WO2019062657A1 - Nitrogen heterocyclic derivative, preparation method therefor, and pharmaceutical use thereof - Google Patents

Abstract

The present invention relates to a nitrogen heterocyclic derivative, a preparation method therefor, and a pharmaceutical use thereof. In particular, the present invention relates to a nitrogen heterocyclic derivative represented by the general formula (I), a preparation method therefor, a pharmaceutical composition containing the same, and a use thereof as an SMO antagonist, particularly in the treatment of Hedgehog signaling pathway-associated diseases such as cancer. The definitions of the groups in the general formula (I) are the same as those in the specification.

Description

Nitrogen heterocyclic derivative, preparation method thereof and medical use thereof Technical field

The present invention relates to a novel nitrogen heterocyclic derivative, a process for the preparation thereof, a pharmaceutical composition containing the same, and its use as an SMO antagonist, particularly in the treatment of diseases associated with the Hedgehog signaling pathway, such as cancer .

Background technique

The Hedgehog (Hh) signaling pathway is an important embryonic pathway that plays an important regulatory role in cell proliferation and differentiation during embryonic development. There are three homologous Hedgehog proteins that have been identified by humans: Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh). There is much evidence that Shh plays a very important role in the carcinogenic mechanisms of some cancers, including basal cancer cells. The Hh signal is transmitted by the seven-transmembrane protein Smoothened (SMO) associated with the G protein-coupled receptor. In adulthood, the Hh signaling pathway is generally in a closed state, but the abnormal activation of the Hh signaling pathway plays a pivotal role in the occurrence and development of tumors. Mutation analysis of Hh information channels in basal cancer cells showed that most of the variation occurred on PTCH-1 and SMO. PTCH-1 is a membrane protein with 12 transmembrane structures, which is a direct acting receptor for Shh. Under normal circumstances, the concentration of Hedgehog protein in the human body is very low. In this case, PTCH-1 interacts with SMO to inhibit the biological activity of SMO and put the channel in a closed state. Once Shh binds to PTCH-1, it will cause PTCH-1 to detach from SMO, thus freeing SMO from the suppressed state. Activation of SMO will further induce activation of downstream transcription factors Gli (including Gli1, Gli2 and Gli3), thereby regulating genes. Transcription and cell growth. Therefore, SMO acts as a switch for Gli. Disturbing its effects will induce excessive cell growth and canceration. For example, most basal cell carcinomas are hyperactive Hedgehog signaling pathways due to genetic mutations or other causes. Therefore, inhibition of the activity of the excessively high Hedgehog signaling pathway can inhibit the growth of cancer cells to achieve treatment of various cancers caused by this mechanism.

In recent years, the research on the Hedgehog pathway has received more and more attention from the scientific community, and the small molecule inhibitors targeting the Hh pathway, especially the novel target G protein coupled receptor Smoothened (SMO), have become pharmaceutical companies and research institutions. Research hotspots. The Hedgehog pathway antagonists Vismodegib (GDC-0449) and Sonidegib (LDE225) were approved by the US Food and Drug Administration (FDA) in 2012 and 2015, respectively, for the treatment of adult basal cell carcinoma patients. These antagonists inhibit the activity of SMO and inhibit the activity of the Hh signaling pathway, thereby achieving anticancer effects. In addition to basal cell carcinoma and medulloblastic cancer, many other cancers are also associated with abnormal activation of the Hh signaling pathway, including esophageal cancer, gastric cancer, pancreatic cancer, and lung cancer. Moreover, more and more studies have shown that the activity of the Hh signaling pathway is closely related to the problem of acquired resistance that is currently plagued by various cancer treatments. For example, the augmentation of the SMO gene and the activation of the Hh pathway are considered to be one of the main reasons for the loss of therapeutic effect on the cell epidermal growth factor receptor (EGFR) inhibitor of non-small cell lung cancer. Therefore, the development of Hedgehog inhibitors as anticancer drugs, especially in combination with other antibiotics to treat various cancers is very promising.

Summary of the invention

The inventors have deliberately studied and designed a series of nitrogen-containing heterocyclic compounds, and the results of in-depth studies show that the compounds can antagonize SMO and inhibit Hedgehog signaling pathway, and can be developed to treat Hedgehog signaling pathways. The disease of the drug.

Accordingly, the present invention relates to a compound of the formula (I) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable form thereof salt,

among them:

Q, V, U ₀ are each independently selected from C or N;

R, W, U ₁ , U ₂ , U ₃ , U ₄ are each independently selected from CR ³ or N;

Y is selected from N or CH;

Ar is selected from aryl or heteroaryl, preferably 5- to 6-membered aryl or heteroaryl, more preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; said aryl or heteroaryl Optionally further substituted with one or more groups selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl;

R ^{1 is} selected from the group consisting of hydrogen, halogen, amino, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a , -C(O)R ^a , O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -NHS(O)R ^a , -NHS(O) ₂ R ^a ; wherein the alkyl group, a cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further substituted with one or more groups R ⁵ ;

R ^{5 is} selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R ^a , -S(O)R ^a , -S(O) ₂ R ^a , -P(O)R ^a R ^b , -B(OH) ₂ , or -NR ^a R ^b ; wherein the alkyl group, alkoxy group, alkenyl group, alkyne a group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, optionally further selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, decyl, oxo, cycloalkyl, heterocyclyl Or a plurality of groups;

Each R ^{2 is} independently selected from the group consisting of hydrogen, halogen, amino, thiol, oxo, alkyl, cycloalkyl; wherein, two R ² may also be joined together to form a ring or a bridged ring;

R ^{3 is} selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, The heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl, carboxy, alkyl, alkoxy, cycloalkyl, heterocyclyl Substituting one or more groups of an aryl group or a heteroaryl group;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, alkylamino, alkylsulfonyl, alkane Substituting one or more groups of a aminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

Or R ^a and R ^b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

n is an integer from 1 to 4;

i is an integer from 1 to 3;

j is an integer from 1 to 3;

Wherein each H atom of the compound of formula (I) may optionally be independently replaced by a D atom.

In a preferred embodiment of the invention, the compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer thereof, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein: U ₁ , U ₂ , U ₃ , U ₄ are each independently selected from CR ³ ;

R ^{3 is} as defined in claim 1.

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II), (III), (IV) or (V) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkane The group, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl, carboxy, alkyl, alkoxy, cyclo Substituting one or more groups of an alkyl group, a heterocyclic group, an aryl group, or a heteroaryl group

p is an integer from 1 to 4;

Ar, Y, R ¹ , R ² , n, i, j are as defined in the formula (I).

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (VI), (VII), (VIII) or (IX) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkane The group, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl, carboxy, alkyl, alkoxy, cyclo Substituting one or more groups of an alkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

Each R ^{4 is} each independently selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl;

q is an integer from 1 to 4;

p is an integer from 1 to 4;

Y, R ¹ , R ² , n, i, j are as defined in the formula (I).

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (X), (XI), (XII) or (XIII) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkane The group, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl, carboxy, alkyl, alkoxy, cyclo Substituting one or more groups of an alkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

Each R ^{4 is} independently selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl;

q is an integer from 1 to 4;

p is an integer from 1 to 4;

R ¹ , R ² and n are as defined in the formula (I).

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (X), (XI), (XII) or (XIII) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein R ^{1 is} selected from aryl or heteroaryl, preferably 5- to 7-membered aryl or heteroaryl, more preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; said aryl or hetero The aryl group is optionally further substituted with one or more groups R ⁵ ;

R ^{5 is} selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, -C(O)R ^a , -S(O)R ^a , -S(O) ₂ R ^a , -P(O)R ^a R ^b , -B(OH) ₂ , -NR ^a R ^b ; wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic ring The base is optionally further substituted with one or more groups selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, decyl, oxo, cycloalkyl, heterocyclyl;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, wherein the alkyl, cycloalkyl, heterocyclyl is optionally further selected from the group consisting of halogen, amino, Substituting one or more groups of a cyano group, a hydroxyl group, a decyl group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, or a heterocyclic group;

Or R ^a and R ^b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, preferably a 4 to 7 membered nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, cyano Substituting one or more groups of oxo, hydroxy, decyl, carboxy, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl.

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (XIV), (XV), (XVI) or (XVII) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

Z ₁ , Z ₂ , Z ₃ , Z ₄ are independently selected from N or CH;

R ^{5 is} selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, -C(O)R ^a , -S(O)R ^a , -S(O) ₂ R ^a , -P(O)R ^a R ^b , -B(OH) ₂ , -NR ^a R ^b ; wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic ring The base is optionally further substituted with one or more groups selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, decyl, oxo, cycloalkyl, heterocyclyl;

Each R ^{4 is} independently selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl;

R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, alkyl, and the alkyl group is optionally further substituted by halogen;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, wherein the alkyl, cycloalkyl is optionally further selected from one or more groups selected from the group consisting of halogen, hydroxy, and fluorenyl. Replace

q is an integer from 1 to 4;

p is an integer from 1 to 4;

R ² and n are as defined in the formula (I).

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (XIV), (XV), (XVI) or (XVII) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

选自： Among them, the group

From:

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (XIV), (XV), (XVI) or (XVII) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

R ^{5 is} selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, 3-7 membered cycloalkyl, -C(O)R ^a , -S ( O) R ^a , -S(O) ₂ R ^a , -P(O)R ^a R ^b , -B(OH) ₂ , -NR ^a R ^b ; wherein the alkyl group, alkoxy group, alkenyl group , the cycloalkyl group is optionally further substituted with one or more groups selected from the group consisting of halogen, hydroxy, cyano, oxo, cycloalkyl, heterocyclyl;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, and C ₁ -C ₆ alkyl.

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (XIV), (XV), (XVI) or (XVII) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

R ^{4 is} selected from halogen or C ₁ -C ₆ alkyl,

q is 1 or 2.

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (XIV), (XV), (XVI) or (XVII) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, which is optionally further substituted by halogen,

p is 1 or 2.

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (XVIII), (XIX), (XX) or (XXI) or a racemate, a racemate thereof, or an enantiomer thereof Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

Each R ^{4 is} independently selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl;

R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, alkyl, and the alkyl group is optionally further substituted by halogen;

R' _a is R ^a or NR ^a R ^b ;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, wherein the alkyl, cycloalkyl, heterocyclyl is optionally further selected from the group consisting of halogen, amino, Substituting one or more groups of a hydroxyl group, a mercapto group, an oxo group, an alkyl group, an alkoxy group, an alkylamino group, an alkylsulfonyl group, an alkylamino group, a cycloalkyl group, a heterocyclic group;

Or R ^a and R ^b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, preferably a 4 to 7 membered nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, One or more groups of cyano, oxo, hydroxy, decyl, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Replace

i is 2 and j is 2, or i is 1 and j is 1, or i is 1 and j is 3, or i is 3 and j is 1;

Y is selected from N or CH;

R ² and n are as defined in the formula (I).

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (XVIII), (XIX), (XX) or (XXI) or a racemate, a racemate thereof, or an enantiomer thereof Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

选自： Among them, the group

From:

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (XVIII), (XIX), (XX) or (XXI) or a racemate, a racemate thereof, or an enantiomer thereof Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

R ^{4 is} selected from halogen or C ₁ -C ₆ alkyl,

q is 1 or 2.

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (XVIII), (XIX), (XX) or (XXI) or a racemate, a racemate thereof, or an enantiomer thereof Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, which is optionally further substituted by halogen,

p is 1 or 2.

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (XVIII), (XIX), (XX) or (XXI) or a racemate, a racemate thereof, or an enantiomer thereof Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

R' _a is R ^a ;

R ^{a is} selected from the group consisting of hydrogen, halogen, hydroxy, C ₁ -C ₆ alkyl, C ₄ -C ₇ cycloalkyl, 4 to 7 membered heterocyclic group, wherein the alkyl group, cycloalkyl group, heterocyclic group is optional Further selected from halogen, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylsulfonyl, C ₁ Substituting one or more groups of a -C ₆ alkylamino group.

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (XVIII), (XIX), (XX) or (XXI) or a racemate, a racemate thereof, or an enantiomer thereof Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

R' _a is NR ^a R ^b ;

R ^a and R ^b are each independently selected from hydrogen, alkyl, wherein the alkyl is optionally further substituted with one or more groups selected from halo, hydroxy;

Or R ^a and R ^b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, preferably a 4 to 7 membered nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, oxo, hydroxy Substituting one or more groups of an alkyl group or an alkoxy group.

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

R ^{2 is} selected from hydrogen, oxo or C ₁ -C ₆ alkyl;

n is 1.

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (I') or a mesogen, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

Q, V, U ₀ are each independently selected from CH or N;

R, W, U ₁ , U ₂ , U ₃ , U ₄ are each independently selected from CR ³ or N;

Y is selected from N or CH;

Ar is selected from aryl or heteroaryl, preferably 5- to 7-membered aryl or heteroaryl, more preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; said aryl or heteroaryl Optionally further substituted with one or more groups selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl;

R ^{1 is} selected from the group consisting of hydrogen, halogen, amino, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a , -C(O)R ^a , O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -NHS(O)R ^a , -NHS(O) ₂ R ^a ; wherein the alkyl group, The cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, hydroxy, hydroxyalkyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, One of -C(O)R ^a , -S(O)R ^a , -S(O) ₂ R ^a , -P(O)R ^a R ^b , -B(OH) ₂ , -NR ^a R ^b or Substituting multiple groups;

Each R ^{2 is} independently selected from the group consisting of hydrogen, halogen, amino, fluorenyl, oxo, alkyl, cycloalkyl;

R ^{3 is} selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, The heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl, carboxy, alkyl, alkoxy, cycloalkyl, heterocyclyl Substituting one or more groups of an aryl group or a heteroaryl group;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, alkylamino, alkylsulfonyl, alkane Substituting one or more groups of a aminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

Or R ^a and R ^b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

n is an integer from 1 to 4.

In a preferred embodiment of the invention, the compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer thereof, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (II'), (III'), (IV') or (V') or a racemate or a racemate thereof , enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them,

R ^{1 is} selected from aryl, heteroaryl, -C(O)R ^a , or -C(O)NR ^a R ^b ; wherein the aryl or heteroaryl is optionally further selected from the group consisting of halogen, hydroxy, hydroxy Substituting one or more groups of an alkyl group, an alkyl group, -S(O) ₂ R ^a , -P(O)R ^a R ^b , -B(OH) ₂ , -NR ^a R ^b ; said aryl group Or a heteroaryl group is preferably a 5- to 7-membered aryl or heteroaryl group, more preferably a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group or a pyridazinyl group;

Each R ^{2 is} independently selected from hydrogen, oxo or C ₁ -C ₆ alkyl;

Each R ^{4 is} independently selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl;

R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, alkyl, and the alkyl group is optionally further substituted by halogen;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, wherein the alkyl, cycloalkyl, heterocyclyl is optionally further selected from the group consisting of halogen, amino, Substituting one or more groups of a hydroxyl group, a mercapto group, an oxo group, an alkyl group, an alkoxy group, an alkylamino group, an alkylsulfonyl group, an alkylamino group, a cycloalkyl group, a heterocyclic group;

Or R ^a and R ^b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, preferably a 4 to 7 membered nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, One or more groups of cyano, oxo, hydroxy, decyl, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Replace

n is 1 or 2;

p is 1 or 2;

q is 1 or 2.

Exemplary compounds of the invention include, but are not limited to, the following compounds:

Or a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention provides a compound of the formula (I) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or A method for preparing a medicinal salt, comprising the steps of:

The compound of the formula (I) and the compound of the formula (IB) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction to obtain a compound of the formula (I);

Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C;

among them,

X is a halogen, preferably Br;

Ar, Q, W, V, R, U ₀ , U ₁ , U ₂ , U ₃ , U ₄ , R ¹ , R ² , n, i, j are as defined in the general formula (I).

In another aspect, the present invention provides a compound of the formula (II), (III), (IV) or (V) or a racemate, a racemate, an enantiomer thereof, a diastereomer A process for the preparation of an isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of the formula (IA) and the compound of the formula (IIB), (IIIB), (IVB) or (VB) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction to obtain a pass. a compound of formula (II), (III), (IV) or (V);

Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C;

among them,

X is a halogen, preferably Br;

Ar, Y, R ¹ , R ² , R ^3a , R ^3b , n, q, i, j are as defined in the formula (II), (III), (IV) or (V).

In another aspect, the present invention provides a compound of the formula (VI), (VII), (VIII) or (IX) or a racemate, a racemate, an enantiomer thereof, a diastereomer A process for the preparation of an isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of the formula (IA) and the compound of the formula (VIB), (VIIB), (VIIIB) or (IXB) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction to obtain a pass. a compound of formula (VI), (VII), (VIII) or (IX);

Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C;

among them,

X is a halogen, preferably Br;

Y, R ¹ , R ² , R ^3a , R ^3b , R ⁴ , n, p, q, i, j are as defined in (VI), (VII), (VIII) or (IX).

In another aspect, the present invention provides a compound of the formula (X), (XI), (XII) or (XIII) or a racemate, a racemate, an enantiomer thereof, a diastereomer A process for the preparation of an isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of the formula (IA') and the compound of the formula (XB), (XIB), (XIIB) or (XIIIB) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction. a compound of the formula (X), (XI), (XII) or (XIII);

Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C;

among them,

X is a halogen, preferably Br;

R ¹ , R ² , R ^3a , R ^3b , R ⁴ , n, p, q are as defined in (X), (XI), (XII) or (XIII).

According to a further aspect of the invention there is provided a compound of the formula (XIV), (XV), (XVI) or (XVII) or a racemate, a racemate, an enantiomer thereof, a diastereomer A process for the preparation of an isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of the formula (IA") is heated with a compound of the formula (XIVB), (XVB), (XVIB) or (XVIIB) in the presence of a metal palladium catalyst under basic conditions, and subjected to a Buckwald amination coupling reaction. a compound of the formula (XIV), (XV), (XVI) or (XVII);

Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C;

among them,

X is a halogen, preferably Br;

Z ₁ , Z ₂ , Z ₃ , Z ₄ , R ⁵ , R ² , R ^3a , R ^3b , R ⁴ , n, p, q as in (XIV), (XV), (XVI) or (XVII) definition.

According to a further aspect of the invention there is provided a compound of the formula (XVIII), (XIX), (XX) or (XXI) or a racemate, a racemate, an enantiomer thereof, a diastereomer A process for the preparation of an isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

Compounds of formula (IA"') and compounds of formula (XVIIIB), (XIXB), (XXB), or (XXIB) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction. Obtaining a compound of the formula (XVIII), (XIX), (XX) or (XXI);

Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C;

among them,

X is a halogen, preferably Br;

R' _a , R ² , R ^3a , R ^3b , R ⁴ , i, j, n, p, q are as defined in (XVIII), (XIX), (XX) or (XXI).

In another aspect, the present invention provides a compound of the formula (I') or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or A method for preparing a pharmaceutically acceptable salt, comprising the steps of:

The compound of the formula (I'A) and the compound of the formula (I'B) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction to give a compound of the formula (I');

Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C;

among them,

X is a halogen, preferably Br;

Ar, Q, W, V, R, U ₀ , U ₁ , U ₂ , U ₃ , U ₄ , R ¹ , R ² , n, i, j are as defined by the general formula (I').

According to a further aspect of the invention there is provided a compound of the formula (II'), (III'), (IV') or (V') or a mesogen, racemate or enantiomer thereof And a method for preparing a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

Compounds of formula (I'A) and compounds of formula (II'B), (III'B), (IV'B), or (V'B) are heated under basic conditions in the presence of a metal palladium catalyst, Obtaining a compound of the formula (II'), (III'), (IV') or (V') by a Buckwald amination coupling reaction;

Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C;

among them,

X is a halogen, preferably Br;

R ¹ , R ² , R ^3a , R ^3b , R ⁴ , n, p, q are as defined in (II'), (III'), (IV') or (V').

The invention further provides a pharmaceutical composition comprising a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer thereof, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The pharmaceutical composition may further comprise another therapeutically active ingredient, preferably another therapeutically active ingredient, preferably a rectal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, For gastric cancer, blood cancer, lung cancer, brain cancer, skin cancer, head and neck cancer, ovarian cancer, bladder cancer, and kidney cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer are more preferable.

The present invention also relates to a process for the preparation of the above composition, which comprises the compound of the formula (I) or a racemate, a racemate, an enantiomer thereof, a diastereomer thereof, Or a mixture thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, is admixed with a pharmaceutically acceptable carrier, diluent or excipient.

The invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use in the preparation of a SMO antagonist.

The invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the treatment of a disease associated with the Hedgehog signaling pathway. The disease associated with the Hedgehog signaling pathway may be cancer, and the cancer is preferably from rectal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, brain cancer, skin cancer, head and neck cancer, ovary Cancer, bladder cancer and kidney cancer, more preferably lung cancer, breast cancer, pancreatic cancer and gastric cancer.

The invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as an SMO antagonist.

The invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment of a disease associated with the Hedgehog signaling pathway, wherein the disease associated with the Hedgehog signaling pathway may be cancer, The cancer is preferably selected from the group consisting of rectal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, brain cancer, skin cancer, head and neck cancer, ovarian cancer, bladder cancer and kidney cancer, and more preferably lung cancer, breast cancer, Pancreatic cancer and stomach cancer.

The invention further provides a method for the treatment of a disease associated with the Hedgehog signaling pathway comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) according to the invention or its internal elimination a rotatide, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein said Hedgehog signaling pathway is associated The disease may be cancer, preferably from rectal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, brain cancer, skin cancer, head and neck cancer, ovarian cancer, bladder cancer and kidney cancer. Preferred are lung cancer, breast cancer, pancreatic cancer and gastric cancer.

According to a further aspect of the invention there is provided a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, in combination with another therapeutically active ingredient, for use in the manufacture of a medicament for the treatment of cancer, wherein the other therapeutically active ingredient is simultaneously, separately or sequentially with the compound of formula (I) The therapeutically active ingredient is preferably a drug for treating cancer, and the cancer is preferably rectal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, brain cancer, skin cancer, head and neck cancer. , ovarian cancer, bladder cancer and kidney cancer, more preferably lung cancer, breast cancer, pancreatic cancer and gastric cancer.

The compound of the formula (I) of the present invention can form a pharmaceutically acceptable acid addition salt with an acid according to a conventional method in the art to which the present invention pertains. The acid includes inorganic acids and organic acids, and acceptable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. Acceptable organic acids include methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, Naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.

The compound of the formula (I) of the present invention can form a pharmaceutically acceptable base addition salt with a base. The base includes an inorganic base and an organic base, and acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc., and acceptable inorganic bases include aluminum hydroxide and hydroxide. Calcium, potassium hydroxide, sodium carbonate and sodium hydroxide.

The pharmaceutical composition of the present invention includes any one or more of the compounds of the present invention (or a pharmaceutically acceptable salt, solvate, hydrate, prodrug or derivative thereof) and optionally a pharmaceutically acceptable Carrier. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. Alternatively, the compounds of the invention may be administered to a patient in need thereof in combination with one or more other therapeutic agents. It will also be understood that certain compounds of the invention may exist in free form or, where appropriate, in the form of their pharmaceutically acceptable salts for therapeutic use.

As stated above, the pharmaceutical compositions of the present invention also include a pharmaceutically acceptable carrier. As used herein, the carrier includes any or all solvents, diluents, or other liquid carriers, dispersion or suspending adjuvants, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricating agents Agents, etc., which are adjusted to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutical compositions, as well as known techniques for their preparation. The use of any conventional carrier medium is contemplated to be within the scope of the invention unless it is incompatible with the compounds of the invention, for example, by producing any undesirable biological effects or interacting in a deleterious manner with any other component of the pharmaceutical composition. Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl Cellulose and cellulose acetate; powdered tragacanth; maltose; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and Soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; and, depending on the formulator's judgment, coloring may also be present in the composition. Agents, release agents, coating agents, sweeteners, flavoring and fragrances, preservatives and antioxidants.

The compounds of the invention can be administered to a patient by a variety of routes of administration. These routes of administration include, but are not limited to, oral, sublingual, subcutaneous, intravenous, nasal, topical, dermal, intraperitoneal, intramuscular, pulmonary, and the like.

The pharmaceutical compositions containing the active ingredient may be in the form of solids, semi-solids, liquids and aerosols, for example, tablets, granules, capsules, powders, liquids, suspensions, suppositories, and the like. It can also be administered in a sustained release manner, for example, by a long-acting injection, an osmotic pump, a pill, a patch, or the like.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as a) filler or filler, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) viscous Mixtures such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch , alginic acid, certain silicates and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and mono-hard Glycerol, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixture. In the case of capsules, tablets, and pills, the dosage form can also include a buffer.

Solid compositions of a similar type may also be employed as fillers in filling soft or hard gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells (e.g., enteric coatings and other coatings well known in the pharmaceutical formulation art). It may optionally comprise an opacifying agent, and may also be a composition which is released only, or preferably in certain parts of the intestinal tract, optionally releasing the active ingredient in a delayed manner. Examples of useful embedding compositions include polymeric materials and waxes.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Benzyl ester, propylene glycol, 1,3-butanediol, dimethylformamide, oil (especially cottonseed, groundnut (peanut), corn, germ, olive, ramie and sesame oil), glycerin, tetrahydrofurfuryl alcohol, Polyethylene glycol and sorbitan fatty acid esters, and mixtures thereof. Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, may be formulated in accordance with the prior art using suitable dispersion or wetting agents and suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable carriers or solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspension. For this purpose any bland fixed oil may be employed, including the prepared mono or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The injectable preparation may be sterile, for example, by filtration through a bacteria-resistance filter, or by adding a bactericidal agent in the form of a sterile solid composition before use, which may be dissolved or dispersed in sterile water or other In bacteria injectable medium.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by admixing a compound of the present invention with a suitable non- irritating excipient or carrier (for example, cocoa butter, polyethylene glycol or suppository wax) in the environment It is a solid at temperature and is a liquid at body temperature, thus melting and releasing the active compound in the rectum or vaginal cavity.

It is well known to those skilled in the art that the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, the patient Diet, time of administration, mode of administration, rate of excretion, combination of drugs, and the like. In addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound of the formula, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment regimens.

It will also be understood that the compounds or pharmaceutical compositions of the invention may be formulated and used in combination therapy, i.e., the compounds and pharmaceutical compositions may be formulated simultaneously, prior or subsequently with one or more other desired therapies or procedures. Apply. The particular combination of treatments (therapies or procedures) employed in the combination regimen will take into account the compatibility of the desired therapy and/or procedure, as well as the desired therapeutic effect to be achieved.

Detailed description of the invention

Terms used in the specification and claims have the following meanings unless stated to the contrary.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons. The alkyl group of the atom. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 , 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-B Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-B Hexyl group, 2,2- Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.

The term "alkynyl" refers to an alkyl radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl and the like. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene A polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.

The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O). A hetero atom of _m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably comprising from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; most preferably from 3 to 8 ring atoms, wherein from 1 to 3 are heteroatoms; most preferably from 5 to 7 ring atoms, wherein 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine. The group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like are preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) _m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:

The term "fused heterocyclyl" refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the remaining rings The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

The term "bridge heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A π-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridge heterocyclic groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:

The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, and has 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridyl An oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more selective Pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.

The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

The term "hydroxy" refers to an -OH group.

The term "halogen" means fluoro, chloro, bromo or iodo.

The term "amino" means -NH _2.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "oxo" refers to =0.

The term "carboxy" refers to -C(O)OH.

The term "mercapto" refers to -SH.

The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

The term "acyl" refers to a compound containing a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "sulfonic acid group" refers to -S(O) ₂ OH.

The term "sulfonate group" refers to -S (O) ₂ O (alkyl), or -S (O) ₂ O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.

Method for synthesizing the compound of the present invention

In order to accomplish the object of the present invention, the present invention adopts the following technical solutions.

The preparation method of the specific compound of the present invention is as follows.

