WO2019223715A1 - Benzopiperidine or heteroarylpiperidine derivative, preparation method therefor, and medical application thereof - Google Patents

Abstract

The present invention relates to a benzopiperidine or heteroarylpiperidine derivative, a preparation method therefor, and a medical application thereof. In particular, the present invention relates to a benzopiperidine derivative or a heteroarylpiperidine derivative represented by general formula (I), a preparation method therefor, a pharmaceutical composition comprising the derivative, and use thereof as an estrogen receptor modulator in the prevention and/or treatment of estrogen receptor mediated or dependent diseases or conditions, the diseases particularly and preferably being breast cancers. The definition of each substituent in general formula (I) is the same as that in the description.

Description

Benzopiperidine or heteroaryl piperidine derivatives, preparation method and application thereof in medicine

This application claims priority from Chinese patent application CN201810503475.0 with a filing date of May 23, 2018 and Chinese patent application CN201910148770.3 with a filing date of February 28, 2019. This application cites the full text of the aforementioned Chinese patent application.

Technical field

The invention belongs to the field of medicine, and relates to a benzopiperidine or a heteroaryl piperidine derivative, a preparation method thereof and application in medicine, and the invention discloses that it is used as an estrogen receptor modulator for prevention and / or Or use for the treatment of an estrogen receptor-mediated or dependent disease or condition, which is particularly preferably breast cancer.

Background technique

Breast cancer is one of the most common malignant tumors in women. According to 2012 GLOBALCAN statistics (CACANCERJCLIN2015; 65: 87–108), there are approximately 1.7 million new cancer cases and 520,000 deaths worldwide each year. Regardless of morbidity and mortality, it ranks first among female malignancies. According to the 2017 China Cancer Registry Annual Report released by the National Cancer Center, breast cancer ranks first in the incidence of malignant tumors in women, with about 279,000 new cases each year, which is increasing at a rate of about 2% per year.

About 70% of breast cancer patients are estrogen receptor (ER) positive breast cancer. Endocrine therapy plays an important role in the treatment of this part of breast cancer patients. Endocrine therapy is mainly divided into three categories, namely aromatase inhibitors (aromatase inhibitors), which can inhibit the conversion of androgens to estrogen, reduce the level of estrogen in the body, and selective estrogen receptor modulators (selective estrogen receptor modulators). (SERM), antagonistic estrogen receptor activity, and selective estrogen receptor degrader (SERD), can not only antagonize the activity of estrogen receptors, but also promote the degradation of receptors (Pharmacol Ther .2017Dec 28). Although endocrine therapy is the first choice for estrogen receptor-positive breast cancer, about 30% of patients receiving adjuvant therapy will relapse, and almost all patients with metastatic breast cancer will develop resistance and progress. The mechanisms of resistance to endocrine therapy are mainly divided into two categories. One focuses on the estrogen receptor signaling pathway itself, including activation mutations, amplifications, and fusions with other genes encoding the estrogen receptor gene ESR1. Co-regulatory factors and downstream control of cell cycle factor imbalances, etc. Another type of mechanism includes the activation of signaling pathways that cross-react with the estrogen receptor signaling pathway, such as the growth factor receptor pathway (Nat RevClin Oncol. 2015) 12 (10): 573-83).

In two studies in 2013, ESR1 gene mutations were detected in 11 to 55% of patients with estrogen receptor-positive metastatic breast cancer who had been treated with aromatase inhibitors. Further research found that mutant receptors can occur independently of estrogen Phosphorylation, play a role in transcription, so that estrogen-dependent MCF7-vaccinated tumors can no longer rely on estrogen growth in the body, and mutant receptors will make the SERM tamoxifen and SERD fulvestrant Reduced activity. Therefore, ESR1 gene mutation may be one of the mechanisms of resistance in estrogen-positive breast cancer (Nat Rev Rev Clin Oncol. 2015 Oct; 12 (10): 573-83 and Nat Genet 2013; 45: 1439-45). In subsequent studies, a certain percentage of ESR1 gene mutations were found in patients with estrogen receptor-positive metastatic breast cancer, and the mutation rate was about 30%. ERY537S and ERD538G mutations were found in ctDNA of estrogen receptor-positive metastatic breast cancer patients who progressed after AIs treatment in the BOLERO-2 clinical trial. In the exemestane single-use group, the progression-free survival (PFS) and overall survival (OS) of patients with mutations were shorter than those without mutations [Nat Genet 2013; 45: 1446–51].

In summary, most of the ESR1 gene mutations occur in patients with metastatic estrogen receptor-positive breast cancer who have progressed after AIs treatment. These patients are no longer sensitive to AIs treatment, so the development of estrogen receptors for ESR1 gene mutations is needed. Antagonist.

The first-in-class estrogen receptor covalent binding antagonist H3B-6545 developed by Eisai Company has strong inhibitory activity on wild-type and mutant estrogen receptors and can covalently bind to the receptor To exert longer-term efficacy, clinical Phase I and Phase II trials are currently underway. Currently published patents for estrogen receptor antagonists against ESR1 gene mutations are WO2016196346 and WO2016196342.

Summary of the Invention

An object of the present invention is to provide a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or the In the form of a mixture, or a pharmaceutically acceptable salt thereof, the structure of the compound represented by the general formula (I) is as follows:

Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

among them:

Ring A is selected from

Ring B is cycloalkyl, heterocyclyl, aryl or heteroaryl;

W is selected from O, NH or S;

G is CH or N;

Z is selected from CR ⁵ R ⁶ , O and NR ⁷ ;

Y is selected from cycloalkyl, heterocyclyl, alkylene and

R ^{a is} selected from -CH ₂ CH = CHC (O) NR ⁸ R ⁹ , -C (O) CH = CR ¹⁰ R ¹¹ and -C (O) C≡CR ¹² ;

R ^c and ^{Rd are the} same or different, and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl;

Or R ^c and ^Rd together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group;

R ^{1 is} selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl Optionally selected from one or more substituents selected from alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl Replaced by

R ^{2 is} selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, amino, cyano, nitro, carboxy, aldehyde, hydroxy, hydroxyalkyl, cycloalkyl, aryl, and heteroaryl;

R ^{3 is the} same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, and cycloalkyl , Heterocyclyl, aryl, and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from the group consisting of alkyl, halogen, cyano, and amino , Nitro, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl with one or more substituents;

R ^{b is the} same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cyclic Alkyl, heterocyclyl, aryl and heteroaryl;

R ^{4 is the} same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl;

R ⁵ and R ^{6 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cyclic Alkyl, heterocyclyl, aryl and heteroaryl;

R ^{7 is} selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ⁸ and R ^{9 are the} same or different and each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

Alternatively, the R ⁸ and R ⁹ form a heterocyclic group together with a nitrogen atom connected thereto, wherein the heterocyclic group optionally contains 1 to 2 nitrogen atoms, and optionally contains 1 to 2 same or different Heteroatoms of N, O and S, and said heterocyclic group is optionally selected from alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic Substituted with one or more substituents of aryl, aryl and heteroaryl;

R ¹⁰ and R ^{11 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cyclic Alkyl, heterocyclyl, aryl and heteroaryl;

R ^{12 is} selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

m is 0 or 1;

n is 0, 1, 2, 3, or 4;

p is 0, 1, or 2;

s is 0, 1, 2 or 3 and

t is an integer from 1 to 6.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, which is optionally a compound represented by the general formula (II):

Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

among them:

Ring ^{A, G, R a, Z} , Y, R 1, R 2, R 4, m and s in the general formula (I) as defined above.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, which is optionally a compound represented by the general formula (III), the general formula (IV), or the general formula (V):

Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

among them:

Ring B is heteroaryl; preferably 5-membered heteroaryl, more preferably pyrazolyl, most preferably

R ^a , G, Z, Y, W, R ¹ to R ⁴ , R ^b , m, n, p, and s are as defined in the general formula (I).

