the reaction system and stirred for 30 minutes, followed by separation of the liquid to obtain a dichloromethane phase. The aqueous phase was subjected to extraction with dichloromethane (10 ml × 2). The dichloromethane phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to provide intermediate 172-5 (1.01 g, 93.02% purity) as a white solid. LC-MS: [M+H] ⁺ =499.8.

Step (6) Preparation of methyl-(S)-2-((2-(4-(benzylthio)-2,6-difluorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine -4-carboxylate

Intermediate 172-5 (0.73 g, 1.0 eq) was dissolved in dioxane (4 ml) and BnSH (0.24 g, 1.3 eq), Pd ₂ (dba) ₃ (0.04 g, 0.03 eq), xanthos (0.04 g, 0.05 eq) and DIEA (0.60 g, 3.0 eq). The reaction system was purged with N2 three times and reacted at 80°C overnight. The starting material was completely consumed, as shown by control using the LCMS method. Dichloromethane (10 ml) and water (10 ml) were added to the reaction system, followed by liquid separation to obtain a dichloromethane phase. The aqueous phase was subjected to extraction with dichloromethane (10 ml × 2). The dichloromethane phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to provide intermediate 172-6 (0.82 g, 91.53% purity) as a white solid. LC-MS: [M+H] ⁺ =544.2.

Step (7) Preparation of methyl-(S)-2-((7-chloro-2-(4-(chlorosulfonyl)-2,6-difluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl) morpholine-4-carboxylate

Intermediate 172-6 (510 mg) was added to the reaction flask and dissolved with acetonitrile (3 mL) followed by the addition of glacial acetic acid (281 mg, 5.0 eq.). SO ₂ Cl ₂ (506 mg, 4.0 eq.) was added dropwise to the reaction system in an ice bath and reacted at 0°C for 1 hour. The starting material was consumed and intermediate 172-7 was prepared as was detected using LCMS. The reaction system was used directly in the next step without treatment.

Step (8) Preparation of methyl-(S)-2-((7-chloro-2-(2,6-difluoro-4-sulfamoylphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine- 4-carboxylate

Aqueous ammonia (2 ml) was diluted with acetonitrile (1 ml) and added dropwise to the above reaction system at 0°C. The reaction system was reacted at room temperature for 0.5 h. The starting material was completely consumed, and the target product was obtained, as detected by LCMS. The reaction system was extracted twice with water and ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative chromatography to give compound 172 (185 mg, 99.74% purity) as a white solid. LC-MS: [M+H] ⁺ =501.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.11 (d, J=7.4, 1 H), 7.29 (d, J=1.6, 1H), 7.22 (s , 2H), 7.14 (d, J=6.6, 2H), 6.60 (dd, J=7.4, 2.1, 1H), 3.33 (d, J=12.8, 1H), 3.13 (d, J=11.3, 2H), 3.07 (s,3H), 2.97 (d, J=7.8, 1H), 2.77-2.69 ( m, 1H), 2.69-2.61 (m, 1H), 2.53 (dd, J=15.5, 8.3, 1H).

Example 173:

Step (1) Preparation of (S)-3,5-difluoro-N,N-bis(4-methoxybenzyl)-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-a] pyridin-2-yl)benzenesulfonamide

Intermediate 171-6 was prepared according to the steps in Example 1. Intermediate 171-6 (620 mg, 0.94 mmol, 1.0 eq) was dissolved in DCM (5 ml) and Et ₃ N (236 mg, 2 .34 mmol, 2.5 equiv) followed by dropwise addition of acetic anhydride (191 mg, 1.88 mmol, 2 equiv). The reaction system was reacted for 1.0 h. After completion of the reaction as determined by TLC, water (30 mL) and DCM (50 mL) were added to the reaction system and stirred for 10 min, followed by separation of the liquid to obtain the DCM phase. The aqueous phase was subjected to extraction with DCM (20 ml × 2). The DCM phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to give intermediate 173-1 (450 mg, 68.3% yield) as a white solid. LC-MS: [M+H] ⁺ =705.2.

Step (2) Preparation of (S)-4-(3-((4-acetylmorpholin-2-yl)methyl)-7-methylimidazo[1,2-a]pyridin-2-yl)-3,5-difluorobenzenesulfonamide

Intermediate 173-1 (420 mg) was dissolved in DCM (2 ml) and TFA (2 ml) was added. The reaction system was stirred at room temperature overnight. The reaction system was then heated to 35° C., reacted for 4.0 hours, and processed. Water (20 ml) and DCM (20 ml) were added to the reaction system. The aqueous phase was adjusted to pH 9 with sodium carbonate solution, followed by liquid separation to obtain the DCM phase. The aqueous phase was subjected to extraction with DCM (20 ml × 2). The DCM phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The residue was purified by column chromatography to give the product, which was then suspended with DCM/PE (1:10) to give compound 173 (104 mg, 37.5% yield) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.23 (1H, dd, J 36.9, 6.8), 7.60 (1H, s), 7.53 (2H, t, J 6.0 ), 6.80 (2H, t, J 12.6), 6.57 (1H, s), 4.37 (1H, t, J 11.4), 3.91-3.72 (1H, m ), 3.51 (2H, d, J 12.1), 3.35 (1H, dd, J 21.8, 11.9), 3.16 (0.5 H, t, J 11.6) , 3.09-2.78 (2H, m), 2.66 (0.5H, t, J 11.1), 2.47 (3H, d, J 3.8), 2.44-2, 32 (0.5H, m), 2.04 (2H, s), 1.98 (1H, s), 1.82 (2H, s).

Example 174:

Step (1) Preparation of tert-butyl-(S)-2-((2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2,6-difluorophenyl)-7-chloroimidazo[1,2 -a]pyridin-3-yl)methyl)morpholine-4-carboxylate

3,5-difluoro-4-formyl-N,N-bis(4-methoxybenzyl)benzenesulfonamide (29 g, 62.84 mmol), 4-chloropyridin-2-amine (8.08 g, 62.84 mmol) and tert-butyl-(S)-2-ethynylmorpholine-4-carboxylate (13.28 g, 62.84 mmol) was dissolved in toluene (150 ml) and dimethylacetamide (150 ml). The reaction system was stirred well and to which copper(I) chloride (1.87 g, 18.85 mmol) and copper(II) trifluoromethanesulfonate (6.82 g, 18.85 mmol) were added and reacted at 85°C for 16 hours in a nitrogen atmosphere. The reaction system was then added to water (750 ml) and extracted with ethyl acetate (150 ml x 2). The organic phase was washed successively with aqueous ammonia (100 ml x 1) and brine (100 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1-3:1) to give intermediate 174-1 (18 g, 85% purity, 39% yield) as a brownish-yellow foamy solid . LC-MS: [M+H] ⁺ =783.0.

Step (2) Preparation of (S)-4-(7-chloro-3-(morpholin-2-ylmethyl)imidazo[1,2-a]pyridin-2-yl)-3,5-difluoro-N,N- bis(4-methoxybenzyl)benzenesulfonamide

Intermediate 174-1 (17 g, 21.7 mmol) was dissolved in dichloromethane (60 ml) and a solution of HCI in ethyl acetate (60 ml, 3 M) was added dropwise while maintaining the temperature at 0°C. After the dropwise addition was completed, the reaction system was reacted at room temperature for 2 hours. The starting material was completely consumed according to TLC (PE/EA = 3/1, Rf = 0.1). The reaction system was concentrated under reduced pressure. The crude product was adjusted to pH 8 with aqueous sodium bicarbonate, extracted with ethyl acetate (150 ml x 2), dried over anhydrous sodium sulfate with stirring for 20 min, filtered and concentrated to give intermediate 174-2 (13 g, 90% purity, 87% yield) as a brown foamy solid, LC-MS (M+H) ⁺ =683.0.

Step (3) Preparation of (S)-4-(3-(((4-acetylmorpholin-2-yl)methyl)-7-chloroimidazo[1,2-a]pyridin-2-yl)-3,5-difluoro -N,N-bis(4-methoxybenzyl)benzenesulfonamide

Intermediate 174-2 (1.5 g, 2.2 mmol) was dissolved in dichloromethane (15 ml) and triethylamine (444 mg, 4.39 mmol) was added at 0°C followed by dropwise addition of acetic anhydride (336 g, 3.29 mmol). The reaction system was reacted at 0°C for 1 hour. Then, the reaction system was added with saturated aqueous sodium chloride (40 ml), extracted with dichloromethane (50 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (PE/EA = 1/4-1/2) to give intermediate 174-3 (1.1 g, 69% yield) as an off-white solid, LC-MS : [M+H] ⁺ =725.1.

Step (4) Preparation of (S)-4-(3-((4-acetylmorpholin-2-yl)methyl)-7-chlorimidazo[1,2-a]pyridin-2-yl)-3,5-difluorobensulfonamide

Intermediate 174-3 (1.1 g, 1.52 mmol) was dissolved in dichloromethane (15 ml) and trifluoroacetic acid (3 ml) was added at 0°C. The reaction system was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added dropwise to the reaction system to adjust the pH to 8, and extraction was carried out with dichloromethane (50 ml × 3). The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative chromatography. The resulting phases of acetonitrile, water and trifluoroacetic acid were concentrated, adjusted to pH 8 with sodium bicarbonate solution, extracted with ethyl acetate (300 ml × 3), washed with saturated saline (100 ml × 2), dried over anhydrous sodium sulfate with stirring for 20 min, filtered and concentrated. The solid, after concentration, was washed with acetonitrile three times, acetonitrile (10 ml) and pure water (30 ml) were added and lyophilized to give compound 174 (358 mg, 97% purity) as a white solid. LC-MS: [M+H] ⁺ =484.2.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (t, J=7.3 Hz, 1H), 7.82-7.77 (m, 1H), 7.73 (d, J=2, 3 Hz, 2H), 7.64 (d, J=6.6 Hz, 2H), 7.10 (td, J=7.3.2, 3Hz, 1H), 4.26-4.19 (m , 1H), 4.05 (d, J=13.3 Hz, 1H), 3.78 (d, J=12.7 Hz, 1H), 3.69-3.60 (m, 1H), 3 .56 (d, J=13.3 Hz, 1H), 3.52-3.37 (m, 1H), 3.25 (td, J=11.5, 2.3 Hz, 1H), 3, 20-2.97 (m, 3H), 2.80 (dd, J=12.9, 10.5 Hz, 1H), 2.54 (dd, J=12.7,2.9 Hz, 1H) , 2.29 (dd, J=12.8, 10.9 Hz, 1H), 1.94 (d, J=4.2 Hz, 3H).

Example 175:

Step (1) Preparation of tert-butyl-(S)-2-((2-(2,6-difluoro-4-(methylsulfonyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl) methyl)morpholine-4-carboxylate

Intermediate 2-4 was prepared according to the steps in Example 2. Intermediate 2-4 (90 mg), NaSO ₂ Me (22 mg), Cu(OAc) ₂ (32 mg) and KOAc (34 mg) were added sequentially into a reaction flask containing DMSO (5 ml). The reaction system was reacted at 100°C overnight. The starting material was consumed and a new spot was obtained, detected by TLC (PE/EtOAc = 1/1). The reaction system was sequentially added EtOAc (10 mL), washed with NH ₄ Cl (10 mL x 3) and brine (10 mL x 3), dried over Na ₂ SO ₄ and concentrated to give the crude product. The crude product was purified using rep. TLC yielded intermediate 175-1 (28 mg) as a white solid. LC-MS: [M+H] ⁺ =522.1.

Step (2) Preparation of (S)-2-((2-(2,6-difluoro-4-(methylsulfonyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine

A solution of HCl in methanol (3 mL, 4 M) was added to intermediate 175-1 (0.1 g) at room temperature. The reaction system was allowed to react at room temperature for 1 hour. The reaction mixture was then concentrated by rotary evaporation to give intermediate 175-2 (80 mg) as a yellow solid, which was used directly in the next step without purification.

Step (3) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-(methylsulfonyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl) morpholine-4-carboxylate

Intermediate 175-2 (80 mg) was added to the reaction flask containing DCM (5 ml) and triethylamine (30 mg) was added. The reaction system was added with methyl chloroformate (27 mg) at 0° C. and reacted at this temperature for 1 hour. The starting material was consumed and the expected product was obtained as detected by TLC. The product was purified by preparative chromatography to provide compound 175 (20 mg, 99.1% purity) as a white solid. LC-MS: [M+H] ⁺ =480.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (d, J=7.2 Hz, 1H), 7.81 (d, J=6.1 Hz, 1H), 7.37 (s, 1H), 6.85 (d, J=6.9 Hz, 1H), 3.77 (d, J=11.6 Hz, 1H), 3.63 (d, J=11.9 Hz, 2H) , 3.55 (s, 2H), 3.46 (s, 1H), 3.39 (s, 2H), 3.28-3.16 (m, 1H), 3.13-2.97 (m , 1H), 2.38 (s, 2H).