The compound of the formula (VI) can be prepared according to the following scheme 1:

Step 1: The substituted benzoic acid VIa and the o-phenylenediamine VIb are subjected to a condensation reaction under the action of a condensing agent under basic conditions to obtain a compound VIc; and the reagent for providing the basic condition may be an organic base such as TEA or DIPEA, preferably DIPEA. The condensing agent may be HATU, HBTU or EDCI/HOBt, preferably HATU;

Step 2: cyclizing the compound VIc under the catalysis of an acid to obtain a compound VId; the acid may be various organic acids, preferably acetic acid;

Step 3: Ammonia coupling reaction of compound IA with compound VId under Buckwald conditions to obtain a compound of the formula (VI), which is a metal palladium (Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ) as a catalyst, Cs ₂ CO ₃ as a base, and a reaction temperature of 100 to 120 °C.

The compound of the formula (VII) can be prepared according to the following scheme 2:

Step 1: Starting from compound VIIa, by Sandmeyer reaction, compound VIIb is obtained; the Sandmeyer reaction uses t-BuONO as a preferred diazonium reagent, and TMSN _{3 is used to} provide a nucleophilic azide source; the reaction temperature is 0 ° C. To room temperature;

Step 2: Condensation reaction of compound VIIb with compound VIIc under the catalysis of Lewis acid to obtain compound VIId; the Lewis acid may be Ti(OiPr) ₄ , TiCl(OiPr) ₃ , preferably TiCl ₄ ;

Step 3: Compound VIId is subjected to a cyclization reaction in the presence of a catalyst to obtain a compound VIIe; the catalyst may be Cu ₂ O and CuCl, preferably CuI;

Step 4: Ammonia coupling reaction of compound VIIe with compound IA under Buckwald conditions to obtain a compound of the formula (VII), which is a metal palladium (Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ) as a catalyst, Cs ₂ CO ₃ as a base, and a reaction temperature of 100 to 120 °C.

Compounds of the general formula (VIII) can be prepared according to the following scheme 3:

Step 1: using benzaldehyde compound VIIIa as a starting material, and condensing with a nitro compound to obtain compound VIIIb; the reaction temperature is 80-100 ° C

Step 2: reacting compound VIIIb with compound VIIIc under the action of a reducing agent to obtain compound VIIId; the reducing agent may be FeCl ₂ , SnCl ₂ , Cu(OAc), preferably FeCl ₂ ;

Step 3: Ammonia coupling reaction of compound VIIId with compound IA under Buckwald conditions to obtain a compound of the formula (VIII), which is a metal palladium (Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ) as a catalyst, Cs ₂ CO ₃ as a base, and a reaction temperature of 100 to 120 °C.

For the compound of the formula (IX), it can be prepared according to the following scheme 4:

Step 1: Compound IXa and compound IXb are stirred at room temperature to undergo condensation cyclization reaction by air oxidation to obtain compound IXc;

Step 2: Ammonia coupling reaction of compound IXc with compound IA under Buckwald conditions to obtain a compound of the formula (IX), which is a metal palladium (Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ) as a catalyst, Cs ₂ CO ₃ as a base, and a reaction temperature of 100 to 120 °C.

Y, R ¹ , R ² , R ^3a , R ^3b , R ⁴ , n, p, q, i, j are as defined in the formula (VI), (VII), (VIII) or (IX).

Detailed ways

The compounds of the invention and their preparation are further understood by the examples which illustrate some methods of preparing or using the compounds. However, it is to be understood that these examples do not limit the invention. Variations of the invention now known or further developed are considered to be within the scope of the invention as described and claimed herein.

The compounds of the present invention are prepared using convenient starting materials and common preparatory procedures. The present invention provides typical or propensating reaction conditions such as reaction temperature, time, solvent, pressure, molar ratio of reactants. However, other reaction conditions can be adopted unless otherwise stated. Optimization conditions may vary with the use of a particular reactant or solvent, but under normal circumstances, the reaction optimization steps and conditions can be determined.

In addition, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Protecting groups suitable for the various functional groups and their protection or deprotection conditions are well known to those skilled in the art. For example, T. W. Greene and G. M. Wuts, "Protective Groups in Organic Preparation" (3rd edition, Wiley, New York, 1999, and references cited in the book) describe in detail the protection or deprotection of a large number of protecting groups.

The separation and purification of the compounds and intermediates are carried out according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer chromatography, preparative high performance liquid chromatography or a mixture of the above methods. The specific method of use can be referred to the examples described in the present invention. Of course, other similar separation and purification methods can be employed. It can be characterized using conventional methods, including physical constants and spectral data.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift is given in units of 10 ^-6 (ppm). The NMR was determined by using a Brukerdps300 type nuclear magnetic instrument. The solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was tetramethyl. Silane (TMS).

The MS was measured using an ACQUITY H-Class UPLC mass spectrometer (QDa Detector) (manufacturer: Waters).

The liquid phase was prepared using a Waters 2545 high performance liquid chromatograph (Waters 2489 UV/visible detector, 2767 sample MGR, single C18, 5 μm 20 mm x 250 mm) (manufacturer: Waters).

The microwave reaction was carried out using an Initiator + EU type microwave reactor (manufacturer: Biotage).

Thin layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specification for thin layer chromatography separation and purification is 0.4mm～0.5. Mm.

Column chromatography generally uses Qingdao Ocean Silicone 100-200 mesh and 200-300 mesh silica gel as carriers.

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Netcom Mall, Beijing Coupling, Sigma, Belling, Yi Shiming, Shanghai Shuya, Shanghai Inoke, An Nike Chemical, Shanghai Bi De and other companies.

Unless otherwise specified in the examples, the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.

An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

The reaction solvent, organic solvent or inert solvent is each expressed as a solvent which does not participate in the reaction under the described reaction conditions, and includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform. Methylene chloride, diethyl ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, and the like. Unless otherwise stated in the examples, the solution means an aqueous solution.

The chemical reactions described in the present invention are generally carried out under normal pressure. The reaction temperature is between -78 ° C and 200 ° C. The reaction time and conditions are, for example, one atmosphere, between -78 ° C and 200 ° C, and completed in about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. There is no particular description in the examples, and the reaction temperature is room temperature and is 20 ° C to 30 ° C.

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.

Purification Compounds The column chromatography eluent system and the thin layer chromatography developer system include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: petroleum ether and acetic acid In the ester system, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.

Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described may be employed in the methods of the invention.

Abbreviations

μL=microliter;

μM=micromolar;

NMR = nuclear magnetic resonance;

Boc=tert-butoxycarbonyl

Br=wide peak

d=double peak

δ=chemical shift

°C=degree Celsius

Dd=double peak

DMF=N,N-dimethylformamide

DMSO = dimethyl sulfoxide

DCM = dichloromethane

EA=ethyl acetate

HPLC = high performance liquid phase

Hz=hertz

IC ₅₀ = concentration that inhibits 50% activity

J = coupling constant (Hz)

m=multiple peak

M+H ⁺ = parent compound mass + one proton

Mg=mg

mL=ml

Mmmol = millimolar

MS=MS

nM=Namol

PE = petroleum ether

Ppm = per million points

s=single peak

t=triple peak

TFA = trifluoroacetic acid

THF = tetrahydrofuran

Preparation Example 1: Preparation of 2-(5-bromo-2-chlorophenyl)-3-methyl-2H-indazole (intermediate a)

Step 1: Preparation of 1-(2-azidophenyl)ethane-1-one

1-(2-Aminophenyl)ethane-1-one (2.0 g, 14.8 mmol) was added to a reaction flask containing acetonitrile (20 mL). The reaction solution was cooled to 0 ° C, and azidotrimethylsilane (2.05 g, 17.76 mmol) and tert-butyl nitrite (1.68 g, 16.28 mmol) were added dropwise with stirring, and the mixture was added to room temperature and stirring was continued. hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc = EtOAc: : 87.5%).

LC-MS (ESI): m / z 162.2 [M + H +].

Step 2: Preparation of (E)-1-(2-azidophenyl)-N-(5-bromo-2-chlorophenyl)ethan-1-amine

Add 1-(2-azidophenyl)ethane-1-one (500 mg, 3.1 mmol) and 5-bromo-2-chloroaniline to a reaction vial containing dichloromethane (20 mL) under nitrogen. (578 mg, 2.8 mmol). The reaction mixture was cooled to 0 ° C, and triethylamine (858 mg, 8.5 mmol) and titanium tetrachloride (323 mg, 1.7 mmol) were added dropwise with stirring. After the addition, stirring was continued at this temperature for 1 hour. After completion of the reaction, it was quenched with ice water (5 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate Phenyl) ethyl-1-imine (1.2 g, red solid). It was used directly in the next reaction without purification.

LC-MS (ESI): m / z 349.0 / 351.0 [M + H +].

Step 3: Preparation of 2-(5-bromo-2-chlorophenyl)-3-methyl-2H-indazole

In a reaction flask containing tetrahydrofuran (15 mL), (E)-1-(2-azidophenyl)-N-(5-bromo-2-chlorophenyl)ethan-1-amine (1.2 g, 3.44 mmol), cuprous iodide (650 mg, 3.44 mmol) and triethylamine (444 mg, 3.44 mmol) were stirred at room temperature for 4 h. After the reaction was completed, the reaction mixture was filtered and evaporated. The residue was purified by silica gel column chromatography (eluent: EA=5:1) to give 2-(5-bromo-2-chlorophenyl)-3-methyl-2H-carbazole (120 mg) , white solid, yield: 10.8%).

LC-MS (ESI): m / z 321.0 / 323.0 [M + H +].

Preparation Example 2: Preparation of 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine (Intermediate b)

Step 1: Preparation of (E)-4-bromo-1-chloro-2-(2-nitroprop-1-en-1-yl)benzene

5-bromo-2-chlorobenzaldehyde (3.0 g, 13.66 mmol) and amine acetate (1.36 g, 17.77 mmol) were added to a reaction flask containing nitroethane (25 mL). The reaction mixture was stirred at 85 <0>C for 2 h then cooled to rt then EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: EA=20:1) to afford (E)-4-bromo-1-chloro-2-(2-nitroprop-1-ene- 1-yl)benzene (2.9 g, yellow solid, yield 69.8%).

Step 2: Preparation of 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine

(E)-4-Bromo-1-chloro-2-(2-nitroprop-1-en-1-yl)benzene (1.13 g, 4.3 mmol), pyridine was added to a reaction flask containing DMF (20 mL) 2-Amine (311 mg, 3.3 mmol) and ferrous chloride tetrahydrate (65.7 mg, 0.33 mmol). The reaction mixture was stirred at 150 ° C for 5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (50 mL) was evaporated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: EtOAc = EtOAc = EtOAc) a] pyridine (790 mg, yellow solid, yield 74.5%).

LC-MS (ESI): m / z 320.9 / 322.9 [M + H +].

Preparation Example 3: Preparation of 2-(5-bromo-2-chlorophenyl)-3-methylpyrazolo[1,5-a]pyridine (Intermediate c)

Add (Z)-4-bromo-1-chloro-2-(2-nitroprop-1-en-1-yl)benzene (300 mg, 1.08 mmol) to a reaction vial containing N-methylpyrrolidone (10 mL) And 1-aminopyridine-1-iodide (200 mg, 0.9 mmol). After stirring at room temperature for 72 hours, it was diluted with ethyl acetate (30 mL). The organic layer was washed with water and brine brine The residue was purified by silica gel column chromatography (eluent: EA=3:1) to afford 2-(5-bromo-2-chlorophenyl)-3-methylpyrazole[1,5 -a]pyridine (90 mg, pale yellow liquid, yield: 26%).

LC-MS (ESI): m / z 320.9 / 322.6 [M + H +].

Preparation Example 4: Preparation of 2-(3-bromo-6-chloro-2-fluorophenyl)-1-methyl-1H-benzo[d]imidazole (intermediate d)

Step 1: Preparation of 3-bromo-6-chloro-2-fluorobenzoic acid

1-Bromo-4-chloro-2-fluorobenzene (5.68 g, 27.11 mmol) was dissolved in a reaction flask containing anhydrous tetrahydrofuran (60 mL) under nitrogen. After cooling the reaction mixture to -78 ° C, LDA (11.44 mL, 2M tetrahydrofuran solution) was added dropwise. Stirring was continued for 1 hour, then dry carbon dioxide gas was introduced and slowly warmed to room temperature. After the reaction was completed, the reaction solution was cooled again to 0 ° C, quenched with saturated aqueous NaHCO ₃ (100 mL), and extracted with diethyl ether (80 mL), the organic phase was discarded, and the aqueous phase was adjusted to pH with 3N hydrochloric acid. After 2 to 3, it was extracted with ethyl acetate (100 mL×3). Fluorobenzoic acid (3.4 g, yellow solid, yield 49.4%).

LC-MS (ESI): m / z 253.0 / 255.0 [M + H +].

Step 2: 3-Bromo-6-chloro-2-fluoro-N-(2-(methylamino)phenyl)benzamide

Add 3-bromo-6-chloro-2-fluorobenzoic acid (1.05 g, 4.14 mmol), N-1-methylbenzene-1,2-diamine (506 mg) to a reaction flask containing dichloromethane (20 mL). , 4.14 mmol), DIPEA (1.06 g, 8.28 mmol) and HATU (1.88 g, 4.96 mmol). After the reaction mixture was stirred at room temperature for 2 hr, EtOAc EtOAc (EtOAc m. . The residue was purified by silica gel column chromatography (eluent: EA = 1:1) to give 3-bromo-6-chloro-2-fluoro-N-(2-(methylamino)phenyl) Benzoylamide (1.06 g, yellow solid, yield: 71.6%).

LC-MS (ESI): m / z 357.0 / 359.1 [M + H +].

Step 3: Preparation of 2-(3-bromo-6-chloro-2-fluorophenyl)-1-methyl-1H-benzo[d]imidazole

To a reaction flask containing acetic acid (15 mL) was added 3-bromo-6-chloro-2-fluoro-N-(2-(methylamino)phenyl)benzamide (1.16 g, 3.24 mmol). After the reaction solution was stirred at 100 ° C for 1 hour, concentrated under reduced pressure to remove AcOH. The resulting solid was dissolved was added 100mL of ethyl acetate, washed with saturated NaHCO ₃ solution until basic, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EtOAc====================== Benzo[d]imidazole (652 mg, white solid, yield 62.6%).

LC-MS (ESI): m / z 339.1 / 341.1 [M + H +].

Preparation Example 5: Preparation of 2-(2-bromo-5-chloropyridin-4-yl)-1-methyl-1H-benzo[d]imidazole (Intermediate e)

Step 1: Preparation of 2-bromo-5-chloroisonicotinic acid

Under a nitrogen atmosphere, diisopropylamine (4 mL) was added to a reaction flask containing anhydrous THF (45 mL), cooled to -5 ° C, and n-butyllithium solution (12.5 mL, 23% n-hexane solution) was slowly added dropwise. After the addition was continued for 0.5 hour, it was cooled to -78 ° C, and a solution of 2-bromo-5-chloropyridine (5.0 g, 26.00 mmol) in tetrahydrofuran (45 mL) was slowly added dropwise. After stirring for 15 minutes, the dried carbon dioxide was passed and stirred for 30 minutes. Then, the reaction solution was warmed to room temperature, and slowly added dropwise to a saturated sodium hydrogencarbonate solution (100 mL), and the mixture was extracted with diethyl ether (50 mL), the organic phase was discarded, and the aqueous phase was adjusted to pH 2-3 with 1 N hydrochloric acid. The precipitated white solid was filtered and dried to give 2-bromo-5-chloroisonicotinic acid (4.3 g, yield: 73%).

LC-MS (ESI): m / z 235.8 / 237.9 [M + H +].

Step 2: Preparation of 2-bromo-5-chloro-N-(2-(methylamino)phenyl)isonicotinamide

Add 2-bromo-5-chloroisonicotinic acid (1.9 g, 8.18 mmol), N-1-methylbenzene-1,2-diamine (1.0 g, 8.18) to a reaction flask containing dichloromethane (50 mL). Methyl), N,N-diisopropylethylamine (DIPEA) (3.2 g, 25.0 mmol) and 2-(7-azobenzotriazole)-tetramethyluron hexafluorophosphate (HATU) ( 4.7 g, 12.27 mmol). The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate (3.2 g, black solid). It was used directly in the next reaction without purification.

LC-MS (ESI): m.

Step 3: Preparation of 2-(2-bromo-5-chloropyridin-4-yl)-1-methyl-1H-benzo[d]imidazole

2-Bromo-5-chloro-N-(2-(methylamino)phenyl)isonicotinamide (3.2 g, 9.412 mmol) was evaporated. The resulting solid was dissolved in 100mL of ethyl acetate, and then were washed with saturated NaHCO ₃ and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EA=2:1) to give 2-(2-bromo-5-chloropyridin-4-yl)-1-methyl-1H-benzene And [d] imidazole (1.2 g, white solid, yield: 40%).

LC-MS (ESI): m / z 322.0 / 324.0 [M + H +].

Preparation Example 6 Preparation of 2-(5-bromo-2-chlorophenyl)-1-(difluoromethyl)-1H-benzo[d]imidazole (Intermediate f)

Step 1: Preparation of N-(2-aminophenyl)-5-bromo-2-chlorobenzamide

In a reaction flask containing dichloromethane (20 mL), 5-bromo-2-chlorobenzoic acid (1.0 g, 4.25 mmol), benzene-1,2-diamine (460 mg, 4.25 mmol), DIPEA (1.6 g, 12.75 mmol) and HATU (2.4 g, 6.37 mmol). The reaction mixture was stirred at rt EtOAc (EtOAc) The obtained organic phase was washed with brine, dried over anhydrous sodium sulfate Solid, yield: 87%).

LC-MS (ESI): m.

Step 2: Preparation of 2-(5-bromo-2-chlorophenyl)-1H-benzo[d]imidazole

N-(2-Aminophenyl)-5-bromo-2-chlorobenzamide (1.2 g, 3.69 mmol). The resulting solid was dissolved in 100mL of ethyl acetate, and then were washed with saturated NaHCO ₃ and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: EtOAc = 1:1) to give 2-(5-bromo-2-chlorophenyl)-1H-benzo[d]imidazole (800 mg, Milky white solid, yield: 70%).

LC-MS (ESI): m/z.

Step 3: Preparation of 2-(5-bromo-2-chlorophenyl)-1-(difluoromethyl)-1H-benzo[d]imidazole

Add 2-(5-bromo-2-chlorophenyl)-1H-benzo[d]imidazole (200 mg, 0.65 mmol), (difluoromethane) to a reaction flask containing acetonitrile (5 mL) and water (1 mL). The sulfonyl)benzene (250 mg, 1.3 mmol) and potassium hydroxide (364 mg, 6.5 mmol) were warmed to 60 ° C and stirred overnight. After the reaction was completed, it was concentrated under reduced pressure. The obtained solid was dissolved in ethyl acetate (100 mL). The residue was purified by silica gel column chromatography (eluent: EtOAc======================================= Benzo[d]imidazole (80 mg, yellow liquid, yield: 35%).

LC-MS (ESI): m.

Preparation Example 7: Preparation of 2-(5-bromo-2-chlorophenyl)-1-methyl-1H-benzo[d]imidazole (intermediate g)

Step 1: Preparation of 5-bromo-2-chloro-N-(2-(methylamino)phenyl)benzamide

5-bromo-2-chlorobenzoic acid (9.6 g, 40.80 mmol) and N-methylbenzene-1,2-diamine (5 g, 40.80 mmol) were sequentially added to a reaction flask containing 100 mL of dichloromethane at room temperature. HATU (23.34 g, 61.38 mmol) and DIPEA (21 mL, 122.40 mmol). After the reaction mixture was stirred for 2 hours, it was diluted with saturated NaHCO ₃ The combined organic layers were washed with EtOAc EtOAc m. It was used directly in the next reaction without purification.

LC-MS (ESI): m / z338.9 / 340.9 [M + H +].

Step 2: Preparation of 2-(5-bromo-2-chlorophenyl)-1-methyl-1H-benzimidazole

5-bromo-2-chloro-N-(2-(methylamino)phenyl)benzamide prepared in Step 1 was added to a reaction flask containing 100 mL of AcOH. After stirring at 100 ° C for 1 hour, the mixture was concentrated under reduced pressure to remove AcOH. The resulting solid was dissolved was added 100mL of ethyl acetate, washed with saturated NaHCO ₃ solution until basic, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EA=5:1) to give 2-(5-bromo-2-chlorophenyl)-1-methyl-1H-benzimidazole ( 10 g, white solid, two-step yield: 76.6%).

LC-MS (ESI): m / z 320.9 / 322.9 [M + H +].

PREPARATIVE EXAMPLE 8 Preparation of 2-(5-Bromo-2-chloro-4-fluorophenyl)-1-methyl-1H-benzo[d]imidazole (Intermediate h)

Similar to the method of Preparation Example 7, except that 5-bromo-2-chloro-4-fluorobenzoic acid was used in place of 5-bromo-2-chlorobenzoic acid to give 2-(5-bromo-2-chloro-4-). Fluorophenyl)-1-methyl-1H-benzo[d]imidazole (milky solid, yield in two steps 48.2%).

LC-MS (ESI): m / z339.0 / 341.0 [M + H +].

Preparation example 9: Preparation of 2-(3,6-dichloropyridin-2-yl)-1-methyl-1H-benzo[d]imidazole (intermediate i)

Similar to the method of Preparation Example 7, except that 3,6-dichloropicolinic acid was used in place of 5-bromo-2-chlorobenzoic acid to give 2-(3,6-dichloropyridin-2-yl)-1- Methyl-1H-benzo[d]imidazole (milky solid, 50.2% yield in two steps).

LC-MS (ESI): m / z278.0 / 280.0 [M + H +].

PREPARATIVE EXAMPLE 10 Preparation of 2-(5-Bromo-2-chlorophenyl)-6-fluoro-1-methyl-1H-benzo[d]imidazole (Intermediate j)

Similar to the method of Preparation Example 7, except that 5-fluoro-N-methylbenzene-1,2-diamine was used in place of N-methylbenzene-1,2-diamine to obtain 2-(5-bromo- 2-Chlorophenyl)-6-fluoro-1-methyl-1H-benzo[d]imidazole (milky solid, 29.8% yield in two steps).

LC-MS (ESI): m / z339.0 / 341.0 [M + H +].

PREPARATIVE EXAMPLE 11 Preparation of 2-(5-Bromo-2-methylphenyl)-1-methyl-1H-benzo[d]imidazole (Intermediate k)

Similar to the method of Preparation Example 7, except that 5-bromo-2-methylbenzoic acid was used in place of 5-bromo-2-chlorobenzoic acid to give 2-(5-bromo-2-methylphenyl)-1. -Methyl-1H-benzo[d]imidazole (milky solid, yield of 40.3% in two steps).

LC-MS (ESI): m / z301.0 / 303.0 [M + H +].

PREPARATIVE EXAMPLE 12 Preparation of 2-(5-Bromo-2-chloro-4-fluorophenyl)-3-methylimidazo[1,2-a]pyridine (Intermediate 1)

Similar to the method of Preparation Example 2, except that 5-bromo-2-chloro-4-fluorobenzoic acid was used instead of 5-bromo-2-chlorobenzoic acid to obtain 2-(5-bromo-2-chloro-4- Fluorophenyl)-3-methylimidazo[1,2-a]pyridine (milky solid, 36.2% yield in two steps).

LC-MS (ESI): m / z339.0 / 341.0 [M + H +].

PREPARATIVE EXAMPLE 13 Preparation of 2-(5-Bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyrazine (Intermediate m)

Similar to the method of Preparation Example 2, except that pyridin-2-amine was used in place of pyridin-2-amine to obtain 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2 -a] Pyrazine (milky solid, 24.6% yield in two steps).

LC-MS (ESI): m / z322.0 / 323.9 [M + H +].

Example 1: 2-(2-Chloro-5-(4-(5-(methylsulfonyl)pyridin-2-yl)piperazin-1-yl)phenyl)-1-methyl-1H-benzene And [d] preparation of imidazole

Step 1: Preparation of 4-(4-chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

2-(5-Bromo-2-chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g) (600 mg, 1.24 mmol), piperazine-1-carboxylic acid tert-butyl at room temperature The ester (301 mg, 1.62 mmol), BINAP (154.8 mg, 0.25 mmol), cesium carbonate (1.2 g, 3.73 mmol), Pd ₂ (dba) ₃ (113.8 mg, 0.12 mmol) and toluene (8 mL) were added to the reaction flask. After sealing, the mixture was replaced with nitrogen three times, and then heated to 100 ° C and stirred for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc. The residue was purified by silica gel column chromatography (eluent: EtOAc========================================= -Phenyl)piperazine-l-carboxylic acid tert-butyl ester (620 mg, yellow solid, yield: 77.8%).

LC-MS (ESI): m / z427.2 / 429.2 [M + H +].

Step 2: Preparation of 2-(2-chloro-5-(piperazin-1-yl)phenyl)-1-methyl-1H-benzo[d]imidazole hydrochloride (1a)

Add 4-(4-chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazine-1-carboxylic acid to a reaction flask containing dichloromethane (8 mL) tert-Butyl ester (620 mg, 1.45 mmol) and dioxane hydrochloride (2 mL, 4M). After stirring at room temperature for 0.5 hour, the reaction solution was concentrated under reduced pressure to give 2-(2-chloro-5-(piperazin-1-yl)phenyl)-1-methyl-1H-benzo[d]imidazole hydrochloride. salt. (410 mg, yellow solid).

LC-MS (ESI), m / z 327.1 / 329.0 [M + H +].

Step 2: Preparation of 2-chloro-5-(methylthio)pyridine (1c)

5-Bromo-2-chloropyridine (1 g, 5.19 mmol) was dissolved in a reaction flask containing anhydrous diethyl ether (20 mL). The reaction solution was cooled to -78 ° C. After about 10 minutes, n-butyllithium (2.3 mL, 2.5 M THF solution) was slowly added dropwise to the reaction flask and stirred for 1.5 hours. Then, 1,2-dimethyldisulfane (538 mg, 5.72 mmol) was added dropwise to the reaction mixture, stirring was continued for 1 hour, and the mixture was further stirred at 0 ° C for 1 hour. After the reaction was completed, the reaction mixture was crystallised eluted with EtOAc (EtOAc) The combined organic layers were washed with EtOAc EtOAc EtOAc m. It was used directly in the next reaction without purification.

LC-MS (ESI): m / z 161.1 / 163.0 [M + H +].

Step 3: Preparation of 2-chloro-5-(methylsulfonyl)pyridine (1d)

2-Chloro-5-(methylthio)pyridine (460 mg, 2.88 mmol) and m-chloroperoxybenzoic acid (mCPBA) (994 mg, 5.76 mmol) were added to dichloromethane (10 mL) at 0 °C In the bottle. The reaction mixture was warmed to room temperature and stirred for 2 hr then EtOAc EtOAc (EtOAc m. concentrate. The residue was purified by silica gel column chromatography (EtOAc: EtOAc:

LC-MS (ESI), m / z 192.1 / 194.1 [M + H +].

Step 4: 2-(2-Chloro-5-(4-(5-(methylsulfonyl)pyridin-2-yl)piperazin-1-yl)phenyl)-1-methyl-1H-benzo [d] Preparation of imidazole (1) 2-(2-chloro-5-(piperazin-1-yl)phenyl)- was added to a microwave reaction tube containing N,N-dimethylacetamide (2 mL) 1-Methyl-1H-benzo[d]imidazolium hydrochloride (80 mg, 0.24 mmol), 2-chloro-5-(methylsulfonyl)pyridine (70.3 mg, 0.37 mmol) and DIPEA (94.6 mg, 0.73) Mm). The mixture was heated to 130 ° C for 1 hour. After the reaction mixture was cooled to room temperature, ethyl acetate (30 mL) was evaporated. The residue was purified by preparative EtOAc (EtOAc (EtOAc:EtOAc) Peptazin-1-yl)phenyl)-1-methyl-1H-benzo[d]imidazole (50 mg, white solid, yield 42.4%).

LC-MS (ESI), m / z 482.2 / 484.2 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ8.53 (d, J = 2.5Hz, 1H) ,. 92 (dd, J = 9.2,2.6Hz, 1H), 7.71-7.66 (m, 1H), 7.62 (dd, J = 7.6, 1.2 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.35 - 7.20 (m, 3H), 7.17 (d, J = 3.0 Hz, 1H), 7.03 (d, J = 9.2 Hz, 1H), 3.84 (t, J = 5.2 Hz, 4H), 3.64 (s, 3H), 3.16 (s, 3H).