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is selected from a C _3-6 cycloalkyl group, a 3 to 6 membered heterocyclic group,-(CH ₂ ) _k -and

The heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S; k is an integer from 1 to 6; t is an integer from 1 to 6; R ^c and ^Rd are alkyl groups, or R ^c And R ^d together with the carbon atom to which they are attached form a cycloalkyl group.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is a C _3-6 cycloalkyl group, a 3- to 6-membered heterocyclic group, or-(CH ₂ ) _k- , and the heterocyclic group contains 1 to 3 Heteroatom selected from N, O or S; k is an integer from 1 to 6.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is selected from -CH ₂ CH _2- , -CH ₂ CH ₂ CH _2- ,

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, which is optionally a compound represented by the general formula (VI), the general formula (VII), the general formula (VIII), or the general formula (IX):

Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

among them:

R ^c and ^{Rd are the} same or different, and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl;

Or R ^c and ^Rd together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group;

t is an integer from 1 to 6;

q is 1, 2 or 3;

k is an integer from 1 to 6;

Ring ^{A, G, R a, Z} , R 1, R 2, R 4 and s are as in formula (I) as defined above. In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is an alkyl group, preferably a methyl group.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z is O or NH.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein Z is O.

In a preferred embodiment of the present invention, the compounds represented by the general formulae (III) and (V) or tautomers, mesomers, racemates, enantiomers, non- An enantiomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III-C) or the general formula (VC):

Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

among them:

Ring B is heteroaryl; preferably 5-membered heteroaryl, more preferably pyrazolyl, most preferably

k is an integer from 1 to 6;

R ^b and p are as defined in general formula (III);

^{G, R a, R 1,} R 3, R 4, n and s are as in formula (III) or formula (V) as defined above.

In a preferred embodiment of the present invention, the compounds represented by the general formulae (III) and (V) or tautomers, mesomers, racemates, enantiomers, non- An enantiomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III-c) or the general formula (Vc):

Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

among them:

Ring B is heteroaryl; preferably 5-membered heteroaryl, more preferably pyrazolyl, most preferably

k is an integer from 1 to 6;

R ^b and p are as defined in general formula (III);

^{G, R a, R 1,} R 3, R 4, n and s are as in formula (III) or formula (V) as defined above.

In a preferred embodiment of the present invention, the compound represented by the general formula (IV) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, which is optionally a compound represented by the general formula (IV-A), the general formula (IV-B), or the general formula (IV-C):

Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

among them:

R ^c and ^{Rd are the} same or different, and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl;

Or R ^c and ^Rd together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group;

t is an integer from 1 to 6;

q is 1, 2 or 3;

k is an integer from 1 to 6;

^{G, W, R a, R} 1, R 3, R 4, n , and s are as formula (IV) as defined above.

In a preferred embodiment of the present invention, the compound represented by general formula (III) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, which is optionally a compound represented by the general formula (III-A), the general formula (III-B), or the general formula (III-C):

Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

among them:

R ^c and ^{Rd are the} same or different, and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl;

Or R ^c and ^Rd together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group;

t is an integer from 1 to 6;

q is 1, 2 or 3;

k is an integer from 1 to 6;

Ring ^{B, G, R a, R} 1, R 3, R 4, R b, n, s and p are as defined in the general formula (III).

In a preferred embodiment of the present invention, the compound represented by the general formula (V) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, which is optionally a compound represented by the general formula (VA), the general formula (VB), or the general formula (VC):

Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

among them:

q is 1, 2 or 3;

k is an integer from 1 to 6;

^{G, R a, R 1,} R 3, R 4, n , and s are as formula (V) as defined above.

In a preferred embodiment of the present invention, the compound represented by general formula (IV-A), general formula (IV-B) or general formula (IV-C) or a tautomer, meso, Racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, which are optionally of the general formula (IV-a), (IV-b) or general Compound represented by formula (IV-c):

Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

among them:

R ^c and ^{Rd are the} same or different, and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl;

Or R ^c and ^Rd together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group;

t is an integer from 1 to 6;

q is 1, 2 or 3;

k is an integer from 1 to 6;

^{G, W, R a, R} 1, R 3, R 4, n , and s are as in formula (I) as defined above.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from the group consisting of alkyl, haloalkyl, cycloalkyl, and aryl, and the alkyl, cycloalkyl, and aryl are optionally selected from alkyl, halogen , Amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, and heterocyclyl.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{3 is the} same or different and each is independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, or a heteroaryl group, wherein the heteroaryl group is further substituted by one or Multiple alkyl substitutions.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{4 is the} same or different, each is independently selected from a hydrogen atom, a halogen, an alkyl group, and an alkoxy group.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{a is} selected from -CH ₂ CH = CHC (O) NR ⁸ R ⁹ , -C (O) CH = CR ¹⁰ R ¹¹ and -C (O) C≡CR ¹² ; R ¹⁰ to R ^{12 are the} same or different and each is independently a hydrogen atom or an alkyl group; R ⁸ and R ^{9 are the} same or different and each is independently selected from a hydrogen atom or an alkyl group; or R ⁸ and R ⁹ and the phase The connected nitrogen atoms together form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 nitrogen atoms, and optionally contains 1 to 2 heteroatoms which are the same or different and are selected from N, O and S, and The heterocyclic group is optionally selected from one of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl Or multiple substituents.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{a is} selected from -CH ₂ CH = CHC (O) NR ⁸ R ⁹ , -C (O) CH = CR ¹⁰ R ¹¹ and -C (O) C≡CR ¹² , R ⁸ to R ^{12 are the} same or different, and each is independently a hydrogen atom or an alkyl group.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{a is} selected from -CH ₂ CH = CHC (O) N (CH ₃ ) ₂ , -C (O) CH = CH ₂ , -C (O) C≡CCH ₃

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{a is} selected from

R ⁸ , R ⁹ and R ¹² are as defined in the general formula (I).

Typical compounds of general formula (I), including but not limited to:

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

Another aspect of the present invention provides a compound represented by the general formula (IA),

Or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a synthetic formula (I ) Intermediates,

among them:

Ring A is selected from

Ring B is cycloalkyl, heterocyclyl, aryl or heteroaryl;

W is selected from O, NH or S;

G is CH or N;

Z is selected from CR ⁵ R ⁶ , O and NR ⁷ ;

Y is cycloalkyl or alkylene;

R ^{1 is} selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl Optionally selected from one or more substituents selected from alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl Replaced by

R ^{2 is} selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, amino, cyano, nitro, carboxy, aldehyde, hydroxy, hydroxyalkyl, cycloalkyl, aryl, and heteroaryl;

R ^{3 is the} same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, and cycloalkyl , Heterocyclyl, aryl, and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of alkyl, halogen, cyano, amino, and nitro Substituted with one or more of the hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups;

R ^{b is the} same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, and cycloalkyl , Heterocyclyl, aryl and heteroaryl;

R ^{4 is the} same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl;

R ⁵ and R ^{6 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cyclic Alkyl, heterocyclyl, aryl and heteroaryl;

R ^{7 is} selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

m is 1;

n is 0, 1, 2, 3, or 4;

p is 0, 1, or 2 and

s is 0, 1, 2, or 3.