Example 176:

Step (1) Preparation of tert-butyl-(S)-2-((2-(4-bromo-2-chlorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

To a 100 mL round bottom flask, 4-bromo-2-chlorobenzaldehyde (2.0 g, 1 eq., compound 176-1), compound 1-4 (1.9 g, 1 eq.), compound 1-5 was added sequentially (1.0 g, 1 eq.), CuCl (0.27 g, 0.3 eq.), Cu(OTf) ₂ (0.99 g, 0.3 eq.), toluene (20 ml) and DMA (2 ml). The reaction system was purged with nitrogen 3 times, heated in an oil bath at 85°C and reacted overnight (12 hours). The starting material (compound 176-1) was consumed by TLC. The reaction system was then cooled to room temperature, aqueous ammonia (10 ml) and water (15 ml) were added and stirred for 5 minutes, followed by separation of the liquid to obtain a toluene phase. The aqueous phase was subjected to extraction with DCM (15 ml × 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give intermediate 176-2 (1.46 g, 95% pure) as a yellow oil. LC-MS: [M+H] ⁺ =520.2.

Step (2) Preparation of (S)-2-(((2-(4-bromo-2-chlorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine

Intermediate 176-2 (1.46 g) was dissolved in methanol (5 ml) and a solution of HCl in EtOAc (4 M, 10 ml) was added. The reaction system was stirred at room temperature for 1 hour. After completion of the reaction, which was detected by TLC, water (10 ml) and dichloromethane (20 ml) were added to the reaction system. The aqueous phase is adjusted to pH 9-10 (weak alkalinity) with sodium carbonate, followed by separation of the liquid to obtain the DCM phase. The aqueous phase was subjected to extraction with DCM (10 ml × 2). The DCM phases were combined, washed with brine, dried and concentrated on a rotary evaporator to give intermediate 176-3 (1.05 g, 90% purity) as a yellow oil. LC-MS: [M+H] ⁺ =420.1.

Step (3) Preparation of methyl (S)-2-((2-(4-bromo-2-chlorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 176-3 (1.05 g, 1.0 eq) was dissolved in DCM (10 ml) and DIPEA (0.65 g, 2.0 eq) was added followed by dropwise addition of methyl chloroacetate (0.27 g, 1 .5 eq). The reaction system was reacted for 1 hour. After completion of the reaction as detected by TLC, water (10 ml) and DCM (20 ml) were added to the reaction system and stirred for 10 minutes, followed by separation of the liquid to obtain the DCM phase . The aqueous phase was subjected to extraction with DCM (10 ml × 2). The DCM phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to give intermediate 176-4 (0.88 g, 96% purity). LC-MS: [M+H] ⁺ =478.2.

Step (4) Preparation of methyl-(S)-2-((2-(4-(benzylthio)-2-chlorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

Intermediate 176-4 (0.78 g, 1.0 eq) was dissolved in dioxane (10 ml) and BnSH (0.23 g, 1.1 eq), Pd ₂ (dba) ₃ (0.15 g, 0.1 eq.), xanthos (0.1 g, 0.1 eq.) and DIPEA (0.42 g, 2.0 eq.). The reaction system was purged with N ₂ three times and reacted at 85°C overnight. The starting material was completely consumed, which was shown by TLC control. After completion of the reaction, the reaction system was added to water (10 ml) and EA (20 ml) and stirred for 10 min, followed by separation of the liquid to obtain the EtOAc phase. The aqueous phase was subjected to extraction with EtOAc (10 ml x 2). The EtOAc phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The residue was purified by column chromatography to give intermediate 176-5 (0.85 g, 92% purity) as a yellow oil. LC-MS: [M+H] ⁺ =522.0.

Step (5) Preparation of methyl-(S)-2-((2-(2-chloro-4-(chlorosulfonyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine- 4-carboxylate

Intermediate 176-5 (150 mg) was added to a reaction flask containing DCM (1 ml), glacial acetic acid (86.3 mg, 5.0 eq.) and SO ₂ Cl ₂ (154.9 mg, 4.0 eq. eq.) were added dropwise in an ice bath. The reaction system was reacted at room temperature for 2 hours. The starting material was consumed and intermediate 176-6 was obtained, which was detected by LCMS. The reaction system was used directly in the next step without treatment.

Step (6) Preparation of methyl (S)-2-((2-(2-chloro-4-sulfamoylphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

A solution of NH ₃ in THF (0.4 M, 5 ml) was slowly added dropwise to the above reaction system at 0°C. The reaction system was reacted at room temperature for 2 hours. The starting material was completely consumed and the target product was obtained, as detected by LCMS. The reaction system was concentrated to dryness and purified by preparative chromatography to give compound 176 (18 mg) as a white solid. LC-MS: [M+H] ⁺ =479.0.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (d, J=7.1 Hz, 1H), 7.96 (d, J=1.7 Hz, 1H), 7.83 (dd , J=8.0, 1.8 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.59 (s, 2H), 7.36 (s, 1H), 6 .83 (dd, J=7.1, 1.6 Hz, 1H), 3.79-3.59 (m, 3H), 3.56 (s, 3H), 3.51 (s, 1H), 3.23 (dd, J=11.8, 9.1 Hz, 1H), 3.05 (qd, J=15.6, 6.3 Hz, 2H), 2.82 (s, 1H),2 .51 (s, 1H), 2.38 (s, 3H).

Example 177:

Step (1) Preparation of 4-bromo-2-chloro-6-fluorobenzaldehyde

Methyl 4-bromo-2-chloro-6-fluorobenzoate (1.0 g, 1.0 eq., compound 177-1) and anhydrous tetrahydrofuran were added sequentially to a 100 mL round bottom flask. The reaction system was cooled to -70°C, then DIBAL-H (3.8 ml, 1.2 eq.) was slowly added and reacted at this temperature for 2 hours. The starting material was completely consumed and a new spot was obtained, detected by TLC. An aqueous solution of HCl (1 M) was added to the reaction system to quench the reaction, then stirred at room temperature for 20 min and extracted with dichloromethane (30 ml × 3). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The residue was purified by column chromatography to give intermediate 177-2 (0.9 g, 80% purity) as a colorless oil. LC-MS: [M+H] ⁺ =237.1.

Step (2) Preparation of tert-butyl-(S)-2-((2-(4-bromo-2-chloro-6-fluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

To toluene (20 ml) and DMA (2 ml) was added intermediate 177-2 (0.75 g, 1.0 eq), compound 1-5 (0.67 g, 1.0 eq), compound 1 -4 (0.34 g, 1.0 eq.), CuCl (0.19 g, 0.3 eq.) and Cu(OTf) ₂ (0.69 g, 0.3 eq.). The reaction system was purged with nitrogen 3 times, heated in an oil bath at 85°C and reacted overnight (12 hours). The starting material (compound 1-4) was consumed by TLC. The reaction system was then cooled to room temperature, aqueous ammonia (10 ml) and water (15 ml) were added and stirred for 5 minutes, followed by separation of the liquid to obtain a toluene phase. The aqueous phase was subjected to extraction with dichloromethane (15 ml x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The residue was purified by column chromatography to give intermediate 177-3 (0.2 g, 99% purity) as a brown foamy solid. LC-MS: [M+H] ⁺ =538.1.

Step (3) Preparation of (S)-2-(((2-(4-bromo-2-chloro-6-fluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine

Intermediate 177-3 (0.2 g) was dissolved in methanol (5 ml) and a solution of HCl in EA (10 ml) was added. The reaction system was stirred at room temperature for 1.0 hour. After completion of the reaction, which was detected by TLC, water (10 ml) and dichloromethane (20 ml) were added to the reaction system. The aqueous phase was adjusted to pH 9-10 (slight alkalinity) with sodium carbonate, followed by liquid separation to obtain the dichloromethane phase. The aqueous phase was subjected to extraction with dichloromethane (10 ml × 2). The dichloromethane phases were combined, washed with brine, dried, filtered and concentrated on a rotary evaporator to give intermediate 177-4 (170 mg) as a yellow solid. The crude product was used directly in the next step. LC-MS: [M+H] ⁺ =438.1.

Step (4) Preparation of methyl-(S)-2-((2-(4-bromo-2-chloro-6-fluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine -4-carboxylate

Intermediate 177-4 (170 mg, 1.0 eq.) was dissolved in dichloromethane (2 ml) and triethylamine (120 mg, 2.0 eq.) was added, followed by dropwise addition of methyl chloroacetate (55 mg, 1.5 eq. ). The reaction system was reacted for 1.0 h. After completion of the reaction as determined by TLC, water (10 mL) and dichloromethane (20 mL) were added to the reaction system and stirred for 10 min, followed by separation of the liquid to obtain a dichloromethane phase. The aqueous phase was subjected to extraction with dichloromethane (10 ml × 2). The dichloromethane phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to give intermediate 177-5 (175 mg, 96% purity) as a white solid. LC-MS: [M+H] ⁺ =496.1.

Step (5) Preparation of methyl-(S)-2-((2-(4-(benzylthio)-2-chloro-6-fluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

Intermediate 177-5 (175 mg, 1.0 eq) was dissolved in dioxane (10 ml) and BnSH (53 mg, 1.1 eq), Pd ₂ (dba) ₃ (36 mg, 0.1 eq) was added .), xanthos (25 mg, 0.1 eq.) and DIPEA (95 mg, 2.0 eq.). The reaction system was purged with N ₂ three times and reacted at 85°C overnight. The starting material was completely consumed, which was shown by TLC control. After completion of the reaction, water (10 ml) and ethyl acetate (20 ml) were added to the reaction system and stirred for 10 minutes, followed by separation of the liquid to obtain an ethyl acetate phase. The aqueous phase was subjected to extraction with ethyl acetate (10 ml × 2). The ethyl acetate phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to give intermediate 177-7 (165 mg, 95% purity) as a white solid. LC-MS: [M+H] ⁺ =540.0.

Step (6) Preparation of methyl-(S)-2-((2-(2-chloro-4-(chlorosulfonyl)-6-fluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

Intermediate 177-7 (160 mg) was added to a reaction flask containing dichloromethane (5 ml), glacial acetic acid (90 mg, 5.0 eq) was added and SO ₂ Cl ₂ (160 mg, 4.0 eq) was added at drops in an ice bath. The reaction system was reacted at 0°C for 1 hour. The starting material was consumed and intermediate 177-8 was obtained, which was detected by LCMS. The reaction system was used directly in the next step without treatment.

Step (7) Preparation of methyl-(S)-2-((2-(2-chloro-6-fluoro-4-sulfamoylphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine -4-carboxylate

Aqueous ammonia (10 ml) was slowly added dropwise to the above reaction system at 0°C. The reaction system was reacted at 0° C. for 0.2 h. The starting material was completely consumed and the target product was obtained, as detected by LCMS. The reaction system was concentrated to dryness and purified by preparative chromatography. to give compound 177 (80 mg, 98.982% purity) as a white solid. LC-MS: [M+H] ⁺ =497.2.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (d, J=7.1 Hz, 1H), 7.85 (s, 1H), 7.72 (s, 2H), 7.70 (s, 1H), 6.86 (d, J=7.1 Hz, 1H), 3.77 (d, J=11.6 Hz, 1H), 3.63 (d, J=11.9 Hz , 2H), 3.55 (s, 3H), 3.43 (s, 1H), 3.19 (dt, J=11.8, 5.8 Hz, 1H), 3.01 (qd, J= 15.5, 6.0 Hz, 2H), 2.78 (s, 1H), 2.52 (s, 1H), 2.38 (s, 3H).

Example 178:

Step (1) Preparation of tert-butyl-(S)-2-((2-(4-bromo-2-chlorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4 -carboxylate

Compound 1-4 (680 mg, 1.0 eq), compound 176-1 (706 mg, 1.0 eq), 4-chloropyridin-2-amine (413 mg, 1 0eq., compound 178-1), Cul (61 mg, 0.1 eq.), Cu(OTf) ₂ (116 mg, 0.1 eq.) and DMSO (7 ml). The reaction system was purged with nitrogen 3 times, heated in an oil bath at 85°C and reacted overnight (12 hours). The starting material (compound 1-4) was consumed by TLC. After the reaction system was cooled to room temperature, aqueous ammonium chloride (10 ml) and ethyl acetate (15 ml) were added. The reaction system was shaken for 5 min, followed by separation of the liquid to obtain the organic phase. The aqueous phase was subjected to extraction with ethyl acetate (15 ml x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The residue was purified by column chromatography to give intermediate 178-2 (0.65 g) as a yellow oil. LC-MS: [M+H] ⁺ =540.2.

Step (2) Preparation of (S)-2-((2-(4-bromo-2-chlorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine

Intermediate 178-2 (0.65 g) was dissolved in dichloromethane (2 ml) and a solution of HCl in dioxane (6 ml) was added. The reaction system was stirred at room temperature for 1.0 hour. After completion of the reaction as detected by TLC, the reaction system was concentrated by rotary evaporation, water (10 ml) and dichloromethane (20 ml) were added and extracted to obtain an aqueous phase. The aqueous phase was brought to pH 8-9 (slight alkalinity) with an aqueous solution of sodium carbonate, followed by liquid separation to obtain a dichloromethane phase. The aqueous phase was subjected to extraction with dichloromethane (10 ml × 2). The dichloromethane phases were combined, washed with brine, dried, filtered and concentrated on a rotary evaporator to give intermediate 178-3 (512 mg, 95% purity) as a yellow oil. LC-MS: [M+H] ⁺ =440.1.

Step (3) Preparation of methyl (S)-2-((2-(4-bromo-2-chlorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 178-3 (500 mg, 1.0 eq.) was dissolved in dichloromethane (5 ml) and triethylamine (206 mg, 2.0 eq.) was added, followed by dropwise addition of methyl chloroacetate (115 mg, 1.2 eq. ). The reaction system was reacted for 1.0 h to obtain the product as detected by LC-MS. After completion of the reaction, water (15 ml) was added to the reaction system and stirred for 30 minutes, followed by separation of the liquid to obtain a dichloromethane phase. The aqueous phase was subjected to extraction with dichloromethane (10 ml × 2). The dichloromethane phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give intermediate 178-4 (0.52 g) as a yellow oil. LC-MS: [M+H] ⁺ =498.2.