Example 2: (6-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridine-3- Preparation of boric acid

Add 2-(2-chloro-5-(piperazin-1-yl)phenyl)-1-methyl-1H-benzo[d]imidazole in a microwave tube containing N-methylpyrrolidone (2 mL) 1a) (50mg, 0.15mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Shanghai Bi (54.96 mg, 0.24 mmol) and DIPEA (59.1 mg, 0.46 mmol). The reaction solution was heated in a microwave to react at 200 ° C for 1 hour. After the reaction mixture was cooled to room temperature, ethyl acetate (30 mL) was evaporated. The residue was purified by preparative HPLC (C18, EtOAc/water (0.1% EtOAc), 10% to 100%) to yield (6-(4-(4-chloro-3-(1-methyl-1H-benzo[ d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)boronic acid (8 mg, white solid, yield: 11.69%).

LC-MS (ESI): m / z 448.1 / 450.1 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (d, J = 2.0 Hz, 1H), 7.91 - 7.84 (m, 3H), 7.69 (dd, J = 7.5, 1.3 Hz, 1H), 7.62 ( d, J = 8.1 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.35 - 7.20 (m, 4H), 7.17 (d, J = 3.0 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 3.69 (d, J = 5.0 Hz, 4H), 3.64 (s, 4H).

Example 3: 2-(6-(4-(4-methyl-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridine Preparation of -3-yl)propan-2-yl alcohol

Step 1: Preparation of 4-(5-(ethoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3b)

Ethyl 6-chloronicotinate (498 mg, 2.68 mmol), N-Boc-piperazine (500 mg, 2.68 mmol) and N,N-diisopropylethylenediamine (N,N-diisopropylethylenediamine) were added to a microwave tube containing DMF (15 mL). 1.04 g, 8.04 mmol), sealed, stirred in a microwave to 130 ° C for 2 hours. After the reaction mixture was cooled, EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (eluent: EtOAc=======================~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Ester (700 mg, yellow solid, yield: 77.6%).

LC-MS (ESI): m.

Step 2: Preparation of 6-(piperazin-1-yl)nicotinic acid ethyl ester hydrochloride (3c)

Add 4-(5-(ethoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester to a reaction flask containing dichloromethane (15 mL), and add dioxane hydrochloride dropwise with stirring. Solution (15 mL, 4 M). After stirring at room temperature for 0.5 hours, the reaction mixture was evaporated. mjjjjjjjj

LC-MS (ESI): m.

Step 3: 6-(4-(4-Methyl-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)nicotinic acid ethyl ester ( Preparation of 3d)

Add 2-(5-bromo-2-methylphenyl)-1-methyl-1H-benzo[d]imidazole (k) (50 mg, 0.166 mmol), 6 to a reaction flask containing toluene (6 mL). -(Piperazine-1-yl)nicotinic acid ethyl ester hydrochloride (47 mg, 0.20 mmol), BINAP (21 mg, 0.033 mmol), cesium carbonate (160 mg, 0.50 mmol) and Pd ₂ (dba) ₃ (30 mg, 0.033) Mold), replaced with nitrogen 3 times, heated to 100 ° C and stirred overnight. After completion of the reaction, the mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjj 1-Methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)ethyl nicotinate (10 mg, white solid, yield: 13%).

LC-MS (ESI): m / z 456.3 [M + H +].

Step 4: 2-(6-(4-(4-Methyl-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridine- Preparation of 3-yl)propan-2-ol (3)

Add 6-(4-(4-methyl-3-(1-methyl-1H-benzo[d]imidazol-2-yl)benzene to a reaction flask containing anhydrous THF (5 mL) under N2 Ethyl piperazine-1-yl)ethyl nicotinate (10 mg, 0.02 mmol) was cooled to 0 °C. Methylmagnesium bromide solution (0.1 mL, 3 M in diethyl ether) was added dropwise, and the mixture was warmed to room temperature and stirring was continued for one hour. After the reaction was completed, ice water (0.1 mL) was evaporated and evaporated. The combined organic layers were washed with brine, dried over sodium sulfate The residue was purified by preparative hp~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol (4 mg, white solid, yield: 45%).

LC-MS (ESI): m / z 442.2 [M + H +].

_{^{1 H NMR (400MHz, CHCl 3}} -d) δ8.25 (s, 1H), 7.75 (s, 1H), 7.60 (d, J = 8.8Hz, 1H), 7.32 (s, 1H), 7.30-7.22 ( m, 2H), 7.17 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.94 (s, 1H), 6.62 (d, J = 8.7 Hz, 1H), 3.64 - 3.56 (m, 7H) ), 3.29–3.20 (m, 4H), 2.08 (s, 3H), 1.50 (s, 6H).

Example 4: 2-(6-(4-(4-Chloro-3-(6-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazine-1- Preparation of pyridin-3-yl)propan-2-ol (4)

Step 1: 6-(4-(4-Chloro-3-(6-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)nicotinic acid Preparation of ethyl ester (4a)

Add 2-(5-bromo-2-chlorophenyl)-6-fluoro-1-methyl-1H-benzo[d]imidazole (j) (50 mg, 0.147 mmol) to a reaction flask containing toluene (6 mL) , 6-(piperazin-1-yl)nicotinic acid ethyl ester (3c) (42 mg, 0.177 mmol), BINAP (19 mg, 0.03 mmol), cesium carbonate (144 mg, 0.441 mmol) and Pd ₂ (dba) ₃ ( 28 mg, 0.03 mmol), sealed, replaced with nitrogen three times, heated to 100 ° C and stirred overnight. After the reaction mixture was cooled to room temperature, the reaction mixture was filtered, and the filtrate was evaporated, evaporated, mjjjjjjjjj Chloro-3-(6-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)nicotinic acid ethyl ester (20 mg, white solid, yield: 27.5%).

LC-MS (ESI): m / z 494.2 / 496.2 [M + H +].

Step 2: 2-(6-(4-(4-Chloro-3-(6-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl) Preparation of pyridin-3-yl)propan-2-ol (4)

Add 6-(4-(4-chloro-3-(6-fluoro-1-methyl-1H-benzo[d]imidazole-2-) to a reaction flask containing anhydrous THF (3 mL) under nitrogen. Ethyl phenyl) piperazin-1-yl) ethyl nicotinate (20 mg, 0.04 mmol) was cooled to 0 °C. Methylmagnesium bromide solution (0.1 mL, 3 M in diethyl ether) was added dropwise, and the mixture was warmed to room temperature and stirring was continued for one hour. The mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by preparative hp~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -1H-Benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol (9.8 mg, white solid, yield: 51.2%).

LC-MS (ESI): m / z 480.2 / 482.3 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 8.59 (s, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.9 Hz, 2H), 7.37 (s, 2H), 7.09 (s, 1H), 6.99 (s, 1H), 4.28 (s, 2H), 4.18 (s, 2H), 3.74 (s, 3H), 3.67 ( s, 2H), 1.63 (s, 6H).

Example 5: 6-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)-N,N- Preparation of dimethyl-pyridazin-3-amine (5)

Step 1: Preparation of 6-chloro-N,N-dimethyl-pyridazin-3-amine (5b)

3,6-Dichloropyridazine (500 mg, 3.38 mmol) was added portionwise in a reaction flask containing methanol (10 mL) and stirred at room temperature overnight. After the reaction was completed, the reaction mixture was evaporated to dryness crystals crystals crystals crystals It was used directly in the next reaction without purification.

LC-MS (ESI): m / z 158.0 / 160.1 [M + H +].

Step 2: 6-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)-N,N-di Preparation of methyl-pyridazin-3-amine (5)

Add 6-chloro-N,N-dimethyl-pyridin-3-amine (36 mg, 0.23 mmol), 2-(2-chloro-5) to a microwave tube containing N-methylpyrrolidone (NMP) (4 mL) -(piperazin-1-yl)phenyl)-1-methyl-1H-benzo[d]imidazole (1a) (50 mg, 0.15 mmol) and N,N-diisopropylethylamine (DIPEA) 59 mg, 0.46 mmol), heated to 200 ° C under microwave for 1 hour. After the reaction was completed, EtOAc (EtOAc m. The residue was purified by preparative HPLC (C18, EtOAc/water (0.1% EtOAc), 10% to 100%) to afford 6-(4-(4-chloro-3-(1-methyl-1H-benzo[d] Imidazol-2-yl)phenyl)piperazin-1-yl)-N,N-dimethyl-pyridazin-3-amine (9.7 mg, white solid, yield: 14.5%).

LC-MS (ESI): m / z 448.2 / 450.3 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 7.77 (d, J = 7.0 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.27 (dd, J = 7.3, 5.1 Hz, 2H), 7.07 ( d, J = 2.9 Hz, 1H), 6.99 (dd, J = 8.9, 2.9 Hz, 1H), 6.91 (d, J = 9.8 Hz, 1H), 6.80 (d, J = 9.9 Hz, 1H), 3.63 ( s, 3H), 3.56 to 3.48 (m, 4H), 3.33 to 3.25 (m, 4H), 3.02 (s, 6H).

Example 6: 2-(6-(4-(5-chloro-6-(1-methyl-1H-benzo[d]imidazol-2-yl)pyridin-2-yl)piperazin-1-yl Preparation of pyridin-3-yl)propan-2-ol (6)

Step 1: 6-(4-(5-Chloro-6-(1-methyl-1H-benzo[d]imidazol-2-yl)pyridin-2-yl)piperazin-1-yl)nicotinic acid B Preparation of ester (6a)

Add 2-(3,6-dichloropyridin-2-yl)-1-methyl-1H-benzo[d]imidazole (i) (50 mg, 0.18 mmol) to a microwave tube containing NMP (4 mL). Ethyl 6-(piperazin-1-yl)nicotinate (3c) (42 mg, 0.18 mmol) and N,N-diisopropylethylamine (70 mg, 0.54 mmol). The mixture was heated to 200 ° C under microwave for 1 hour. After the reaction was completed, EtOAc (EtOAc m. The residue was chromatographed on silica gel column (eluent: PE: EA = 1:1) to give 6-(4-(5-chloro-6-(1-methyl-1H-benzo[d]] Imidazol-2-yl)pyridin-2-yl)piperazin-1-yl)ethyl nicotinate (25 mg, white solid, yield: 29%).

LC-MS (ESI): m / z 477.2 / 479.2 [M + H +].

Step 2: 2-(6-(4-(5-Chloro-6-(1-methyl-1H-benzo[d]imidazol-2-yl)pyridin-2-yl)piperazin-1-yl) Preparation of pyridin-3-yl)propan-2-ol (6)

Under a nitrogen atmosphere, 6-(4-(5-chloro-6-(1-methyl-1H-benzo[d]imidazol-2-yl)pyridine) was added to a reaction flask containing anhydrous THF (3 mL). Ethyl 2-phenyl)piperazin-1-yl)nicotinic acid (25 mg, 0.052 mmol), cooled to 0 ° C, slowly added dropwise methyl magnesium bromide solution (0.1 mL, 3M in diethyl ether), and then warmed to room temperature , continue to stir for 1 hour. The mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by preparative HPLC (C18, EtOAc/water (0.1% EtOAc), 10% to 100%) to afford 2-(6-(4-(6-chloro-6-(1-methyl-1H-benzene) And [d]imidazol-2-yl)pyridin-2-ylpiperazin-1-yl)pyridin-3-yl)propan-2-ol (7.2 mg, white solid, yield: 30%).

LC-MS (ESI): m / z 463.3 / 465.4 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 8.25 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.59 (t, J = 9.4 Hz, 2H), 7.39 – 7.25 (m, 3H), 6.70 (d, J = 9.0 Hz, 1H), 6.59 (d, J = 8.8 Hz, 1H), 3.76 (s, 3H), 3.62 (d, J = 11.1 Hz, 8H) , 1.50 (s, 6H).

Example 7: 2-(6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridine Preparation of -3-yl)-2propanol (7)

Step 1: 6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)nicotinic acid ethyl ester ( Preparation of 7a)

2-(5-Bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine (b) (100 mg, 0.31 mmol), 6-(piperazin-1- at room temperature Ethyl nicotinate (3c) (95 mg, 0.40 mmol), BINAP (38.6 mg, 0.06 mmol), cesium carbonate (303 mg, 0.93 mmol), Pd ₂ (dba) ₃ (7.3 mg, 0.008 mmol) and toluene ( 4 mL) was added to the reaction flask, sealed, replaced with nitrogen three times, and heated to 120 ° C overnight. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EA/1:1) to give 6-(4-(4-chloro-3-) 3-Methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)ethyl nicotinate (80 mg, yellow solid, yield 54%).

LC-MS (ESI): m / z 476.2 / 478.2 [M + H +].

Step 2: 2-(6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridine- Preparation of 3-yl)-2-propanol (7)

6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)nicotinic acid under nitrogen Ethyl ester (80 mg, 0.17 mmol) was dissolved in a reaction flask containing anhydrous tetrahydrofuran (2 mL). After cooling to 0 ° C, methylmagnesium bromide (0.15 mL, 3 M in diethyl ether) was slowly added dropwise, and after the addition was completed, the reaction mixture was stirred at room temperature for 0.5 hour. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate The residue was purified by preparative hp~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ , 2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)-2-propanol (23 mg, white solid, yield: 29.6%).

LC-MS (ESI): m / z 462.3 / 464.2 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 8.32 (dd, J = 2.6, 0.7 Hz, 1H), 7.94 (dt, J = 6.9, 1.1 Hz, 1H), 7.82 - 7.60 (m, 2H), 7.37 (d, J = 8.8 Hz, 1H), 7.26 (s, 1H), 7.15 (d, J = 3.0 Hz, 1H), 6.99 - 6.89 (m, 2H), 6.69 (dd, J = 8.9, 0.8 Hz) , 1H), 3.71 - 3.63 (m, 4H), 3.41 - 3.27 (m, 4H), 2.45 (s, 3H), 1.57 (s, 6H).

Example 8: 2-(6-(4-(4-Chloro-3-(3-methyl-2H-indazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl) Preparation of propan-2-ol (8)

Step 1: Preparation of 6-(4-(4-chloro-3-(3-methyl-2H-indazol-2-yl)phenyl)piperazin-1-yl)nicotinic acid ethyl ester (8a)

Add 2-(5-bromo-2-chlorophenyl)-3-methyl-2H-indazole (a) (45 mg, 0.14 mmol), 6-(piperazine) to a reaction flask containing toluene (6 mL). 1-Base) ethyl nicotinic acid (3c) (40 mg, 0.17 mmol), BINAP (17 mg, 0.028 mmol), cesium carbonate (137 mg, 0.42 mmol) and Pd ₂ (dba) ₃ (26 mg, 0.03 mmol), sealed, The mixture was replaced with nitrogen three times, and heated to 100 ° C and stirred overnight. After the reaction was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EA = 1:1) to afford 6-(4-(4-chloro-3-(3-methyl-2H-carbazole-2-) Ethyl phenyl) piperazin-1-yl) ethyl nicotinate (40 mg, white solid, yield: 60.0%).

LC-MS (ESI): m / z 476.5 / 478.2 [M + H +].

Step 2: 2-(6-(4-(4-Chloro-3-(3-methyl-2H-indazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)propan Preparation of 2-Alcohol (8) Under a nitrogen atmosphere, 6-(4-(4-chloro-3-(3-methyl-2H-carbazole-2) was added to a reaction flask containing anhydrous THF (4 mL). Ethyl)phenyl)piperazin-1-yl)nicotinic acid ethyl ester (40 mg, 0.08 mmol) was cooled to 0. Methylmagnesium bromide solution (0.1 mL, 3 M in diethyl ether) was added dropwise, and the mixture was warmed to room temperature and stirring was continued for one hour. The mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by preparative hp~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Zyridin-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol (13.2 mg, white solid, yield: 34.0%).

LC-MS (ESI): m / z 462.2 / 464.2 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 8.25 (d, J = 2.2 Hz, 1H), 7.61 (ddd, J = 13.7, 11.6, 8.6 Hz, 3H), 7.36 (d, J = 8.9 Hz, 1H), 7.30–7.23 (m, 1H), 7.07–6.93 (m, 3H), 6.61 (d, J=8.7 Hz, 1H), 3.66–3.58 (m, 4H), 3.35–3.21 (m, 4H) , 2.45 (s, 3H), 1.50 (s, 6H).

Example 9: 2-(6-(4-(4-Chloro-3-(3-methylpyrazolo[1,5-a]pyridin-2-yl)phenyl)piperazin-1-yl) Preparation of pyridin-3-yl)propan-2-ol (9)

Step 1: 6-(4-(4-Chloro-3-(3-methylpyrazolo[1,5-a]pyridin-2-yl)phenyl)piperazin-1-yl)nicotinic acid ethyl ester Preparation of (9a)

Add 2-(5-bromo-2-chlorophenyl)-3-methylpyrazolo[1,5-a]pyridine (c) (35 mg, 0.11 mmol) to a reaction flask containing toluene (6 mL). 6-(Piperazin-1-yl)nicotinic acid ethyl ester (3c) (31 mg, 0.13 mmol), BINAP (14 mg, 0.022 mmol), cesium carbonate (143 mg, 0.44 mmol) and Pd ₂ (dba) ₃ (20 mg, 0.022 mmol), sealed, replaced with nitrogen three times, heated to 100 ° C and stirred overnight. The reaction solution was cooled to room temperature, filtered and evaporated. The residue was purified by silica gel column chromatography (eluent: EA = 1:1) to give 6-(4-(3-chloro-3-(3-methylpyrazolo[1,5- a] Pyridin-2-yl)phenyl)piperazin-1-yl)ethyl nicotinate (25 mg, white solid, yield: 48%).

LC-MS (ESI): m / z 476.2 / 478.2 [M + H +].

Step 2: 2-(6-(4-(4-Chloro-3-(3-methylpyrazolo[1,5-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridine Preparation of -3-yl)propan-2-ol

6-(4-(4-Chloro-3-(3-methylpyrazolo[1,5-a]pyridin-2-yl)phenyl) was added to a reaction flask containing THF (5 mL) under nitrogen. Piperazine-1-yl)nicotinic acid ethyl ester (25 mg, 0.052 mmol) was cooled to 0 °C. A solution of methylmagnesium bromide (0.3 mL, 3M in diethyl ether) was added dropwise, and the mixture was warmed to room temperature and stirring was continued for one hour. The mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by preparative hp~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 1,5-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol (9.5 mg, white solid, yield: 40%).

LC-MS (ESI): m / z 462.3 / 464.2 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 8.36 (d, J = 7.0 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = 8.8, 2.6 Hz, 1H) , 7.39 (d, J = 8.9 Hz, 1H), 7.31 (d, J = 8.9 Hz, 1H), 7.06 - 6.99 (m, 1H), 6.97 (d, J = 3.1 Hz, 1H), 6.91 (dd, J=8.9, 3.0 Hz, 1H), 6.69–6.58 (m, 2H), 3.69–3.55 (m, 4H), 3.29–3.16 (m, 4H), 2.17 (s, 3H), 1.50 (s, 6H) .

Example 10: 2-(6-(4-(4-Chloro-2-fluoro-5-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazine-1- Of pyridyl-3-yl)propan-2-ol (10)

Step 1: 6-(4-(4-Chloro-2-fluoro-5-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)nicotinic acid Preparation of ethyl ester (10a)

Add 2-(5-bromo-2-chloro-4-fluorophenyl)-1-methyl-1H-benzo[d]imidazole (h) (100 mg, 0.29 mmol) to a reaction flask containing toluene (6 mL) , 6-(Piperazin-1-yl)nicotinic acid ethyl ester (3c) (83 mg, 0.35 mmol), BINAP (37 mg, 0.059 mmol), cesium carbonate (383 mg, 1.176 mmol) and Pd2 (dba) 3 (54 mg) , 0.059 mmol), sealed, replaced with nitrogen three times, heated to 100 ° C and stirred overnight. The reaction was cooled to room temperature, filtered and the filtrate was evaporated. The residue was purified by silica gel column chromatography (eluent: EA = 1:1) to give 6-(4-(4-chloro-2-fluoro-5-(1-methyl-1H-benzene) And [d]imidazol-2-yl)phenyl)piperazin-1-yl)nicotinic acid ethyl ester (50 mg, white solid, yield: 34%).

LC-MS (ESI): m.

Step 2: 2-(6-(4-(4-Chloro-2-fluoro-5-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl) Preparation of pyridin-3-yl)propan-2-ol (10)

6-(4-(4-Chloro-2-fluoro-5-(1-methyl-1H-benzo[d]imidazole-2-) was added to a reaction flask containing anhydrous THF (5 mL) under nitrogen. Ethyl phenyl) piperazin-1-yl) ethyl nicotinate (50 mg, 0.10 mmol) was cooled to 0 °C. Methylmagnesium bromide solution (0.3 mL, 3 M in diethyl ether) was slowly added dropwise, and the reaction was allowed to warm to room temperature and stirring was continued for 1 hour. The mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by preparative EtOAc (EtOAc (EtOAc) elute -1H-Benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol (20 mg, white solid, yield: 41%).

LC-MS (ESI): m / z 480.2 / 482.2 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 8.32 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 7.0 Hz, 1H), 7.67 (dd, J = 8.8, 2.6 Hz, 1H) , 7.42 (d, J = 7.1 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.24 (s, 1H), 7.19 (d, J = 8.9 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 3.69 (d, J = 8.8 Hz, 7H), 3.27 - 3.20 (m, 4H), 1.57 (s, 6H).

Example 11: 2-(6-(4-(4-Chloro-3-(1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)piperazine-1- Of pyridyl-3-yl)propan-2-ol (11)

Add 2-(5-bromo-2-chlorophenyl)-1-(difluoromethyl)-1H-benzo[d]imidazole (f) (80 mg, 0.22 mmol) to a reaction flask containing toluene (5 mL) , 2-(6-(piperazin-1-yl)pyridin-3-yl)propan-2-ol hydrochloride (see synthesis of 18d in the preparation of Example 18) (63 mg, 0.28 mmol), BINAP (28 mg) , 0.045 mmol), cesium carbonate (219 mg, 0.67 mmol) and Pd ₂ (dba) ₃ (41 mg, 0.045 mmol), sealed, replaced with nitrogen three times, and heated to 100 ° C overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was purified by preparative EtOAc (EtOAc (EtOAc:EtOAc) -1H-Benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol (11.6 mg, white solid, yield: 11%).

LC-MS (ESI): m.

¹ H NMR (400 MHz, CHCl ₃ -d) δ 8.26 (d, J = 2.4 Hz, 1H), 7.85 - 7.76 (m, 1H), 7.71 (d, J = 5.0 Hz, 1H), 7.61 (dd, J=8.8, 2.6 Hz, 1H), 7.40–7.32 (m, 3H), 7.09–7.04 (m, 1H), 7.02 (dd, J=8.9, 3.1 Hz, 1H), 6.62 (d, J=8.8 Hz) , 1H), 3.71 - 3.50 (m, 4H), 3.39 - 3.20 (m, 4H), 1.50 (s, 6H).

Example 12: 2-(5-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyrimidine- Preparation of 2-yl)propan-2-ol (12)

Step 1: Preparation of 5-bromopyrimidine-2-carboxylic acid (12b)

5-bromopyrimidine-2-carbonitrile (2.0 g, 10.87 mmol) and sodium hydroxide (1.3 g, 32.6 mmol) were added to a reaction flask containing water (30 mL), and the mixture was stirred at 60 ° C for 1 hour. After completion of the reaction, the pH was adjusted to pH 6 by dropwise addition of 1N hydrochloric acid, and the precipitated yellow solid was filtered and dried to give 5-bromopyrimidine-2-carboxylic acid (1.0 g,yield: yield: 50%).

LC-MS (ESI): m / z 201.1 [MH +].

Step 2: Preparation of methyl 5-bromopyrimidine-2-carboxylate (12c)

5-bromopyrimidine-2-carboxylic acid (1.5 g, 7.46 mmol) was added to a reaction flask containing methanol (20 mL), and thionyl chloride (5 mL) was slowly added dropwise, and the mixture was warmed to reflux overnight. After completion of the reaction, the reaction mixture was concentrated to dryness crystals crystals crystals

LC-MS (ESI): m / z 217.1 / 219.2 [M + H +].

Step 3: 5-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyrimidine-2-carboxylic acid Preparation of ester (12d)

Add methyl 5-bromopyrimidine-2-carboxylate (33 mg, 0.15 mmol), 2-(2-chloro-5-(piperazin-1-yl)phenyl)- to a reaction flask containing toluene (6 mL). 1-Methyl-1H-benzo[d]imidazole (1a) (50 mg, 0.15 mmol), BINAP (19 mg, 0.31 mmol), cesium carbonate (150 mg, 0.46 mmol) and Pd ₂ (dba) ₃ (28 mg, 0.031) Mold), sealed, replaced with nitrogen 3 times, heated to 100 ° C and stirred overnight. The reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc:EtOAc: Methyl imidazol-2-yl)phenyl)piperazin-1 -yl)pyrimidine-2-carboxylate (20 mg, white solid, yield: 28%).

LC-MS (ESI): m / z 463.2 / 465.2 [M + H +].

Step 4: 2-(5-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyrimidine-2 -base) Preparation of propan-2-ol (12)

5-(4-(4-chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl) was added to a reaction flask containing anhydrous THF (3 mL) under nitrogen. Methyl piperazin-l-yl)pyrimidine-2-carboxylate (20 mg, 0.04 mmol) was cooled to 0. Methylmagnesium bromide solution (0.1 mL, 3 M in diethyl ether) was added dropwise, and the mixture was warmed to room temperature and stirring was continued for one hour. The mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by preparative HPLC (C18, EtOAc/water (0.1% EtOAc), 10% to 100%) to yield 2-(5-(4-(4-chloro-3-(1-methyl-1H-benzene) And [d]imidazol-2-yl)phenyl)piperazin-1-yl)pyrimidin-2-yl)propan-2-ol (4 mg, white solid, yield: 20%).

LC-MS (ESI): m / z463.2 / 465.2 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 8.36 (d, J = 28.4 Hz, 2H), 7.77 (d, J = 6.8 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.33 - 7.24 ( m, 2H), 7.09 (d, J = 3.1 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 3.65 (s, 3H), 3.33 (d, J = 3.7 Hz, 8H), 1.51 ( s, 6H).

Example 13: 2-(2-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyrimidine- Preparation of 5-yl)propan-2-ol (13)

Step 1: 2-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyrimidine-5-carboxylic acid Preparation of ester (13b)

Add 2-chloropyrimidine-5-carboxylic acid ethyl ester (32 mg, 0.17 mmol), 2-(2-chloro-5-(piperazin-1-yl)phenyl)-1 to a microwave tube containing DMF (2 mL) Methyl-1H-benzo[d]imidazole (1a) (50 mg, 0.15 mmol) and N,N-diisopropylethylamine (60 mg, 0.46 mmol). The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc. The residue was purified by silica gel column chromatography (eluent: EtOAc = EtOAc: EtOAc) to afford 2-(4-(4-chloro-3-(1-methyl-1H-benzo[d] Ethyl imidazol-2-yl)phenyl)piperazin-1-yl)pyrimidine-5-carboxylate (15 mg, colorless liquid, yield: 21%).

LC-MS (ESI): m / z 477.2 / 479.2 [M + H +].

Step 2: 2-(2-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyrimidine-5 -base) Preparation of propan-2-ol (13)

2-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)peridine was added to a reaction flask containing THF (5 mL) under nitrogen. Ethylzin-1-ylpyrimidine-5-carboxylate (15 mg, 0.031 mmol) was cooled to 0 °C. Methylmagnesium bromide solution (0.1 mL, 3 M in diethyl ether) was added dropwise, and the mixture was warmed to room temperature and stirring was continued for one hour. The mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by preparative HPLC (C18, EtOAc/water (0.1% EtOAc), 10% to 100%) to yield 2-(2-(4-(4-chloro-3-(1-methyl-1H-benzene) And [d]imidazol-2-yl)phenyl)piperazin-1-yl)pyrimidin-5-yl)propan-2-ol (8.1 mg, white solid, yield: 57%).