In a preferred embodiment of the present invention, the compound represented by the general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer, or A mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is selected from cycloalkyl, alkylene, and

R ^c and ^{Rd are the} same or different, and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl;

Or R ^c and ^Rd together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group;

t is an integer from 1 to 6.

In another aspect of the present invention, a compound of general formula (VIIA) or a compound of general formula (VIIIA) is provided:

Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

among them:

q is 1 or 2;

k is an integer from 1 to 6;

Rings A, G, Z, R ¹ , R ² , R ⁴ and s are as defined in the general formula (IA).

In another aspect of the invention, a compound of general formula (IXA) is provided:

Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

among them:

R ^c and ^{Rd are the} same or different, and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl;

Or R ^c and ^Rd together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group;

t is an integer from 1 to 6;

q is 1, 2 or 3;

k is an integer from 1 to 6;

Rings A, G, Z, R ¹ , R ² , R ⁴ and s are as defined in (IA).

Typical compounds of general formula (IA), including but not limited to:

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

In another aspect of the present invention, there is provided a method for preparing a compound according to general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or A method of a mixture, or a pharmaceutically acceptable salt thereof, the method comprising:

Formula (IA) compound is reacted with R ^a -X, to give compounds of general formula (the I);

among them:

m is 1;

X is halogen;

Rings A, G, Z, Y, Ra, R ¹ , R ² , R ⁴ and s are as defined in general formula (I).

In another aspect of the present invention, there is provided a method for preparing a compound according to general formula (VII) or general formula (VIII) or a tautomer, meso, racemate, enantiomer, diastereomer thereof. A method of isomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of general formula (VIIA) or formula (VIIIA of) reacted with R ^a -X, to give formula (VII) or a compound of formula (VIII) compound;

among them:

m is 1;

X is halogen

Ring ^{A, G, Z, R a} , R 1, R 2, R 4 and s are as formula (VII) or formula (VIII) as defined above.

In another aspect of the present invention, there is provided a method for preparing a compound according to general formula (IX) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, Or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of general formula (IXA) is reacted with R ^a -X, to give a compound of formula (IX);

among them:

m is 1;

X is halogen;

Ring ^{A, G, Z, R a} , R 1, R 2, R 4 and s are as formula (IX) as defined above.

Another aspect of the present invention relates to a pharmaceutical composition containing a therapeutically effective dose of a compound represented by each of the above formulae or a tautomer, a racemate, a racemate, an enantiomer thereof. , Diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt as an active ingredient, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The present invention also relates to a method for preparing the above-mentioned pharmaceutical composition, which comprises compound represented by each formula or a tautomer, meso, racemate, enantiomer, diastereomer The enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable carrier, diluent or excipient.

The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the preparation of an estrogen receptor modulator.

The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the prevention and / or treatment of an estrogen receptor-mediated or dependent disease or disorder. Wherein, the estrogen receptor-mediated or dependent disease or condition is cancer, preferably breast cancer, ovarian cancer, endometrial cancer, prostate cancer or uterine cancer; more preferably breast cancer.

The present invention further relates to a compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof.

The present invention further relates to a compound represented by the general formula (I) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a A mixture, or a pharmaceutically acceptable salt thereof, as a medicament for the treatment of an estrogen receptor-mediated or dependent disease or condition. Wherein the estrogen receptor-mediated or dependent disease or disorder is as defined above.

The present invention further relates to a method for treating an estrogen receptor-mediated or dependent disease or condition, which method comprises administering to a patient in need thereof a therapeutically effective dose of a compound represented by the general formula (I) of the present invention or Tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof. This method shows outstanding efficacy and fewer side effects. Wherein the estrogen receptor-mediated or dependent disease or disorder is as defined above.

The active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants and preservatives, To provide pleasing and delicious medicinal preparations. Tablets contain the active ingredients and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients; granulating and disintegrating agents; and lubricants. These tablets can be uncoated or they can be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period. For example, water-soluble taste masking substances can be used. Oral formulations may also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or in which the active ingredient is mixed with a water-soluble carrier.

Aqueous suspensions contain the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending, dispersing or wetting agents. The active ingredient of the aqueous suspension may be a dispersible powder or granule. By adding water, the active ingredient is mixed with one or more dispersing, wetting or suspending agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. The sweeteners and flavoring agents described above can be added to provide a palatable formulation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable or mineral oil or a mixture thereof. A suitable emulsifier may be a naturally occurring phospholipid. Sweeteners are available. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.

The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. Injections or microemulsions can be injected into the patient's bloodstream by local, large injections. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of a compound of the invention. To maintain this constant concentration, continuous intravenous drug delivery devices can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

The pharmaceutical composition of the present invention may be in the form of a sterile injectable water or oily suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, a sterile fixed oil can be conveniently used as a solvent or a suspension medium. In addition, fatty acids can also be prepared for injection.

The compounds of the invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and therefore will dissolve in the rectum to release the drug.

As is well known to those skilled in the art, the dosage of a drug depends on many factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the patient's health, and the patient's behavior , The patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc .; In addition, the best treatment methods such as the mode of treatment, the daily dosage of the general compound (I) or the pharmaceutically acceptable salt The type can be verified according to the traditional treatment plan. The invention introduces a covalent binding group into a small molecule inhibitor, so that the molecule can covalently bind with a thiol group in the ER protein, thereby forming an irreversible covalent compound with the ER protein.

Detailed description of the invention

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 2,2-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 Amyl, 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-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2- Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Methyl, 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 Butylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups, which are independently selected from alkane Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 2 residues derived from the same carbon atom or two different carbon atoms of the parent alkane, which is derived from A straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 carbon atoms, and more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH _2- ), 1,1-ethylene (-CH (CH ₃ )-), 1,2-ethylene (-CH ₂ CH ₂ )-, 1,1-propylene (-CH (CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH (CH ₃ )-), 1,3-propylene (-CH ₂ CH ₂ CH _2- ), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH _2- ), and the like. The alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy Is substituted with one or more substituents of the group, cycloalkylthio, heterocycloalkylthio and oxo.

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

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 Carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl groups, and the like; polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl.

The term "spirocycloalkyl" refers to a 5- to 20-membered monocyclic polycyclic group that shares one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings have complete conjugation. Π electronic system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. Spirocycloalkyl is divided into monospirocycloalkyl, bisspirocycloalkyl or polyspirocycloalkyl according to the number of common spiro atoms between the rings, preferably monospirocycloalkyl and bisspirocycloalkyl. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, or 5 yuan / 6 yuan monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

The term "fused cycloalkyl" refers to a 5- to 20-membered, full-cyclic polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more of the rings may contain one or Multiple double bonds, but none of the rings have a completely conjugated π-electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of constituent rings, preferably bicyclic or tricyclic, and more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl include:

The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a complete Conjugate π electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

The cycloalkyl ring includes the above cycloalkyl (for example, spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl) fused to an aryl, heteroaryl, or heterocycloalkyl ring, and is connected to the parent structure The rings taken together are cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl and the like. A cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that contains 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O) A heteroatom of _m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, piperidinyl and pyrrolidinyl are preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group that shares one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O ) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a completely conjugated π-electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. Spiro heterocyclyl is divided into monospiroheterocyclyl, bispiroheterocyclyl or polyspiroheterocyclyl according to the number of common spiro atoms between the rings, preferably monospiroheterocyclyl and bispiroheterocyclyl. More preferred are 4-membered / 4-membered, 4-membered-5-membered, 4-membered-6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bonds, but none of the rings have a completely 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 Atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclyl include:

The term "bridged heterocyclyl" refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, and may contain one or more double bonds, but none of the rings have a total A y-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 of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyls include:

The heterocyclyl ring includes the above heterocyclic groups (such as spiroheterocyclyl, fused heterocyclyl and bridged heterocyclyl) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the parent structure is connected to The rings taken together are heterocyclyl, non-limiting examples of which include:

The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "aryl" refers to a 6 to 14 membered, all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 members, such as benzene And naphthyl. The aryl ring includes the above aryl group fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:

Aryl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate, preferably phenyl.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, Pyrimidinyl, thiadiazole, pyrazinyl and the like are preferably imidazolyl, pyrazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring includes the above heteroaryl group fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.