Step (4) Preparation of methyl (S)-2-((2-(4-benzylthio-2-chlorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 178-4 (0.52 g, 1.0 eq) was dissolved in dioxane (6 ml) and BnSH (0.16 g, 1.2 eq), Pd ₂ (dba) ₃ (0.05 g, 0.05 eq.), xanthos (0.06 g, 0.1 eq.) and DIEA (0.41 g, 3.0 eq.). The reaction system was purged with N ₂ three times and reacted at 80°C overnight. The starting material was completely consumed, as shown by control using LCMS. After completion of the reaction, water (10 ml) and ethyl acetate (20 ml) were added to the reaction system, followed by separation of the liquid to obtain an ethyl acetate phase. The aqueous phase was subjected to extraction with ethyl acetate (10 ml × 2). The ethyl acetate phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to give intermediate 178-5 (0.48 g, 86% purity) as a yellow oil. LC-MS: [M+H] ⁺ =542.2.

Step (5) Preparation of methyl-(S)-2-((7-chloro-2-(2-chloro-4-(chlorosulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine -4-carboxylate

Intermediate 178-5 (220 mg) was added to the reaction flask with acetonitrile (3 mL), glacial acetic acid (121 mg, 5.0 eq.) and SO ₂ Cl ₂ (218 mg, 4.0 eq.) were added dropwise in an ice bath. The reaction system was reacted at 0°C for 1 hour. The starting material was consumed and intermediate 178-6 was obtained, which was detected by LCMS. The reaction system was used directly in the next step without treatment.

Step (6) Preparation of methyl-(S)-2-((7-chloro-2-(2-chloro-4-sulfamoylphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4- carboxylate

Aqueous ammonia (1.5 ml) was diluted with acetonitrile (1 ml) and added dropwise to the above reaction system at 0°C. The reaction system was reacted at room temperature for 0.5 h. The starting material was completely consumed, and the target product was obtained and detected by LC-MS. The reaction system was extracted twice with water and ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative chromatography to give compound 178 (30 mg, 99.6% purity) as a white solid. LC-MS: [M+H] ⁺ =499.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (d, J=7.4 Hz, 1H), 7.98 (s, 1H), 7.85 (d, J=9.6 Hz , 1H), 7.79 (d, J=2.1 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.61 (s, 2H), 7.09 (dd , J=7.4, 2.1 Hz, 1H), 3.79 (d, J=12.5 Hz, 1H), 3.63 (d, J=11.5 Hz, 3H), 3, 56 (s, 4H), 3.51 (s, 1H), 3.26-3.21 (m, 2H), 3.20-3.14 (m, 1H), 3.12 (s, 1H) , 3.03 (dd, J=15.6, 8.4 Hz, 1H), 2.81 (s, 1H).

Example 179:

Step (1) Preparation of tert-butyl-(S)-2-((2-(4-bromo-2-chloro-6-fluorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

Intermediate 177-2 (2.16 g, 1.0 eq), 4-chloropyridin-2-amine (1.17 g, 1.0 eq, compound 179-1), compound 1-4 (1. 92 g, 1.0 eq.), Cul (0.19 g, 0.1 eq.) and Cu(OTf) ₂ (0.33 g, 0.1 eq.) were added to isopropanol (25 ml). The reaction system was purged with nitrogen 3 times, heated in an oil bath at 85°C and reacted overnight (12 hours). The starting material (compound 1-4) was consumed by TLC; the reaction system was cooled to room temperature, aqueous ammonia (10 ml) and water (15 ml) were added and stirred for 5 min, followed by separation of the liquid to obtain the toluene phase. Aqueous phase extracted with dichloromethane (15 mL x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to give intermediate 179-2 (0.93 g, 92% purity ) as a light yellow foamy solid. LC-MS: [M+H] ⁺ =558.0.

Step (2) Preparation of (S)-2-(((2-(4-bromo-2-chloro-6-fluorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine

Intermediate 179-2 (0.93 g) was dissolved in methanol (10 ml) and a solution of HCl in dioxane (10 ml) was added. The reaction system was stirred at room temperature for 1.0 hour. After completion of the reaction, which was detected by TLC, water (10 ml) and dichloromethane (20 ml) were added to the reaction system. The aqueous phase is adjusted to pH 9-10 (weak alkalinity) with sodium carbonate, followed by separation of the liquid to obtain a dichloromethane phase. The aqueous phase was subjected to extraction with dichloromethane (10 ml × 2). The dichloromethane phases were combined, washed with brine, dried and concentrated on a rotary evaporator to give intermediate 179-3 (0.78 g) as a white solid, LC-MS: [M+H] ⁺ =458.1. The crude product was used directly in the next step.

Step (3) Preparation of methyl-(S)-2-((2-(4-bromo-2-chloro-6-fluorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine -4-carboxylate

Intermediate 179-3 (690 mg, 1.0 eq) was dissolved in dichloromethane (10 ml) and triethylamine (380 mg, 2.0 eq) was added, followed by dropwise addition of methyl chloroacetate (213 mg, 1.5 eq). The reaction system was reacted for 1.0 h. After completion of the reaction as determined by TLC, water (10 mL) and dichloromethane (20 mL) were added to the reaction system and stirred for 10 min, followed by separation of the liquid to obtain a dichloromethane phase. The aqueous phase was subjected to extraction with dichloromethane (10 ml × 2). The dichloromethane phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to give intermediate 179-4 (472 mg, 96% purity) as a white solid. LC-MS: [M+H] ⁺ =515.9.

Step (4) Preparation of methyl-(S)-2-((2-(4-(benzylthio)-2-chloro-6-fluorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

Intermediate 179-4 (420 mg, 1.0 eq) was dissolved in dioxane (10 ml) and BnSH (130 mg, 1.2 eq), Pd ₂ (dba) ₃ (84 mg, 0.1 eq) was added .), xanthos (50 mg, 0.1 eq.) and DIPEA (210 mg, 2.0 eq.). The reaction system was purged with N ₂ three times and reacted at 85°C overnight. The starting material was completely consumed, which was shown by TLC control. After completion of the reaction, water (10 ml) and ethyl acetate (20 ml) were added to the reaction system and stirred for 10 minutes, followed by separation of the liquid to obtain an ethyl acetate phase.

The aqueous phase was subjected to extraction with ethyl acetate (10 ml × 2). The ethyl acetate phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to give intermediate 179-5 (465 mg, 94% purity) as a white solid. LC-MS: [M+H] ⁺ =560.1.

Step (5) Preparation of methyl-(S)-2-((7-chloro-2-(2-chloro-4-(chlorosulfonyl)-6-fluorophenyl)imidazo[1,2-a]pyridin-3-yl) methyl)morpholine-4-carboxylate

Intermediate 179-5 (415 mg) was added to the reaction flask of dichloromethane (5 ml), glacial acetic acid (224 mg, 5.0 eq.) was added and SO ₂ Cl ₂ (415 mg, 4.0 eq.) was added at drops in an ice bath. The reaction system was reacted at 0°C for 1 hour. The starting material was consumed and intermediate 179-6 was obtained, which was detected by LCMS. The reaction system was used directly in the next step without treatment.

Step (6) Preparation of methyl-(S)-2-((7-chloro-2-(2-chloro-6-fluoro-4-sulfamoylphenyl)imidazo[1,2-a]pyridin-3-yl)methyl) morpholine-4-carboxylate

Aqueous ammonia (10 ml) was slowly added dropwise to the above reaction system at 0°C. The reaction system was reacted at 0° C. for 0.2 h. The starting material was completely consumed and the target product was obtained, as detected by LCMS. The reaction system was concentrated to dryness. The residue was purified by preparative chromatography to give compound 179 (170 mg, 99.778% purity) as a white solid. LC-MS: [M+H] ⁺ =517.2.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (d, J=7.4 Hz, 1H), 7.79 (dd, J=6.5, 4.4 Hz, 2H), 7 .64 (dt, J=8.0, 4.0 Hz, 1H), 7.14-7.05 (m, 1H), 6.94 (s, 1H), 3.81 (d, J=11 ,7 Hz, 1H), 3.63 (d, J=11.6 Hz, 2H), 3.56 (s, 3H), 3.45 (d, J=3.5 Hz, 1H), 3, 20 (td, J=11.4, 2.2 Hz, 1H), 3.04 (ddd, J=23.5, 15.5, 5.9 Hz, 2H), 2.79 (s, 1H) , 2.51 (s, 1H).

Example 180:

Step (1) Preparation of tert-butyl-(S)-2-((2-(4-bromo-2-chloro-5-fluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

4-Bromo-2-chloro-5-fluorobenzaldehyde (1.5 g, 6.4 mmol, compound 180-1), compound 1-4 (2.67 g, 12.6 mmol) were added sequentially to a 100 mL round bottom flask. and compound 1-5 (0.68 g, 6.4 mmol), and then added toluene (15 ml) and N,N-dimethylacetamide (1 ml) followed by the addition of copper (I) chloride catalysts (187.6 mg, 1.9 mmol) and copper (II) trifluoromethanesulfonate (685.4 mg, 1.9 mmol). The reaction system was purged with nitrogen three times and reacted at 85°C for 4 hours. After completion of the reaction, the desired product was obtained, detected by LC-MS. The reaction system was concentrated on a rotary evaporator to remove the solvent, dissolved with dichloromethane (50 ml), aqueous ammonia (50 ml) was added and stirred, followed by separation of the liquid to obtain an organic phase. The aqueous phase was subjected to extraction with DCM (150 ml × 3). The organic phase was washed with saturated citric acid solution and saturated brine 3 times, respectively, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to give intermediate 180-2 (1.9 g, 59.9% yield) as a light yellow foamy solid. LC-MS: [M+H] ⁺ =538.1.

Step (2) Preparation of (S)-2-(((2-(4-bromo-2-chloro-5-fluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine

Intermediate 180-2 (0.7 g, 1.4 mmol) was dissolved in dichloromethane (5 ml). The reaction system was added with a solution of HCl in 1,4-dioxane solution (4 mL, 4.0 mol/L) in an ice bath, and then reacted at room temperature for 1.0 h. After completion of the reaction, TLC showed that the reaction system was concentrated by rotary evaporation to remove the solvent, water (5 ml) and ethyl acetate (5 ml) were added and allowed to separate to obtain an aqueous phase. The aqueous phase was adjusted to pH 9-10 (slight alkalinity) with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate (5 ml x 3). The organic phases were combined, washed with brine 3 times and concentrated to give intermediate 180-3 (560 mg, 91.5% yield) as a light yellow oil, which was used directly in the next step. LC-MS: [M+H] ⁺ =438.1.

Step (3) Preparation of methyl-(S)-2-((2-(4-bromo-2-chloro-5-fluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine -4-carboxylate

Intermediate 180-3 (560 mg, 1.28 mmol) was dissolved in dichloromethane (5 ml) and triethylamine (260 mg, 2.56 mmol) was added. The reaction system was added with methyl chloroformate (145.5 mg, 1.54 mmol) in an ice bath, reacted at room temperature for 0.5 h to obtain the product as determined by LC-MS. After completion of the reaction, water (5 ml) was added to the reaction system to quench the reaction mixture and left to separate the liquid to obtain the dichloromethane phase. The aqueous phase was subjected to extraction with dichloromethane (5 ml × 2). The dichloromethane phases were combined, washed with brine 3 times, dried over anhydrous sodium sulfate and concentrated to give intermediate 180-4 (520 mg, 81.9% yield) as a white solid. LC-MS: [M+H] ⁺ =496.1.

Step (4) Preparation of methyl-(S)-2-((2-(4-(benzylthio)-2-chloro-5-fluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

Intermediate 180-4 (520 mg, 1.05 mmol) was dissolved in 1,4-dioxane (10 ml) and Pd ₂ (dba) ₃ (28.8 mg, 0.0315 mmol), xantphos (30.3 mg, 0.0525 mmol), DIEA (401.7 mg, 3.15 mmol) and BnSH (169.6 mg, 1.36 mmol). The reaction system was purged with nitrogen 3 times and reacted at 80°C overnight. The starting material was completely consumed according to LC-MS data. After completion of the reaction, water (10 ml) and ethyl acetate (20 ml) were added. The reaction system was stirred and left to separate the liquid to obtain the ethyl acetate phase. The aqueous phase was subjected to extraction with ethyl acetate (10 ml × 2). The ethyl acetate phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give intermediate 180-5 (500 mg, 88.5% yield) as a light yellow solid. LC-MS: [M+H] ⁺ =440.2.

Step (5) Preparation of methyl-(S)-2-((2-(2-chloro-4-(chlorosulfonyl)-5-fluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

Substrate intermediate 180-5 (500 mg, 0.92 mmol) was added to the reaction flask with acetonitrile (15 mL), glacial acetic acid (276 mg, 4.6 mmol) was added and sulfonyl chloride (500 mg, 3.7 mmol) was added slowly added dropwise in an ice bath. The reaction system was reacted at 0°C for 1 hour. The starting material was consumed and intermediate 180-6 was obtained, which was determined by LC-MS, LC-MS: [M+H] ⁺ =515.9. The reaction system was used directly in the next step without treatment.