LC-MS (ESI): m / z 463.2 / 465.2 [M + H +].

_{^{1 H NMR (400MHz, CHCl 3}} -d) δ8.40 (s, 2H), 7.77 (d, J = 6.8Hz, 1H), 7.38-7.23 (m, 4H), 7.06 (d, J = 2.9Hz, 1H), 6.98 (dd, J = 8.9, 2.9 Hz, 1H), 3.96 - 3.79 (m, 4H), 3.63 (s, 3H), 3.28 - 3.16 (m, 4H), 1.50 (s, 6H).

Example 14: 2-(6-((1S,4S)-5-(4-chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2, Preparation of 5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)propan-2-ol (14)

Step 1: (1S,4S)-5-(5-(Methoxycarbonyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester Preparation of (14b)

Add (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg, 1.01 mmol), 6-chloro in a microwave tube containing DMF (4 mL) Methyl nicotinic acid (173 mg, 1.01 mmol) and N,N-diisopropylethylamine (392 mg, 3.03 mmol) were stirred and stirred at 140 ° C for one hour. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc. The residue was purified by silica gel column chromatography (eluent: EA=2:1) to afford (1S,4S)-5-(5-(methoxycarbonyl)pyridin-2-yl)-2 , 5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (130 mg, pale yellow solid, yield: 39%).

LC-MS (ESI): m / z 334.9 [M + H +].

Step 2: Preparation of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)nicotinate methyl ester hydrochloride (14c)

In a reaction flask containing dichloromethane, (1S,4S)-5-(5-(methoxycarbonyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane- tert-Butyl 2-carboxylate (130 mg, 0.39 mmol), a solution of dioxane hydrochloride (2 mL, 4M) was added dropwise and stirred at room temperature for 0.5 hour. The reaction solution was concentrated under reduced pressure to give crude crystals of crude product 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl nicotinate hydrochloride (130 mg, yellow) solid).

LC-MS (ESI): m.

Step 3: 6-((1S,4S)-5-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2,5-diaza Preparation of heterobicyclo[2.2.1]heptan-2-yl)nicotinic acid ethyl ester (14d)

Add 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl nicotinate (130 mg, 0.56 mmol) to a reaction flask containing toluene (4 mL). 2-(5-Bromo-2-chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g) (150 mg, 0.46 mmol), BINAP (70 mg, 0.11 mmol), cesium carbonate (547 mg) , 1.68 mmol) and Pd ₂ (dba) ₃ (103 mg, 0.11 mmol), sealed, replaced with nitrogen three times, heated to 100 ° C and stirred overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (eluent: EA = 1:1) to give 6-((1S,4S)-5-(4-chloro-3-(1-methyl-1H) -Benzo[d]imidazol-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)nicotinic acid ethyl ester (50 mg, yellow solid, yield: 23 %).

LC-MS (ESI): m / z 474.2 / 476.2 [M + H +].

Step 4: 2-(6-((1S,4S)-5-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2,5 -Preparation of diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)propan-2-ol (14)

Under a nitrogen atmosphere, 6-((1S,4S)-5-(4-chloro-3-(1-methyl-1H-benzo[d]imidazole-) was added to a reaction flask containing anhydrous THF (5 mL). Ethyl 2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)nicotinate (50 mg, 0.105 mmol) was cooled to 0. The solution of methylmagnesium bromide (0.3 mL, 3M in diethyl ether) was added dropwise, and the mixture was warmed to room temperature, stirring was continued for 1 hour, and then ice water (0.1 mL) was added dropwise, and ethyl acetate (10 mL x 3) was combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by preparative hp~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)propan-2- Alcohol (14 mg, white solid, yield: 28%).

LC-MS (ESI): m / z 474.2 / 476.2 [M + H +].

_{^{1 H NMR (400MHz, CHCl 3}} -d) δ8.15 (d, J = 2.2Hz, 1H), 7.75 (d, J = 7.0Hz, 1H), 7.52 (dd, J = 8.8,2.6Hz, 1H) , 7.33 (d, J = 7.0 Hz, 1H), 7.30 - 7.20 (m, 3H), 6.65 (d, J = 2.9 Hz, 1H), 6.55 (dd, J = 8.8, 2.9 Hz, 1H), 6.22 ( d, J = 8.7 Hz, 1H), 4.86 (s, 1H), 4.44 (s, 1H), 3.64 - 3.48 (m, 5H), 3.36 (d, J = 9.2 Hz, 1H), 3.18 (d, J = 8.8 Hz, 1H), 2.04 (s, 2H), 1.48 (s, 6H).

Example 15: 4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-1-(5-(2-hydroxypropan-2-yl) Preparation of pyridin-2-yl) piperazin-2-one (15)

Step 1: Preparation of 2-(6-chloropyridin-3-yl)propan-2-ol (15b)

Methyl 6-chloronicotinate (500 mg, 2.91 mmol) and anhydrous THF (5 mL) were added to a reaction flask containing anhydrous THF (5 mL) and cooled to 0. Methylmagnesium bromide solution (4.5 mL, 3M in diethyl ether) was slowly added dropwise, and the mixture was warmed to room temperature and stirring was continued for one hour. The mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (eluent: EtOAc===================================================================== Rate: 84%).

LC-MS (ESI): m / z 172.4 [M + H +].

Step 2: Preparation of 4-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester (15c)

Add 2-(6-chloropyridin-3-yl)propan-2-ol (420 mg, 2.45 mmol), 3-oxopiperazine-1-carboxylic acid tert-butyl ester (588 mg) to a reaction flask containing toluene (10 mL). , 2.94 mmol), XantPHOS (289 mg, 0.50 mmol), cesium carbonate (2.4 g, 7.35 mmol) and Pd ₂ (dba) ₃ (457 mg, 0.50 mmol), sealed, and replaced with nitrogen three times, heated to 100 ° C and stirred overnight. The reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EA=2:1) to give 4-(5-(2-hydroxypropyl-2-yl)pyridin-2-yl)-3-ox Tert-butyl piperazine-1-carboxylate (350 mg, white solid, yield: 45%).

LC-MS (ESI): m / z 336.8 [M + H +].

Step 3: Preparation of 1-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)piperazin-2-one hydrochloride (15d)

Add 4-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester (100 mg) to a reaction flask containing dichloromethane (2 mL) , 0.298 mmol), a solution of dioxane hydrochloride (2 mL, 4 M) was added dropwise and stirred for 0.5 hour. The reaction mixture was concentrated under reduced vacuo toield-1jjjjjjjjjjjj

LC-MS (ESI): m / z 236.4 [M + H +].

Step 4: 4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-1-(5-(2-hydroxypropan-2-yl) Preparation of pyridin-2-yl) piperazin-2-one (15)

Add 1-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)piperazin-2-one (50 mg, 0.213 mmol), 2-(5-) to a reaction flask containing toluene (6 mL). Bromo-2-chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g) (82 mg, 0.26 mmol), BINAP (28 mg, 0.043 mmol), cesium carbonate (278 mg, 0.85 mmol) and Pd ₂ (dba) ₃ (40 mg, 0.043 mmol), sealed, and replaced with nitrogen three times, then warmed to 100 ° C and stirred overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was purified by preparative hp~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2-yl)phenyl)-1-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)piperazin-2-one (10 mg, white solid, yield: 10%).

LC-MS (ESI): m / z 476.3 / 478.3 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 8.59 (s, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.9 Hz, 2H), 7.37 (s, 2H), 7.09 (s, 1H), 6.99 (s, 1H), 4.28 (s, 2H), 4.18 (s, 2H), 3.74 (s, 3H), 3.67 ( s, 2H), 1.63 (s, 6H).

Example 16: 2-(5-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridine- Preparation of 2-yl)propan-2-ol

Step 1: Preparation of 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (16b)

Add methyl 5-bromopicolinate (200 mg, 0.93 mmol), N-Boc-piperazine (206 mg, 1.11 mmol), BINAP (118 mg, 0.19 mmol), cesium carbonate (906 mg) in a reaction flask containing toluene (6 mL). , 2.78 mmol) and Pd ₂ (dba) ₃ (85 mg, 0.093 mmol), sealed, replaced with nitrogen three times, heated to 100 ° C and stirred overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (eluent: EtOAc = EtOAc = EtOAc) Ester (115 mg, white solid, yield: 38%).

LC-MS (ESI): m / z 322.2 [M + H +].

Step 2: Preparation of 4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (16c)

4-(6-(Methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (386 mg, 1.2 mmol) was added to a reaction flask containing anhydrous THF (5 mL). Cool to 0 °C. Methylmagnesium bromide solution (2 mL, 3M in diethyl ether) was slowly added dropwise, and the mixture was warmed to room temperature and stirring was continued for one hour. The mixture was diluted with EtOAc EtOAc. The residue was purified by silica gel column chromatography (eluent: EA = 1:1) to give 4-(6-(2-hydroxypropyl-2-yl)pyridin-3-yl)piperazine-1 - tert-butyl formate (180 mg, white solid, yield: 47%).

LC-MS (ESI): m / z 322.8 [M + H +].

Step 3: Preparation of 2-(5-(piperazin-1-yl)pyridin-2-yl)propan-2-ol hydrochloride (16d)

Add 4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (180 mg, 0.56 mmol) in a reaction flask containing dichloromethane (5 mL). A solution of dioxane hydrochloride (2 mL, 4 M) was added dropwise and stirred for 0.5 h. The reaction mixture was concentrated under reduced vacuoielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielieliel It was used directly in the next step without purification.

LC-MS (ESI): m / z 222.7 [M + H +].

Step 4: 2-(5-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridine-2 -base) Preparation of propan-2-ol (16)

Add 2-(5-(piperazin-1-yl)pyridin-2-yl)propan-2-ol hydrochloride (120 mg, 0.41 mmol), 2-(5-) to a reaction flask containing toluene (8 mL). Bromo-2-chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g) (109 mg, 0.34 mmol), BINAP (44 mg, 0.07 mmol), cesium carbonate (554 mg, 1.70 mmol) and Pd ₂ (dba) ₃ (31 mg, 0.034 mmol), sealed, and replaced with nitrogen three times, then warmed to 100 ° C and stirred overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was purified by preparative HPLC (C18, EtOAc/water (0.1% EtOAc), 10% to 100%) to yield 2-(5-(4-(4-chloro-3-(1-methyl-1H-benzene) And [d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridin-2-yl)propan-2-ol (7 mg, white solid, yield: 5.0%).

LC-MS (ESI): m / z 462.3 / 464.3 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 8.24 (s, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.37 (s, 2H) , 7.30 (s, 2H), 7.18 (s, 1H), 7.10 (s, 1H), 3.74 (s, 3H), 3.39 (d, J = 12.3 Hz, 8H), 1.54 (s, 6H).

Example 17: 2-(6-(4-(4-Chloro-3-(1-methyl-1H-benzimidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl Preparation of propan-2-ol (17)

Step 1: Preparation of 6-(4-(4-chloro-3-(1-methyl-1H-benzimidazol-2-yl)phenyl)piperazin-1-yl)nicotinic acid ethyl ester (17a)

Add 6-(piperazin-1-yl)nicotinic acid ethyl ester hydrochloride (3c) (548 mg / 1.77 mmol), 2-(5-bromo-2-) to a reaction flask containing toluene (6 mL) at room temperature Chlorophenyl)-1-methyl-1H-benzimidazole (g) (500 mg / 1.55 mmol), BINAP (193 mg / 0.31 mmol), cesium carbonate (1.52 g / 4.65 mmol) and Pd ₂ (dba) ₃ ( 142 mg / 0.155 mmol), sealed, replaced with nitrogen three times, heated to 100 ° C and stirred overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc. The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc: EtOAc) -Phenyl)phenyl)piperazin-1-yl)nicotinic acid ethyl ester (white solid, 450 mg, yield: 61.1%).

LC-MS (ESI): m / z476.24 / 478.2 [M + H +].

Step 2: 2-(6-(4-(4-Chloro-3-(1-methyl-1H-benzimidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl) Preparation of propan-2-ol (17)

6-(4-(4-Chloro-3-(1-methyl-1H-benzimidazol-2-yl)phenyl)piperazine-1 was added to a reaction flask containing 8 mL of anhydrous THF under nitrogen. -Based ethyl nicotinic acid (450 mg, 0.95 mmol). After the reaction solution was cooled to 0 ° C, a solution of methyl magnesium bromide in diethyl ether (1.6 mL, 3M diethyl ether) was added dropwise. The reaction mixture was slowly added to an ammonium chloride solution, and then extracted with ethyl acetate (15 mL×3). The organic phase was combined, washed with saturated aqueous concentrate. The residue was purified by flash chromatography on silica gel column chromatography (eluent 10% CH ₃ OH / DCM solution) and preparative HPLC (C18, acetonitrile / water (0.1% formic acid), 20% to 100%;) to afford, 2-(6-(4-(4-Chloro-3-(1-methyl-1H-benzimidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)propane- 2-alcohol (white solid; 200 mg, yield: 45.8%).

LC-MS (ESI): m / z 462.3 / 464.3 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 8.34 (d, J = 2.5 Hz, 1H), 7.86 (dd, J = 6.7, 2.1 Hz, 1H), 7.70 (dd, J = 8.9, 2.6 Hz, 1H), 7.47 - 7.33 (m, 4H), 7.16 (d, J = 3.0 Hz, 1H), 7.08 (dd, J = 8.9, 3.0 Hz, 1H), 6.71 (d, J = 8.9 Hz, 1H), 3.76–3.66 (m, 7H), 3.37 (dd, J=6.3, 4.0 Hz, 4H), 1.59 (s, 6H).

Example 18: 2-(5-(4-(4-Chloro-2-fluoro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazine-1- Of pyridyl-2-yl)propan-2-ol (18)

Step 1: Preparation of 4-(5-(ethoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (18b)

Add N-Boc-piperazine (500 mg / 2.68 mmol), ethyl 6-chloronicotinate (498 mg / 2.68 mmol) and N, N-diisopropyl B in a reaction flask containing DMF (10 mL) at room temperature The amine (1.04 g, 8.04 mmol) was sealed and heated to 130 ° C for 6 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (30 mL) was evaporated. The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc======================== Ester (700 mg, pale yellow solid, yield: 77.6%).

LC-MS (ESI): m / z 336.2 [M + H +].

Step 2: Preparation of 4-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (18c)

4-(5-(ethoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.55 mmol) was added to a reaction flask containing anhydrous THF (8 mL). Cool to 0 °C. Methylmagnesium bromide diethyl ether solution (2.0 mL, 3M in diethyl ether) was slowly added dropwise, and then the mixture was warmed to room temperature and stirring was continued for one hour. It was diluted with ice water (0.5 mL), EtOAc (EtOAc) The residue was purified by silica gel column chromatography (eluent:EtOAc: EtOAc======================== - tert-butyl formate (250 mg, white solid, yield: 52%).

LC-MS (ESI): m / z 322.8 [M +, H +].

Step 3: Preparation of 2-(6-(piperazin-1-yl)pyridin-3-yl)propan-2-ol hydrochloride (18d)

Add 4-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.78 mmol) in a reaction flask containing dichloromethane (4 mL). A solution of dioxane hydrochloride (2 mL, 4 M) was added dropwise and stirred at room temperature for 0.5 hour. The reaction mixture was concentrated under reduced vacuoielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielieliel It was used directly in the next step without purification.

LC-MS (ESI): m / z 222.7 [M + H +].

Step 4: 2-(5-(4-(4-Chloro-2-fluoro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl) Preparation of pyridin-2-yl)propan-2-ol (18)

To a reaction flask containing toluene (5 mL) was added 2-(6-(piperazin-1-yl)pyridin-3-yl)propan-2-ol hydrochloride (120 mg, 0.41 mmol), 2- (3-Bromo-6-chloro-2-fluorophenyl)-1-methyl-1H-benzo[d]imidazole (d) (115 mg, 0.34 mmol), BINAP (44 mg, 0.07 mmol), cesium carbonate ( 554 mg, 1.7 mmol) and Pd ₂ (dba) ₃ (31 mg, 0.034 mmol), sealed, replaced with nitrogen three times, heated to 100 ° C and stirred overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was purified by preparative hp~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ -1H-Benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol (8 mg, white solid, yield: 5.0%).

LC-MS (ESI): m / z 480.2 / 482.4 [M + H +].

_{^{1 H NMR (400MHz, CHCl 3}} -d) δ8.25 (s, 1H), 7.89 (s, 1H), 7.47 (s, 1H), 7.39 (s, 5H), 7.13 (s, 1H), 3.71 ( s, 3H), 3.40 (d, J = 5.9 Hz, 8H), 1.54 (s, 6H).

Example 19: 4-(4-Chloro-2-fluoro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-1-(5-(2-hydroxypropane) Preparation of 2-yl)pyridin-2-ylpiperazin-2-one (19)

In a reaction flask containing toluene (6 mL) was added 1-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)piperazin-2-one (15d) (50 mg, 0.21 mmol), 2- (3-Bromo-6-chloro-2-fluorophenyl)-1-methyl-1H-benzo[d]imidazole (d) (86 mg, 0.26 mmol), BINAP (28 mg, 0.043 mmol), cesium carbonate ( 278 mg, 0.85 mmol) and Pd ₂ (dba) ₃ (40 mg, 0.043 mmol) were sealed, replaced with nitrogen three times and heated to 100 ° C overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was purified by preparative EtOAc (EtOAc (EtOAc:EtOAc) d]imidazol-2-yl)phenyl)-1-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)piperazin-2-one (12 mg, white solid, yield: 11.4% ).

LC-MS (ESI): m / z 494.2 / 496.2 [M + H +].

_{^{1 H NMR (400MHz, CHCl 3}} -d) δ8.58 (s, 1H), 7.98-7.83 (m, 3H), 7.48 (d, J = 7.7Hz, 1H), 7.43-7.33 (m, 3H), 7.10 (t, J = 8.8 Hz, 1H), 4.18 (s, 2H), 4.07 (d, J = 11.4 Hz, 2H), 3.72 (s, 4H), 1.63 (s, 6H).

Example 20: 2-(4-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)benzene Preparation of propan-2-ol (20)

Step 1: Preparation of 2-(4-bromophenyl)-2-propanol (20b)

Methyl p-bromobenzoate (2 g, 9.3 mmol) and 50 mL of anhydrous tetrahydrofuran were added to a 100 mL round bottom flask under nitrogen, and methyl magnesium bromide (28 mL, 1 M in THF) was slowly added dropwise at 0 °C. After the addition was completed, stirring was continued for 1 hour at room temperature. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc %).

LC-MS (ESI): m / z 215.0 / 217.0 [M + H +].

Step 2: Preparation of 2-(4-(4-tert-butoxycarbonyl-piperazinone)phenyl)-2-propanol (20c)

2-(4-Bromophenyl)-2-propanol (500 mg, 2.3 mmol), 4-BOC-piperazinone (560 mg, 2.8 mmol), cesium carbonate (2.3 g, 6.9 mmol), Xantphos at room temperature (135 mg, 0.2 mmol), tris(dibenzylideneacetone)dipalladium (426 mg, 0.4 mmol) and 30 mL of toluene were added to a 50 mL round bottom flask. Sealed, replaced with nitrogen three times, heated to 120 ° C, and stirred for 4 hours. After the reaction liquid was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut (440 mg, yellow oil, yield 57%).

LC-MS (ESI): m / z 335.2 [M + H +].

Step 3: Preparation of 2-(4-(4-piperazinone)phenyl)-2-propanol (20d)

2-(4-(4-tert-Butoxycarbonyl-piperazinone)phenyl)-2-propanol (200 mg, 0.6 mmol), 2 mL dichloromethane and hydrochloric acid in dioxane (4N, 2 mL) Add to a 25 mL round bottom flask. The mixture was stirred at room temperature for 0.5 hr.

LC-MS (ESI): m / z 235.2 [M + H +].

Step 4: 2-(4-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)phenyl Preparation of propan-2-ol (20)

2-(4-(4-piperazinone)phenyl)-2-propanol (50 mg, 0.21 mmol), 2-(5-bromo-2-chlorophenyl)-1-methyl- 1H-benzo[d]imidazole (g) (57 mg, 0.16 mmol), cesium carbonate (243 mg, 0.65 mmol), BINAP (12 mg, 0.02 mmol), tris(dibenzylideneacetone) dipalladium (34 mg, 0.04 mmol) And 5 mL of toluene was added to a 25 mL round bottom flask. Sealed, replaced with nitrogen three times, heated to 120 ° C, and stirred for 4 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was purified by preparative hp~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ And [d]imidazol-2-yl)phenyl)piperazin-1-yl)phenylpropan-2-ol (22 mg, white solid, yield: 26%).

LC-MS (ESI): m / z 475.2 / 477.2 [M + H +].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.86 (d, J = 7.7Hz, 1H), 7.57 (d, J = 8.4Hz, 2H), 7.49-7.43 (m, 2H), 7.42-7.35 (m, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.13 (s, 1H), 7.01 (d, J = 9.0 Hz, 1H), 4.13 (s, 2H), 3.89 (d, J = 5.6 Hz, 2H), 3.74 (s, 3H), 3.69 (d, J = 5.5 Hz, 2H), 1.61 (s, 6H).

Example 21: 2-(4-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)phenyl Preparation of propan-2-ol (21)

Step 1: 1 - Preparation of tert-butoxycarbonyl-4-(4-methoxyformylphenyl)piperazine (21a)

Methyl p-bromobenzoate (500 mg, 2.3 mmol), 1-tert-butoxycarbonylpiperazine (480 mg, 2.5 mmol), sodium tert-butoxide (313 mg, 3.3 mmol), BINAP (58 mg, 0.090 mmol) at room temperature Palladium acetate (10 mg, 0.05 mmol) and 30 mL of DMF were added to a 100 mL round bottom flask. Sealed, replaced with nitrogen three times, heated to 120 ° C, and stirred for 4 hours. After the reaction liquid was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc:EtOAc: Yellow oil, yield 68%).

LC-MS (ESI): m / z 321.2 [M + H +].

Step 2: Preparation of 4-piperazin-1-ylbenzoic acid methyl ester hydrochloride (21b)

Add 1-tert-butoxycarbonyl-4-(4-methoxyformylphenyl)piperazine (250 mg, 0.79 mmol), 2 mL of dichloromethane and 2 mL of hydrochloric acid in dioxane (4N) to 25 mL circle In the bottom flask. The mixture was stirred at room temperature for 0.5 hr.

LC-MS (ESI): m / z 221.2 [M + H +].

Step 3: Preparation of 4-methyl-(4-(4-chloro-3-(1-methyl-1H-benzo[d]imidazolium)phenyl)piperazine-1yl)benzoic acid methyl ester (21c)

Methyl 4-piperazin-1-ylbenzoate hydrochloride (50 mg, 0.19 mmol), 2-(5-bromo-2-chlorophenyl)-1-methyl-1H-benzo[ d] imidazole (g) (60 mg, 0.16 mmol), cesium carbonate (243 mg, 0.65 mmol), BINAP (12 mg, 0.02 mmol), tris(dibenzylideneacetone) dipalladium (34 mg, 0.01 mmol) and 5 mL of toluene In a 25 mL round bottom flask, sealed, replaced with nitrogen three times, heated to 120 ° C, and stirred for 4 hours. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut eluting elut [d] Imidazole) phenyl)piperazine-1 -yl)benzoic acid methyl ester (30 mg, yellow oil, yield 41%).

LC-MS (ESI): m / z 461.2 / 463.2 [M + H +].

Step 4: 2-(4-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)phenyl) Preparation of propan-2-ol

Methyl 4-methyl-(4-(4-chloro-3-(1-methyl-1H-benzo[d]imidazolium)phenyl)piperazine-1 yl)benzoate (30 mg under N2) , 0.065 mmol) and 2 mL of anhydrous tetrahydrofuran were added to a 25 mL round bottom flask, cooled to 0 ° C, and methyl magnesium bromide (0.3 mL, 3 M diethyl ether) was added dropwise. After the addition, the mixture was stirred at room temperature for 1 hr. The residue was purified by preparative HPLC (C18, EtOAc/water (0.1% EtOAc), 20% to 100%) to afford 2-(4-(4-(4-chloro-3-(1-methyl-1H-benzene) And [d]imidazol-2-yl)phenyl)piperazin-1-yl)phenyl)propan-2-ol (3 mg, white solid, 10% yield).

LC-MS (ESI): m / z 461.4 / 463.4 [M + H +].

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 - 7.85 (m, 1H), 7.44 (s, 4H), 7.40 - 7.32 (m, 2H), 7.17 (s, 1H), 7.11 - 7.05 (m, 1H) ), 6.97 (d, J = 8.3 Hz, 2H), 3.73 (s, 3H), 3.37 (d, J = 15.2 Hz, 8H), 1.60 (s, 6H).

Example 22: (6-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridine-3- Preparation of dimethyl phosphine oxide (22)

Step 1: Preparation of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (22a)

Piperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.68 mmol), 5-bromo-2-chloropyridine (516 mg, 2.68 mmol) and three were added to a reaction flask containing nitrogen methylpyrrolidone (NMP) (5 mL). Ethylamine (1.1 mL, 8.05 mmol) was heated to 180 ° C for 1 hour. After the reaction was completed, the mixture was evaporated. The residue was purified by silica gel column chromatography (eluent: EtOAc================================== Yellow solid, yield: 54%).

LC-MS (ESI): m / z 342.2 / 344.2 [M + H +].

Step 2: Preparation of 4-(5-(dimethylphosphonoyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (22b)

4-(5-Bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.73 mmol) was added to a reaction flask containing anhydrous THF (5 mL), sealed, and replaced with nitrogen three times. -78 ° C. A solution of n-butyllithium (0.35 mL, 2.5 M in n-hexane) was slowly added dropwise, and stirring was continued for 45 minutes. Further, a solution of dimethylphosphoryl chloride (162 mg, 1.44 mmol) in THF (1 mL) was added dropwise, and the mixture was warmed to -30 ° C and stirred for 3 hours. After the reaction was completed, EtOAc (EtOAc) (EtOAc) The residue was purified by silica gel column chromatography (eluent: EA = 1:1) to give 4-(5-(dimethylphosphonyl)pyridin-2-yl)piperazine-1-carboxylic acid Butyl ester (100 mg, white solid, yield: 40%).

LC-MS (ESI): m / z 340.4 [M + H +].

Step 3: Preparation of dimethyl(6-(piperazin-1-yl)pyridin-3-yl)phosphine hydrochloride hydrochloride (22c)

Add 4-(5-(dimethylphosphono)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol) to a reaction flask containing dichloromethane (2 mL), and add hydrochloric acid dropwise. The dioxane solution (2 mL) was stirred at room temperature for 0.5 hr, and the reaction was concentrated under reduced pressure to give crude dimethyl(6-(piperazin-1-yl)pyridin-3-yl)phosphine oxide hydrochloride. (100 mg, pale yellow solid). It was used in the next step without purification.

LC-MS (ESI): m / z 240.2 [M + H +].

Step 4: (6-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl Preparation of dimethyl phosphine oxide

Add dimethyl (6-(piperazin-1-yl)pyridin-3-yl)phosphine oxide hydrochloride (35 mg, 0.46 mmol), 2-(5-bromo-) to a reaction flask containing toluene (4 mL). 2-Chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g) (56 mg, 0.176 mmol), BINAP (19 mg, 0.03 mmol), cesium carbonate (192 mg, 0.584 mmol) and Pd ₂ ( Dba) ₃ (27 mg, 0.03 mmol), sealed, replaced with nitrogen three times, heated to 100 ° C and stirred overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was purified by preparative HPLC (C18, EtOAc/water (0.1% EtOAc), 20% to 100%) to afford (6-(4-(4-chloro-3-(1-methyl-1H-benzo[ d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)dimethylphosphine oxide (7 mg, white solid, yield: 10%).