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

The term "haloalkyl" refers to an alkyl group substituted with halogen, wherein alkyl is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with a deuterium atom, wherein alkyl is as defined above.

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

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" means -NH _2.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO _2.

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

The term "aldehyde group" refers to -CHO.

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

The term "acyl halide" refers to a compound containing a -C (O) -halogen group.

"Optional" or "optionally" means that the event or environment described later can, but need not, occur, and the description includes situations where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted with alkyl group" means that the alkyl group may but need not exist, and this 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 a group, preferably up to 5 and more preferably 1 to 3 hydrogen atoms independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.

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

"Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention. Such salts are safe and effective when used in mammals, and have due biological activity.

In the present invention, "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", "X is A, B, or C" are expressed in different terms The same meaning, that is, X can be any one or more of A, B, C.

The invention provides a novel estrogen receptor antagonist represented by the general formula (I), and finds that compounds of this type of structure have good in vitro activity. Compared with the prior art, α contained in this type of structure , Β-unsaturated amide compounds, which can inactivate the estrogen receptor through specific binding to the cysteine of the estrogen receptor ligand binding domain. The small molecule inhibitor of the present invention introduces europium and β unsaturated double bonds, and can perform conjugate addition with the thiol group in the ER protein, thereby forming an irreversible covalent compound with the ER protein.

Method for synthesizing compounds of the present invention

In order to achieve the objective of the present invention, the present invention adopts the following technical solutions:

Option One

The compound represented by the general formula (I) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable compound thereof The method for preparing salt includes the following steps:

(IA) with a compound of formula R ^a -X is reacted of general formula (I) compounds; the reaction may occur or occurs directly under basic conditions, preferably under basic conditions;

among them:

m is 1;

X is halogen;

Ring A, G, Z, Y, R a, R 1, R 2, R 4 and s are as in formula (I) as defined above.

The reagents for providing basic conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, Sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate, sodium hydroxide and lithium hydroxide; preferably diisopropylethyl amine.

The above reaction is preferably performed in a solvent. The solvents used include, but are not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethylsulfoxide, 1,4-dioxane, water, N, N- Dimethylformamide or a mixed solvent thereof.

Option II

The compound represented by the general formula (II) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable compound thereof The method for preparing salt includes the following steps:

(IIA) with a compound of formula R ^a -X is reacted to give compound (II) of the general formula; The reaction may occur or occurs directly under basic conditions, preferably under basic conditions;

among them:

m is 1;

X is halogen;

Ring A, G, Z, Y, R a, R 1, R 2, R 4 and s are as formula (II) as defined above.

The reagents for providing basic conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, Sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate, sodium hydroxide and lithium hydroxide; preferably diisopropylethyl amine.

The above reaction is preferably performed in a solvent. The solvents used include, but are not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethylsulfoxide, 1,4-dioxane, water, N, N- Dimethylformamide or a mixed solvent thereof.

third solution

The compound represented by the general formula (III), the general formula (IV) or the general formula (V) of the present invention or a tautomer, meso, racemate, enantiomer, diastereomer A method for preparing an isomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, includes the following steps:

Compounds of general formula (IIIA), the general formula (IV-1) or the general formula (VA) and R ^a -X is reacted of general formula (III), a compound of formula (IV) or general formula (V); and the reaction It can happen directly or under alkaline conditions, preferably under alkaline conditions;

among them:

m is 1;

X is halogen;

Ring A, G, Z, Y, R a, R 1, R 2, R 4 and s are as formula (III), general formula (IV) or formula (V) as defined above.

The reagents for providing basic conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, Sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate, sodium hydroxide and lithium hydroxide; preferably diisopropylethyl amine.

The above reaction is preferably performed in a solvent. The solvents used include, but are not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethylsulfoxide, 1,4-dioxane, water, N, N- Dimethylformamide or a mixed solvent thereof.

Option four

The compound represented by the general formula (VII) or the general formula (VIII) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof A method for preparing a form, or a pharmaceutically acceptable salt thereof, comprising the following steps:

Compounds of general formula (VIIA) or formula (VIIIA of) the R ^a -X is reacted of general formula (VII) or formula (VIII) compound; the reaction may occur directly or occurs under alkaline conditions, preferably an alkali Sexual conditions

among them:

m is 1;

X is halogen;

Ring ^{A, G, Z, R a} , R 1, R 2, R 4 and s are as formula (VII) or formula (VIII) as defined above.

The reagents for providing basic conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, Sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate, sodium hydroxide and lithium hydroxide; preferably diisopropylethyl amine.

The above reaction is preferably performed in a solvent. The solvents used include, but are not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethylsulfoxide, 1,4-dioxane, water, N, N- Dimethylformamide or a mixed solvent thereof.

Option five

The compound represented by the general formula (IX) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable compound thereof The method for preparing salt includes the following steps:

(IXA) and a compound of the general formula R ^a -X is reacted to give a compound of formula (IX); or the reaction may occur directly occurs under alkaline conditions, preferably under basic conditions;

among them:

m is 1;

X is halogen;

Ring ^{A, G, Z, R a} , R 1, R 2, R 4 and s are as formula (IX) as defined above.

The reagents for providing basic conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, Sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate, sodium hydroxide and lithium hydroxide; preferably diisopropylethyl amine.

The above reaction is preferably performed in a solvent. The solvents used include, but are not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethylsulfoxide, 1,4-dioxane, water, N, N- Dimethylformamide or a mixed solvent thereof.

Option six

The compound represented by the general formula (III-C) or the general formula (VC) of the present invention or a tautomer, meso, racemate, enantiomer, diastereomer, or A method for preparing the mixture, or a pharmaceutically acceptable salt thereof, includes the following steps:

A compound of the general formula (III-CA) or general formula (V-CA) with R ^a -X reacted of general formula (III-C) or the general formula (VC) compound; the reaction may occur directly or alkaline Occurs under conditions, preferably under alkaline conditions;

among them:

X is halogen;

Ring A, G, Z, Y, R a, R 1, R 2, R ⁴ and s in the general formula (III-C) or the general formula (VC) are defined.

The reagents for providing basic conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, Sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate, sodium hydroxide and lithium hydroxide; preferably diisopropylethyl amine.

The above reaction is preferably performed in a solvent. The solvents used include, but are not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethylsulfoxide, 1,4-dioxane, water, N, N- Dimethylformamide or a mixed solvent thereof.

Detailed ways

The present invention is further described below with reference to the examples, but these examples do not limit the scope of the present invention.

Examples

The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). The NMR measurement was performed using Bruker AVANCE-400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD). The internal standard was 4 Methylsilane (TMS).

MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200 DAD, Agilent HPLC 1200 VWD, and Waters HPLC 2695-2489 high pressure liquid chromatography.

Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatography.

HPLC was prepared using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatography.

Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The thin-layer chromatography (TLC) silica gel plate uses a size of 0.15mm to 0.2mm, and the thin-layer chromatography purification product uses a size of 0.4mm. ~ 0.5mm.

Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The average inhibition rate of the kinase and the IC ₅₀ value were measured using a NovoStar microplate reader (BMG, Germany).