Step (6) Preparation of methyl-(S)-2-(2-(2-chloro-5-fluoro-4-sulfamoylphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine- 4-carboxylate

Aqueous ammonia (15 ml) was diluted with acetonitrile (10 ml) and added dropwise to the reaction system of the previous step at 0°C. The reaction system was reacted at room temperature for 0.5 h. The starting material was completely consumed, and the target product was obtained and detected by LC-MS. The reaction system was left standing to separate the liquid to obtain the organic phase. The aqueous phase was subjected to extraction with ethyl acetate 2 times. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative chromatography and separated by preparative TLC to give compound 180 (140 mg, 99.5% purity) as a white solid, LC-MS: [M+H] ⁺ =497.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (d, J=7.1 Hz, 1H), 7.89 (s, 2H), 7.87 (d, J=6.6 Hz , 1H), 7.62 (d, J=10.2 Hz, 1H), 7.35 (s, 1H), 6.83 (dd, J=7.1, 1.6 Hz, 1H), 3 ,84-3.73 (m, 1H), 3.64 (t, J=11.0 Hz, 2H), 3.58-3.52 (m, 3H), 3.53-3.45 (m , 1H), 3.22 (td, J=11.7, 2.7 Hz, 1H), 3.12 (dd, J=15.6, 4.1 Hz, 1H), 3.00 (dd, J=15.6, 8.2 Hz, 1H), 2.81 (s, 1H), 2.53 (d, J=7.6 Hz, 1H), 2.42-2.29 (m, 3H ).

Example 181:

Step (1) Preparation of tert-butyl-(S)-2-((2-(4-bromo-2-chloro-5-fluorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

Intermediate 180-1 (1.5 g, 1.0 eq), Intermediate 179-1 (0.81 g, 1.0 eq), Compound 1-4 (1.3 eq) were added sequentially to a 100 mL round bottom flask. g, 1.0 eq.), CuCl (0.19 g, 0.3 eq.), Cu(OTf) ₂ (0.69 g, 0.3 eq.), toluene (20 ml) and DMA (2 ml). The reaction system was purged with nitrogen 3 times, heated in an oil bath at 85°C and reacted overnight (12 hours). The starting material (compound 1-4) was consumed by TLC. The reaction system was then cooled to room temperature, aqueous ammonia (10 ml) and water (15 ml) were added and stirred for 5 minutes, followed by separation of the liquid to obtain a toluene phase. The aqueous phase was subjected to extraction with dichloromethane (15 ml x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The residue was purified by column chromatography to give intermediate 181-1 (0.35 g, 99% purity) as a light yellow foamy solid. LC-MS: [M+H] ⁺ =558.1.

Step (2) Preparation of (S)-2-((2-(4-bromo-2-chloro-5-fluorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine

Intermediate 181-1 (0.1 g) was dissolved in methanol (5 ml) and HCl/EtOAc (10 ml, 3 M) was added. The reaction system was stirred at room temperature for 1.0 hour. After completion of the reaction, which was detected by TLC, water (10 ml) and dichloromethane (20 ml) were added to the reaction system. The aqueous phase was adjusted to pH 9-10 (slight alkalinity) with sodium carbonate, followed by liquid separation to obtain the dichloromethane phase. The aqueous phase was subjected to extraction with dichloromethane (10 ml × 2). The dichloromethane phases were combined, washed with brine, dried and concentrated on a rotary evaporator to give intermediate 181-2 (80 mg) as a white solid. The crude product was used directly in the next step. LC-MS: [M+H] ⁺ =458.1.

Step (3) Preparation of methyl-(S)-2-((2-(4-bromo-2-chloro-5-fluorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine -4-carboxylate

Intermediate 181-2 (80 mg, 1.0 eq) was dissolved in dichloromethane (2 ml) and triethylamine (36 mg, 2.0 eq) was added, followed by dropwise addition of methyl chloroacetate (25 mg, 1.5 eq). The reaction system was reacted for 1.0 h. After completion of the reaction as determined by TLC, water (10 mL) and dichloromethane (20 mL) were added to the reaction system and stirred for 10 min, followed by separation of the liquid to obtain a dichloromethane phase. The aqueous phase was subjected to extraction with dichloromethane (10 ml × 2). The dichloromethane phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to give intermediate 181-3 (0.1 g, 96% purity) as a white solid. LC-MS: [M+H] ⁺ =515.9.

Step (4) Preparation of methyl-(S)-2-((2-(4-(benzylthio)-2-chloro-5-fluorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

Intermediate 181-3 (0.45 g, 1.0 eq) was dissolved in dioxane (10 ml) and BnSH (0.13 g, 1.1 eq), Pd ₂ (dba) ₃ (0.08 g, 0.1 eq.), xanthos (0.05 g, 0.1 eq.) and DIPEA (0.23 g, 2.0 eq.). The reaction system was purged with N ₂ three times and reacted at 85°C overnight. The starting material was completely consumed, which was shown by TLC control. After completion of the reaction, water (10 ml) and ethyl acetate (20 ml) were added to the reaction system and stirred for 10 minutes, followed by separation of the liquid to obtain an ethyl acetate phase. The aqueous phase was subjected to extraction with ethyl acetate (10 ml × 2). The ethyl acetate phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to give intermediate 181-4 (0.3 g, 95% purity) as a white solid. LC-MS: [M+H] ⁺ =560.2.

Step (5) Preparation of methyl-(S)-2-((7-chloro-2-(2-chloro-4-(chlorosulfonyl)-5-fluorophenyl)imidazo[1,2-a]pyridin-3-yl) methyl)morpholine-4-carboxylate

Intermediate 181-4 (280 mg) was added to the reaction flask dichloromethane (5 ml), glacial acetic acid (150 mg, 5.0 eq) was added and SO ₂ Cl ₂ (270 mg, 4.0 eq) was added dropwise to ice bath. The reaction system was reacted at room temperature for 1 hour. The starting material was consumed and intermediate 181-5 was obtained as detected by LCMS. The reaction system was used directly in the next step without treatment.

Step (6) Preparation of methyl-(S)-2-((7-chloro-2-(2-chloro-5-fluoro-4-sulfamoylphenyl)imidazo[1,2-a]pyridin-3-yl)methyl) morpholine-4-carboxylate

A solution of NH ₃ in tetrahydrofuran (0.4 M, 5 ml) was slowly added dropwise to the above reaction system at 0°C. The reaction system was reacted at room temperature for 2 hours. The starting material was completely consumed and the desired product was obtained as detected by LCMS. The reaction system was concentrated to dryness. The residue was purified by preparative chromatography to give compound 181 (30 mg, 99% pure) as a white solid. LC-MS: [M+H] ⁺ =517.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (d, J=7.4 Hz, 1H), 7.94 (s, 2H), 7.90 (d, J=6.6 Hz , 1H), 7.81-7.79 (m, 1H), 7.67 (d, J=10.1 Hz, 1H), 7.10 (dd, J=7.4, 2.2 Hz, 1H), 3.84 (s, 1H), 3.65 (s, 2H), 3.57 (s, 3H), 3.52 (t, J=9.4 Hz, 1H), 3.27- 3.16 (m, 2H), 3.04 (dd, J=15.6, 8.5 Hz, 1H), 2.82 (s, 1H), 2.52 (d, J=1.9 Hz , 1H).

Example 182:

Step (1) Preparation of tert-butyl-(S)-2-((2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2,6-difluorophenyl)-6-fluoro-7-methylimidazo [1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 171-4 (1.5 g, 3.25 mmol), 5-fluoro-4-methylpyridin-2-amine (410 mg, 3.25 mmol) and intermediate 1-4 ( 686.7 mg, 3.25 mmol), and then toluene (15 ml) and dimethylacetamide (5 ml) were added, followed by the addition of copper (I) chloride (96.5 mg, 0.98 mmol) and copper (II) trifluoromethanesulfonate catalysts ) (353 mg, 0.98 mmol). The reaction system was purged with nitrogen three times and reacted at 80°C overnight. After completion of the reaction, the target product was obtained, detected by LC-MS. The reaction system was concentrated on a rotary evaporator to remove the solvent, dissolved with dichloromethane (50 ml), aqueous ammonia (50 ml) was added and stirred, followed by separation of the liquid to obtain an organic phase. The aqueous phase was subjected to extraction with dichloromethane (150 ml x 3). The organic phase was washed with saturated citric acid solution and saturated brine 3 times, respectively, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by column chromatography to give intermediate 182-2 (920 mg, 36.3% yield) as a light yellow oily liquid.

Step (2) Preparation of (S)-3,5-difluoro-4-(6-fluoro-7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-a]pyridin-2-yl)- N,N-bis(4-methoxybenzyl)benzenesulfonamide

Intermediate 182-2 (410 mg, 0.53 mmol) was dissolved in ethyl acetate (2 ml). The reaction system was added with a solution of HCl in 1,4-dioxane solution (2 mL, 4.0 mol/L) in an ice bath and then reacted at room temperature for 1.0 h. The reaction was complete as determined by TLC. Analysis: The reaction system was concentrated on a rotary evaporator to remove the solvent, water (2 ml) and ethyl acetate (2 ml) were added and left to separate the liquid to obtain the aqueous phase. The aqueous phase was adjusted to pH 8-9 (slight alkalinity) with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate (3 ml x 3). The organic phases were combined, washed with brine 3 times and concentrated to give intermediate 182-3 (330 mg, 92.5% yield) as a light yellow oil, which was used directly in the next step. LC-MS: [M+H] ⁺ =681.2.

Step (3) Preparation of methyl-(S)-2-((2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2,6-difluorophenyl)-6-fluoro-7-methylimidazo[1 ,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 182-3 (330 mg, 0.49 mmol) was dissolved in dichloromethane (2 mL) and triethylamine (100 mg, 0.98 mmol) was added followed by dropwise addition of methyl chloroformate (70 mg, 0.73 mmol) in ice cold water. bath. Once the addition was complete, the reaction system was reacted at room temperature for 1 hour. Once the reaction was complete as detected by TLC, the reaction system was added with water (5 mL) to quench the reaction mixture and allowed to separate to give a dichloromethane phase. The aqueous phase was subjected to extraction with dichloromethane (5 ml × 2). The dichloromethane phases were combined, washed with brine 3 times, dried over anhydrous sodium sulfate and concentrated to give intermediate 182-4 (200 mg, 55.1% yield) as a yellow oily liquid. LC-MS: [M+H] ⁺ =739.1.

Step (4) Preparation of methyl-(S)-2-((2-(2,6-difluoro-4-sulfamoylphenyl)-6-fluoro-7-methylimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

Intermediate 182-4 (200 mg, 0.27 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (2 ml) was added. The reaction system was reacted at room temperature overnight. The starting material was completely consumed, as detected by TLC, and then work-up was performed. The reaction system was added with water (5 ml) to quench the reaction, then dichloromethane (3 ml) was added and left to separate the liquid to obtain the aqueous phase. The aqueous phase was adjusted to pH 8-9 (slight alkalinity) with saturated aqueous sodium bicarbonate and then extracted with dichloromethane (5 ml x 3). The dichloromethane phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to remove solvent and purified by preparative chromatography to give compound 182 (82 mg, 97.8% purity, 60.98% yield) as white powdery solid. LC-MS: [M+H] ⁺ =499.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.71 (d, J=5.5 Hz, 1H), 7.68 (s, 2H), 7.59 (d, J=6.6 Hz , 2H), 7.50 (d, J=7.2 Hz, 1H), 3.80 (d, J=12.3 Hz, 1H), 3.59 (d, J=11.4 Hz, 2H ), 3.53 (s, 3H), 3.44 (s, 1H), 3.26 (s, 1H), 3.18 (dd, J=11.8, 9.1 Hz, 1H), 3 .06 (dd, J=15.4, 3.8 Hz, 1H), 2.98 (d, J=8.4 Hz, 1H), 2.76 (s, 1H), 2.32 (s, 3H).

Example 183:

Step (1) Preparation of methyl-(S)-2-(2-(4-(tert-butoxycarbonyl)amino)-2,6-difluorophenyl)-7-chloro-6-fluorimidazo[1,2-a]pyridin- 3-yl)methyl)morpholine-4-carboxylate

Tert-butyl (3,5-difluoro-4-formylphenyl)carboxylate (0.75 g, 1.0 eq., compound 183-1), 4-chloro-5-fluoropyridine- 2-amine (0.43 g, 1.0 eq., compound 183-2), compound 1-4 (0.5 g, 1.0 eq.), Cul (0.17 g, 0.3 eq. ), Cu(OTf) ₂ (0.32 g, 0.3 eq.), toluene (10 ml) and DMA (1 ml). The reaction system was purged with nitrogen 3 times, heated in an oil bath at 85°C and reacted overnight (12 hours). The starting material (compound 1-4) was consumed by TLC. The reaction system was cooled to room temperature, aqueous ammonia (5 ml) and water (15 ml) were added and stirred for 5 minutes, followed by separation of the liquid to obtain a toluene phase. The aqueous phase was subjected to extraction with DCM (15 ml × 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The residue was purified by column chromatography to give intermediate 183-3 (0.18 g) as a white solid. LC-MS: [M+H] ⁺ =555.0.