LC-MS (ESI): m / z 480.1 / 482.1 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 8.34 (d, J = 4.3 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.55 - 7.36 (m, 2H), 7.30 - 7.26 (m, 2H) ), 7.06 (d, J = 3.1 Hz, 1H), 6.97 (dd, J = 8.9, 3.1 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 3.78 - 3.70 (m, 4H), 3.64 (s, 3H), 3.33–3.24 (m, 4H), 1.63 (s, 6H).

Example 23: 1-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-(5-(2-hydroxypropan-2-yl) Preparation of pyridin-2-yl) piperazin-2-one (23)

Step 1: 4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester ( Preparation of 23b)

Add 3-oxopiperazine-1-carboxylic acid tert-butyl ester (104 mg, 0.52 mmol), 2-(5-bromo-2-chlorophenyl)-1-methyl- to a reaction flask containing toluene (4 mL). 1H-benzo[d]imidazole (g) (200 mg, 0.62 mmol), XantPhOS (71 mg, 0.124 mmol), cesium carbonate (606 mg, 1.86 mmol) and Pd ₂ (dba) ₃ (114 mg, 0.124 mmol), sealed, The mixture was replaced with nitrogen three times, and heated to 100 ° C and stirred overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (eluent: EtOAc========================================= -Phenyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester (50 mg, yellow liquid, yield: 24%).

LC-MS (ESI): m / z 441.3 / 443.3 [M + H +].

Step 2: Preparation of 1-(4-chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-2-one hydrochloride (23c)

Add 4-(4-chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-3-oxoperidine to a reaction flask containing dichloromethane (2 mL) tert-Butyl-1-carboxylic acid tert-butyl ester (50 mg, 0.113 mmol) was added dropwise with aq. The reaction solution was concentrated under reduced pressure to give the crude product 1-(4-chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl) piperazine-2-one hydrochloride. (50 mg, yellow solid).

LC-MS (ESI): m / z 341.2 / 343.2 [M + H +].

Step 3: 1-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-(5-(2-hydroxypropan-2-yl) Preparation of pyridin-2-yl) piperazine-2-one

Add 1-(4-chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)peridine to a reaction flask containing N-methylpyrrolidone (NMP) (5 mL) Pyrazin-2-one hydrochloride (50 mg, 0.147 mmol), 2-(6-chloropyridin-3-yl)propan-2-ol (25 mg, 0.147 mmol) and DIPEA (0.12 mL, 0.735 mmol). The reaction was allowed to rise to 180 ° C and stirred for 1 hour. After the reaction was completed, the mixture was evaporated. The residue was purified by preparative EtOAc (EtOAc (EtOAc:EtOAc) 2-yl)phenyl)-4-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)piperazin-2-one (5 mg, white solid, yield: 8%).

LC-MS (ESI): m / z 476.2 / 478.2 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 8.28 (d, J = 2.1 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.65 (dd, J = 8.8, 2.6 Hz, 1H) , 7.55 - 7.49 (m, 2H), 7.46 (dd, J = 8.7, 2.4 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.33 - 7.24 (m, 2H), 6.55 (d, J = 8.8 Hz, 1H), 4.21 (s, 2H), 3.90 (dt, J = 46.3, 4.8 Hz, 4H), 3.67 (s, 3H), 1.51 (s, 6H).

Example 24: 2-(2-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyrimidine Preparation of -5-yl)propan-2-ol (24)

Step 1: Preparation of 4-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (24a)

Add 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1.2-a]pyridine (b) (230 mg, 0.72 mmol), tert-butyl in a reaction flask containing toluene (5 mL) Piperazine (150 mg, 0.80 mmol), cesium carbonate (1.2 g, 3.6 mmol), BINAP (100 mg, 0.14 mmol) and tris(dibenzylideneacetone) dipalladium (132 mg, 0.14 mmol) were sealed and replaced with nitrogen three times. Heat to 100 ° C and stir overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated evaporated. mjjjjjjjjjj tert-Butyl 3-methylimidazo[1.2-a]pyridin-2-yl)phenyl)piperazine-1-carboxylate (150 mg, white solid, yield: 49%).

LC-MS (ESI): m / z 427.2 / 429.2 [M + H +].

Step 2: Preparation of 2-(2-chloro-5-(piperazin-1-yl)phenyl)-3-methylimidazo[1,2-a]pyridine hydrochloride (24b)

Add 4-(4-chloro-3-(3-methylimidazo[1.2-a]pyridin-2-yl)phenyl)piperazine-1-carboxylic acid to a reaction flask containing dichloromethane (2 mL) tert-Butyl ester (150 mg, 0.35 mmol) was added dropwise with a solution of dioxane hydrochloride (2 mL). The reaction solution was concentrated under reduced pressure to give ethyl 2-(2-chloro-5-(piperazin-1-yl)phenyl)-3-methylimidazo[1,2-a]pyridine hydrochloride (140 mg). , light yellow solid). The product was used directly in the next step without purification.

LC-MS (ESI), m / z 327.4 / 329.4 [M + H +]. Step 3: 2-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyrimidine-5-carboxylate Preparation of ethyl acetate (24c)

In a reaction flask containing N-methylpyrrolidone (NMP) (2 mL) was added 2-(2-chloro-5-(piperazin-1-yl)phenyl)-3-methylimidazo[1.2-a] Pyridine hydrochloride (30 mg, 0.092 mmol), ethyl 2-chloropyrimidine-5-carboxylate (26 mg, 0.14 mmol) and DIPEA (48 mg, 0.37 mmol). After the reaction mixture was cooled to room temperature, ethyl acetate (10 mL) was evaporated. The residue was purified by silica gel column chromatography (eluent: EA: EtOAc: 1:1) to give 2-(4-(4-chloro-3-(3-methylimidazo[ Ethyl 2-yl)phenyl)piperazin-1-yl)pyrimidine-5-carboxylate (30 mg, yellow solid, yield 68%).

LC-MS (ESI): m / z 477.2 / 479.2 [M + H +].

Step 4: 2-(2-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyrimidine- Preparation of 5-yl)propan-2-ol (24)

2-(4-(4-Chloro-3-(3-methylimidazo[1.2-a]pyridin-2-yl)phenyl) was added to a reaction flask containing anhydrous THF (8 mL) under nitrogen. Ethyl piperazine-1-yl)pyrimidine-5-carboxylate ((30 mg, 0.063 mmol)) was cooled to 0 °C. A solution of methylmagnesium bromide in diethyl ether (0.1 mL, 3M in diethyl ether) was slowly added dropwise, and the mixture was warmed to room temperature and stirring was continued for one hour. It was quenched with ice water (0.5 mL). The residue was purified by preparative hp~~~~~~~~~~~~~~~~~~~~~~~~~~~~^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ , 2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyrimidin-5-yl)propan-2-ol (20 mg, white solid, yield: 68%).

LC-MS (ESI): m / z 463.3 / 465.3 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (s, 2H), 8.32 (d, J = 7.0 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.28 (s, 1H), 7.06 (s, 2H), 6.99 (s, 1H), 5.15 - 5.03 (m, 1H), 3.85 (s, 4H), 3.25 (s, 4H), 2.40 (s, 3H), 1.41 (s, 6H).

Example 25: 2-(5-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyrazine Preparation of 2-yl)propyl-2-ol (25)

In the same manner as in Example 13, except that ethyl 2-chloropyridazine-2-carboxylate was used in place of ethyl 2-chloropyrimidine-5-carboxylate to give 2-(5-(4-(4-chloro-)- 3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyrazin-2-yl)propyl-2-ol (white solid, two steps Yield 13%).

LC-MS (ESI): m / z463.2 / 465.2 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ8.34 (s, 1H), 8.27 (s, 1H), 7.69 (d, J = 7.7Hz, 1H), 7.62 (d, J = 7.8Hz, 1H) , 7.50 (d, J = 8.9 Hz, 1H), 7.35 - 7.17 (m, 4H), 5.14 (s, 1H), 3.66 (d, J = 12.2 Hz, 7H), 3.36 (s, 4H), 1.41 ( s, 6H).

Example 26: 4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)-1-(5-(2-hydroxypropane-2-) Of pyridyl-2-yl)piperazin-2-one (26)

In the same manner as in Example 15, except that 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1.2-a]pyridine (b) was used instead of 2-(5-bromo-2- Chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g) to give 4-(4-chloro-3-(3-methylimidazo[1,2-a]pyridine-2 -Phenyl)-1-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)piperazin-2-one (white solid, one step yield 57%).

LC-MS (ESI): m / z476.2 / 478.2 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d ₆ ) δ 8.49 (d, J = 2.1 Hz, 1H), 7.78 (dd, J = 15.8, 7.8 Hz, 2H), 7.76 (dd, J = 8.7, 2.6 Hz , 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.18 - 7.11 (m, 1H), 7.02 (d, J = 3.1 Hz, 1H), 6.87 – 6.75 (m, 2H), 4.21–3.99 (m, 4H), 3.63–3.53 (m, 2H), 2.39 (s, 3H), 1.54 (s, 6H).

Example 27: 2-(6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyrazin-2-yl)phenyl)piperazin-1-yl) Preparation of pyridin-3-yl)propan-2-ol (27)

In the same manner as in Example 7, except that 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyrazine (m) was used instead of 2-(5-bromo). 2-(2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine (b) to give 2-(6-(4-(4-chloro-3-(3-methylimidazo) [1,2-a]pyrazin-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol (white solid, 14% yield in two steps).

LC-MS (ESI): m / z463.2 / 465.1 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.22 (d, J = 2.6 Hz, 1H), 7.97 (d, J = 4.6 Hz, 1H), 7.63 (dd, J = 8.8, 2.6 Hz, 1H) , 7.50–7.20 (m, 2H), 7.15–7.06 (m, 1H), 6.91 (dd, J=58.8, 12.8 Hz, 3H), 3.64–3.54 (m, 4H), 3.25 (s, 4H), 2.43 (d, J = 16.0 Hz, 3H), 1.40 (s, 6H).

Example 28: 2-(2-Chloro-4-fluoro-5-(4-(5-(methylsulfonyl)pyridin-2-yl)piperazin-1-yl)phenyl)-3-methyl Preparation of imidazo[1,2-a]pyridine (28)

In the same manner as in Example 1, except that 2-(5-bromo-2-chloro-4-fluorophenyl)-3-methylimidazo[1,2-a]pyridine (1) was used instead of 2-( 5-bromo-2-chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g) to give 2-(2-chloro-4-fluoro-5-(4-(5-() Methylsulfonyl)pyridin-2-yl)piperazin-1-yl)phenyl)-3-methylimidazo[1,2-a]pyridine (white solid, yield 36% in three steps).

LC-MS (ESI): m / z500.1 / 02.2 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ8.53 (d, J = 2.5Hz, 1H), 8.32 (dd, J = 7.0,1.3Hz, 1H), 7.92 (dd, J = 9.2,2.6Hz, 1H), 7.63 - 7.56 (m, 1H), 7.52 (d, J = 12.3 Hz, 1H), 7.28 (ddd, J = 9.0, 6.7, 1.3 Hz, 1H), 7.15 (d, J = 9.4 Hz, 1H) ), 7.06 - 6.95 (m, 2H), 3.85 (t, J = 5.0 Hz, 4H), 3.15 (d, J = 6.4 Hz, 7H), 2.40 (s, 3H).

Example 29: 2-(2-Chloro-5-(4-(5-(methylsulfonyl)pyridin-2-yl)piperazin-1-yl)phenyl)-3-methylimidazo[1 Preparation of 2-a]pyridine (29)

In the same manner as in Example 1, except that 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine (b) was used instead of 2-(5-bromo- 2-Chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g) to give 2-(2-chloro-5-(4-(5-(methylsulfonyl))pyridine-2 -yl)piperazin-1-yl)phenyl)-3-methylimidazo[1,2-a]pyridine (white solid, 47% yield).

LC-MS (ESI): m / z482.2 / 484.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ8.53 (d, J = 2.6Hz, 1H), 8.32 (d, J = 6.9Hz, 1H), 7.92 (dd, J = 9.2,2.6Hz, 1H) , 7.59 (d, J = 9.1 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.32 - 7.24 (m, 1H), 7.12 - 6.96 (m, 4H), 3.92 - 3.77 (m, 4H) ), 3.30–3.36 (m, 4H), 3.16 (s, 3H), 2.40 (s, 3H).

Example 30: 2-(5-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyrimidine Preparation of 2-yl)propan-2-ol (30)

The same procedure as in Example 12 was carried out except that 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine (b) was used instead of 2-(5-bromo- 2-Chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g) to give 2-(5-(4-(4-chloro-3-(3-methylimidazo[1] , 2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyrimidin-2-yl)propan-2-ol (white solid, 12% yield in two steps).

LC-MS (ESI): m / z 463.2 / 465.2 [M + H +].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.54 (s, 2H), 8.34 - 8.31 (m, 1H), 7.61 - 7.56 (m, 1H), 7.43 - 7.39 (m, 1H), 7.30 - 7.25 (m,1H), 7.14–7.07 (m, 2H), 7.02–6.96 (m, 1H), 4.91–4.85 (m, 1H), 3.43–3.34 (m, 8H), 2.54 (s, 3H), 2.40 (s, 3H), 1.45 (s, 3H).

Example 31: 2-(6-(4-(4-Chloro-2-fluoro-5-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazine-1 Of -pyridin-3-yl)propan-2-ol (31)

The same procedure as in Example 10 was carried out except that 2-(5-bromo-2-chloro-4-fluorophenyl)-3-methylimidazo[1,2-a]pyridine (1) was used instead of 2-( 5-(bromo-2-chloro-4-fluorophenyl)-1-methyl-1H-benzo[d]imidazole (h) to give 2-(6-(4-(4-chloro-2-fluoro) -5-(3-Methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol (white solid, two steps Yield 18%).

LC-MS (ESI): m / z 480.1 / 482.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.58 (d, J = 6.8 Hz, 1H), 8.25 - 8.11 (m, 1H), 7.85 - 7.51 (m, 4H), 7.27 (dd, J = 18.4) , 8.3 Hz, 2H), 6.92 (dd, J = 13.5, 8.9 Hz, 1H), 3.67 (dt, J = 10.2, 4.6 Hz, 4H), 3.22 - 3.12 (m, 4H), 2.46 (s, 3H) , 1.32 (d, J = 68.4 Hz, 6H).

Example 32: (2-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyrimidine-5 -base) preparation of dimethylphosphine oxide (32)

The same procedure as in Example 22 was employed except that 2-chloro-5-bromopyrimidine and 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine were used. ) (2-(4) was prepared by substituting 2-chloro-5-bromopyridine and 2-(5-bromo-2-chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g), respectively. -(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyrimidin-5-yl)dimethylphosphine oxide ( White solid, 7% yield in four steps).

LC-MS (ESI): m / z481.2 / 483.2 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ8.62 (s, 1H), 8.35 (s, 1H), 7.80 (d, J = 2.4Hz, 1H), 7.67 (s, 1H), 7.61 (d, J=1.3 Hz, 1H), 7.53–7.51 (m, 1H), 7.42 (s, 1H), 7.10–7.06 (m, 2H), 3.96 (t, J=5.2 Hz, 4H), 3.41 (s, 4H) ), 2.40 (s, 3H), 1.66 (s, 3H), 1.63 (s, 3H).

Example 33: (6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridine-3 -base) preparation of dimethylphosphine oxide (33)

The same procedure as in Example 22 was carried out except that 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine (b) was used instead of 2-(5-bromo- 2-Chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g), (6-(4-(4-chloro-3-(3-methylimidazo[1,2] -a] Pyridin-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)dimethylphosphine oxide (white solid, one step yield: 18%).

LC-MS (ESI): m / z 480.1 / 482.1 [M + H +].

_{^{1 H NMR (400MHz, CHCl 3}} -d 6) δ8.34 (s, 1H), 7.85 (d, J = 6.8Hz, 1H), 7.76 (s, 1H), 7.59 (d, J = 9.0Hz, 1H ), 7.31 (d, J = 8.8 Hz, 1H), 7.14 (s, 1H), 7.08 (d, J = 3.1 Hz, 1H), 6.91 - 6.80 (m, 2H), 6.66 (d, J = 8.8 Hz) , 1H), 3.79 - 3.67 (m, 4H), 3.31 - 3.17 (m, 4H), 2.38 (s, 3H), 1.66 (s, 3H), 1.63 (s, 3H).

Example 34: 2-(2-Chloro-5-(4-(5-(methylsulfonyl)pyrimidin-2-yl)piperazin-1-yl)phenyl)-3-methylimidazo[1 Preparation of 2-a]pyridine (34)

The same procedure as in Example 1 was carried out except that 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine (b) and 5-bromo-2-chloro were used. Pyrimidine is substituted for 2-(5-bromo-2-chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g) and 5-bromo-2-chloropyridine, respectively, to give 2-(2- Chloro-5-(4-(5-(methylsulfonyl)pyrimidin-2-yl)piperazin-1-yl)phenyl)-3-methylimidazo[1,2-a]pyridine (white solid) , three steps yield 5%).

LC-MS (ESI): m / z 483.1 / 485.2 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ8.75 (s, 2H), 8.32 (dt, J = 6.9,1.2Hz, 1H), 7.58 (dt, J = 9.0,1.2Hz, 1H), 7.41 ( d, J = 8.5 Hz, 1H), 7.27 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 7.14 - 7.05 (m, 2H), 6.99 (td, J = 6.8, 1.2 Hz, 1H), 4.02 (t, J = 5.2 Hz, 4H), 3.31 (t, J = 5.2 Hz, 4H), 3.23 (s, 3H), 2.40 (s, 3H).

Example 35: 2-(6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridine Preparation of -3-yl)-2-methylpropionitrile (35)

Step 1: Preparation of 2-(6-chloropyridin-3-yl)acetonitrile (35a)

2-Chloro-5-(chloromethyl)pyridine (5 g, 30.86 mmol), trimethylsilylonitrile (6.1 g, 61.72 mmol), potassium carbonate (8.6 g, 61.72) were added to a reaction flask containing acetonitrile (30 mL). Methyl) and potassium iodide (10 g, 1.72 mmol) were stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut

LC-MS (ESI): m / z153.2 / 155.1 [M + H +].

Step 2: Preparation of 2-(6-chloropyridin-3-yl)-2-methylpropanenitrile (35b)

Sodium hydroxide (3.9 g, 98.4 mmol), 2-(6-chloropyridin-3-yl)acetonitrile (500 mg, 3.28 mmol), benzyltriethyl chloride were added to a reaction flask containing H ₂ O (10 mL). Ammonium (187 mg, 0.82 mmol) and iodomethane (1.1 g, 7.54 mmol) were taken and the mixture was warmed to 60 ° C and stirred for 2 hr. After the reaction was completed, the mixture was evaporated. The residue was purified by silica gel column chromatography eluting elut elut elut eluting elut , yield 76%).

LC-MS (ESI): m / z181.0 / 183.0 [M + H +].

Step 3: Preparation of tert-butyl 4-(5-(2-cyanopropan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (35c)

Add 2-(6-chloropyridin-3-yl)-2-methylpropanenitrile (200 mg, 1.10 mmol) and piperazine-1-carboxylic acid tert-butyl ester (410 mg, 2.20) to a reaction flask containing NMP (5 mL). Methyl) and N,N-diisopropylethylamine (426 mg, 3.30 mmol). The reaction mixture was heated to 180 ° C and stirred for 2 h. After the reaction was completed, the mixture was evaporated, evaporated, evaporated. The residue was purified by silica gel column chromatography (eluent: EA: EtOAc: 1:1) to afford 4-(5-(2-cyanopropan-2-yl)pyridin-2-yl)piperazine- tert-Butyl 1-carboxylate (150 mg, white solid, yield 41%).

LC-MS (ESI): m / z331.4 [M + H +].

Step 4: Preparation of 2-methyl-2-(6-(piperazin-1-yl)pyridin-3-yl)propanenitrile hydrochloride (35d)

Add 4-(5-(2-cyanopropan-2-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.45 mmol) to a reaction flask containing dichloromethane (1 mL) A solution of dioxane hydrochloride (1 mL) was added dropwise. Stir at room temperature for 0.5 hours. The reaction mixture was concentrated to dryness crystals crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal It was used directly in the next step without purification.

LC-MS (ESI): m / z 231.2 [M + H +].

Step 5: 2-(6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridine- Preparation of 3-yl)-2-methylpropionitrile (35)

Add 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1.2-a]pyridine (b) (106 mg, 0.33 mmol), 2-A to a reaction flask containing toluene (5 mL) 2-(6-(piperazin-1-yl)pyridin-3-yl)propanenitrile hydrochloride (50 mg, 0.22 mmol), cesium carbonate (433 mg, 1.32 mmol), BINAP (27 mg, 0.044 mmol) and Tris(dibenzylideneacetone)dipalladium (20 mg, 0.022 mmol) was sealed, replaced with nitrogen three times and heated to 100 ° C overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid), 20% to 100%) to give 2-(6-(4-(4) -Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)-2-methylpropanenitrile (23 mg , white solid, yield 23%).

LC-MS (ESI): m / z 471.3 / 473.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (d, J = 7.0 Hz, 1H), 8.26 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.9, 2.8 Hz, 1H) , 7.59 (d, J = 9.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.31 - 7.24 (m, 1H), 7.13 - 7.04 (m, 2H), 7.02 - 6.92 (m, 2H) ), 3.71 - 3.59 (m, 4H), 3.28 (d, J = 5.0 Hz, 4H), 2.40 (s, 3H), 1.66 (s, 6H).

Example 36: 1-(6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridine Preparation of -3-yl)cyclopropane-1-carbonitrile (36)

In the same manner as in Example 35 except that dibromoethane was used in place of methyl iodide to obtain 1-(6-(4-(4-chloro-3-(3-methylimidazo[1,2-a]] Pyridin-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)cyclopropane-1-carbonitrile (white solid, 15% yield in four steps).

LC-MS (ESI): m / z469.3 / 471.1 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (d, J = 6.8 Hz, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.53 (dd, J=8.9, 2.7 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.31–7.24 (m, 1H), 7.13–7.03 (m, 2H), 7.02–6.97 (m, 1H) ), 6.91 (d, J = 8.9 Hz, 1H), 3.69 - 3.58 (m, 4H), 3.29 - 3.22 (m, 4H), 2.40 (s, 3H), 1.71 - 1.57 (m, 2H), 1.46 - 1.35 (m, 2H).

Example 37: 1-(6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridine Preparation of -3-yl)cyclopropan-1-ol (37)

6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl) was added to a reaction flask containing THF (5 mL) under nitrogen. Piperazine-1-yl)ethyl nicotinic acid (7a) (50 mg, 0.11 mmol) and tetraisopropyl titanate (31 mg, 0.11 mmol). The mixture was stirred at room temperature for 0.5 hour and then cooled to -78 °C. A solution of ethylmagnesium bromide in THF (0.1 mL, 0.4 mmol) was slowly added dropwise, and the mixture was stirred for further 4 hours, then warmed to room temperature overnight. After the reaction was completed, ice water (0.1 mL) was evaporated and evaporated. The residue was purified by preparative hp~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ , 2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)cyclopropan-1-ol.

LC-MS (ESI): m / z460.2 / 462.1 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ8.34-8.29 (m, 1H), 8.08 (d, J = 2.5Hz, 1H), 7.58 (dd, J = 9.1,1.2Hz, 1H), 7.44- 7.37 (m, 2H), 7.27 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 7.13 - 7.04 (m, 2H), 6.99 (td, J = 6.8, 1.2 Hz, 1H), 6.84 (d, J=8.9 Hz, 1H), 5.84 (s, 1H), 3.58 (dd, J=6.6, 3.8 Hz, 4H), 2.40 (s, 3H), 1.03–0.95 (m, 2H), 0.87–0.82 (m) , 2H).

Example 38: 2-(2-Chloro-5-(4-(5-cyclopropylpyridin-2-yl)piperazin-1-yl)phenyl)-3-methylimidazo[1,2- a] Preparation of pyridine (38)

Step 1: 2-(5-(4-(5-Bromopyridin-2-yl)piperazin-1-yl)-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine Preparation of (38a)

Add 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1.2-a]pyridine (b) (200 mg, 0.61 mmol), N, N to a reaction flask containing NMP (10 mL) -Diisopropylethylamine (158 mg, 1.22 mmol) and 2-chloro-5-bromopyridine (116 mg, 0.61 mmol), and the mixture was stirred and stirred at 180 ° C for 1 hour. After the reaction was completed, ethyl acetate (20 mL) was evaporated. The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc: EtOAc) 2-Chlorophenyl)-3-methylimidazo[1,2-a]pyridine (150 mg, yellow solid, yield 51%).

LC-MS (ESI): m / z 482.0 / 484.0 [M + H +].

Step 2: 2-(2-Chloro-5-(4-(5-cyclopropylpyridin-2-yl)piperazin-1-yl)phenyl)-3-methylimidazo[1,2-a Preparation of pyridine (38)

Add 2-(5-(4-(5-bromopyridin-2-yl)piperazin-1-yl)-2-chlorophenyl) to a reaction vial containing 1,4-dioxane (10 mL) 3-methylimidazo[1,2-a]pyridine (100 mg, 0.21 mmol), cyclopropylboronic acid (27 mg, 0.31 mmol), cesium carbonate (138 mg, 0.42 mmol) and tetratriphenylphosphine palladium (46 mg) , 0.04 mmol), sealed, replaced with nitrogen three times, heated to 100 ° C and stirred for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated, evaporated, evaporated, mjjjjjjjjjjjjjjjjjj 4-(5-Cyclopropylpyridin-2-yl)piperazin-1-yl)phenyl)-3-methylimidazo[1,2-a]pyridine.

LC-MS (ESI): m / z 444.2 / 446.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (d, J = 7.0 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.30 - 7.19 (m, 2H), 7.11 - 7.04 (m, 2H), 6.99 (t, J = 6.8 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 3.60–3.50 (m, 4H), 3.26 (d, J=4.9 Hz, 4H), 2.40 (s, 3H), 1.23 (s, 1H), 0.91–0.83 (m, 2H), 0.58 (q) , J = 5.2, 4.4 Hz, 2H).

Example 40: 1-(6-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridine- Preparation of 3-yl)-2,2,2-trifluoroethyl alcohol (40)

Preparation of Step 1 : 1-(6-Bromopyridin-3-yl)-2,2,2-trifluoroethyl Alcohol (40a)

In a reaction flask containing ethylene glycol dimethyl ether (30 mL), 6-bromo-nicotinic acid (2 g, 10.75 mmol), trimethyl(trifluoromethyl)silane (2.3 g, 16.13 mmol) and cesium fluoride ( 327 mg, 2.15 mmol), the mixture was stirred at room temperature overnight. After completion of the reaction, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc: EtOAc) 2.3 g, yellow liquid, yield 85%).

LC-MS (ESI): m / z256.0 / 25.9 [M + H +].

Step 2: 1-(6-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridine-3 Preparation of 2-yl-2,2,2-trifluoroethyl alcohol (40)

Add 2-(2-chloro-5-(piperazin-1-yl)phenyl)-1-methyl-1H-benzo[d]imidazole hydrochloride (1a) to a reaction flask containing toluene (5 mL) (98 mg, 0.30 mmol), 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl alcohol (50 mg, 0.19 mmol), cesium carbonate (394 mg, 1.2 mmol), BINAP ( 25 mg, 0.04 mmol) and tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), sealed, three times with nitrogen and heated to 100 ° C overnight. The reaction liquid was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid), 30% to 100%) to give 1-(6-(4-(4) -Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl Alcohol (46 mg, white solid, yield 46%).

LC-MS (ESI): m / z502.2 / 504.1 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.49 (d, J = 8.9 Hz, 1H), 7.36 - 7.15 (m, 4H), 6.93 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 5.6 Hz, 1H), 5.06 (d, J = 6.0 Hz, 1H), 3.65 (d, J = 10.1 Hz, 7H), 3.35 (d, J = 5.3 Hz, 4H).