The known starting materials of the present invention can be synthesized by or in accordance with methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Darui Chemical companies.

There is no special description in the examples, and the reaction can be performed under an argon atmosphere or a nitrogen atmosphere.

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

The hydrogen atmosphere means that a reaction balloon is connected to a hydrogen gas balloon with a volume of about 1 L.

Pressurized hydrogenation reaction uses Parr 3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.

The hydrogenation reaction is usually evacuated and charged with hydrogen, and the operation is repeated 3 times.

For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.

There is no special description in the examples, and the solution means an aqueous solution.

There is no special description in the examples, and the reaction temperature is room temperature, which is 20 ° C to 30 ° C.

The monitoring of the reaction progress in the examples uses thin layer chromatography (TLC), a developing agent used in the reaction, a column chromatography eluent system for purifying compounds, and a thin layer chromatography developing system including: A: Dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and Adjust with alkaline or acidic reagents such as acetic acid.

Example 1

(E) -4-((2-((5-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methyl (Propyl) -3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) pyridin-2-yl) oxy) ethyl) amino) -N, N-dimethylbutyl -2-enamide 1

first step

(R)-(1- (3- (Benzyloxy) phenyl) propyl-2-yl) carbamic acid tert-butyl ester 1c

Benzyloxy-3-bromobenzene 1a (3.65g, 13.91mmol) was dissolved in tetrahydrofuran (40mL), protected by argon, and after stirring, n-butyllithium (13.9mmol, 5.8mL) was added, and stirred at -78 ° C for 30 minutes . After 30 minutes, (R) -4-methyl-1,2,3-oxothiazolidine-3-carboxylic acid tert-butyl 2,2-dioxide 1b (3.3 g, 13.90 mmol, using the patent application "WO2017182493 "Produced by the disclosed method) was dissolved in 20 mL of tetrahydrofuran, the above solution was added to the reaction solution, and the reaction was stirred at -78 ° C for 0.5 hours. When the temperature was gradually raised to 0 ° C, the reaction was stopped after stirring for 30 minutes in an ice bath. The reaction was quenched with a 10% citric acid solution (20 mL), and water (100 mL) was added, followed by stirring for 10 minutes. Extract with ethyl acetate (100 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the resulting residue by thin-layer chromatography with developer system B to give the title product 1c (2.37 g ), Yield: 49.5%. MS m / z (ESI): 286.2 [M-56 + 1]

Second step

(R) -1- (3- (benzyloxy) phenyl) propyl-2-amine 1d

Compound 1c (2.66 g, 7.79 mmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (3 mL) was added, and the reaction was stirred at room temperature for 5 hours to stop the reaction. The reaction solution was concentrated under reduced pressure. The reaction solution was adjusted to a pH of about 8 with a saturated sodium bicarbonate solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 1d (2.28 g). The purification was carried on directly to the next reaction. MS m / z (ESI): 242.2 [M + 1]

third step

(R) -N- (1- (3- (benzyloxy) phenyl) propyl-2-yl) -2-fluoro-2-methylpropyl-1-amine 1f

The crude compound 1d (0.24 g, 998.64umol) was dissolved in dioxane (10 mL), and diisopropylethylamine (0.38 g, 2.99 mmol) was added, and (2-fluoro-2-methyl-propyl) triol was added. Fluormethanesulfonate 1e (0.34 g, 1.49 mmol, prepared by the method disclosed in the patent application "WO2017182493"), protected by argon. The reaction was stirred at 90 ° C in an oil bath for 3 hours. The starting material disappeared and the reaction was stopped. The reaction solution was cooled, and the reaction solution was concentrated. A saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by the developing system B to obtain the title product 1f (170 mg), yield: 54%. MS m / z (ESI): 316.3 [M + 1]

the fourth step

1 g of (R) -3- (2-((2-fluoro-2-methylpropyl) amino) propyl) phenol

Compound 1f (0.70 g, 2.21 mmol) was dissolved in methanol (10 mL), 50% wet palladium on carbon (140 mg) was added, and the reaction was stirred for 3 hours to replace the reaction after 3 times of hydrogen replacement to stop the reaction. Filtration and concentration of the filtrate under reduced pressure gave 1 g (499 mg) of the crude title product. The product was subjected to the next reaction without purification. MS m / z (ESI): 226.2 [M + 1]

the fifth step

(1S, 3R) -2- (2-fluoro-2-methylpropyl) -1- (6-fluoropyridin-3-yl) -3-methyl-1,2,3,4-tetrahydroiso Quinoline-6-phenol 1i

1 g of crude compound (0.10 g, 443.84 umol) was dissolved in N, N-dimethylformamide (3 mL), and 6-fluoropyridine-3-carbaldehyde was added for 1 h (0.08 g, 663.46 umol), and triisopropylchlorosilane (0.60 g, 1.78 mmol). The reaction was stirred at 130 ° C in an oil bath for 3 hours, and the reaction was stopped. Cool the reaction, concentrate, add water (25 mL), extract with ethyl acetate (50 mL x 2), add saturated sodium bicarbonate solution (20 mL) to the aqueous phase, extract with ethyl acetate (50 mL x 2), combine all organic phases, It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography with developing system B to obtain the title product 1i (250 mg), yield: 42%. MS m / z (ESI): 333.2 [M + 1]

Step Six

(1S, 3R) -2- (2-fluoro-2-methylpropyl) -1- (6-fluoropyridin-3-yl) -3-methyl-1,2,3,4-tetrahydroiso Quinoline-6-yl triflate 1j

Compound 1i (0.22g, 661.87umol) was dissolved in dichloromethane (12mL), cooled to -40 ° C under argon protection, 2,6-lutidine (0.10g, 989.23umol) was added, and trifluoro was slowly added dropwise. Methanesulfonic anhydride (0.28 g, 992.41 umol) was naturally warmed to room temperature for 1 hour. The reaction was cooled, a saturated sodium bicarbonate solution (20 mL) was added, and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Thin layer chromatography was used to develop the solvent system. B The resulting residue was purified to give the title product 1j (180 mg), yield: 59%. MS m / z (ESI): 465.2 [M + 1]

Step Seven

(1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methylpropyl) -1- (6-fluoropyridin-3-yl ) -3-methyl-1,2,3,4-tetrahydroisoquinoline 1l

Compound 1j (0.18g, 387.55umol) was dissolved in 12.4mL of a dioxane and water (V: V = 5: 1) mixed solvent, and 1-ethyl-4- (4,4,5,5- Tetramethyl-1,3,2-dioxolane-2-yl) -1H-pyrazole 1k (0.17g, 774.45umol, Shaoyuan), potassium carbonate (0.16g, 1.15mmol), [1 , 1'-bis (diphenylphosphino) ferrocene] palladium dichloride (0.03g, 38.35umol, Wokai), protected by argon. The reaction was stirred at 80 ° C in an oil bath for 16 hours. Stop reaction. The reaction solution was cooled, concentrated, saturated sodium bicarbonate solution (20 mL) was added, and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by the developing system B to obtain the title product (120 mg), yield: 75%. MS m / z (ESI): 411.2 [M + 1]

Step eight

(2-((5-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methylpropyl) -3-form -1,2,3,4-tetrahydroisoquinolin-1-yl) pyridin-2-yl) oxy) ethyl) carbamic acid tert-butyl ester 1n