Step (2) Preparation of methyl-(S)-2-((2-(4-amino-2,6-difluorophenyl)-7-chloro-6-fluorimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

Intermediate 183-3 (0.18 g) was dissolved in methanol (2 ml) and HCl/EtOAc (3 M, 5 ml) was added. The reaction system was stirred at room temperature overnight. After completion of the reaction, which was detected by TLC, water (10 ml) and dichloromethane (20 ml) were added to the reaction system. The aqueous phase was adjusted to pH 9-10 (slight alkalinity) with sodium carbonate, followed by liquid separation to obtain the DCM phase. The aqueous phase was subjected to extraction with DCM (10 ml × 2). The DCM phases were combined, washed with brine, dried and concentrated on a rotary evaporator to give intermediate 183-4 (0.12 g) as a white solid. LC-MS: [M+H] ⁺ =455.0.

Step (3) Preparation of methyl-(S)-2-((2-(4-(benzylthio)-2,6-difluorophenyl)-7-chloro-6-fluorimidazo[1,2-a]pyridin-3-yl )methyl)morpholine-4-carboxylate

Intermediate 183-4 (0.2 g, 1.0 eq) and BnSSBn (0.11 g, 1.0 eq) were dissolved in MeCN (3 mL). The reaction system was purged with nitrogen three times. Ascorbic acid (40 mg, 0.5 eq.) was dissolved with DMSO (0.5 ml) and added to the reaction system, which was then stirred and reacted for 10 min, and then added with t-BuONO (70 mg, 1 .5 eq.). The starting material was completely consumed, which was detected by TLC. Water (2 mL) was added to the reaction system, followed by extraction with EtOAc (10 mL x 3). The EtOAc phase was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give intermediate 183-5 (0.11 g) as a yellow solid. LC-MS: [M+H] ⁺ =562.1.

Step (4) Preparation of methyl-(2S)-2-((7-chloro-2-(4-(chlorosulfonyl)-2,6-difluorocyclohexa-2,4-dien-1-yl)-6-fluorimidazo[1 ,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 183-5 (100 mg) was added to the reaction flask with DCM (1 mL), glacial acetic acid (53.4 mg, 5.0 eq.) and SO ₂ Cl ₂ (96.1 mg, 4.0 eq. ) was added dropwise in an ice bath. The reaction system was reacted at room temperature for 2 hours. The starting material was consumed and intermediate 183-6 was obtained, which was detected by LCMS. The reaction system was used directly in the next step without treatment. LC-MS: [M+H] ⁺ =540.2.

Step (5) Preparation of methyl (S)-2-((7-chloro-2-(2,6-difluoro-4-sulfamoylphenyl)-6-fluorimidazo[1,2-a]pyridin-3-yl)methyl )morpholine-4-carboxylate

NH ₃ /MeOH (2 ml, 7 M) was slowly added dropwise to the above reaction system at 0°C and reacted at room temperature for 2 hours. The starting material was completely consumed, and the desired product was obtained, detected by LC -MS. The reaction system was concentrated to dryness. The residue was purified by preparative chromatography to give compound 183 (3.0 mg) as a white solid. LC-MS: [M+H] ⁺ =519.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (d, J=5.3 Hz, 1H), 8.04 (d, J=7.1 Hz, 1H), 7.73 (s , 2H), 7.64 (d, J=6.7 Hz, 2H), 3.87 (d, J=12.7 Hz, 1H), 3.61 (d, J=8.1 Hz, 3H ), 3.57 (s, 4H), 3.50 (d, J=9.9 Hz, 2H), 3.23-3.13 (m, 3H), 3.05-2.80 (m, 1H).

Example 184:

Step (1) Preparation of 4-(benzylthio)-2-methylbenzonitrile

4-fluoro-2-methylbenzonitrile (5.00 g, 37.00 mmol) was dissolved in N,N-dimethylformamide (30 ml) and potassium carbonate (7.50 g, 54.35 mmol) and benzylthiol (3.5 ml). The reaction system was stirred at 50°C overnight. The reaction system was then cooled to room temperature, water (80 mL) was added to quench the reaction, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give intermediate 184-2 (4.88 g, 52.4% yield) as a yellow solid, LC-MS: [M+H] ⁺ =239.8.

Step (2) Preparation of 4-cyano-3-methylbenzenesulfonyl chloride

Under nitrogen, intermediate 184-2 (4.88 g, 20.39 mmol) was dissolved in the prepared solvent (75 mL acetonitrile, 3.5 mL acetic acid, 1.5 mL water). The reaction system was cooled to 0°C, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (8.04 g, 40.78 mmol) was added in portions and reacted for 2 hours. The reaction system was then added water (100 ml) to quench the reaction mixture and extracted with ethyl acetate (50 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to provide intermediate 184-4 (2.8 g, 60.3% yield) as a white solid. ^1H NMR (301 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.96 (d, J=8.2, 1H), 7.87 (d, J=8.2 Hz, 1H) , 2.71 (s, 3H).

Step (3) Preparation of 4-cyano-N,N-bis(4-methoxybenzyl)-3-methylbenzenesulfonamide

Bis(4-methoxybenzyl)amine (2.80 g, 11.13 mmol) and triethylamine (3.40 g, 33.39 mmol) were dissolved in dichloromethane (50 ml). The reaction system was added with intermediate 184-4 (2.40 g, 11.13 mmol) in an ice water bath and stirred at room temperature overnight. The reaction system was then added with water (50 ml) to quench the reaction and extracted with dichloromethane (50 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to provide intermediate 184-5 (3.30 g, 64.9% yield) as a light yellow solid. LC-MS [M+H] ⁺ =458.6.

Step (4) Preparation of 4-formyl-N,N-bis(4-methoxybenzyl)-3-methylbenzenesulfonamide

Intermediate 184-5 (3.00 g, 6.87 mmol) was dissolved in anhydrous tetrahydrofuran (60 ml). The reaction system was cooled to 0°C, then a solution of diisobutylaluminum hydride in n-hexane (1 N, 17.2 ml) was added dropwise and stirred at 0°C overnight. Dilute hydrochloric acid (60 ml, 1 N) was then added to the reaction system to quench the reaction and filtered. The filtrate was extracted with ethyl acetate (50 ml x 3). The organic phases were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography to provide intermediate 184-6 (1.68 g, 55.7% yield) as a white solid. LC-MS [M+H] ⁺ =461.6.

Step (5) Preparation of tert-butyl-(S)-2-((2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-methylphenyl)-7-methylimidazo[1,2-a ]pyridin-3-yl)methyl)morpholine-4-carboxylate

Under nitrogen, intermediate 184-6 (500 mg, 1.14 mmol), 4-methylpyridin-2-amine (123 mg, 1.14 mmol), tert-butyl (S)-2-ethynylmorpholine-4-carboxylate (242 mg, 1.14 mmol), copper(I) chloride (35 mg, 0.34 mmol) and copper(II) trifluoromethanesulfonate (124 mg, 0.34 mmol) were dissolved in anhydrous toluene (5 ml). The reaction system was heated to 85°C, then N,N'-dimethylacetamide (0.1 ml) was added and stirred at 85°C overnight. After completion of the reaction, the reaction system was filtered and concentrated on a rotary evaporator to obtain the crude product. The crude product was purified by silica gel column chromatography to provide intermediate 184-7 (380 mg, 42.7% yield) as a white solid. LC-MS [M+H] ⁺ =740.5.

Step (6) Preparation of (S)-N,N-(4-methoxybenzyl)-3-methyl-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-a]pyridin-2 -yl)benzenesulfonamide

Intermediate 184-7 (380 mg, 0.51 mmol) was dissolved in anhydrous dichloromethane (5 ml) and a solution of HCl in ethanol (1.5 ml, 4 N) was added. The reaction system was stirred at room temperature for 3 hours. After completion of the reaction, the reaction system was concentrated on a rotary evaporator to give intermediate 184-8 (450 mg, crude) as a white solid, LC-MS [M+H] ⁺ =640.5.

Step (7) Preparation of methyl-(S)-2-((2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-methylphenyl)-7-methylimidazo[1,2-a]pyridine -3-yl)methyl)morpholine-4-carboxylate

Intermediate 184-8 (450 mg, crude) and N,N'-diisopropylethylamine (325 mg, 2.53 mmol) were dissolved in anhydrous dichloromethane (5 ml) under nitrogen. The reaction system was cooled in an ice water bath and a solution of methyl chloroformate in dichloromethane (10 mg/ml, 4.5 ml) was added dropwise. After the dropwise addition was completed, the reaction system was reacted at 0° C. for 2 hours. After the reaction was completed, water (20 ml) was added to the reaction system and extraction was carried out with dichloromethane (15 ml × 3). The organic phases were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to give the crude product. The crude product was purified by silica gel column chromatography to give intermediate 184-9 (150 mg, 35.4% yield) as a white solid, LC-MS [M+H] ⁺ =698.5.

Step (9) Preparation of methyl-(S)-2-((7-methyl-2-(2-methyl-4-sulfamoylphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4- carboxylate

Intermediate 184-9 (150 mg, 0.21 mmol) was dissolved in anhydrous dichloromethane (1 ml) and trifluoroacetic acid (2 ml) was added. The reaction system was stirred overnight at room temperature. After completion of the reaction, the reaction system was directly concentrated by rotary evaporation and purified by preparative reverse phase chromatography to obtain compound 184 (17 mg, 17.3% yield) as a white solid. LC-MS [M+H] ⁺ =458.5.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.16 (s, 1H), 7.87 (s, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.56(s , 1H), 7.42 (d, J=7.8 Hz, 1H), 6.80 (d, J=7.0 Hz, 1H), 5.53 (brs, 2H), 3.98-3 .76 (m, 3H), 3.69 (s, 3H), 3.58-3.47 (m, 1H), 3.43-3.31 (m, 1H), 3.05-2.85 (m, 3H), 2.60-2.50 (m, 1H), 2.49 (s, 3H), 2.35 (s, 3H).

Example 185:

The compound was prepared in accordance with the preparation method described in Example 181. LC-MS: [M+H] ⁺ =472.1.

Example 186:

The compound was prepared in accordance with the preparation method described in Example 181. LC-MS: [M+H] ⁺ =440.2.

Example 187:

The compound was prepared in accordance with the preparation method described in Example 181. LC-MS: [M+H] ⁺ =479.1.

Example 188:

The compound was prepared in accordance with the preparation method described in Example 181. LC-MS: [M+H] ⁺ =499.1.

Example 189:

Step (1) Preparation of 4-(benzylthio)-2-(trifluoromethyl)benzonitrile

4-fluoro-2-(trifluoromethyl)benzonitrile (5.00 g, 26.44 mmol) was dissolved in N,N-dimethylformamide (30 ml) and potassium carbonate (7.50 g, 54.35 mmol) was added. Benzyl mercaptan (2.80 ml) was added to the reaction system, heated to 50°C and stirred overnight. The reaction system was then cooled to room temperature, water (80 mL) was added to quench the reaction, and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to give intermediate 189-2 (6.80 g, 83.3% yield) as a yellow solid. LC-MS: [M+H] ⁺ =293.7.

Step (2) Preparation of 4-cyano-3-(trifluoromethyl)benzenesulfonyl chloride

Intermediate 189-2 (6.80 g, 23.18 mmol) was dissolved in the resulting solvent (95 mL acetonitrile, 4 mL acetic acid, 2.5 mL water) under nitrogen. The reaction system was cooled to 0°C, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (9.14 g, 46.37 mmol) was added in portions and reacted for 2 hours. The reaction system was then added water (100) to quench the reaction mixture and extracted with ethyl acetate (60 ml x 3). The organic phases were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to provide intermediate 189-3 (3.50 g, 51.5% yield) as a white solid. LC-MS: [M+H] ⁺ =270.2.

Step (3) Preparation of 4-cyano-N,N-bis(4-methoxybenzyl)-3-(trifluoromethyl)benzenesulfonamide

Triethylamine (3.93 g, 38.94 mmol) and bis(4-methoxybenzyl)amine (3.34 g, 12.98 mmol) were dissolved in dichloromethane (85 ml) under nitrogen atmosphere. The reaction system was cooled periodically to 0°C, intermediate 189-3 (3.50 g, 12.98 mmol) was added, warmed to room temperature and stirred overnight. The reaction system was then added to water (50 ml) to quench the reaction. The aqueous phase was subjected to extraction with dichloromethane (50 ml x 2). The organic phases were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give intermediate 189-4 (5.00 g, 75.1% yield) as a light yellow solid, LC-MS: [M+H] ⁺ =512.7 .

Step (4) Preparation of 4-(hydroxymethyl)-N,N-bis(4-methoxybenzyl)-3-(trifluoromethyl)benzenesulfonamide

Intermediate 189-4 (4.40 g, 8.97 mmol) was dissolved in anhydrous tetrahydrofuran (80 ml). The reaction system was cooled to 0°C, a solution of diisobutylaluminum hydride in n-hexane (1 N, 27 ml) was added dropwise, slowly warmed to room temperature and stirred overnight. Dilute hydrochloric acid (80 mL, 1N) was then added to the reaction system to quench the reaction mixture, then filtered, and the filtrate was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give intermediate 189-5 (5.00 g, crude product) as a white solid, which was used directly at the next stage. LC-MS: [M+H] ⁺ =494.6.