Example 41: 2-(2-Chloro-5-(4-(5-(prop-1-en-2-yl)pyridin-2-yl)piperazin-1-yl)phenyl)-1-yl Preparation of keto-1H-benzo[d]imidazole (41)

Add 2-(5-(4-(4-chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl) to a reaction flask containing dichloromethane (2 mL) Piperazine-1-yl)pyridin-2-yl)propan-2-ol (16) (50 mg, 0.11 mmol), a solution of dioxane hydrochloride (0.1 mL, 0.4 mmol) was slowly added dropwise. Stir overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative hp~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Pyridin-2-yl)piperazin-1-yl)phenyl)-1-methyl-1H-benzo[d]imidazole (22 mg, white solid, 48%).

LC-MS (ESI): m / z 444.2 / 446.2 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ8.28 (d, J = 2.3Hz, 1H), 7.77-7.67 (m, 2H), 7.62 (d, J = 7.7Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.36 - 7.21 (m, 3H), 7.18 (d, J = 3.1 Hz, 1H), 6.89 (d, J = 8.9 Hz, 1H), 5.33 (s, 1H), 4.95 ( s, 1H), 3.65 (d, J = 7.8 Hz, 7H), 3.32 - 3.36 (m, 4H), 2.07 (s, 3H).

Example 42: 1-(6-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridine- Preparation of 3-yl)-2,2,2-trifluoroethanone (42)

Add 1-(6-(4-(4-chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl) to a reaction flask containing dichloromethane (2 mL) Piperazine-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl alcohol (40) (50 mg, 0.1 mmol) and Dess-Martin high iodide (85 mg, 0.2 mmol), reaction The mixture was stirred at room temperature for 3 hours. After the reaction was completed, it was diluted with methylene chloride (5 mL), and evaporated. The residue was purified by preparative EtOAc (EtOAc (EtOAc)EtOAc And [d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl ketone.

LC-MS (ESI): m/z.

^{1 H NMR (400MHz, DMSO-} d 6) δ8.29 (s, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.52-7.47 (m, 3H), 7.35-7.26 (m, 3H ), 7.18 (s, 1H), 3.65 (d, J = 10.9 Hz, 8H), 1.23 (s, 3H).

Example 43: 2-(6-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridine- Preparation of 3-yl)-2-methylpropionitrile (43)

The same procedure as in Example 35 was carried out except that 2-(5-bromo-2-chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g) was used instead of 2-(5-bromo-2). -Chlorophenyl)-3-methylimidazo[1,2-a]pyridine (b) to give 2-(6-(4-(4-chloro-3-(1-methyl-1H-benzene) And [d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)-2-methylpropanenitrile (white solid, one step yield: 27%).

LC-MS (ESI): m / z471.2 / 473.1 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.26 (d, J = 2.3 Hz, 1H), 7.72 - 7.66 (m, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.49 (d, J=8.9 Hz, 1H), 7.35–7.22 (m, 3H), 7.18 (d, J=2.9 Hz, 1H), 6.95 (d, J=8.9 Hz, 1H), 3.65 (d, J=6.4 Hz, 7H), 3.33 (s, 4H), 1.66 (s, 6H).

Example 44: (4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(morpholin-2- Preparation of ketone (44)

Step 1: 2-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazine-1-carbonyl)morpholine-4- Preparation of tert-butyl carboxylate (44b)

Add 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (85 mg, 0.367 mmol), 2-(2-chloro-5-(piperazin-1-yl) to a reaction flask containing DMF (2 mL) Phenyl)-3-methylimidazo[1,2-a]pyridine (1a) (100 mg, 0.306 mmol), HATU (175 mg, 0.459 mmol) and N,N-diisopropylethylamine (119 mg, 0.918 mmol), stirred at room temperature for 1 hour. After the reaction was completed, the mixture was evaporated, evaporated, evaporated. The residue was purified by silica gel column chromatography (eluent: EA = 1:1) to give 2-(4-(4-chloro-3-(3-methylimidazo[1,2-a] Pyridin-2-yl)phenyl)piperazine-1-carbonyl)morpholine-4-carboxylic acid tert-butyl ester (80 mg, pale yellow solid, yield: 52%).

LC-MS (ESI): m / z 540.2 / 542.1 [M + H +].

Step 2: (4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl) (morpholin-2-yl) Preparation of ketone (44)

Add 2-(4-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazine to a reaction flask containing dichloromethane (2 mL) tert-Butyl ester of -1-carbonyl)morpholine-4-carboxylate (80 mg, 0.15 mmol) was added dropwise aq. After the addition, the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjj [1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(morpholin-2-yl)methanone (24 mg, white solid, yield: 38%).

LC-MS (ESI): m / z440.2 / 442.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (d, J = 6.9 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.32 - 7.23 (m, 1H), 7.10–6.89 (m, 3H), 4.27 (dd, J=8.9, 3.1 Hz, 1H), 3.79–3.59 (m, 6H), 3.18 (s, 4H), 2.91–2.68 ( m, 4H), 2.39 (s, 3H), 1.23 (s, 1H).

Example 45: (4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(4-hydroxypiperidine) Preparation of -1-yl)methanone (45)

Step 1: Preparation of 4-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazine-1-carbonyl chloride (45a)

Add 2-(2-chloro-5-(piperazin-1-yl)phenyl)-3-methylimidazo[1,2-a]pyridine to a reaction flask containing anhydrous dichloromethane (5 mL) (1a) (100 mg, 0.306 mmol) and DIPEA (119 mg, 0.918 mmol), which were sealed with nitrogen three times and cooled to 0 °C. A solution of triphosgene (91 mg, 0.306 mmol) in dichloromethane (1 mL) was slowly added dropwise, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was evaporated to dryness crystals crystals Imidazo[1,2-a]pyridin-2-yl)phenyl)piperazine-1-carbonyl chloride (70 mg, white solid, yield: 59%).

LC-MS (ESI): m / z 389.0 / 391.0 [M + H +].

Step 2: (4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(4-hydroxypiperidine- Preparation of 1-yl)methanone (45)

Add 4-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazine-1- to a reaction flask containing dichloromethane (5 mL) Carbonyl chloride (30 mg, 0.076 mmol), piperidin-4-ol (8 mg, 0.076 mmol) and DIPEA (40 mg, 0.304 mmol). After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, EtOAc/water (0.1% EtOAc), 10% to 100%) to yield (4-(4-chloro-3-(3-methylimidazo[1,2-a]] Pyridin-2-yl)phenyl)piperazin-1-yl)(4-hydroxypiperidin-1-yl)methanone (12 mg, white solid, yield: 34%).

LC-MS (ESI): m / z 454.18 / 457.21 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.31 - 7.24(m,1H), 7.09–6.91(m,3H), 3.62(s,1H), 3.45(s,6H), 3.20(d,J=29.3Hz,8H),2.88(t,J=10.1Hz , 2H), 2.39 (s, 3H).

Example 46: (4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(4-hydroxypyrrolidine) Preparation of 2-yl)methanone (46)

In the same manner as in Example 44 except that 1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid was used instead of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid. (4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(4-hydroxypyrrolidin-2-yl) ) ketone (white solid, 25% yield in two steps).

LC-MS (ESI): m / z440.2 / 442.3 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (d, J = 6.9 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.28 (ddd, J=8.8, 6.8, 1.3 Hz, 1H), 7.14–6.91 (m, 3H), 4.42–4.27 (m, 2H), 3.63 (q, J=7.9, 6.5 Hz, 4H), 3.19 (q) , J = 7.9, 6.5 Hz, 4H), 2.80 (dd, J = 11.8, 2.1 Hz, 3H), 2.39 (s, 3H), 2.13 - 1.79 (m, 3H).

Example 47: (4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(morpholino)- Preparation of ketone (47)

In the same manner as in Example 45 except that morpholine was used in place of piperidin-4-ol, 4-(4-chloro-3-(3-methylimidazo[1,2-a]pyridine-2 was obtained. -yl)phenyl)piperazin-1-yl)(morpholino)methanone (white solid, 55% yield).

LC-MS (ESI): m / z440.2 / 442.3 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J = 6.8 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.31 –7.22 (m, 1H), 7.07–6.93 (m, 3H), 3.61–3.53 (m, 4H), 3.29 (d, J=5.4 Hz, 4H), 3.22–3.10 (m, 8H), 2.39 (s) , 3H).

Example 48: (4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(piperidin-4- Preparation of ketone (48)

Using the same procedure as in the synthesis of 44b of Example 44, except that 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid was used instead of 4-(tert-butoxycarbonyl)morpholin-2-carboxylic acid. 4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(piperidin-4-yl)methanone ( White solid, 35% yield in two steps).

LC-MS (ESI): m / z438.3 / 440.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (d, J = 6.8 Hz, 1H), 7.59 (d, J = 9.1 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.04 (td, J = 13.2, 4.8 Hz, 3H), 3.64 (d, J = 27.5 Hz, 4H), 3.25 - 2.84 (m, 8H), 2.40 (s, 3H), 1.90–1.14 (m, 6H).

Example 49: (4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl) (1,1-sulfened sulfur) Preparation of ketone (49)

In the same manner as in Example 45, except that thiomorpholine 1,1-dioxide was used in place of piperidin-4-ol, 4-(4-chloro-3-(3-methylimidazo[ 1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(1,1-sulfoxide)methanone (white solid, one step yield 29%).

LC-MS (ESI): m / z488.2 / 490.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.31 -7.23 (m, 1H), 7.10 - 6.95 (m, 3H), 3.60 (s, 4H), 3.35 (s, 4H), 3.18 (s, 8H), 2.39 (s, 3H).

Example 50: (4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(tetrahydro-2H- Preparation of pyran-4-yl)methanone (50)

Using the same procedure as in the synthesis of 44b in Example 44, except that 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid was replaced by tetrahydro-2H-pyran-4-carboxylic acid (4-( 4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)- Ketone (white solid, one step yield 59%).

LC-MS (ESI): m / z 439.3 / 441.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.31 –7.23 (m, 1H), 7.09–6.95 (m, 3H), 3.84 (d, J = 11.1 Hz, 2H), 3.63 (d, J = 26.9 Hz, 4H), 3.39 (dd, J = 11.4, 8.6 Hz, 6H), 3.16 (d, J = 19.9 Hz, 4H), 2.92 (s, 1H), 2.39 (s, 3H).

Example 51: Preparation of 2-(2-chloro-5-(4-prolylpiperazin-1-yl)phenyl)-3-methylimidazo[1,2-a]pyridine (51)

In the same manner as in Example 44 except that (t-butoxycarbonyl)proline was used instead of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid to give 2-(2-chloro-5-). (4-Prolylpiperazin-1-yl)phenyl)-3-methylimidazo[1,2-a]pyridine (white solid, yield 29% in two steps).

LC-MS (ESI): m / z424.2 / 426.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (dd, J = 6.9, 1.3 Hz, 1H), 7.61 - 7.54 (m, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.28 ( Ddd, J=9.1, 6.7, 1.3 Hz, 1H), 7.10–6.95 (m, 3H), 4.35–4.27 (m, 1H), 3.63 (h, J=6.1 Hz, 4H), 3.18 (ddd, J= 27.3, 10.5, 5.5 Hz, 6H), 2.39 (s, 3H), 2.24 - 1.70 (m, 5H).

Example 52: (4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(piperidin-2- Preparation of ketone (52)

In the same manner as in Example 44 except that 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid was used instead of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid, (4-( 4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(piperidin-2-yl)methanone (white solid, The yield in two steps is 24%).

LC-MS (ESI): m / z438.3 / 440.3 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.49 (d, J = 11.3 Hz, 1H), 8.85 (d, J = 6.9 Hz, 1H), 8.65 - 8.49 (m, 1H), 7.63 - 7.49 ( m, 2H), 7.30–7.19 (m, 2H), 4.45 (t, J = 11.1 Hz, 1H), 3.83–3.54 (m, 4H), 3.30–2.79 (m, 6H), 2.52 (s, 3H) , 1.98 (d, J = 13.6 Hz, 1H), 1.80 - 1.21 (m, 6H).

Example 53: 1-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-2-yl Preparation of oxy-1-ketone (53)

Using the same procedure as in the synthesis of 44b of Example 44, except that 2-(t-butoxycarbonyl)morpholine-2-carboxylic acid was replaced by 2-methoxyacetic acid to give 1-(4-(4-chloro-)- 3-(3-Methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-2-methoxy-1-one (white solid, one step yield 44 %).

LC-MS (ESI): m / z399.2 / 401.3 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (d, J = 6.7 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 10.4 Hz, 3H), 4.12 (s, 2H), 3.56 (d, J = 20.7 Hz, 4H), 3.19 (s, 7H), 2.41 (s, 3H).

Example 54: (4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(piperidin-3- Preparation of ketone (54)

In the same manner as in Example 44 except that 2-(tert-butoxycarbonyl)piperidine-2-carboxylic acid was used instead of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid, (4-( 4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(piperidin-3-yl)methanone (white solid, The yield in two steps is 34%).

LC-MS (ESI): m / z438.3 / 440.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (d, J = 6.7 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.33 -7.25 (m, 1H), 7.11 - 6.91 (m, 3H), 3.64 (s, 6H), 3.26 - 2.67 (m, 12H), 2.39 (s, 3H).

Example 55: 1-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-2-( Preparation of dimethylamino)ethane-1-one (55)

Using the same procedure as in the synthesis of 44b in Example 44, except that dimethylglycine was used in place of 4-(tert-butoxycarbonyl)morpholin-2-carboxylic acid to give 1-(4-(4-chloro-3-) (3-Methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-2-(dimethylamino)ethane-1-one (white solid, one step Yield 39%).

LC-MS (ESI): m / z412.1 / 414.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J = 7.0 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.27 (s, 1H), 7.10 - 6.92 (m, 3H), 3.62 (d, J = 30.7 Hz, 4H), 3.18 (s, 6H), 2.39 (s, 3H), 2.22 (s, 6H).

Example 56: (4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(3-hydroxypyrrolidine) Preparation of -1-yl)methanone (56)

In the same manner as in Example 45 except that a piperidin-4-ol was replaced with azetidin-3-ol, (4-(4-chloro-3-(3-methylimidazo[1, 2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(3-hydroxypyrrolidin-1-yl)methanone (white solid, one step yield 19%).

LC-MS (ESI): m / z426.2 / 428.1 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.31 –7.22 (m, 1H), 7.09–6.89 (m, 3H), 4.38 (s, 1H), 4.13–4.01 (m, 2H), 3.67 (dd, J=9.1, 4.8 Hz, 2H), 3.18–3.07 (m, 4H), 2.51 - 2.50 (m, 4H), 2.39 (s, 3H).

Example 57: 1-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-2-ethyl Preparation of oxy-1-ketone (57)

Using the same procedure as in the synthesis of 44b of Example 44, except that 2-(t-butoxycarbonyl)morpholine-2-carboxylic acid was replaced by 2-ethoxyacetic acid to give 1-(4-(4-chloro-)- 3-(3-Methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-2-ethoxy-1-one (white solid, one step yield 44 %).

LC-MS (ESI): m / z413.2 / 415.3 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.34 (d, J = 6.8 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.31 (s, 1H), 7.04 (t, J = 9.0 Hz, 3H), 4.14 (s, 2H), 3.62 - 3.43 (m, 6H), 3.20 (s, 4H), 2.40 (s, 3H), 1.13 ( t, J = 7.0 Hz, 3H).

Example 58: 1-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-2-( Preparation of piperidin-1-yl)ethan-1-one (58)

Using the same procedure as in the synthesis of 44b in Example 44, except that 2-(piperidin-1-yl)acetic acid was used instead of 4-(tert-butoxycarbonyl)morpholin-2-carboxylic acid to give 1-(4- (4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-2-(piperidin-1-yl)- 1-ketone (white solid, 58% yield).

LC-MS (ESI): m / z452.3 / 454.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (d, J = 6.9 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.31 –7.23(m,1H), 7.10–6.90(m,3H),3.71–3.56(m,4H), 3.18(dt,J=29.1,5.1Hz,6H),2.54(s,2H),2.44(s , 2H), 2.39 (s, 3H), 1.56 - 1.47 (m, 4H), 1.39 (s, 2H).

Example 59: (4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl) (1-methylpiperidin) Preparation of pyridine-4-yl)methanone (59)

Using the same procedure as in the synthesis of 44b in Example 44, except that 4-(t-butoxycarbonyl)morpholine-2-carboxylic acid was replaced by 1-methylpiperidine-4-carboxylic acid to give (4-(4- Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(1-methylpiperidin-4-yl)methanone (white Solid, one step yield 42%).

LC-MS (ESI): m / z 452.2 / 454.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (d, J = 6.9 Hz, 1H), 7.58 (d, J = 9.1 Hz, 1H), 7.45 - 7.36 (m, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.12 - 6.89 (m, 3H), 3.62 (s, 4H), 3.22 - 2.87 (m, 9H), 2.35 (d, J = 32.4 Hz, 6H), 1.67 (d, J) = 8.2 Hz, 2H), 1.24 (s, 2H).

Example 60: 1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)-4-(tetrahydro-2H-pyran-4- Preparation of carbonyl) piperazin-2-one (60)

The same procedure as in the synthesis of 44b of Example 44 was employed except for using tetrahydro-2H-pyran-4-carboxylic acid and 1-(4-chloro-3-(1-methyl-1H-benzo[d]imidazole. -2-yl)phenyl)piperazin-2-one hydrochloride (23c) instead of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid and 2-(2-chloro-5-(piperidin) Benzyl-1-yl)phenyl)-3-methylimidazo[1,2-a]pyridine (1a), 1-(4-chloro-3-(3-methylimidazo[1,2] -a]pyridin-2-yl)phenyl)-4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-2-one (white solid, one step yield 24%).

LC-MS (ESI): m / z453.2 / 455.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.37 (d, J = 6.9 Hz, 1H), 7.69 - 7.54 (m, 3H), 7.47 (dd, J = 8.6, 2.6 Hz, 1H), 7.34 ( s, 1H), 7.04 (t, J = 6.7 Hz, 1H), 4.28 (d, J = 82.5 Hz, 2H), 3.99 - 3.72 (m, 6H), 3.40 (d, J = 7.9 Hz, 2H), 2.43 (s, 3H), 1.59 (s, 4H), 1.24 (s, 1H).

Example 61:1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)-4-(3-(methylsulfonyl)propanoyl Preparation of piperazin-2-one (61)

Step 1: Preparation of 3-(methylsulfonyl)propionic acid (61a)

3-(Methylthio)propanoic acid (300 mg, 2.49 mmol) and H ₂ O ₂ (1.5 mL) were added to a reaction mixture containing acetic acid (2 mL) and acetic acid (2 mL) and stirred at room temperature overnight. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was evaporated. mjjjjjj It was used directly in the next step without purification.

LC-MS (ESI): m / z149.12 [MH +].

Step 2: 1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)-4-(3-(methylsulfonyl)propanoyl) Preparation of piperazin-2-one (61)

In the same manner as in Example 60, except that 3-(methylsulfonyl)propionic acid was used in place of tetrahydro-2H-pyran-4-carboxylic acid, 1-(4-chloro-3-(3-methyl) was obtained. Imidazo[1,2-a]pyridin-2-yl)phenyl)-4-(3-(methylsulfonyl)propionyl)piperazin-2-one (15 mg, white solid, yield 42% ).

LC-MS (ESI): m / z475.1 / 477.2 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ8.36-8.31 (m, 1H), 7.66-7.52 (m, 3H), 7.45 (dt, J = 8.8,2.4Hz, 1H), 7.29 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 7.00 (td, J = 6.8, 1.2 Hz, 1H), 4.34 (s, 1H), 4.20 (s, 1H), 3.91 - 3.71 (m, 4H), 3.37 ( d, J = 7.1 Hz, 2H), 3.02 (s, 3H), 2.88 (q, J = 8.3 Hz, 2H), 2.42 (s, 3H).

Example 62: 4-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-N-iso Preparation of propyl-4-oxobutanamide (62)

Step 1: 4-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-4-oxo Preparation of ethyl butyrate (62a)

The same procedure as in the synthesis of 44b in Example 44, except that 4-(t-butoxycarbonyl)morpholine-2-carboxylic acid was replaced by 4-ethoxy-4-oxobutanoic acid to give 4-(4- (4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-4-oxobutanoate (200 mg, white Solid, yield 59%).

LC-MS (ESI): m / z455.2 / 457.2 [M + H +].

Step 2: 4-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-4-oxo Preparation of butyric acid (62b)

Add 4-(4-(4-chloro-3-(3-methylimidazo[1,2-a]pyridine) to a reaction flask containing H ₂ O (1 mL), THF (1 mL) and methanol (1 mL) Ethyl 2-yl)phenyl)piperazin-l-yl)-4-oxobutanoate (100 mg, 0.22 mmol) was stirred at 70 ° C overnight. The reaction solution was cooled to room temperature, and the filtrate was concentrated under reduced pressure, 4-(4-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazine- 1-yl)-4-oxobutanoic acid (100 mg, white solid). It was used directly in the next step without purification.

Step 3: 4-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-N-isopropyl Preparation of keto-4-oxobutanamide (62)

Add 4-(4-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazine-1 to a reaction flask containing DMF (1 mL) 4-ylbutyric acid (50 mg, 0.12 mmol), isopropylamine (11 mg, 0.18 mmol), HATU (92 mg, 0.24 mmol) and DIPEA (62 mg, 0.49 mmol). The reaction mixture was stirred at room temperature for 30 min. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by preparative HPLC (C18, EtOAc/water (0.1% EtOAc): 20% to 100%) to afford 4-(4-(3-chloro-3-(3-methylimidazo[1,2- a] Pyridin-2-yl)phenyl)piperazin-1-yl)-N-isopropyl-4-oxobutanamide (18 mg, white solid, yield 33%).

LC-MS (ESI): m / z468.2 / 470.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J = 6.8 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.30 - 7.22 (m, 1H), 7.08 - 6.94 (m, 3H), 3.85 - 3.77 (m, 1H), 3.58 (s, 4H), 3.17 (d, J) = 29.0 Hz, 4H), 2.55 (t, J = 7.2 Hz, 2H), 2.39 (s, 3H), 2.29 (t, J = 7.2 Hz, 2H), 1.02 (d, J = 6.6 Hz, 6H).

Example 63: 1-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-3-( Preparation of methylsulfonyl)propan-1-one (63)

Using the same procedure as in the synthesis of 44b in Example 44, except that 3-(methylsulfonyl)propionic acid (61a) was used instead of 4-(tert-butoxycarbonyl)morpholin-2-carboxylic acid to give 1-( 4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-3-(methylsulfonyl)propene- 1-ketone (white solid, one step yield 31%).

LC-MS (ESI): m / z 461.2 / 463.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.85 (d, J = 7.0 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.18 –7.11(m,1H),7.05(d,J=2.9Hz,1H),6.88–6.78(m,2H),3.75–3.66(m,2H),3.56(d,J=5.3Hz,2H), 3.38 (t, J = 7.2 Hz, 2H), 3.15 (dt, J = 15.9, 5.2 Hz, 4H), 2.92 (s, 3H), 2.87 (t, J = 7.3 Hz, 2H), 2.37 (s, 3H) ).

Example 64: 1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)-N-(3-hydroxy-3-methylbutyl Preparation of piperidine-3-carboxamide (64)

Step 1: 1-(Preparation of ethyl 4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidine-3-carboxylate (64a)

Add 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine (g) (900 mg, 2.8 mmol) to a reaction flask containing toluene (12 mL) at room temperature Ethyl piperidine-3-carboxylate (880 mg, 5.6 mmol), cesium carbonate (2.7 g, 8.4 mmol), BINAP (348 mg, 0.56 mmol) and palladium acetate (125 mg, 0.56 mmol). Sealed, replaced with nitrogen three times, and heated to 120 ° C for 50 minutes. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (eluent: EtOAc====================================== Ethyl 2-phenyl)phenyl)piperidine-3-carboxylate. (450 mg, yellow solid, yield: 40%).

LC-MS (ESI): m / z 398.2 / 400.2 [M + H +].

Step 2: Preparation of 1-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidine-3-carboxylic acid (64b)

Add 1-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)peridine to a reaction flask containing (6 mL) ethanol and (1.5 mL) water Ethyl pyridine-3-carboxylate (450 mg, 1.13 mmol) and sodium hydroxide (90 mg, 2.26 mmol). After the reaction mixture was stirred at room temperature for 2 hr, then concentrated under reduced pressure to give 1-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidine-3 - Formic acid, which was used directly in the next reaction without purification.

LC-MS (ESI): m / z 370.2 / 372.2 [M + H +].

Step 3: 3-(1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidine-3-carboxamido)propanoic acid B Preparation of ester (64c)

Add 1-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidine-3-carboxylic acid to a reaction flask containing DMF (2 mL). 60 mg, 0.16 mmol), 3-aminopropionic acid ethyl ester hydrochloride (37.4 mg, 0.24 mmol), HATU (92 mg, 0.24 mmol) and DIPEA (62 mg, 0.49 mmol). The reaction mixture was stirred at room temperature for 30 min. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate Ethyl 1-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidine-3-carboxamido)propanoate. (40 mg, yellow solid, yield: 52.6%).

LC-MS (ESI): m / z469.3 / 471.2 [M + H +].

Step 4: 1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)-N-(3-hydroxy-3-methylbutyl) Preparation of piperidine-3-carboxamide (64)

3-(1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidine-3-carboxamido) under N2 Ethyl propionate (40 mg, 0.08 mmol) was added to a reaction flask containing anhydrous tetrahydrofuran (2 mL), and a solution of methylmagnesium bromide (0.15 mL, 3M) in diethyl ether was slowly added dropwise at 0 °C. After the addition, the mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by preparative hp~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2-yl)phenyl)-N-(3-hydroxy-3-methylbutyl)piperidine-3-carboxamide (11 mg, white solid, yield: 28.3%).

LC-MS (ESI): m / z 455.3 / 457.3 [M + H +].

_{^{1 H NMR (400MHz, CHCl 3}} -d) δ7.93 (dt, J = 6.9,1.2Hz, 1H), 7.64 (dt, J = 9.1,1.1Hz, 1H), 7.36-7.30 (m, 1H), 7.26–7.17(m,2H), 6.94–6.86(m,2H), 3.43–3.35(m,3H), 3.20(dtd,J=14.8,11.6,10.6,7.5Hz,2H),2.52(dq,J =10.2, 3.7 Hz, 2H), 2.45 (s, 3H), 2.02 - 1.90 (m, 1H), 1.82 - 1.56 (m, 5H), 1.24 (d, J = 24.5 Hz, 6H).

Example 65: (1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidin-3-yl)(3-hydroxypyrrolidine) Preparation of -1-yl)methanone (65)

Using the same procedure as in the synthesis of 64c in Example 64, except that pyrrolidin-3-ol was used in place of ethyl 3-aminopropionate hydrochloride to give (1-(4-chloro-3-(3-methylimidazole). And [1,2-a]pyridin-2-yl)phenyl)piperidin-3-yl)(3-hydroxypyrrolidin-1-yl)methanone (white solid, one step yield 33%).

LC-MS (ESI): m / z 439.2 / 441.2 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 7.92 (dq, J = 6.8, 1.3 Hz, 1H), 7.73 - 7.59 (m, 1H), 7.33 (dd, J = 8.9, 4.0 Hz, 1H), 7.25–7.18(m,1H), 7.17–7.06(m,1H), 6.97–6.84(m,2H),4.64–4.44(m,1H),3.79–3.41(m,5H),3.09–2.92(m , 1H), 2.88 - 2.54 (m, 2H), 2.49 - 2.41 (m, 3H), 2.07 - 2.02 (m, 2H), 1.96 - 1.85 (m, 2H), 1.84 - 1.53 (m, 3H).

Example 66: (1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidin-3-yl)(4-hydroxypiperidine) Preparation of -1-yl)methanone (66)

Using (1-(4-chloro-3-(3-methylimidazole), in the same manner as in the synthesis of 64c in Example 64, except that piperidin-4-ol was used in place of ethyl 3-aminopropionate hydrochloride. And [1,2-a]pyridin-2-yl)phenyl)piperidin-3-yl)(4-hydroxypiperidin-1-yl)methanone (white solid, one step yield 28%).

LC-MS (ESI): m / z 453.2 / 455.2 [M + H +].