Compound 11 (0.10 g, 243.60 umol) was dissolved in 1-m (3.92 g, 24.35 mmol) of (2-hydroxyethyl) carbamate, and sodium hydride (0.05 g, 2.43 mmol) was added at room temperature, and the reaction was maintained at room temperature. After 30 minutes. The reaction was stirred at 90 ° C in an oil bath for 8 hours, and the reaction was stopped. The reaction solution was cooled, concentrated, and a saturated sodium bicarbonate solution (25 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 2), washed with water (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography with developing system B to obtain the title product 1n (47 mg), yield: 35%. MS m / z (ESI): 552.3 [M + 1]

Step Nine

2-((5-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methylpropyl) -3-methyl -1,2,3,4-tetrahydroisoquinolin-1-yl) pyridin-2-yl) oxy) ethylamine 1o

Compound 1n (0.07g, 126.88umol) was dissolved in a dioxane solution (4N, 5mL) of hydrogen chloride, and the reaction was stirred for 3 hours. Stop and cool the reaction, concentrate the reaction solution, add saturated sodium bicarbonate solution (15mL), extract with dichloromethane (50mL × 4), wash with water (30mL × 3), wash with saturated sodium chloride solution (50mL × 1), and combine The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 1o (57 mg). Yield: 99.4%. MS m / z (ESI): 452.3 [M + 1]

Step ten

(E) -4-((2-((5-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methyl (Propyl) -3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) pyridin-2-yl) oxy) ethyl) amino) -N, N-dimethylbutyl -2-enamide 1

Compound 1o (0.060g, 126.22umol) was dissolved in N, N-dimethylformamide (6mL), and diisopropylethylamine (0.032g, 0.248mmol) was added at room temperature, and then (E) -4- Bromine-N, N-dimethylbut-2-enamide 1p (0.019g, 98.93umol, prepared by the method disclosed in the patent application "US20160347717") was stirred and reacted for 2 hours. Stop and cool the reaction, add saturated sodium bicarbonate solution (15 mL), extract with ethyl acetate (50 mL x 2), wash with saturated sodium chloride (50 mL x 4), combine the organic phases, dry over anhydrous sodium sulfate, filter, and filtrate Concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing system A to give the title product 1 (25 mg), yield: 35%. MS m / z (ESI): 563.4 [M + 1]; ¹ H NMR (400MHz, DMSO-d ₆ ) 8.15 (s, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 7.52-7.50 (dd, 1H), 7.36 (s, 1H), 7.31-7.29 (d, 1H), 6.85-6.83 (d, 1H), 6.77-6.75 (d, 1H), 6.63-6.61 (m, 2H), 4.88 (s, 1H), 4.35-4.25 (m, 2H), 4.20-4.11 (m, 2H), 3.50-3.40 (m, 2H), 3.28-3.25 (m, 2H), 3.02 (s, 3H), 2.98 -2.90 (m, 2H), 2.86 (s, 3H), 2.85-2.80 (m, 1H), 2.78-2.72 (m, 1H), 2.62-2.55 (m, 1H), 2.42-2.33 (m, 1H) , 1.41-1.38 (m, 3H), 1.29-1.26 (d, 3H), 1.25-1.22 (d, 3H), 0.98-0.96 (d, 3H).

Example 2

(E) -4-((2-((5-((1S, 3R) -2- (4-cyclopropylphenyl) -6- (1-ethyl-1H-pyrazol-4-yl) -3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) pyridin-2-yl) oxy) ethyl) amino) -N, N-dimethylbut-2- Enamide 2

first step

(R) -N- (1- (3- (benzyloxy) phenyl) prop-2-yl) -4-cyclopropylaniline 2b

1d (700mg, 2.90mmol) was dissolved in toluene (15mL), and 1-bromo-4-cyclopropyl-benzene 2a (629mg, 3.19mmol), tris (dibenzylideneacetone) dipalladium (133mg, 0.15) was added. mmol), sodium tert-butoxide (558 mg, 5.80 mmol), 1,1'-binapthyl-2,2'-bisdiphenylphosphine (90 mg, 0.15 mmol), protected by argon. The reaction was stirred at 105 ° C in an oil bath for 17 hours. The reaction was cooled, water (100 mL) was added, and ethyl acetate (100 mL × 2) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system B. This gave the title product 2b (704 mg) in a yield of 68%. MS m / z (ESI): 358.2 [M + 1]

Second step

(R) -3- (2-((4-cyclopropylphenyl) amino) propyl) phenol 2c

Compound 2b (477 mg, 1.33 mmol) was dissolved in toluene (2.5 mL), trifluoroacetic acid (2.5 mL) was added, and the mixture was reacted at 130 ° C for 4 hours. The reaction was monitored by LC-MS until the starting material disappeared and the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title product 2c (273 mg). Yield: 76%. MS m / z (ESI): 268.2 [M + 1]

third step

(1S, 3R) -2- (4-cyclopropylphenyl) -1- (6-fluoropyridin-3-yl) -3-methyl-1,2,3,4-tetrahydroisoquinoline- 6-alcohol 2d

Compound 2c (273 mg, 1.02 mmol) was dissolved in N, N-dimethylformamide (7 mL), and 2-fluoropyridine-5-carbaldehyde (255 mg, 2.04 mmol) and triisopropylchlorosilane (0.44 mL, 2.04 mmol). The reaction was stirred at 130 ° C in an oil bath for 4 hours. The reaction was monitored by LC-MS until the starting material disappeared and the reaction was stopped. The reaction was cooled, washed with water (100 mL × 2), extracted with ethyl acetate (100 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography using eluent system B The obtained residue gave the title product 2d (330 mg) in a yield of 86%. MS m / z (ESI): 375.2 [M + 1]

the fourth step

(1S, 3R) -2- (4-cyclopropylphenyl) -1- (6-fluoropyridin-3-yl) -3-methyl-1,2,3,4-tetrahydroisoquinoline- 6-yl triflate 2e

2d (235 mg, 0.63 mmol) was dissolved in dichloromethane (10 mL), and 2,6-dimethylpyridine (135 mg, 1.25 mmol) was added. The mixture was transferred to an ice bath, and trifluoromethanesulfonic anhydride (265 mg, 0.94 mmol) was added dropwise. After the addition was completed, the ice bath was removed, and the reaction was stirred at room temperature for 5 hours. Water (20 ml) was added to quench the reaction and extracted with dichloromethane (50 mL x 1). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title product 2e (251 mg), yield: 79%.

the fifth step

(1S, 3R) -2- (4-cyclopropylphenyl) -6- (1-ethyl-1H-pyrazol-4-yl) -1- (6-fluoropyridin-3-yl) -3 -Methyl-1,2,3,4-tetrahydroisoquinoline 2f

2e (251mg, 0.49mmol) was dissolved in 6.5mL of a mixed solution of dioxane and water (V: V = 10: 3), and 1-ethyl-4- (4,4,5,5-tetracycline) was added. Methyl-1,3,2-dioxolane-2-yl) -1H-pyrazole (220 mg, 0.99 mmol), [1,1'-bis (diphenylphosphino) ferrocene] Palladium dichloride (36 mg, 0.05 mmol), sodium carbonate (105 mg, 0.99 mmol), argon. The reaction was stirred at 110 ° C in an oil bath for 18 hours. The reaction was monitored by LC-MS until the starting material disappeared and the reaction was stopped. The reaction was cooled, washed with water (100 mL), extracted with ethyl acetate (100 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system B The title product 2f (208 mg) was obtained in a yield of 92%. MS m / z (ESI): 453.3 [M + 1]

Step Six

(2-((5-((1S, 3R) -2- (4-cyclopropylphenyl) -6- (1-ethyl-1H-pyrazol-4-yl) -3-methyl-1 Tert-butyl 2,2,3,4-tetrahydroisoquinolin-1-yl) pyridin-2-yl) oxy) ethyl) carbamate 2g