Step (5) Preparation of 4-formyl-N,N-bis(4-methoxybenzyl)-3-(trifluoromethyl)benzenesulfonamide

Intermediate 189-5 (5.00 g, crude product) was dissolved in anhydrous dichloromethane (70 ml) and Dess-Martin periodinane (4.85 g, 11.56 mmol) was added portionwise. The reaction system was stirred at room temperature for 1.5 hours. Then, a saturated aqueous solution of sodium thiosulfate (20 ml) was added to the reaction system to quench the reaction, and then water (30 ml) was added. The aqueous phase was subjected to extraction with dichloromethane (40 ml x 2). The organic phases were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and rotary dried. The crude product was purified by silica gel column chromatography to give intermediate 189-6 (2.00 g, 45.2% yield over two steps) as a white solid. LC-MS: [M+H] ⁺ =515.5.

Step (6) Preparation of tert-butyl-(S)-2-((2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(trifluoromethyl)phenyl)-7-methylimidazo[1, 2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 189-6 (500 mg, 1.01 mmol), 4-methylpyridin-2-amine (110 mg, 1.01 mmol), tert-butyl (5)-2-ethynylmorpholine-4-carboxylate (214 mg , 1.01 mmol), copper (I) chloride (30 mg, 0.30 mmol) and copper (II) trifluoromethanesulfonate (110 mg, 0.30 mmol) were dissolved in anhydrous toluene (5 ml) under a nitrogen atmosphere. The reaction system was heated to 85°C, 5 drops of N,N'-dimethylacetamide were added and stirred at 85°C overnight. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to give intermediate 189-7 (280 mg, 34.8% yield) as a colorless, clear oil, LC-MS: [M+H] ⁺ =794.4.

Step (7) Preparation of (S)-N,N-bis(4-methoxybenzyl)-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-a]pyridin-2-yl) -3-(trifluoromethyl)benzenesulfonamide

Intermediate 189-7 (280 mg, 0.35 mmol) was dissolved in anhydrous dichloromethane (5 ml) and a solution of HCl in ethanol (0.6 ml, 4 N) was added dropwise. The reaction system was stirred at room temperature for 3 hours. The reaction system was then concentrated under reduced pressure to give intermediate 189-8 (300 mg, crude) as a white solid, LC-MS: [M+H] ⁺ =694.5.

Step (8) Preparation of methyl-(S)-2-((2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(trifluoromethyl)phenyl)-7-methylimidazo[1,2- a]pyridin-3-yl)methyl)morpholine-4-carboxylate

Intermediate 189-8 (300 mg, crude product) was dissolved in anhydrous dichloromethane (4 ml) under nitrogen and N,N'-diisopropylethylamine (225 mg, 1.75 mmol) was added under nitrogen. The reaction system was cooled in an ice water bath, a solution of methyl chloroformate in dichloromethane (10 mg/mL, 3.3 mL) was added dropwise, and then reacted at 0°C for 4 hours. Then, water (20 mL) was added to the reaction system to quench reaction and extraction was carried out with dichloromethane (10 ml × 3). The organic phases were combined, washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography to give intermediate 189-9 (200 mg, 74.2% yield) as a white solid, LC-MS [M+H] ⁺ =752.4.

Step (9) Preparation of methyl-(S)-2-((7-methyl-2-(4-sulfamoyl-2-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine -4-carboxylate

Intermediate 189-9 (200 mg, 0.26 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (2 ml) was added. The reaction system was stirred overnight at room temperature. The reaction system was then directly concentrated on a rotary evaporator and purified by preparative reverse phase chromatography to obtain compound 189 (51 mg, 37.5% yield) as a white solid, LC-MS: [M+H] ⁺ =512. 6.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 (brs, 1H), 8.13 (brs, 1H), 8.04 (brs, 1H), 7.60 (brs, 1H), 7.47 (brs, 1H), 7.00-6.65 (m, 3H), 4.00-3.70 (m, 3H), 3.38 (s, 3H), 3.52-3.28 (m , 2H), 3.00-2.77 (m, 3H), 2.62-2.50 (m, 1H), 2.49 (s, 3H).

Example 190:

The compound was prepared in accordance with the preparation method described in Example 181. LC-MS: [M+H] ⁺ =480.2.

Example 191:

The compound was prepared in accordance with the preparation method described in Example 181. LC-MS: [M+H] ⁺ =481.4.

Example 192:

Preparation of methyl-(S)-2-((2-(4-(4-cyano-1H-imidazol-1-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2-a]pyridin-3 -yl)methyl)morpholine-4-carboxylate

Compound 110 (100 mg, 0.2 mmol) and triethylamine (89 mg, 0.88 mmol) were dissolved in dichloromethane (5 ml) and a solution of trifluoroacetic anhydride (82 mg, 0.39 mmol) in dichloromethane (1 ml) was added dropwise ) in a nitrogen atmosphere in an ice water bath. The reaction system was stirred overnight at room temperature. The reaction system was then diluted with dichloromethane (30 ml), washed successively with saturated sodium bicarbonate (15 ml x 2) and brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by preparative chromatography to give compound 192 (30 mg, 30% yield) as a white solid. LC-MS: [M+H] ⁺ =492.8.

^1H NMR (400 MHz, MeOD) δ 8.83 (d, J=7.1 Hz, 1H), 8.61 (d, J=1.2 Hz, 1H), 8.54 (d, J= 1.1 Hz, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.72 (s, 1H), 7.39 (d, J=7.1 Hz, 1H), 4 .01 (d, J=12.9 Hz, 1H), 3.83 (d, J=13.4 Hz, 1H), 3.76 (d, J=10.8 Hz, 1H), 3.71 -3.67 (m, 1H), 3.69 (s, 3H), 3.37-3.35 (m, 1H), 3.28-3.25 (m, 2H), 2.97-2 .85 (m, 1H), 2.82-2.67 (m, 1H), 2.64 (s, 3H).

Biological experiments

Example A: In Vitro Biological Activity Assessment

The antagonistic property for the compounds disclosed herein was determined using the FLIPR (Fluorescence Imaging Plates Scanner) method, which showed that the compounds are inhibitors of intracellular calcium elevation induced by activation of hP2X3 (human purinergic P2X receptor subtype 3, accession number NM_002559.4 ), expressed in HEK293 cells (human renal epithelial cell line, ATCC).

HEK293 cells, which stably express hP2X3, were cultured in high glucose DMEM containing 10% FBS (fetal bovine serum, Gibco, 10099-141), 1% penicillin-streptomycin (Gibco, 15140-122) and 1 mg/ml G418 (Invitrogen, 10131027) in a cell incubator at 37°C, 5% humidity. Cells at 400,000 cells/mL were seeded into a 384-well plate (10,000 cells/well) 18–24 hours before the FLIPR experiment and then incubated overnight in a cell incubator. On the day of the experiment, the medium was discarded and the cells were washed in FLIPR buffer (each 30 ml buffer contained 0.3 ml probenecid (Thermo, P36400), 0.6 ml 1 M HEPES (Invitrogen, 15630080) and 29.1 ml HBSS (Invitrogen, 14065056 )). 20 μl of 0.5× calcium-6 fluorescent dye (Molecular Devices, R8190) was added to each well and then subjected to dye loading incubation at 37°C for 1.5 h. 10 μl of test compound (which had been dissolved) was added to each well in DMSO at a concentration of 10 mM and serially diluted with buffer) or vehicle and then allowed to equilibrate for 30 min at room temperature. The cell plate was then placed in FLIPR to determine baseline fluorescence (excitation at 485 nm and emission at 525–535 nm). Then agonist (BZ-ATP (Sigma, B6396) at a final concentration of 2.5 μM) or vehicle (ultrapure water) was added at 10 μl/well, fluorescence values were measured for 2 min at 1 second intervals and finally analyzed fluorescence output values.

The IC ₅₀ values obtained by the above method are given in Table 2.

Positive control connection 1:

Positive control connection 2:

As can be seen from the data in Table 2, the compounds disclosed herein exhibit good P2X3 inhibitory activity, with most of the compounds exhibiting stronger inhibitory activity than Positive Control Compound 2 and some of the compounds exhibiting stronger inhibitory activity than Positive Control 2. Compounds 1. Compounds with stronger inhibitory activity than Positive Control Compound 2 and compounds with stronger inhibitory activity than Positive Control Compound 1 are preferred.

Example B: Assessment of selectivity for P2X2/3 receptors in vitro

The selectivity of the compounds disclosed herein for the P2X2/3 receptor was determined using the FLIPR (Fluorescence Scanning Plates Imaging) method, demonstrating that the compounds were inhibitors of the intracellular calcium elevation induced by activation of hP2X2/3 (heterogeneous and mer receptors formed human purinergic receptors _P2X subtype 2 and subtype 3, accession number NM_002559.4 for P2X2 and accession number NM_002559.4 for P2X3), expressed in HEK293 cells (human renal epithelial cell line, ATCC).

HEK293 cells, which stably express hP2X2/3, were cultured in high glucose DMEM containing 10% FBS (fetal bovine serum, Gibco, 10099-141), 1% penicillin-streptomycin (Gibco, 15140-122) and 1 mg /ml G418 (Invitrogen, 10131027) in a cell incubator at 37°C, 5% humidity. Cells at 250,000 cells/mL were seeded into a 96-well plate (25,000 cells/well) 18–24 hours before the FLIPR experiment and then incubated overnight in a cell incubator. On the day of the experiment, the medium was discarded and the cells were washed in FLIPR buffer (0.3 ml probenecid (Thermo, P36400), 0.6 ml 1 M HEPES (Invitrogen, 15630080) and 29.1 ml HBSS (Invitrogen, 14065056) per 30 ml buffer ). 75 μl of 1 mM fluorescent dye Fluo-4 AM (Thermo, F14202) was added to each well and then incubated with the dye load at 37°C for 1.0 h. The 96-well plate was then washed once with buffer, buffer was added, containing the test compound or vehicle, at 50 μl per well and then incubated for 30 minutes at room temperature. The cell plate was then placed in FLIPR for baseline fluorescence measurements (excitation at 485 nm and emission at 525–535 nm). The agonist (BZ-ATP (Sigma, B6396) at a final concentration of 5.µM) or vehicle (ultrapure water) was then added at 50 µl/well, fluorescence values were measured for 2 min at 1 second intervals, and finally the output was analyzed. fluorescence values.

The IC ₅₀ values obtained by the above method are given in Table 2.

As can be seen from the data in Table 3, the compounds disclosed herein exhibit poor P2X2/3 heterodimeric receptor inhibitory activity and good selectivity for P2X3 and P2X2/3. Selectivity factor = (IC ₅₀ in relation to P2X2/3)/(IC ₅₀ in relation to P2X3). Compounds with a selectivity factor greater than 200 are preferred, and compounds with a selectivity factor greater than 1000 are more preferred.

Example C: Activity Study in Citric Acid Only Models

Male Dunkin Hartley guinea pigs (300–350 g) were placed in an animal spray box, and then the spray box door was closed while the ultrasonic nozzle (Guangdong Yuehua) was turned on. 17.5% citric acid was introduced into the nebulization unit at the maximum nebulization rate (about 2 ml/min) for 20 s, and the animals coughed for 10 min continuously from the start of nebulization. During the 10-minute observation, the animals' coughs were manually counted, and the number of coughs was scored according to coughing-related behaviors of the guinea pigs, such as abdominal twitching, mouth opening, and sudden head downward tilt. The number of coughs during the first 5 minutes and 10 minutes was recorded, as well as the latency of the guinea pigs' cough, namely the time from the start of induction with citric acid to the appearance of the first cough.

The above experiment was carried out on the following typical compounds: compound 2, compound 7, compound 53, compound 149, compound 161, compound 162, compound 164, compound 165 and compound 172. The results are presented in table 4 and figures 1, 2, 3 and 4 demonstrate that, compared to vehicle blank or pre-administration condition, Compound 2, Compound 7, Compound 53, Compound 149, Compound 161, Compound 162, Compound 164, Compound 165, and Compound 172 at 30 mg/kg can effectively reduce the number of coughs and prolong cough latency, and the effectiveness of these compounds is not significantly different from the effectiveness of the positive control compound 1, indicating that compound 2, compound 7, compound 53, compound 149, compound 161, compound 162, compound 164, compound 165 and compound 172 can reduce the amount of cough and improve cough latency, and their effectiveness is equivalent to that of the positive compound.

Example D: Activity Study in ATP-Citric Acid Models of Cough

Male Dunkin Hartley guinea pigs (300-400 g) were placed in a whole-body plethysmography box for acclimation for 3-5 min, followed by 2 min of ATP nebulization, and 3 min later, 5 min of citric acid nebulization, all nebulization rates were approximately 300 μL/min. The amount of coughing and cough latency of the animals were recorded within 10 minutes from the start of citric acid spraying. During the 10-minute observation period, the animals' coughs were manually counted, and the coughs were scored according to cough-related behaviors of the guinea pigs, such as abdominal twitching, mouth opening, head tilting, and the like. The number of coughs within 10 minutes, as well as the cough latency of the guinea pigs, were recorded.

Animals were divided into vehicle group, dextromethorphan positive group (63 mg/kg), AF-219 positive group (30 mg/kg), and Example 173 administration group (3, 10, 30 mg/kg). and all compounds were administered orally. Except that dextromethorphan was administered 40 minutes before ATP-citric acid exposure, the remaining compounds were administered 2 hours before ATP-citric acid exposure.

As shown in Table 5 and FIG. 5 and 6, all compound treatment groups showed a trend to reduce the amount of cough compared to the vehicle group, both dextromethorphan and compound 172 could significantly reduce the amount of cough, and compound 172 showed inhibition in a dose-dependent manner. Compound 172 exhibits a stronger cough suppressant effect than positive control compound 2.