_{^{1 H NMR (400MHz, CHCl 3}} -d) δ7.85 (dt, J = 7.0,1.2Hz, 1H), 7.58 (d, J = 9.1Hz, 1H), 7.25 (d, J = 8.8Hz, 1H) , 7.15 (ddd, J = 9.0, 6.7, 1.3 Hz, 1H), 7.02 (d, J = 3.0 Hz, 1H), 6.83 (ddd, J = 6.9, 4.4, 1.3 Hz, 2H), 4.05 - 3.57 (m) , 5H), 3.26 - 2.63 (m, 5H), 2.37 (s, 3H), 1.78 (s, 8H).

Example 67: (1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidin-3-yl)(3-hydroxypyrrolidine) Preparation of -1-yl)methanone (67)

Using the same procedure as in the synthesis of 64c in Example 64, except that the aziridine-3-ol was used in place of the ethyl 3-aminopropionate hydrochloride, (1-(4-chloro-3-(3-) Methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidin-3-yl)(3-hydroxypyrrolidin-1-yl)methanone (white solid, one step yield 33%) .

LC-MS (ESI): m / z 425.2 / 427.2 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 7.88 (t, J = 8.0 Hz, 1H), 7.58 (t, J = 8.5 Hz, 1H), 7.24 (dd, J = 13.4, 8.4 Hz, 2H) , 7.00 (dd, J = 14.1, 3.0 Hz, 1H), 6.94 - 6.76 (m, 2H), 4.58 - 4.45 (m, 1H), 4.34 - 4.17 (m, 1H), 4.15 - 4.06 (m, 1H) , 3.75 (dd, J = 10.8, 4.4 Hz, 1H), 3.60 (t, J = 15.1 Hz, 2H), 2.95 - 2.63 (m, 2H), 2.43 (d, J = 3.5 Hz, 2H), 2.37 ( d, J = 5.2 Hz, 3H), 1.82 - 1.51 (m, 4H).

Example 68: (1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidin-3-yl)(morpholino) A Preparation of ketone (68)

Using the same procedure as in the synthesis of 64c in Example 64, except that morpholine was used in place of ethyl 3-aminopropionate hydrochloride, (1-(4-chloro-3-(3-methylimidazo[1, 2-a]pyridin-2-yl)phenyl)piperidin-3-yl)(morpholino)methanone (white solid, one step yield 29%).

LC-MS (ESI): m / z439.2 / 441.3 [M + H +].

_{^{1 H NMR (400MHz, CHCl 3}} -d) δ7.91 (dt, J = 6.9,1.2Hz, 1H), 7.61 (dt, J = 9.0,1.1Hz, 1H), 7.28-7.21 (m, 2H), 7.01 (d, J=3.0 Hz, 1H), 6.94–6.79 (m, 2H), 3.68–3.45 (m, 8H), 2.95 (dd, J=12.7, 10.8 Hz, 1H), 2.81–2.67 (m, 2H), 2.39 (s, 3H), 2.22 (s, 2H), 1.87 - 1.57 (m, 4H).

Example 69: (1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidin-3-yl)(4-methylpiperidin Preparation of pyrazin-1-yl)methanone (69)

Using the same procedure as in the synthesis of 64c in Example 64, except that 1-methylpiperazine was used in place of ethyl 3-aminopropionate hydrochloride to give (1-(4-chloro-3-(3-methylimidazole). And [1,2-a]pyridin-2-yl)phenyl)piperidin-3-yl)(4-methylpiperazin-1-yl)methanone (white solid, 21% yield).

LC-MS (ESI): m / z452.2 / 454.1 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 7.86 (dt, J = 6.9, 1.2 Hz, 1H), 7.60 (dt, J = 9.1, 1.2 Hz, 1H), 7.26 (d, J = 8.9 Hz, 1H), 7.16 (ddd, J = 9.2, 6.8, 1.3 Hz, 1H), 7.02 (d, J = 3.0 Hz, 1H), 6.88 - 6.76 (m, 2H), 3.69 - 3.47 (m, 6H), 2.94 (dd, J = 12.6, 10.8 Hz, 1H), 2.83 - 2.67 (m, 2H), 2.37 (s, 7H), 2.27 (s, 3H), 1.83 - 1.57 (m, 4H).

Example 70: (1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidin-3-yl) (1,1-sulfened sulfur) Preparation of ketone (70)

Using the same procedure as in the synthesis of 64c in Example 64, except that thiomorpholine 1,1-dioxide was used in place of ethyl 3-aminopropionate hydrochloride to give (1-(4-chloro-3-( 3-Methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidin-3-yl)(1,1-sulfoxide)methanone (white solid, one step yield 36%).

LC-MS (ESI): m / z487.1 / 489.2 [M + H +].

¹ H NMR (400 MHz, CHCl ₃ -d) δ 7.92 (dt, J = 6.8, 1.2 Hz, 1H), 7.64 (dt, J = 9.1, 1.1 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.23 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 7.09 (d, J = 3.1 Hz, 1H), 6.97 - 6.68 (m, 2H), 3.75 (t, J = 11.6 Hz, 2H) ), 3.05 (dd, J = 12.8, 10.7 Hz, 1H), 2.93 - 2.77 (m, 2H), 2.44 (s, 3H), 1.74 (q, J = 9.1 Hz, 12H).

Example 71: (1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidin-4-yl)(4-hydroxypiperidine) Preparation of -1-yl)methanone (71)

Step 1: 1-(Preparation of methyl 4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidine-4-carboxylate (71a)

Add 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine (g) (700 mg, 2.17 mmol) to a reaction flask containing toluene (6 mL) at room temperature , piperidine-4-carboxylic acid methyl ester hydrochloride (770 mg, 4.34 mmol), BINAP (273 mg, 0.43 mmol), cesium carbonate (2.8 g, 8.68 mmol) and Pd(OAc) ₂ (50 mg, 0.22 mmol) It was sealed, replaced with nitrogen three times, and stirred at 110 ° C overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc. The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc = 1:1) to give 1-(4-chloro-3-(3-methylimidazo[1,2-a]pyridine- Methyl 2-yl)phenyl)piperidine-4-carboxylate (516 mg, yellow solid, yield: 61.9%).

LC-MS (ESI): m / z 384.2 / 386.2 [M + H +].

Step 2: Preparation of 1-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidine-4-carboxylic acid (71b)

In a reaction flask containing ethanol (6 mL), 2 mL of water, 1-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidine- 4-carboxylic acid methyl ester (516 mg, 1.34 mmol) and NaOH (80 mg, 2.68 mmol) were stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure to give 1-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidine-4-carboxylic acid (500 mg, yellow solid).

LC-MS (ESI): m / z 370.2 / 372.2 [M + H +].

Step 3: (1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidin-4-yl)(4-hydroxypiperidine- Preparation of 1-yl)methanone (71)

In a reaction flask containing DMF (3 mL) was added 1-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidine-4-carboxylic acid ( 50 mg, 0.14 mmol) and piperidin-4-ol (27 mg, 0.28 mmol) followed by HATU (77 mg, 0.21 mmol) and DIPEA (53 mg, 0.42 mmol). After stirring at room temperature for 30 minutes, saturated _solution of NaHCO 10mL reaction was quenched and extracted with ethyl acetate (10mL × 3), combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrate. The residue was purified by preparative EtOAc (EtOAc (EtOAc) elute elut elut elut elut elut Pyridin-2-yl)phenyl)piperidin-4-yl)(4-hydroxypiperidin-1-yl)methanone (25.8 mg, white solid, yield: 40.7%)

LC-MS (ESI): m / z 453.2 / 455.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ8.31 (d, J = 6.9Hz, 1H), 7.58 (d, J = 9.0Hz, 1H), 7.35 (d, J = 8.7Hz, 1H), 7.27 (ddd, J=8.9, 6.8, 1.3 Hz, 1H), 7.08–6.90 (m, 3H), 4.74 (s, 1H), 3.91 (d, J=12.7 Hz, 1H), 3.84–3.64 (m, 4H) ), 3.21 (s, 1H), 2.98 (t, J = 11.3 Hz, 1H), 2.81 (p, J = 8.6, 6.6 Hz, 3H), 2.39 (s, 3H), 1.66 (d, J = 7.9 Hz) , 6H), 1.27 (dd, J = 41.9, 10.6 Hz, 2H).

Example 72: (1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidin-4-yl)(3-hydroxypyrrolidine) Preparation of -1-yl)methanone (72)

In a reaction flask containing DMF (3 mL) was added 1-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidine-4-carboxylic acid ( 62b) (50 mg, 0.14 mmol) and azetidine-3-ol hydrochloride (44 mg, 0.42 mmol), then EtOAc (EtOAc) After stirring at room temperature for 30 min, 10mL quenched with saturated NaHCO ₃ solution, extracted with ethyl acetate (10mL × 3), combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure . The residue was purified by preparative HPLC (C18, EtOAc/EtOAc (EtOAc: EtOAc) (20%%%%%%%%%%%%%%%%%) Pyridin-2-yl)phenyl)piperidin-4-yl)(3-hydroxypyrrolidin-1-yl)methanone (21 mg, white solid, yield: 35.3%).

LC-MS (ESI): m / z 425.3 / 427.4 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ8.31 (dt, J = 6.9,1.2Hz, 1H), 7.58 (dt, J = 9.2,1.2Hz, 1H), 7.35 (d, J = 8.7Hz, 1H), 7.27 (ddd, J=9.1, 6.7, 1.3 Hz, 1H), 7.09–6.90 (m, 3H), 5.70 (s, 1H), 4.44 (s, 1H), 4.41–4.30 (m, 1H) , 4.01 (ddd, J = 10.1, 6.8, 1.2 Hz, 1H), 3.89 (dd, J = 9.2, 4.3 Hz, 1H), 3.74 (d, J = 12.6 Hz, 2H), 3.56 (dd, J = 10.4) , 4.5 Hz, 1H), 2.76 (tt, J = 12.5, 3.3 Hz, 2H), 2.39 (s, 4H), 1.73 - 1.50 (m, 4H).

Example 73: 1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)-N-(3-hydroxy-3-methylbutyl Preparation of piperidine-4-carboxamide (73)

Step 1: Propyl-3-(1-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidine-4-carboxamido) Preparation of ethyl propionate (73a)

In a reaction flask containing DMF (5 mL) was added 1-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperidine-4-carboxylic acid ( 71b) (100 mg, 0.27 mmol) and ethyl 3-aminopropanoate (83 mg, 0.54 mmol), then EtOAc ( EtOAc, EtOAc (EtOAc) After stirring at room temperature for 30 min, 15mL quenched with saturated NaHCO ₃ solution, extracted with ethyl acetate (15mL × 3), combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc: EtOAc) Ethyl 2-a]pyridin-2-yl)phenyl)piperidine-4-carboxamido)propanoate (75 mg, white solid, yield: 59.3%).

LC-MS (ESI): m / z 469.3 / 471.3 [M + H +].

Step 2: 1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)-N-(3-hydroxy-3-methylbutyl) Preparation of piperidine-4-carboxamide (73)

Under a nitrogen atmosphere, propyl-3-(1-(4-chloro-3-(3-methylimidazo[1,2-a]pyridine-2-) was added to a reaction flask containing anhydrous THF (2 mL). Ethyl phenyl)piperidine-4-carboxamido)propionic acid ethyl ester (75 mg, 0.16 mmol) was cooled to 0 °C. Methylmagnesium bromide diethyl ether solution (0.27 mL, 3M in diethyl ether) was slowly added dropwise, and the mixture was warmed to room temperature and stirring was continued for 1 hour. The mixture was quenched with EtOAc (EtOAc)EtOAc. The residue was purified by preparative EtOAc (EtOAc (EtOAc:EtOAc) 2-yl)phenyl)-N-(3-hydroxy-3-methylbutyl)piperidine-4-carboxamide (37 mg, white solid, yield: 50.1%).

LC-MS (ESI): m / z 455.3 / 457.3 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (dt, J = 7.0, 1.2 Hz, 1H), 7.70 (t, J = 5.4 Hz, 1H), 7.58 (dt, J = 9.2, 1.1 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.27 (ddd, J = 9.0, 6.7, 1.3 Hz, 1H), 7.06 - 6.95 (m, 3H), 4.26 (s, 1H), 3.81 - 3.69 (m, 2H), 3.16–3.06 (m, 2H), 2.71 (td, J = 12.3, 2.9 Hz, 2H), 2.39 (s, 3H), 2.21–2.27 (m, 1H), 1.66 (dtd, J) = 36.5, 12.8, 12.3, 3.7 Hz, 4H), 1.55 - 1.43 (m, 2H), 1.08 (s, 6H).

Example 74: 4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)-1-(2-(dimethylamino)ethyl Preparation of piperazin-2-one (74)

Step 1: Preparation of tert-butyl 4-(2-(dimethylamino)ethyl)-3-oxopiperazine-1-carboxylate (74a)

Under a nitrogen atmosphere, tert-butyl 3-oxopiperazine-1-carboxylate (23a) (1 g, 5.0 mmol) was added to a reaction flask containing anhydrous DMF (16 mL). After cooling to 0 ° C, NaH (660 mg, 16.5 mmol) was added slowly. After stirring for 30 min, 2-chloro-N,N-dimethylethylamine hydrochloride (800 mg, 5.5 mmol) Stir at room temperature overnight. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography _{(eluent: DCM: CH 3 OH = 5} : 1) to afford 4- (2- (dimethylamino) ethyl) -3-oxo-piperazin -1 - tert-butyl formate (350 mg, yellow oil, yield: 25.8%).

LC-MS (ESI): m / z 272.2 [M + H +].

Step 2: Preparation of 1-(2-(dimethylamino)ethyl)piperazin-2-one hydrochloride (74b)

Add 4-(2-(dimethylamino)ethyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester (350 mg, 1.29 mmol) in a reaction flask containing dichloromethane (4 mL). A solution of dioxane hydrochloride (2 mL, 4 M) was stirred for 0.5 h. The reaction mixture was concentrated under reduced vacuoielielielielielielielielielielielielielielielielielieliel The product was used directly in the next step without purification.

LC-MS (ESI): m / z 172.2 [M + H +].

Step 3: 4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)-1-(2-(dimethylamino)ethyl) Preparation of piperazin-2-one (74)

Add 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine (g) (50 mg, 0.16 mmol) to a reaction flask containing toluene (6 mL) at room temperature , 1-(2-(Dimethylamino)ethyl)piperazin-2-one hydrochloride (65 mg, 1.8 mmol), BINAP (20 mg, 0.032 mmol), cesium carbonate (209 g, 0.64 mmol) and Pd ₂ (dba) ₃ (50 mg, 0.22 mmol), sealed, washed with nitrogen three times and stirred at 110 ° C overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc. The residue was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) 2-yl)phenyl)-1-(2-(dimethylamino)ethyl)piperazin-2-one (white solid).

LC-MS (ESI): m/z 422.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (d, J = 6.9 Hz, 1H), 7.59 (d, J = 9.1 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.28 (dd, J = 9.1, 6.7 Hz, 1H), 7.06 - 6.95 (m, 3H), 3.81 (s, 2H), 3.47 (s, 6H), 2.41 (d, J = 6.9 Hz, 5H), 2.18 ( s, 6H).

Example 75: 1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)-N-(3-hydroxy-3-methylbutyl Preparation of azetidine-3-carboxamide

Step 1: Preparation of 3-methylformate azetidine hydrochloride (75b)

To a round bottom flask containing methanol (10 mL), 3-azetidinecarboxylic acid (1 g, 9.9 mmol) was added, and then thionyl chloride (5 mL) was slowly added dropwise, and the mixture was warmed to reflux overnight. After completion of the reaction, the mixture was cooled to room temperature.

LC-MS (ESI): m / z 116.1 [M + H +].

Step 2: Preparation of methyl 1-(4-chloro-3-(3-methylimidazo[1.2-a]pyridin-2-yl)-phenyl)azetidin-3-carboxylate (66c)

3-Carboxylic acid methyl azetidine hydrochloride (156 mg, 1.0 mmol), 2-(5-bromo-2-chlorophenyl)-3 was added to a round bottom flask containing toluene (8 mL) at room temperature. -Methylimidazo[1.2-a]pyridine (g) (300 mg, 0.93 mmol), cesium carbonate (1.2 g, 3.7 mmol), BINAP (116 mg, 0.19 mmol) and tris(dibenzylideneacetone) dipalladium ( 85 mg, 0.093 mmol). Sealed, replaced with nitrogen three times, heated to 100 ° C and stirred for 4 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was purified by preparative HPLC (C18, EtOAc/EtOAc (EtOAc:EtOAc:EtOAc:EtOAc) Methyl-phenyl)azetidin-3-carboxylate (150 mg, white solid, yield 45%).

LC-MS (ESI), m / z 356.12 / 358.2 [M + H +].

Step 3: Preparation of 1-(4-chloro-3-(3-methylimidazo[1.2-a]pyridin-2-yl)-phenyl)azetidin-3-carboxylic acid (75d)

Add 1-(4-chloro-3-(3-methylimidazo[1.2-a]pyridin-2-yl)-phenyl)azetidin-3-carboxylic acid to a flask containing methanol (5 mL) Methyl ester (150 mg, 0.42 mmol) and EtOAc (EtOAc m. The reaction solution was concentrated under reduced pressure to give 1-(4-chloro-3-(3-methylimidazo[1.2-a]pyridin-2-yl)-phenyl)azetidin-3-carboxylic acid ( 150 mg, white solid).

LC-MS (ESI): m / z 342.1 / 344.1 [M + H +].

Step 4: 3-(1-(4-Chloro-3-(3-methylimidazo[1.2-a]pyridin-2-yl)-phenyl)azetidin-3-carboxamide)propionic acid Preparation of ethyl ester (75e)

Add 1-(4-chloro-3-(3-methylimidazo[1.2-a]pyridin-2-yl)-phenyl)azetidin-3-carboxylate to a flask containing DMF (3 mL) Acid (50 mg, 0.11 mmol), ethyl 3-aminopropanoate (13 mg, 0.11 mmol), EtOAc (EtOAc, EtOAc) The reaction mixture was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel chromatography (eluent _{MeOH: H 2 O = 1:} 20), to give 3- (l- (4-chloro-3- (3- Ethyl imido[1.2-a]pyridin-2-yl)-phenyl)azetidin-3-carboxamide)propionic acid ethyl ester (20 mg, yellow solid, yield 40%).

LC-MS (ESI), m / z 441.1 / 443.1 [M + H +].

Step 5: 1-(4-Chloro-3-(3-methylimidazo[1.2-a]pyridin-2-yl)-phenyl)-N-(3-hydroxy-3-methylbutyl)aza Preparation of cyclobutane-3-carboxamide (75)

3-(1-(4-Chloro-3-(3-methylimidazo[1.2-a]pyridin-2-yl)-phenyl)azetidin-3-carboxamide under nitrogen atmosphere Ethyl propionate (20mg, 0.045mmol) and anhydrous THF (2mL) were added to the round bottom flask, cooled to 0 ° C, slowly added methyl magnesium bromide solution (0.2mL, 3M ether solution), drop After the temperature was raised to room temperature, stirring was continued for 1 hour. The reaction was quenched with water, dried over anhydrous sodium sulfate EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -3-(3-Methylimidazo[1.2-a]pyridin-2-yl)-phenyl)-N-(3-hydroxy-3-methylbutyl)azetidin-3-carboxamide ( 8 mg, white solid, yield: 42%).

LC-MS (ESI): m / z 427.2 / 429.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J = 6.8 Hz, 1H), 7.91 (s, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.38 - 7.22 (m, 2H), 6.98 (t, J = 6.2 Hz, 1H), 6.50 (s, 1H), 4.27 (s, 1H), 3.97 (t, J = 7.8 Hz, 2H), 3.80 (t, J = 6.7 Hz, 2H), 3.43 (s, 1H), 3.19 - 3.08 (m, 2H), 2.38 (s, 3H), 1.52 (d, J = 8.1 Hz, 1H), 1.08 (s, 3H).

Example 76: (1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)azetidin-3-yl)(3- Preparation of hydroxypyrrolidin-1-yl)methanone (76)

Using the same method as the synthesis method of 75e in Example 75, except that aziridine-3-ol was used in place of ethyl 3-aminopropionate to obtain (1-(4-chloro-3-(3-methyl) Imidazo[1,2-a]pyridin-2-yl)phenyl)azetidin-3-yl)(3-hydroxypyrrolidin-1-yl)methanone (white solid, one step yield 41 %).

LC-MS (ESI): m / z 397.2 / 399.3 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 - 8.49 (m, 1H), 7.80 - 7.70 (m, 1H), 7.63 - 7.52 (m, 1H), 7.44 - 7.37 (m, 1H), 7.30 –7.19(m,1H), 6.57(s,2H), 5.79–5.68(m,1H), 4.50–4.40(m,1H), 4.30–4.20(m,1H),4.18–3.95(m,3H) , 3.91 - 3.70 (m, 3H), 3.66 - 3.50 (m, 2H), 2.44 (s, 3H).

Example 77: (1-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)azetidin-3-yl)(4- Preparation of hydroxypiperidin-1-yl)methanone (77)

Using the same procedure as the synthesis of 75e in Example 75, except that the piperidin-4-ol was used in place of ethyl 3-aminopropionate, (1-(4-chloro-3-(3-methylimidazolyl) was obtained. [1,2-a]pyridin-2-yl)phenyl)azetidin-3-yl)(4-hydroxypiperidin-1-yl)methanone (white solid, one step yield 32%).

LC-MS (ESI): m / z 425.1 / 427.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.37 (d, J = 6.7 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.06 (s, 1H), 6.55 (d, J = 7.9 Hz, 2H), 4.74 (s, 1H), 4.05 (d, J = 4.9 Hz, 2H), 4.01 - 3.72 (m, 4H), 3.69 (s, 1H), 3.48 (s, 1H), 3.06 (d, J = 9.8 Hz, 2H), 2.40 (s, 3H), 1.71 (s, 2H), 1.24 (s, 2H).

Example 78: 1-(6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridine Preparation of -3-yl)-2,2-2-trifluoroethyl alcohol (78)

In the same manner as in Example 40 except that 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine (b) was used instead of 2-(5-bromo- 2-Chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g) to give 1-(6-(4-(4-chloro-3-(3-methylimidazo[1] , 2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)-2,2-2-trifluoroethyl alcohol (white solid, one step yield 23%).

LC-MS (ESI): m / z 502.2 / 504.1 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (d, J = 6.8 Hz, 1H), 8.19 (s, 1H), 7.59 (d, J = 9.0 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.07 (s, 2H), 6.99 (s, 1H), 6.93 (d, J = 8.9 Hz, 2H), 3.66 (s, 4H), 2.40 (s, 4H), 1.23 (s, 3H).

Example 79: 2-(6-(4-(3-(1H-Benzo[d]imidazol-2-yl)-4-chlorophenyl)piperazin-1-yl)pyridin-3-yl)- Preparation of 2-methylpropionitrile

In the same manner as in Example 35 except that 2-(5-bromo-2-chlorophenyl)-1H-benzo[d]imidazole (Preparation Example 6, the intermediate obtained in Step 2) was used instead of 2- (5-(4-(4-(1H-benzo[d]imidazole)) (5-bromo-2-chlorophenyl)-3-methylimidazo[1.2-a]pyridine (b) 2-yl)-4-chlorophenyl)piperazin-1-yl)pyridin-3-yl)-2-methylpropanenitrile (18 mg, white solid,yield, 27%).

LC-MS (ESI): m / z457.2 / 459.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ8.22 (s, 1H), 7.83 (d, J = 9.2Hz, 3H), 7.62-7.49 (m, 4H), 7.34 (s, 1H), 7.08 ( s, 1H), 3.73 (s, 8H), 1.67 (s, 6H).

Example 80: 2-(6-(4-(4-Chloro-3-(1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)piperazine-1- Of pyridyl-3-yl)-2-methylpropionitrile

The same procedure as in Example 25 was carried out except that 2-(5-bromo-2-chlorophenyl)-1-(difluoromethyl)-1H-benzo[d]imidazole (f) was used instead of 2-(5). -Bromo-2-chlorophenyl)-3-methylimidazo[1.2-a]pyridine (b) to give 2-(6-(4-(4-chloro-3-(1-(difluoro)) -1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)-2-methylpropanenitrile (20 mg, white solid, m. %).

LC-MS (ESI): m / z507.3 / 509.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ8.27 (s, 1H), 7.81 (dd, J = 15.1,8.0Hz, 2H), 7.70 (d, J = 8.9Hz, 1H), 7.54-7.43 ( m, 3H), 7.28 (d, J = 11.5 Hz, 2H), 6.96 (d, J = 9.0 Hz, 1H), 3.67 (s, 4H), 3.35 (s, 4H), 1.67 (s, 6H).

Biological evaluation

Test Example 1: In vitro cell Hedgehog signaling pathway (SMO) inhibitory activity test of the compound of the present invention

The transcriptional regulation and expression of the Gli gene after SMO inhibition were detected using the transcription factor Gli luciferase reporter assay system to detect and evaluate the agonistic or inhibitory effects of compounds on the transcriptional regulation of Gli gene. In this experiment, the inhibitory effect of compounds on the Hedgehog signaling pathway (SMO) was evaluated by the IC ₅₀ value of the compounds.

1.1 Test materials and instruments

1.2 cell line

Shh-LIGHT2 (Shanghai Huiyuan Bio), a fibroblast cell line Shh-LIGHT2 is formed based on the differentiation and differentiation of mouse fibroblast NIH 3T3. By stably constructing Gli-dependent Firefly Luciferase and Renilla Luciferase on NIH 3T3 cells, the Shh-LIGHT2 cell line possesses a dual biofluorescein reporter gene system, which is ideal. Drug screening cell platform. 1.3 test reagent

1.4 cell culture fluid

Growth medium:

DMEM: Invitrogen, Cat#31053036

10% FBS: Invitrogen, Cat#10099-141

1%PenStrep: Invitrogen, Cat#15140-122

1% sodium pyruvate: Invitrogen, Cat#11360070

1% GlutaMax: Invitrogen, Cat#35050061

Complete medium

DMEM: Invitrogen, Cat#31053036

10% FBS: Invitrogen, Cat#10099-141

1%PenStrep: Invitrogen, Cat#15140-122

1% sodium pyruvate: Invitrogen, Cat#11360070

1% GlutaMax: Invitrogen, Cat#35050061

0.4mg/ml G418: GIBCO, Cat#10131-027

0.15mg/ml antimycin: Invitrogen, Cat#R25005

1.5 cell culture program

a) Cell resuscitation

1) Remove the Shh-LIGHT2 cell cryotube from the liquid nitrogen tank and place it in a 37 ° C water bath, continue to shake the cell cryotube until the cells are frozen, and the entire thawing process is controlled within 30 seconds to 1 minute;

2) Prepare a 15 ml centrifuge tube, add 10 ml of pre-warmed growth medium (without screening antibiotics G418 and antimycin), transfer the cells from the cryotube to the centrifuge tube, and then centrifuge at 1000 rpm for 5 minutes. ;

3) Remove the supernatant, add 10 ml of pre-warmed growth medium to the centrifuge tube, mix and transfer the cells to a 10 cm culture dish, and place them in an incubator at 37 ° C and 5% CO ₂ ;

4) After 24 hours of culture, the growth medium was removed, and 10 ml of complete medium (containing the screening antibiotics G418 and antimycin) was added, and the cells were cultured in an incubator at 37 ° C and 5% CO ₂ .

b) cell passage

1) Observe the cells daily, and after 85% of the 10 cm culture dish is overgrown with the cells, the cells are passaged;

2) Remove the culture solution, wash the surface of the cells with PBS, remove the PBS; digest the cells with 1 ml of 0.25% trypsin-EDTA for 1-3 minutes, then add 2 ml of the culture solution to terminate the digestion; use a pipette to gently blow the cells until the cells are Peel off the surface of the culture dish;

3) Transfer 1 ml of the cell suspension to a new culture dish according to a ratio of 1:3, add 9 ml of the complete culture solution, mix the culture dishes, and place them in an incubator at 37 ° C and 5% CO ₂ .

c) cell cryopreservation

1) The excess cell culture dish can be frozen for later use; the cells are digested and counted, and the cells are collected in a 15 ml centrifuge tube, centrifuged at 1000 rpm for 5 minutes, and centrifuged to prepare a cell cryopreservation solution (90%). FBS + 10% DMSO);

2) Remove the supernatant, add the cell cryopreservation solution, maintain the cell concentration at 2×10 ⁶ cells/ml, resuspend the cells, and take out 1 ml of the cell solution and place it in the cell cryopreservation tube;

3) The cell cryotube was placed in a cell cryopreservation box, placed in a refrigerator at -80 ° C overnight, and transferred to a liquid nitrogen tank (-196 ° C) for long-term storage.