Add sodium hydride (276mg, 6.89mmol) to N- (tert-butoxycarbonyl) ethanolamine (2mL), stir for 15 minutes, add compound 2f (208mg, 0.46mmol), and stir the reaction at 110 ° C in an oil bath under nitrogen protection. hour. It was quenched by adding water (100 mL), extracted with ethyl acetate (100 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system B, This gave 2 g (322 mg) of the crude title product. MS m / z (ESI): 594.3 [M + 1]

Step Seven

2-((5-((1S, 3R) -2- (4-cyclopropylphenyl) -6- (1-ethyl-1H-pyrazol-4-yl) -3-methyl-1, 2,3,4-tetrahydroisoquinolin-1-yl) pyridin-2-yl) oxy) ethyl-1-amine 2h

2 g of crude compound (322 mg) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (4N, 3 mL), and the reaction was stirred for 3 hours. The reaction was monitored by TLC until the starting material disappeared, and the reaction was stopped. The reaction solution was concentrated, a saturated sodium bicarbonate solution (25 mL) was added, and extracted with dichloromethane (50 mL × 2), followed by washing with water (50 mL × 2), saturated sodium chloride (50 mL), and the organic phase was dried over anhydrous sodium sulfate. , Filtered, and the filtrate was concentrated under reduced pressure to give the title compound 2h (84 mg), yield: 32%. MS m / z (ESI): 494.3 [M + 1]

Step eight

(E) -4-((2-((5-((1S, 3R) -2- (4-cyclopropylphenyl) -6- (1-ethyl-1H-pyrazol-4-yl) -3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) pyridin-2-yl) oxy) ethyl) amino) -N, N-dimethylbut-2- Enamide 2

Compound 2h (46 mg, 0.093 mmol) was dissolved in N, N-dimethylformamide (5 mL), and a solution of 1 p (17 mg, 0.093 mmol) in N, N-dimethylformamide (1 mL) was added. The reaction was stirred for 2 hours. It was washed with a saturated sodium chloride solution (50 mL × 2), extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by thin layer chromatography with developing agent system A. The obtained residue gave the title compound 2 (17 mg) in a yield of 30%. MS m / z (ESI): 605.4 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.05 (d, 1H), 7.98 (s, 1H), 7.81 (s, 1H), 7.61 (dd, 1H), 7.40-7.34 (m, 2H), 7.21 (d, 1H), 6.92-6.86 (m, 2H), 6.85-6.80 (m, 2H), 6.80-6.70 (m, 1H), 6.66 (d, 1H), 6.60-6.53 (m, 1H), 5.71 (s, 1H), 4.40-4.34 (m, 1H), 4.32 (t, 2H), 4.20 (q, 2H), 3.47 (d, 2H), 3.39 (dd, 1H), 3.05 (s, 3H), 2.98 (t, 2H), 2.95 (s, 3H), 2.80 (d, 1H), 1.81-1.72 (m, 1H), 1.48 (t, 3H), 1.01 (d, 3H), 0.83 (dd, 2H), 0.53 (t, 2H).

Example 3

(E) -4-((2- (4-((3R) -2- (4-cyclopropylphenyl) -6- (1-ethyl-1H-pyrazol-4-yl) -3- Methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) phenoxy) ethyl) amino) -N, N-dimethylbut-2-enamide 3

first step

4- (2- (1,3-dioxoisoindololin-2-yl) ethoxy) benzaldehyde 3c

P-hydroxybenzaldehyde 3a (2.3 g, 18.74 mmol) was dissolved in acetonitrile (30 mL), and N- (2-bromoethyl) phthalimide 3b (5.0 g, 19.68 mmol) was added, and potassium carbonate (3.6 g, 26.24 mmol) and potassium iodide (311 mg, 1.87 mmol). The oil bath was heated to reflux and the reaction was stirred for 17 hours. Extract with dichloromethane (100 mL x 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the resulting residue with silica gel column chromatography using eluent system B to give the title compound 3c (3.3 g) Yield: 59%. MS m / z (ESI): 296.1 [M + 1]

Second step

2- (2- (4-((3R) -2- (4-cyclopropylphenyl) -6-hydroxy-3-methyl-1,2,3,4-tetrahydroisoquinoline-1- Yl) phenoxy) ethyl) isoindolin-1,3-dione 3d

2c (400 mg, 1.49 mmol) was dissolved in toluene (4 mL), compound 3c (884 mg, 2.99 mmol) and trifluoroacetic acid (1.6 mL) were added, and the reaction was performed at 120 ° C. for 8 hours in an oil bath. The reaction was quenched with a saturated sodium bicarbonate solution (20 mL), and water (100 mL) was added, followed by stirring for 10 minutes. Extracted with dichloromethane (100 mL x 2), combined organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 3d (209 mg) Yield: 26%. MS m / z (ESI): 545.2 [M + 1]

third step

(3R) -2- (4-cyclopropylphenyl) -1- (4- (2- (1,3-dioxoisoindolin-2-yl) ethoxy) phenyl) -3 -Methyl-1,2,3,4-tetrahydroisoquinoline-6-yl triflate 3e

Compound 3d (112 mg, 0.21 mmol) was dissolved in dichloromethane (5 mL), and 2,6-lutidine (44 mg, 0.41 mmol) was added at room temperature. After cooling in an ice bath, trifluoromethanesulfonic anhydride (87 mg, 0.31 mmol) was added dropwise. After the addition was completed, the ice bath was removed and the reaction was stirred at room temperature for 5 hours. The reaction was monitored by LC-MS until the starting material disappeared and the reaction was stopped. The reaction was quenched with a saturated sodium chloride solution (20 mL), and water (100 mL) was added, followed by stirring for 10 minutes. Extract with dichloromethane (100 mL x 2) and combine the organic phases. It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography using developing system B to obtain the title compound 3e (119 mg), yield: 85%. MS m / z (ESI): 677.2 [M + 1]

the fourth step

2-((2- (4-((3R) -2- (4-cyclopropylphenyl) -6- (1-ethyl-1H-pyrazol-4-yl) -3-methyl-1 , 2,3,4-tetrahydroisoquinolin-1-yl) phenoxy) ethyl) carbamoyl) benzoic acid 3f

Compound 3e (119mg, 0.18mmol) was dissolved in 6.5mL of a mixed solution of dioxane and water (V: V = 10: 3), and 1-ethyl-1H-pyrazole-4-boronic acid pinacol was added (78 mg, 0.35 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (13 mg, 0.018 mmol), sodium carbonate (37 mg, 0.35 mmol), argon. The reaction was stirred at 110 ° C in an oil bath for 18 hours. The reaction was monitored by TLC until the starting material disappeared, and the reaction was stopped. Water (100 mL) was added and stirred for 10 minutes. Extracted with dichloromethane (100 mL × 2), combined organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing agent B to give the title compound 3f (100 mg) Yield: 91%. MS m / z (ESI): 641.3 [M + 1]

the fifth step

2- (4-((3R) -2- (4-cyclopropylphenyl) -6- (1-ethyl-1H-pyrazol-4-yl) -3-methyl-1,2,3 3,4-tetrahydroisoquinolin-1-yl) phenoxy) ethylamine

Compound 3f (100 mg, 0.16 mmol) was dissolved in ethanol (3 mL), and hydrazine hydrate (95 mg, 1.61 mmol) was added. Heat to 95 ° C and reflux for 16 hours. The reaction was monitored by LC-MS until the starting material disappeared and the reaction was stopped. The reaction solution was spin-dried, and the resulting residue was purified by thin-layer chromatography using developing system A to obtain 3 g (40 mg) of the title compound, yield: 51%. MS m / z (ESI): 493.3 [M + 1]