Example E: In Vitro Cytotoxicity Assay

In vitro cytotoxicity assays for the compounds disclosed herein were performed in HepG2 cells using the CCK-8 method. HepG2 cells (Beina Bio) in logarithmic growth phase were collected, the concentration of the cell suspension was adjusted, and then the cells were seeded in a 96-well cell culture plate at 50,000 cells/well. The cells were then incubated overnight in a cell incubator with 5% humidity at 37°C, and after reaching 80-90% cell confluence, test compounds or vehicle (DMSO) at various concentration gradients were added after changing the medium. The plate was incubated in a cell incubator with a humidity of 5% at 37°C for 48 hours. After treatment, the medium was discarded from the plate. The plate was washed twice with PBS, CCK-8 working solution (Beyotime) was added in an amount of 100 μl per well, and then incubated at 37°C for 1.5 h in the dark. Absorbance at OD _{450 nm} was measured for each well on a microplate reader, and the CC ₅₀ value of each compound was analyzed and calculated.

The _CC50 values obtained by the above method are given in Table 6.

As can be seen in Table 4, most of the compounds disclosed herein demonstrate relatively good safety, with CC ₅₀ ranges greater than 10 μM, which satisfies the requirement for in vitro cytotoxicity of common compounds. Compounds with a CC ₅₀ value greater than 30 μM are preferred, and compounds with a CC ₅₀ value greater than 50 μM are more preferred.

Example F: In Vitro Metabolic Stability Test The in vitro metabolic stability of the compounds described herein was determined by incubating liver microsomes of various species. The correct amount of test compound was added to the liver microsomal reaction system (1 mg/ml liver microsomal protein, 25 U/ml glucose-6-phosphate dehydrogenase, 1 mM NADP, 6 mM D-glucose-6-phosphate and 5 mM MgCl ₂ ), and the mixture was then incubated in a kettle in a water bath at 37°C to begin the reaction. At each time point, 100 μl of the reaction mixture was added to a centrifuge tube containing 400 μl of internal standard working solution (containing 200 ng/ml solution of dexamethasone, diclofenac, tolbutamide and labetalol in acetonitrile), pre-cooled at 0°C to stop the reaction, and the mixture then centrifuged at 10,000 g for 10 min at 4°C. The supernatant was collected for LC-MS analysis to obtain in vitro metabolic half-life values of the test compounds in liver microsomes of different species.

The T _1/2 values obtained by the above method are given in Table 7.

As can be seen from the data in Table 5, the compounds disclosed herein demonstrate relatively good metabolic stability in humans, rats and guinea pigs. Compared to positive control compound 1, the compounds described herein have a similar metabolic half-life in the human liver microsome, but a longer half-life in rats and guinea pigs. In addition, compared with positive compound 1, the metabolism of the compounds described herein in rats and guinea pigs is more similar to that in humans, which is useful for appropriate experimental evaluation of the compounds in rats and guinea pigs. Compounds with a T1 _/2 >30 min in the human liver microsome are preferred, and compounds with a T1 _/2 >90 min in the human liver microsome are more preferred.

Example G: Two-bottle dysgeusia test

Male SD rats (SPF class, 6-8 weeks old) were subjected to adaptive drinking training for 3 days after being recruited, and the specific content of the training was as follows: the animals were fed in separate cages and were given two bottles of water (both regular drinking water) into each cell; during adaptive training, drinking water was completely prohibited at night each day (drinking water bottles were removed) and then refilled from 8:30 a.m. to 5:30 p.m.; and the operation was repeated for 3 days, the positions of the two water bottles were changed every day, and the animals were allowed to feed freely throughout the adaptive training period. All drinking water bottles were removed 20 h before the start of the formal experiment, and all animals were deprived of water before the start of the experiment. In the experiment, all animals were randomly grouped and then subjected to a single intraperitoneal injection of test compound or vehicle before water replenishment. The administration time was determined in accordance with the _Tmax of the test compound. The animals were then placed in separate cages and given two bottles of drinking water (one bottle of normal drinking water and one bottle of water with 0.3 mM quinine). The water consumption of the animals was observed for 15 minutes, statistical analysis was performed on the basis of quinine water consumption/normal water consumption, and positive control compound 2 was used as a positive control for dysgeusia.

The above experiment was carried out on the following representative compounds: compound 2, compound 7, compound 53, compound 149, compound 161, compound 162, compound 164 and compound 165. The results presented in Table 8 and Fig. 7 show that for compound 2, compounds 7, compounds 53, compounds 149, compounds 161, compounds 162, compounds 164 and compounds 165 at a dose of 20 mg/kg, the quinine/water intake ratio remains almost unchanged compared to vehicle administration, while the quinine/water intake ratio is significantly reduced compared to the administration of positive control compound 2, indicating a lesser effect of compound 2, compound 7, compound 53, compound 149, compound 161, compound 162, compound 164 and compound 165 on the taste of animals.

The above experiment was performed on exemplary compound 172. The results presented in Table 9 and FIG. 8 illustrate that for compound 172 at 5 mg/kg, 10 mg/kg, and 20 mg/kg, the quinine/water intake ratio in rats remained essentially unchanged. unchanged compared to vehicle administration, indicating that compound 172 has little effect on animal palatability; Compared to the positive control compound 2, the quinine/water intake ratio is significantly reduced, and this shows that the risk of dysgeusia with compound 172 is much lower than that of positive compound 2, and compound 172 is shown to be safer.

Although examples of the present invention have been illustrated and described above, it is to be understood that the above examples are illustrative and should not be construed as limiting the present invention, and that changes, modifications, substitutions and variations in the above examples may be made by those skilled in the art within the scope of of the present invention.

Claims (199)

1. Heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof , Where represents , m represents 1, 2, 3 or 4; R ³ represents H, halogen, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ alkyl; when m is not equal to 1, R ³ is independently the same or different; W represents a single bond; is phenyl; n is 1, 2, 3 or 4; R ¹ independently represents H, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl; wherein said substituted C ₁ -C ₆ alkyl is substituted with one to three halogens; and when n is not 1, R ¹ is independently the same or different; Q represents -NH-C(=O)-R ^1-1 , -S(=O) ₂ -N(R ^1-9 R ^1-10 ), -N(R ^1-14 R ^1-15 ), -NH-S(=O) ₂ -R ^1-16 , unsubstituted or substituted C ₃ -C ₄ cycloalkyl, unsubstituted or substituted C ₃ -C ₆ heterocycloalkyl, or unsubstituted or substituted 5-6 membered heteroaryl; wherein said C ₃ -C ₆ heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O and N; said 5-6 membered heteroaryl contains 1-3 heteroatoms selected from N; said substituted C ₃ -C ₄ cycloalkyl, substituted C ₃ -C ₆ heterocycloalkyl, or substituted 5-6 membered heteroaryl is substituted with one or more substituents independently selected from the following: halogen, -OH and -CN; where R ^1-1 , R ^1-9 , R ^1-10 , R ^1-14 , R ^1-15 and R ^1-16 are each independently H, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted C ₂ - C ₃ alkenyl, unsubstituted or substituted C ₃ -C ₆ cycloalkyl, unsubstituted or substituted C ₄ -C ₆ heterocycloalkyl or unsubstituted or substituted phenyl; wherein said C ₄ -C ₆ heterocycloalkyl contains 1 heteroatom selected from O; and said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₆ heterocycloalkyl, phenyl are substituted with one or two substituents independently selected from the following: halogen, -COOH, -COOCH ₃ , -NH ₂ and =O ; R ² independently represents ; where R ^2-1 and R ^2-2 each independently represent H, unsubstituted C ₁ -C ₆ alkyl; X and Y are each independently methylene, -O-, -N(R ^2-3 )- or ; R ^2-3 and R ^2-4 each independently represent H or unsubstituted C ₁ -C ₆ alkyl-O-. 2. A heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein m represents 1 or 2; and/or when R ³ is halogen, said halogen is fluorine, chlorine, bromine or iodine; and/or when R ³ is C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl is C ₁ -C ₄ alkyl; and/or when R ³ is a C ₁ -C ₆ haloalkyl, said halogen is fluorine, chlorine, bromine or iodine; and/or when R ³ represents a C ₁ -C ₆ haloalkyl, said haloalkyl contains one or more halogens; and/or n is 1 or 2; and/or each R ¹ is independently located at the α or β position of the bond between and Z ² ; and/or when R ¹ is halogen, said halogen is fluorine, chlorine, bromine or iodine; and/or when R ¹ is unsubstituted or substituted C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl is independently C ₁ -C ₄ alkyl; when R ¹ represents a substituted C ₁ -C ₆ alkyl and each of the substituents is independently a halogen, said halogen is fluorine, chlorine, bromine or iodine; and/or when R ¹ represents a substituted C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl in the substituents independently represents a C ₁ -C ₄ alkyl; and/or when R ¹ represents a substituted C ₁ -C ₆ alkyl, the number of substituents is independently 1, 2 or 3; and/or Q is located at the β or γ position of the bond between and W; and/or when Q is unsubstituted or substituted C ₃ -C ₄ cycloalkyl, said C ₃ -C ₄ cycloalkyl is cyclopropyl or cyclobutyl; and/or when Q is unsubstituted or substituted C ₃ -C ₆ heterocycloalkyl, said C ₃ -C ₆ heterocycloalkyl is C ₃ -C ₅ heterocycloalkyl, wherein said C ₃ -C ₅ heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O and N; and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, said 5-6 membered heteroaryl is imidazolyl, oxazolyl, furanyl, thienyl, pyrrolyl, pyrazolyl, isoxazolyl, pyridinyl, triazolyl or pyrimidinyl; and/or when Q is substituted C ₃ -C ₄ cycloalkyl, substituted C ₃ -C ₆ heterocycloalkyl or substituted 5-6 membered heteroaryl, the number of substituents is independently 1, 2 or 3; and/or when Q is a substituted C ₃ -C ₄ cycloalkyl, a substituted C ₃ -C ₆ heterocycloalkyl or a substituted 5-6 membered heteroaryl, and the substituent is a halogen, said halogen is independently fluorine, chlorine, bromine or iodine. 3. A heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 2, in which when R ³ represents C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl represents methyl; and/or when R ³ is a C ₁ -C ₆ haloalkyl, said halogen is fluorine, chlorine, bromine or iodine; and/or when R ³ represents a C ₁ -C ₆ haloalkyl, said haloalkyl contains 1, 2 or 3 halogens; and/or when R ¹ represents unsubstituted or substituted C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl represents methyl; and/or when R ¹ represents a substituted C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl in the substituents independently represents methyl; and/or when Q is unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl, said C ₃ -C ₅ heterocycloalkyl is C ₄ -C ₅ heterocycloalkyl, wherein said C ₄ -C ₅ heterocycloalkyl is glycidyl, pyrrolidinyl or piperazinyl; and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, imidazolyl is or ; and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, oxazolyl is ; and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, furanyl is , and/or when Q is unsubstituted or substituted 5-6 membered heteroaryl, thienyl is ; and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, pyrrolyl is or ; and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, pyrazolyl is or ; and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, isoxazolyl is ; and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, pyridinyl is ; and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, pyrimidinyl is ; and/or when Q is unsubstituted or substituted 5-6 membered heteroaryl and triazolyl is , , or ; and/or when Q is a substituted C ₃ -C ₆ heterocycloalkyl or a substituted 5-10 membered heteroaryl and the substituent is a halogen, said halogen is fluorine. 4. A heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein when R ¹ represents a substituted C ₁ -C ₆ alkyl and each of the substituents is independently halogen, said C ₁ -C ₆ alkyl is independently -CF ₃ ; and/or when R ³ is a C ₁ -C ₆ haloalkyl, said C ₁ -C ₆ haloalkyl is -CF ₃ , -CH ₂ F or -CHF ₂ ; and/or represents ; and/or represents , , , , , , , ; and/or at least one R ¹ is located in position α of the connection between and Z ² ; and/or when R ^1-1 represents a substituted C ₁ -C ₆ alkyl, said substituted C ₁ -C ₆ alkyl represents , , , , , , , or ; and/or when each R ^1-1 , R ^1-9 or R ^1-10 is a substituted C ₃ -C ₆ cycloalkyl, said substituted C ₃ -C ₆ cycloalkyl is , , , , , or ; and/or represents . 5. A heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein when n is 2, each of the R ¹ is independently located at the α position of the bond between and Z ² ; or at least one R ¹ is located at the β position of the bond between and Z ² ; and/or when R ^1-1 , R ^1-9 and R ^1-10 are each substituted C ₃ -C ₆ cycloalkyl, said substituted C ₃ -C ₆ cycloalkyl is , , , , , or ; and/or represents or ; or represents . 6. A heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein when is phenyl, represents or wherein R ^1' has the same definition as described for R ¹ and R ^1' is the same or different from R ¹ ; and/or -NH-C(=O)-R ^1-1 represents -NH-C(=O)-CH ₃ , -NH-C(=O)-O-CH ₃ , , , , , , , , , , , , , , , , , , or ; and/or -S(=O) ₂ -N(R ^1-9 R ^1-10 ) is -S(=O) ₂ -NH-CH ₃ or -SO ₂ NH ₂ ; and/or when Q is substituted C ₃ -C ₆ heterocycloalkyl, said substituted C ₃ -C ₆ heterocycloalkyl is , , , or ; and/or when Q is a substituted 5-6 membered heteroaryl, said substituted 5-6 membered heteroaryl is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; and/or when R ² represents , one of X and Y represents , and the other is methylene or -O-. 7. A heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 6, in which represents , , , , , or ; and/or when Q is a substituted C ₃ -C ₆ heterocycloalkyl, said substituted C ₃ -C ₆ heterocycloalkyl is , , or ; and/or when Q is a substituted 5-6 membered heteroaryl, said substituted 5-6 membered heteroaryl is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; and/or R ² represents , or ; or when R ² represents , X or Y is -N(R ^2-3 )-. 8. A heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein represents , , , , , or ; and/or represents , , , , or ; and/or Q represents -NH ₂ , -NH-C(=O)-CH ₃ , -NH-C(=O)-O-CH ₃ , , , , -S(=O) ₂ -NH-CH ₃ , -S(=O) ₂ -NH ₂ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , -NH-S(=O) ₂ -CH ₃ , , , , , , , , , or ; and/or R ² represents , , , or . 9. A heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, in which R ³ represents halogen, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ alkyl; Q represents -NH-C(=O)-R ^1-1 , -S(=O) ₂ -N(R ^1-9 R ^1-10 ), unsubstituted or substituted C ₃ -C ₄ cycloalkyl, unsubstituted or substituted C ₃ -C ₆ heterocycloalkyl or unsubstituted or substituted 5-6 membered heteroaryl, wherein said C ₃ -C ₆ heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O and N, and said 5-6 membered heteroaryl contains 1-3 heteroatoms selected from N; said substituted C ₃ -C ₄ cycloalkyl, substituted C ₃ -C ₆ heterocycloalkyl or substituted 5-6 membered heteroaryl is substituted with one or more substituents independently selected from the following: -OH and -CN; R ² independently represents . 10. A heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, in which the heterocyclic compound of formula I is embodiment I or embodiment II, implementation option I: represents ; m represents 1, 2, 3 or 4; R ³ represents H, halogen, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ alkyl; when m is not equal to 1, R ³ is independently the same or different; W represents a single bond; is phenyl; n is 1, 2, 3 or 4; R ¹ independently represents H, halogen, or unsubstituted or substituted C ₁ -C ₆ alkyl; wherein said substituted C ₁ -C ₆ alkyl is substituted with one to three halogens; and when n is not equal to 1, R ¹ is independently the same or different; Q represents -NH-C(=O)-R ^1-1 , -S(=O) ₂ -N(R ^1-9 R ^1-10 ), -N(R ^1-14 R ^1-15 ), -NH-S(=O) ₂ -R ^1-16 , unsubstituted or substituted C ₃ -C ₄ cycloalkyl, unsubstituted or substituted C ₃ -C ₆ heterocycloalkyl or unsubstituted or substituted 5-6-membered heteroaryl, where the specified C ₃ - C ₆ heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O and N, and said 5-6 membered heteroaryl contains 1-3 heteroatoms selected from N; said substituted C ₃ -C ₄ cycloalkyl, substituted C ₃ -C ₆ heterocycloalkyl or substituted 5-6 membered heteroaryl is substituted with one or more substituents independently selected from halogen, -OH and -CN; R ^1-1 , R ^1-9 , R ^1-10 , R ^1-14 , R ^1-15 and R ^1-16 are each independently H, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted C ₂ -C ₃ alkenyl, unsubstituted or substituted C ₃ -C ₆ cycloalkyl, unsubstituted or substituted C ₄ -C ₆ heterocycloalkyl or unsubstituted or substituted phenyl, wherein said C ₄ -C ₆ heterocycloalkyl contains 1 heteroatom selected from O; and said C ₁ -C ₆ alkyl, substituted C ₃ -C ₆ cycloalkyl, substituted C ₄ -C ₆ heterocycloalkyl, phenyl are substituted with two substituents independently selected from halogen, -COOH, -COOCH ₃ , -NH ₂ and =O; or R ² represents ; R ^2-1 and R ^2-2 each independently represent H, unsubstituted C ₁ -C ₆ alkyl; X and Y are each independently methylene, -O-, -N(R ^2-3 )- or ; R ^2-3 and R ^2-4 are each independently H or unsubstituted C ₁ -C ₆ alkyl-O-; implementation option II: represents ; m represents 1, 2, 3 or 4; R ³ represents H, halogen, -CF ₃ or C ₁ -C ₆ alkyl; when m is not equal to 1, R ³ is the same or different; W represents a single bond; is phenyl; n is 1, 2, 3 or 4; R ¹ independently represents H, halogen, or unsubstituted or substituted C ₁ -C ₆ alkyl; wherein said substituted C ₁ -C ₆ alkyl is substituted with one to three halogens; and when n is not 1, R ¹ is the same or different; Q represents -NH-C(=O)-R ^1-1 , unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl or unsubstituted or substituted 5-6 membered heteroaryl, wherein said C ₃ -C ₅ heterocycloalkyl contains 1-3 heteroatoms , selected from one or more of O and N, and said 5-6 membered heteroaryl contains 1-3 heteroatoms selected from N; and said substituted C ₃ -C ₅ heterocycloalkyl or substituted 5-6 membered heteroaryl is substituted with one or more substituents independently selected from the following: halogen, -OH and -CN; R ² represents ; R ^2-1 and R ^2-2 each independently represent H, unsubstituted C ₁ -C ₆ alkyl; X and Y are each independently methylene, -O-, -N(R ^2-3 )- or ; R ^2-3 and R ^2-4 are each independently H. 11. A heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 2, in which when Q is unsubstituted or substituted C ₃ -C ₅ heterocycloalkyl, said C ₃ -C ₅ heterocycloalkyl is C ₄ -C ₅ heterocycloalkyl, wherein said C ₄ -C ₅ heterocycloalkyl contains 1-2 heteroatoms selected from one or more of N and O; and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, said 5-6 membered heteroaryl is imidazolyl, oxazolyl, furanyl, thienyl, pyrrolyl, pyrazolyl, isoxazolyl, pyridinyl or pyrimidinyl; and/or when Q is a substituted C ₃ -C ₅ heterocycloalkyl or a substituted 5-6 membered heteroaryl and the substituent is a halogen, said halogen is independently fluorine, chlorine, bromine or iodine and preferably fluorine. 12. A heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, in which when Q is unsubstituted or substituted C ₄ -C ₅ heterocycloalkyl, said C ₄ -C ₅ heterocycloalkyl is pyrrolidinyl or piperazinyl, and said pyrrolidinyl is , and said piperazinyl is ; and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, imidazolyl is or ；and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, oxazolyl is ；and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, furanyl is ；and/or when Q is unsubstituted or substituted 5-6 membered heteroaryl, thienyl is ；and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, pyrrolyl is or ；and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, pyrazolyl is or ；and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, oxazolyl is ；and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, pyridinyl is ；and/or when Q is an unsubstituted or substituted 5-6 membered heteroaryl, pyrimidinyl is ；and/or when Q is a substituted C ₃ -C ₅ heterocycloalkyl or a substituted 5-6 membered heteroaryl and the substituent is a halogen, said halogen is fluorine. 13. The heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 12, wherein when Q is a substituted C ₃ -C ₅ heterocycloalkyl, said substituted C ₃ -C ₅ heterocycloalkyl is or ; and/or when Q is a substituted 5-6 membered heteroaryl, said substituted 5-6 membered heteroaryl is , , , , , or ; and/or when Q is -NH-C(=O)-R ^1-1 , said -NH-C(=O)-R ^1-1 is -NH-C(=O)-CH ₃ , -NH-C (=O)-O-CH ₃ , , , or ; and/or when Q is -S(=O) ₂ -N(R ^1-9 R ^1-10 ), said -S(=O) ₂ -N(R ^1-9 R ^1-10 ) is -S(= O) ₂ -NH-CH ₃ ; and/or when R ² represents , one of X and Y represents , and the other is methylene or -O-; preferably X is -O-; and more preferably R ² is or ; or when R ² represents , X or Y is -N(R ^2-3 )-; preferably one of X and Y is -N(R ^2-3 )- and the other is -O-, -N(R ^2-3 )- or ; and more preferably R ² is , , or . 14. A heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1, 9 or 10, in which a heterocyclic compound of formula I has formula IC-1 as shown below: ; or a heterocyclic compound of formula I is a compound of formula I-E, as shown below: ; where R ² independently represents or is an unsubstituted or substituted 5-6 membered heteroaryl. 15. The heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 14, in which a heterocyclic compound of formula I has the formula I-C-2 as shown below: , wherein R1' has the definition as described for ^R1 , R1 ^' is the same or different from ^R1 , and X is methylene or -O-; or a heterocyclic compound of formula I has formula I-E-1, as shown below: . 16. The heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 14, in which the heterocyclic compound of formula I has formula I-E-2, as shown below: . 17. A heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, in which m represents 1 or 2; and/or R ³ represents H, halogen, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ alkyl; and/or W represents a single bond; and/or n is 1 or 2; and/or R ¹ independently represents H, halogen, or unsubstituted or substituted C ₁ -C ₆ alkyl; and/or the substituent on R ¹ independently represents one to three halogens; and/or Q is -NH-C(=O)-R ^1-1 , -S(=O) ₂ -N(R ^1-9 R ^1-10 ), unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₃ -C ₆ heterocycloalkyl or unsubstituted or substituted 5-6 membered heteroaryl; and/or R ² independently represents . 18. A heterocyclic compound of the following formula or a pharmaceutically acceptable salt thereof: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And ; And a pharmaceutically acceptable salt of the heterocyclic compound of formula I is the following compound: . 19. A method for preparing a heterocyclic compound of formula I according to any one of claims. 1-18, where the production method is Scheme I, Scheme II, Scheme III, Scheme IV, Scheme V, Scheme VI, Scheme VII or Scheme VIII, wherein Scheme I involves the following step: performing a Still-coupling reaction as shown below on a compound of formula II-1 and an organic tin reagent of formula III-1 in an organic solvent in the presence of a catalyst to produce a heterocyclic compound of formula I: ; where X ¹ represents Br or Cl; Scheme II includes the following step: performing a Suzuki coupling reaction as shown below on a compound of formula II-2 and a compound of formula III-2 in a solvent in the presence of a catalyst and a basic reagent to produce a heterocyclic compound of formula I: where X ² represents Br or Cl; Scheme III involves the following step: reacting as shown below with a compound of formula II-3, a compound of formula III-3 and formaldehyde in an organic solvent to obtain a heterocyclic compound of formula I: ; Scheme IV includes the following step: reacting as shown below with a compound of formula II-3 and a compound of formula III-4 in an organic solvent to obtain a heterocyclic compound of formula I: ; where X ³ represents a leaving group; Scheme V involves the following step: performing an amidation reaction as shown below on a compound of formula I wherein R ² is and Y is -NH-, and a compound of formula III-5 in an organic solvent in the presence of a basic reagent to produce a heterocyclic compound of formula I, wherein Y is : where X ⁴ represents halogen; Scheme VI includes the following step: carrying out a deprotection reaction as shown below on a compound of formula II-4 and a compound of formula III-5 in an organic solvent in the presence of an acid to obtain a heterocyclic compound of formula I: where Y represents -NH-; Scheme VII includes the following step: carrying out a displacement reaction as shown below on a compound of formula II-5 and NH(R ^1-9 R ^1-10 ) in an organic solvent to obtain a heterocyclic compound of formula I wherein Q is -S( =O) ₂ -N(R ^1-9 R ^1-10 ): ; where X ⁵ represents Br or Cl; Scheme VIII involves the following step: subjecting a compound of Formula II-6 or Formula II-6' to a deprotection reaction as shown below in an organic solvent in the presence of an acid to produce a heterocyclic compound of Formula I: ; where X ⁶ , X ^6' and X ^6'' represent N-protecting groups; And , , R ³ , R ² , R ¹ , Q, W, X, Y, R ^1-9 , R ^1-10 , R ^2-1 , R ^2-2 , R2-4,n and m have the definitions specified in any of paragraphs. 1-14. 20. Compound of formula II-1, II-2, II-3, II-4, II-5, II-6 or II-6': Where , ^R3 , ^R2 , ^R1 , Q, W, X, Y, ^R1-9 , ^R1-10 , ^R2-1 , ^R2-2 , n and m are defined as defined in any of paragraphs. 1-18, and X ¹ , X ⁵ , X ⁶ , X ^6' and X ^6'' have the definitions as defined in paragraph 19. 21. Connections as below: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . 22. A pharmaceutical composition for the prevention, treatment or alleviation of diseases in an animal that are mediated at least in part by P2X3 or associated with P2X3 activity, containing a therapeutically effective amount of a heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-18 and at least one pharmaceutically acceptable excipient. 23. The use of a heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-18 or the pharmaceutical composition according to claim 22 for obtaining a P2X3 inhibitor or drug. 24. The use of claim 23, wherein the medicinal product is used to prevent, treat or alleviate diseases in an animal that are mediated at least in part by P2X3 or associated with P2X3 activity; and/or wherein said medicinal product is used to treat pain, urinary tract diseases or respiratory diseases. 25. Use according to claim 24, wherein the diseases include pain, urinary tract diseases or respiratory diseases. 26. Use according to claim 25, wherein the pain includes: inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine or cluster headache; urinary tract diseases include: urinary incontinence, overactive bladder, dysuria or cystitis; and respiratory diseases include: breathing disorders including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm or chronic cough.