1.6 luciferase reporter gene system detection activity steps

Step 1: Prepare the cell culture plate

a) Prepare cell culture fluid

Growth medium:

DMEM: Invitrogen, Cat#31053036

10% FBS: Invitrogen, Cat#10099-141

1%PenStrep: Invitrogen, Cat#15140-122

1% sodium pyruvate: Invitrogen, Cat#11360070

1% GlutaMax: Invitrogen, Cat#35050061

Detection of culture solution:

DMEM: Invitrogen, Cat#31053036

2% FBS: Invitrogen, Cat#10099-141

1%PenStrep: Invitrogen, Cat#15140-122

1% sodium pyruvate: Invitrogen, Cat#11360070

1% GlutaMax: Invitrogen, Cat#35050061

b) planting cells

1) Digest the cells and perform cell counting;

2) Using a growth medium to adjust the cell density to 3.2*10 ⁵ cells/mL, and plant the cells into a 384-well cell culture plate (Corning #3570), each well: 8 k cells / 25 μL;

3) The cell culture plates were placed in an incubator at 37 ° C and 5% CO ₂ to a density of 80%.

Step 2: Prepare the test compound and test the agonist mode and inhibitor mode separately

a) agonist mode sample preparation

1) The test compound and the 2,6,9-ternary substituted hydrazine are dissolved in DMSO for analysis and stored at -20 ° C;

2) taking out the test compound and 2,6,9-ternary substituted hydrazine, completely thawed;

3) Prepare the concentration of the test compound (the initial concentration is 100 μM, and the concentration is diluted 9 times according to the ratio of 3 times, a total of 10 concentrations to be tested);

4) Prepare 2,6,9-ternary substituted hydrazine as a positive control drug (starting concentration 10 μM, dilution concentration 9 times according to 3 times ratio, a total of 10 concentrations to be tested);

5) Preparation of experimental full positive reference group (HPE) and experimental full negative reference group (ZPE); preparation method of HPE: 4μM 2,6,9-ternary substituted hydrazine; preparation method of ZPE: 0.5% analytical study with DMSO .

6) All compounds to be tested, 2,6,9-ternary substituted hydrazine, HPE, and ZPE were prepared at 35 μl per well and plated on a 384-well plate (drug plate) (Corning #3656).

b) Add sample to the cell culture plate in agonist mode

1) remove the cell culture plate from the incubator;

2) Manually remove the cell liquid in the fine culture plate, and the movement is gentle;

3) Pour the cell culture plate into a centrifuge at a low speed (200 rpm) for 30 seconds to completely remove the culture solution;

4) Using the Bravo instrument to accurately transfer 25 μl of the sample from the drug plate to the cell culture plate;

5) The cell culture plates were placed in an incubator at 37 ° C and 5% CO ₂ for 28 hours, waiting for the luciferase reporter gene test.

c) Inhibitor mode sample preparation

1) The test compound, GDC-0449, GANT61, and 2,6,9-ternary substituted hydrazine are dissolved in DMSO for analysis and stored at -20 ° C;

2) Take out the test compound, GDC-0449, GANT61, 2,6,9-ternary substituted hydrazine, and fully thaw;

3) Prepare the concentration of the test compound (the initial concentration is 1 μM, and the concentration is diluted 9 times according to the ratio of 3 times, a total of 10 concentrations to be tested);

4) Prepare GDC-0449 and GANT61 as positive control drugs (GDC-0449 initial concentration 1μM, dilution concentration 9 times according to 3 times, a total of 10 concentrations to be tested; GANT61 initial concentration 100μM, according to 3 times dilution concentration 9 Times, a total of 10 concentrations to be tested);

5) Preparation of experimental full positive reference group (HPE) and experimental full negative reference group (ZPE); preparation method of HPE: 100μM GANT61; preparation method of ZPE: 0.5% analytical study with DMSO;

6) All test compounds, GDC-0449, GANT61, HPE, ZPE were prepared at 35 μl per well and plated on 384-well plates (inhibitor drug plate) (Corning #3656);

7) Prepare 2,6,9-ternary substituted hydrazine as agonist (concentration 9 μM);

8) 2,6,9-ternary substituted oxime was prepared at 20 μl per well and plated on a 384-well plate (agonist drug plate) (Corning #3656).

d) Add the sample to the cell culture plate in the inhibitor mode

1) remove the cell culture plate from the incubator;

2) Manually remove the cell liquid in the fine culture plate, and the movement is gentle;

3) Pour the cell culture plate into a centrifuge at a low speed (200 rpm) for 30 seconds to completely remove the culture solution;

4) Using the Bravo instrument to accurately transfer 25 μl of the test compound, GDC-0449, GANT61, HPE, ZPE from the inhibitor drug plate to the cell culture plate;

5) The cell culture plate was placed in an incubator at 37 ° C and 5% CO ₂ for 30 minutes;

6) Remove the cell culture plate from the incubator and accurately transfer 5 μl of 2,6,9-ternary substituted sputum from the agonist drug plate to the cell culture plate using the Bravo instrument (2,6,9-ternary at this time) Substituted 嘌呤 final concentration 1.5 μM); 7) Cell culture plates were placed in an incubator at 37 ° C and 5% CO ₂ for 28 hours, waiting for the luciferase reporter gene test.

Step 3: Luciferase reporter assay

1) Thawing Dual-Glo Luciferase Reagent (Promega) at room temperature and formulating according to the instructions;

2) Remove the cell culture plate and leave it at room temperature for 30 minutes;

3) Add 25 μl of Dual-Glo luciferase reagent to the cell culture plate using a multidrop combi instrument, and centrifuge at low speed (1000 rpm) for 1 minute; mix the liquid in each well of the cell plate using a Bravo instrument;

4) After standing at room temperature for 30 minutes, the firefly luciferase value was detected using ViewLux;

5) Prepare Dual-Glo Stop&Glo reagent (Promega) at room temperature, add 25 μl of Dual-Glo Stop&Glo reagent to the cell culture plate using a multidrop combi instrument, and centrifuge at low speed (1000 rpm) for 1 minute; mix each well on the cell culture plate using a Bravo instrument. Liquid

6) After standing at room temperature for 30 minutes, the value of Renilla Fluorescein was detected using ViewLux;

7) The results of the detection of the numerical results were calculated and analyzed using Matlab 4 to obtain IC ₅₀ (nM) values of the compounds of the present invention.

The results are shown in Table 1 below.

Table 1 compounds of the invention in vitro cell Hedgehog signaling pathway (SMO) inhibiting activity IC ₅₀ value

As can be seen from the above Table 1, the compound of the present invention can effectively inhibit the regulation and expression of the transcription factor Gli in the Hedgehog signaling pathway. Compared with the positive control drugs GDC-0449, GANT61, it showed a stronger inhibitory ability.

Test Example 2: Effect of the compound of the present invention on medulloblastoma in primary cell model of medulloblastoma

Test sample: positive control drug Vismodegib (purchased by Selleck) and compounds of the examples of the invention

Test animals: genotype: Ptch +/- p53 +/- original medulloblastoma (MB) mice, Ptch +/- mice and p53 +/- mice from Jackson lab, SPF animals at Suzhou University Ptch +/- p53 +/- mice were obtained after house crosses, and all animals were C57BL/6 background.

experiment method:

1. Primary cell culture and IC ₅₀ determination

About 25% of Ptch+/- p53+/- mice will develop primary cerebellar medulloblastoma after 12 weeks of feeding. The medulloblastoma cells (ie, MB cells) are obtained by primary extraction and inoculated into PDL-embedded. 96-well plate (2X 10 ⁵ /well). Medium (2% B27 supplement (Gibco), 1% penicillin/streptomycin (Gibco), 1% L-glutamine (Gibco) and 1% Na-pyruvate in Neurobasal medium (Gibco) (Gibco) After 4-6 hours of adherent culture, the original medium was aspirated, and the medium containing different concentrations of test samples (3-4 replicates per concentration) was added to each well. After 48 hours of application, CCK-8 reagent (MESGEN) was added at 10 uL/well. Incubation was continued for 3 h at 37 ° C, and the absorbance at 450 nm of each well was measured using a Multiskan Mk3 type microplate reader (Thermo).

2. Sample concentration selection and sample preparation

According to the preliminary experimental results, 8 concentrations were selected from the concentration gradients of 0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, and 3000 nM to treat primary MB cells. Test samples (positive control drug and compound of the present invention) were dissolved in DMSO to prepare a stock solution having a concentration of 10 mM, and stored in a refrigerator at -20 °C. Prior to loading, the stock solution was diluted to a serial concentration with primary MB cell culture medium.

3. Calculation of IC ₅₀

Multiskan Mk3 using Microplate Reader (Thermo) was measured at 450nm absorbance values per well, and the curve fitting calculation performed by the IC ₅₀ and graphpad prism 6.0. IC ₅₀ values for each compound was measured three times, and the mean and standard deviation calculated by graphpad prism 6.0.

The experimental results are listed in Table 2 below.

Table 2 IC ₅₀ values of compounds of the invention against medulloblastoma in vitro

Compound IC ₅₀ (nM) Example 35 0.66 Example 43 3.35 Example 79 3.10 Example 80 3.00 Vismodegib 6.73

As can be seen from the above Table 2, the effect of the compound of the present invention on medulloblastoma in the primary cell model of medulloblastoma showed higher activity than that of the positive control drug.

Claims (35)

a compound of the formula (I) or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them: Q, V, U ₀ are each independently selected from C or N; R, W, U ₁ , U ₂ , U ₃ , U ₄ are each independently selected from CR ³ or N; Y is selected from N or CH; Ar is selected from aryl or heteroaryl, preferably 5- to 6-membered aryl or heteroaryl, more preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; said aryl or heteroaryl Optionally further substituted with one or more groups selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl; R ^{1 is} selected from the group consisting of hydrogen, halogen, amino, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a , -C(O)R ^a , O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -NHS(O)R ^a , -NHS(O) ₂ R ^a ; wherein the alkyl group, a cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further substituted with one or more groups R ⁵ ; R ^{5 is} selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R ^a , -S(O)R ^a , -S(O) ₂ R ^a , -P(O)R ^a R ^b , -B(OH) ₂ , or -NR ^a R ^b ; wherein the alkyl group, alkoxy group, alkenyl group, alkyne a group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, optionally further selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, decyl, oxo, cycloalkyl, heterocyclyl Or a plurality of groups; Each R ^{2 is} independently selected from the group consisting of hydrogen, halogen, amino, thiol, oxo, alkyl, cycloalkyl; wherein, two R ² may also be joined together to form a ring or a bridged ring; R ^{3 is} selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, The heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl, carboxy, alkyl, alkoxy, cycloalkyl, heterocyclyl Substituting one or more groups of an aryl group or a heteroaryl group; R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, alkylamino, alkylsulfonyl, alkane Substituting one or more groups of a aminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; Or R ^a and R ^b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; n is an integer from 1 to 4; i is an integer from 1 to 3; j is an integer from 1 to 3; Wherein each H atom of the compound of formula (I) may optionally be independently replaced by a D atom. The compound of the formula (I) according to claim 1 or a mesogen, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, or a mixture thereof With salt, Wherein: U ₁ , U ₂ , U ₃ , U ₄ are each independently selected from CR ³ ; R ^{3 is} as defined in claim 1. The compound of the formula (I) according to claim 1 or 2, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt which is a compound of the formula (II), (III), (IV) or (V) or a mesogen, a racemate, an enantiomer thereof, a diastereomer a conformation, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them, R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkane The group, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl, carboxy, alkyl, alkoxy, cyclo Substituting one or more groups of an alkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; p is an integer from 1 to 4; Ar, Y, R ¹ , R ² , n, i, j are as defined in claim 1. The compound of the formula (I) according to any one of claims 1 to 3, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (VI), (VII), (VIII) or (IX) or a mesogen, a racemate, an enantiomer thereof, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them, R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkane The group, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl, carboxy, alkyl, alkoxy, cyclo Substituting one or more groups of an alkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; Each R ^{4 is} each independently selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl; q is an integer from 1 to 4; p is an integer from 1 to 4; Y, R ¹ , R ² , n, i, j are as defined in claim 1. The compound of the formula (I) according to any one of claims 1 to 4, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (X), (XI), (XII) or (XIII) or a mesogen, a racemate, an enantiomer thereof, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them, R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkane The group, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl, carboxy, alkyl, alkoxy, cyclo Substituting one or more groups of an alkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; Each R ^{4 is} independently selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl; q is an integer from 1 to 4; p is an integer from 1 to 4; R ¹ , R ² , n are as defined in claim 1. The compound of the formula (I) according to any one of claims 1 to 5, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, Wherein R ^{1 is} selected from aryl or heteroaryl, preferably 5- to 7-membered aryl or heteroaryl, more preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; said aryl or hetero The aryl group is optionally further substituted with one or more groups R ⁵ ; R ^{5 is} selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, -C(O)R ^a , -S(O)R ^a , -S(O) ₂ R ^a , -P(O)R ^a R ^b , -B(OH) ₂ , -NR ^a R ^b ; wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic ring The base is optionally further substituted with one or more groups selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, decyl, oxo, cycloalkyl, heterocyclyl; R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, wherein the alkyl, cycloalkyl, heterocyclyl is optionally further selected from the group consisting of halogen, amino, Substituting one or more groups of a cyano group, a hydroxyl group, a decyl group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, or a heterocyclic group; Or R ^a and R ^b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, preferably a 4 to 7 membered nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, cyano Substituting one or more groups of oxo, hydroxy, decyl, carboxy, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl. The compound of the formula (I) according to any one of claims 1 to 6, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof a form, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (XIV), (XV), (XVI) or (XVII) or a mesogen, a racemate, an enantiomer thereof, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them: Z ₁ , Z ₂ , Z ₃ , Z ₄ are independently selected from N or CH; R ^{5 is} selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, -C(O)R ^a , S(O)R ^a , -S(O) ₂ R ^a , -P(O)R ^a R ^b , -B(OH) ₂ , -NR ^a R ^b ; wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group Optionally further substituted with one or more groups selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, decyl, oxo, cycloalkyl, heterocyclyl; Each R ^{4 is} independently selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl; R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, alkyl, and the alkyl group is optionally further substituted by halogen; R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, wherein the alkyl, cycloalkyl is optionally further selected from one or more groups selected from the group consisting of halogen, hydroxy, and fluorenyl. Replace q is an integer from 1 to 4; p is an integer from 1 to 4; R ² , n are as defined in claim 1. The compound of the formula (I) according to claim 7, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable drug thereof With salt, Among them, the group

From:

The compound of the formula (I) according to claim 7 or 8 or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or Medicinal salt, among them, R ^{5 is} selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, 3-7 membered cycloalkyl, -C(O)R ^a , -S ( O) R ^a , -S(O) ₂ R ^a , -P(O)R ^a R ^b , -B(OH) ₂ , -NR ^a R ^b ; wherein the alkyl group, alkoxy group, alkenyl group , the cycloalkyl group is optionally further substituted with one or more groups selected from the group consisting of halogen, hydroxy, cyano, oxo, cycloalkyl, heterocyclyl; R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, and C ₁ -C ₆ alkyl. The compound of the formula (I) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof according to any one of claims 7 to 9 Form, or a pharmaceutically acceptable salt thereof, among them, R ^{4 is} selected from halogen or C ₁ -C ₆ alkyl, q is 1 or 2. The compound of the formula (I) according to any one of claims 7 to 10, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, among them, R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, which is optionally further substituted by halogen, p is 1 or 2. The compound of the formula (I) according to any one of claims 1 to 4, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof a form, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (XVIII), (XIX), (XX) or (XXI) or a mesogen, a racemate, an enantiomer thereof, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them, Each R ^{4 is} independently selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl; R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, alkyl, and the alkyl group is optionally further substituted by halogen; R' _a is R ^a or NR ^a R ^b ; R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, wherein the alkyl, cycloalkyl, heterocyclyl is optionally further selected from the group consisting of halogen, amino, Substituting one or more groups of a hydroxyl group, a mercapto group, an oxo group, an alkyl group, an alkoxy group, an alkylamino group, an alkylsulfonyl group, an alkylamino group, a cycloalkyl group, a heterocyclic group; Or R ^a and R ^b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, preferably a 4 to 7 membered nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, One or more groups of cyano, oxo, hydroxy, decyl, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Replace i is 2 and j is 2, or i is 1 and j is 1, or i is 1 and j is 3, or i is 3 and j is 1; Y is selected from N or CH; R ² and n are as defined in claim 1. The compound of the formula (I) according to claim 12, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable drug thereof With salt, Among them, the group

From:

The compound of the formula (I) according to claim 12 or 13 or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or Medicinal salt, among them, R ^{4 is} selected from halogen or C ₁ -C ₆ alkyl, q is 1 or 2. The compound of the formula (I) according to any one of claims 12 to 14, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, among them, R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, which is optionally further substituted by halogen, p is 1 or 2. The compound of the formula (I) according to any one of claims 12 to 15, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, among them, R' _a is R ^a ; R ^{a is} selected from the group consisting of hydrogen, halogen, hydroxy, C ₁ -C ₆ alkyl, C ₄ -C ₇ cycloalkyl, 4 to 7 membered heterocyclic group, wherein the alkyl group, cycloalkyl group, heterocyclic group is optional Further selected from halogen, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylsulfonyl, C ₁ Substituting one or more groups of a -C ₆ alkylamino group. The compound of the formula (I) according to any one of claims 12 to 15, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, among them, R' _a is NR ^a R ^b ; R ^a and R ^b are each independently selected from hydrogen, alkyl, wherein the alkyl is optionally further substituted with one or more groups selected from halo, hydroxy; Or R ^a and R ^b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, preferably a 4 to 7 membered nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, oxo, hydroxy Substituting one or more groups of an alkyl group or an alkoxy group. The compound of the formula (I) according to any one of claims 1 to 17, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, among them, R ^{2 is} selected from hydrogen, oxo or C ₁ -C ₆ alkyl; n is 1. The compound of the formula (I) according to claim 1 or a mesogen, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, or a mixture thereof Using a salt which is a compound of the formula (I') or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable form thereof salt,

among them, Q, V, U ₀ are each independently selected from CH or N; R, W, U ₁ , U ₂ , U ₃ , U ₄ are each independently selected from CR ³ or N; Y is selected from N or CH; Ar is selected from aryl or heteroaryl, preferably 5- to 7-membered aryl or heteroaryl, more preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; said aryl or heteroaryl Optionally further substituted with one or more groups selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl; R ^{1 is} selected from the group consisting of hydrogen, halogen, amino, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a , -C(O)R ^a , O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -NHS(O)R ^a , -NHS(O) ₂ R ^a ; wherein the alkyl group, The cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, hydroxy, hydroxyalkyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, One of -C(O)R ^a , -S(O)R ^a , -S(O) ₂ R ^a , -P(O)R ^a R ^b , -B(OH) ₂ , -NR ^a R ^b or Substituting multiple groups; Each R ^{2 is} independently selected from the group consisting of hydrogen, halogen, amino, fluorenyl, oxo, alkyl, cycloalkyl; R ^{3 is} selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, The heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl, carboxy, alkyl, alkoxy, cycloalkyl, heterocyclyl Substituting one or more groups of an aryl group or a heteroaryl group; R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, alkylamino, alkylsulfonyl, alkane Substituting one or more groups of a aminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; Or R ^a and R ^b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; n is an integer from 1 to 4. The compound of the formula (I) according to claim 19, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable drug thereof a salt which is a compound represented by the formula (II'), (III'), (IV') or (V') or a mesogen, a racemate, an enantiomer thereof, a non-pair a conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them, R ^{1 is} selected from aryl, heteroaryl, -C(O)R ^a , or -C(O)NR ^a R ^b ; wherein the aryl or heteroaryl is optionally further selected from the group consisting of halogen, hydroxy, hydroxy Substituting one or more groups of an alkyl group, an alkyl group, -S(O) ₂ R ^a , -P(O)R ^a R ^b , -B(OH) ₂ , -NR ^a R ^b ; said aryl group Or a heteroaryl group is preferably a 5- to 7-membered aryl or heteroaryl group, more preferably a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group or a pyridazinyl group; Each R ^{2 is} independently selected from hydrogen, oxo or C ₁ -C ₆ alkyl; Each R ^{4 is} independently selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl; R ^3a and R ^3b are, independently of each other, selected from the group consisting of hydrogen, halogen, alkyl, and the alkyl group is optionally further substituted by halogen; R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, wherein the alkyl, cycloalkyl, heterocyclyl is optionally further selected from the group consisting of halogen, amino, Substituting one or more groups of a hydroxyl group, a mercapto group, an oxo group, an alkyl group, an alkoxy group, an alkylamino group, an alkylsulfonyl group, an alkylamino group, a cycloalkyl group, a heterocyclic group; Or R ^a and R ^b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, preferably a 4 to 7 membered nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, One or more groups of cyano, oxo, hydroxy, decyl, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Replace n is 1 or 2; p is 1 or 2; q is 1 or 2. The compound of the formula (I) according to any one of claims 1 to 20, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of

The compound of the formula (I) according to any one of claims 1 to 21, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof A method of preparing a form, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of the formula (I) and the compound of the formula (IB) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction to obtain a compound of the formula (I); Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C; among them, X is a halogen, preferably Br; Ar, Q, W, V, R, U ₀ , U ₁ , U ₂ , U ₃ , U ₄ , R ¹ , R ² , n, i, j are as defined in claim 1. The compound of the formula (I) according to claim 3, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a drug thereof A method for preparing a salt, which is a compound represented by the formula (II), (III), (IV) or (V) or a mesogen, a racemate, an enantiomer thereof, a diastereomer A process for the preparation of an isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of the formula (IA) and the compound of the formula (IIB), (IIIB), (IVB) or (VB) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction to obtain a pass. a compound of formula (II), (III), (IV) or (V); Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C; among them, X is a halogen, preferably Br; Ar, Y, R ¹ , R ² , R ^3a , R ^3b , n, q, i, j are as defined in claim 3. The compound of the formula (I) according to claim 4, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a drug thereof A method for preparing a salt, which is a compound represented by the formula (VI), (VII), (VIII) or (IX) or a mesogen, a racemate, an enantiomer thereof, a diastereomer A process for the preparation of an isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of the formula (IA) and the compound of the formula (VIB), (VIIB), (VIIIB) or (IXB) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction to obtain a pass. a compound of formula (VI), (VII), (VIII) or (IX); Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C; among them, X is a halogen, preferably Br; Y, R ¹ , R ² , R ^3a , R ^3b , R ⁴ , n, p, q, i, j are as defined in claim 4. The compound of the formula (I) according to claim 5, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable drug thereof A method for preparing a salt, which is a compound represented by the formula (X), (XI), (XII) or (XIII) or a mesogen, a racemate, an enantiomer thereof, a diastereomer A process for the preparation of an isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of the formula (IA') and the compound of the formula (XB), (XIB), (XIIB) or (XIIIB) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction. a compound of the formula (X), (XI), (XII) or (XIII); Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C; among them, X is a halogen, preferably Br; R ¹ , R ² , R ^3a , R ^3b , R ⁴ , n, p, q are as defined in claim 5. The compound of the formula (I) according to claim 7, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable drug thereof A method for preparing a salt, which is a compound represented by the formula (XIV), (XV), (XVI) or (XVII) or a mesogen, a racemate, an enantiomer thereof, a diastereomer A process for the preparation of an isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of the formula (IA") is heated with a compound of the formula (XIVB), (XVB), (XVIB) or (XVIIB) in the presence of a metal palladium catalyst under basic conditions, and subjected to a Buckwald amination coupling reaction. a compound of the formula (XIV), (XV), (XVI) or (XVII); Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C; among them, X is a halogen, preferably Br; Z ₁ , Z ₂ , Z ₃ , Z ₄ , R ⁵ , R ² , R ^3a , R ^3b , R ⁴ , n, p, q are as defined in claim 7. The compound of the formula (I) according to claim 12, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable drug thereof A method for preparing a salt, which is a compound represented by the formula (XVIII), (XIX), (XX) or (XXI) or a mesogen, a racemate, an enantiomer thereof, a diastereomer A process for the preparation of an isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

Compounds of formula (IA"') and compounds of formula (XVIIIB), (XIXB), (XXB), or (XXIB) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction. Obtaining a compound of the formula (XVIII), (XIX), (XX) or (XXI); Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C; among them, X is a halogen, preferably Br; R' _a , R ² , R ^3a , R ^3b , R ⁴ , i, j, n, p, q are as defined in claim 12. The compound of the formula (I) according to claim 19, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable drug thereof a method for producing a salt, which is a compound represented by the formula (I') or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or A method for preparing a pharmaceutically acceptable salt, comprising the steps of:

The compound of the formula (I'A) and the compound of the formula (I'B) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction to give a compound of the formula (I'); Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C; among them, X is a halogen, preferably Br; Y, Ar, Q, W, V, R, U ₀ , U ₁ , U ₂ , U ₃ , U ₄ , R ¹ , R ² , n are as defined in claim 19. The compound of the formula (I) according to claim 20, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a drug thereof A method for preparing a salt, which is a compound represented by the formula (II'), (III'), (IV') or (V') or a mesogen, a racemate thereof, an enantiomer thereof And a method for preparing a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

Compounds of formula (I'A) and compounds of formula (II'B), (III'B), (IV'B), or (V'B) are heated under basic conditions in the presence of a metal palladium catalyst, Obtaining a compound of the formula (II'), (III'), (IV') or (V') by a Buckwald amination coupling reaction; Wherein, the metal palladium catalyst is preferably Pd ₂ (dba) ₃ /BINAP or Pd(dppf) ₂ Cl ₂ ; the base is preferably Cs ₂ CO ₃ ; heating temperature is preferably 100-120 ° C; among them, X is a halogen, preferably Br; R ¹ , R ² , R ^3a , R ^3b , R ⁴ , n, p, q are as defined in claim 20. A pharmaceutical composition comprising the compound of the formula (I) according to any one of claims 1 to 21, or a mesogen, racemate, enantiomer thereof, non-pair thereof An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The pharmaceutical composition according to claim 30, which further comprises another therapeutically active ingredient, preferably another therapeutically active ingredient, said cancer being preferably rectal cancer, pancreatic cancer, breast cancer, prostate Cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, brain cancer, skin cancer, head and neck cancer, ovarian cancer, bladder cancer, and kidney cancer are more preferably lung cancer, breast cancer, pancreatic cancer, and gastric cancer. The compound of the formula (I) according to any one of claims 1 to 21, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Use of a form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 30 or 31, in the manufacture of an SMO antagonist. The compound of the formula (I) according to any one of claims 1 to 21, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Use of a form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 30 or 31, for the manufacture of a medicament for the treatment of a disease associated with the Hedgehog signaling pathway. The use according to claim 33, wherein the disease associated with the Hedgehog signaling pathway is cancer, preferably from colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, brain cancer. , skin cancer, head and neck cancer, ovarian cancer, bladder cancer and kidney cancer, more preferably lung cancer, breast cancer, pancreatic cancer and gastric cancer. The compound of the formula (I) according to any one of claims 1 to 21, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Use of a form, or a pharmaceutically acceptable salt thereof, in combination with another therapeutically active ingredient, in the manufacture of a medicament for the treatment of cancer, wherein the other therapeutically active ingredient is simultaneously, separately or separately from the compound of formula (I) The therapeutically active ingredient is preferably a drug for treating cancer, and the cancer is preferably rectal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, brain cancer, skin cancer, head and neck. Cancer, ovarian cancer, bladder cancer, and kidney cancer are more preferably lung cancer, breast cancer, pancreatic cancer, blood cancer, and stomach cancer.