Sixth step (E) -4-((2- (4-((3R) -2- (4-cyclopropylphenyl) -6- (1-ethyl-1H-pyrazol-4-yl) -3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) phenoxy) ethyl) amino) -N, N-dimethylbut-2-enamide 3

Dissolve 3g (50mg, 0.10mmol) of compound in N, N-dimethylformamide (3mL), add diisopropylethylamine (39mg, 0.30mmol), 1mL of compound 1p (19mg, 0.10mmol), N, The N-dimethylformamide solution was stirred for 16 hours. The reaction was monitored by LC-MS. The reaction solution was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: NH ₄ HCO ₃ , water, acetonitrile) to obtain the title compound 3 (10 mg), yield: 16%. MS m / z (ESI): 604.3 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 7.96 (s, 1H), 7.79 (s, 1H), 7.39-7.32 (m, 2H), 7.31- 7.25 (m, 1H), 7.22 (d, 1H), 7.12 (d, 1H), 6.91-6.82 (m, 3H), 6.80-6.72 (m, 4H), 6.65-6.53 (m, 1H), 5.63 ( s, 1H), 4.47-4.38 (m, 1H), 4.19 (q, 2H), 4.01 (t, 2H), 3.47 (d, 2H), 3.41-3.33 (m, 1H), 3.04 (s, 3H) , 2.94 (s, 3H), 2.75 (dd, 1H), 2.0-1.95 (m, 2H), 1.78-1.70 (m, 1H), 1.47 (t, 3H), 1.00 (d, 3H), 0.80 (dd , 2H), 0.55-0.48 (m, 2H).

Example 4

(E) -4-((2-((5- (2- (2-fluoro-2-methylpropyl) -3-methyl-1,2,3,4-tetrahydrobenzofuran [2 , 3-c) pyridin-1-yl) pyridin-2-yl) oxy) ethyl) amino) -N, N-dimethylbut-2-enamide 4

first step

2- (2-fluoro-2-methylpropyl) -1- (6-fluoropyridin-3-yl) -3-methyl-1,2,3,4-tetrahydrobenzofuran [2,3 -c] pyridine 4b

Compound N- (1- (benzofuran-3-yl) propane-2-yl) -2-fluoro-2-methyl-1-propylamine 4a (0.20 g, 0.80 mmol, disclosed using patent application "WO2016202161" Prepared by the method) dissolved in N, N-dimethylformamide (10mL), added 1h (0.13g, 1.03mmol), triisopropylchlorosilane (0.80g, 2.40mmol), and stirred at 130 ° C in an oil bath Reaction for 3 hours. Stop reaction. Add saturated sodium bicarbonate solution (20 mL), extract with ethyl acetate (50 mL x 2), wash with saturated sodium chloride (50 mL x 4), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by thin-layer chromatography with developing system B to give the title product 4b (285 mg), yield: 70%. MS m / z (ESI): 357.2 [M + 1]

Second step

(2-((5- (2- (2-fluoro-2-methylpropyl) -3-methyl-1,2,3,4-tetrahydrobenzofuran [2,3-c] pyridine- 1-yl) pyridin-2-yl) oxy) ethyl) t-butyl carbamate 4c

Compound 4b (0.29g, 799.64mmol) was dissolved in 1m (2.57g, 15.99mmol), sodium hydride (0.18g, 7.96mmol) was added, and the reaction was maintained at room temperature for 30 minutes. The reaction was stirred at 90 ° C in an oil bath for 16 hours and stopped reaction. The reaction was cooled, the reaction solution was concentrated, a saturated sodium bicarbonate solution (25 mL) was added, and extracted with ethyl acetate (50 mL × 2), washed with water (50 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography using developing system B to obtain the title product 4c (145 mg), yield: 36%. MS m / z (ESI): 498.2 [M + 1]

third step

2-((5- (2- (2-fluoro-2-methylpropyl) -3-methyl-1,2,3,4-tetrahydrobenzofuran [2,3-c] pyridine-1 -Yl) pyridin-2-yl) oxy) ethylamine 4d

Compound 4c (0.15g, 291.39umol) was dissolved in a dioxane solution (4N, 3mL) of hydrogen chloride, and the reaction was stirred for 2 hours to stop the reaction. The reaction solution was concentrated, a saturated sodium bicarbonate solution (25 mL) was added to neutralize the reaction solution, and then extracted with dichloromethane (50 mL × 3), and the organic phases were combined. It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 4d (115 mg) in a yield of 99%. MS m / z (ESI): 398.2 [M + 1]

the fourth step

(E) -4-((2-((5- (2- (2-fluoro-2-methylpropyl) -3-methyl-1,2,3,4-tetrahydrobenzofuran [2 , 3-c) pyridin-1-yl) pyridin-2-yl) oxy) ethyl) amino) -N, N-dimethylbut-2-enamide 4

Compound 4d (0.12g, 289.31umol) was dissolved in N, N-dimethylformamide (5mL), diisopropylethylamine (0.08g, 572.56umol) was added, and then 1p (0.04g, 194.65umol) was added. N, N-dimethylformamide (1 mL) and stirred for 1 hour. Add saturated sodium bicarbonate solution (20 mL), extract with ethyl acetate (50 mL x 2), wash with saturated sodium chloride (50 mL x 4), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by thin-layer chromatography with developing system A to give the title product 4 (45 mg), yield: 35%. MS m / z (ESI): 509.3 [M + 1]; ¹ H NMR (400MHz, DMSO-d ₆ ) 7.99 (s, 1H), 7.62-7.60 (d, 1H), 7.59-7.57 (d, 1H) , 7.54-7.52 (d, 1H), 7.31-7.26 (m, 2H), 6.83-6.81 (d, 1H), 6.64-6.54 (m, 2H), 4.97 (s, 1H), 4.32-4.29 (m, 2H), 3.42-3.41 (d, 2H), 3.20-3.10 (m, 1H), 3.00 (s, 3H), 2.93-2.87 (m, 2H), 2.85 (s, 3H), 2.84-2.75 (m, 1H), 2.70-2.62 (m, 1H), 2.57-2.45 (m, 2H), 1.43-1.37 (d, 3H), 1.26-1.23 (d, 3H), 1.13-1.08 (d, 3H).

Example 5

(E) -4-((2-((5- (6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methylpropyl) -3- Methyl-1,2,3,4-tetrahydrobenzofuran [2,3-c] pyridin-1-yl) pyridin-2-yl) oxy) ethyl) amino) -N, N-dimethyl Butyl-2-enamide 5

first step

6-bromo-2- (2-fluoro-2-methylpropyl) -1- (6-fluoropyridin-3-yl) -3-methyl-1,2,3,4-tetrahydrobenzofuran [2,3-c] pyridine 5b

The compound N- (1- (5-bromobenzofuran-3-yl) propyl-2-yl) -2-fluoro-2-methylpropyl-1-amine 5a (0.43 g, 1.31 mmol, using Prepared by the method disclosed in the patent application "WO2016202161") dissolved in N, N-dimethylformamide (10mL), added 1h (0.21g, 1.70mmol), triisopropylchlorosilane (2.20g, 6.55mmol) The reaction was stirred at 130 ° C in an oil bath for 3 hours to stop the reaction. Add saturated sodium bicarbonate solution (20 mL), extract with ethyl acetate (50 mL x 2), wash with saturated sodium chloride (50 mL x 4), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue was purified by thin-layer chromatography with developing system B to obtain the title product 5b (342 mg), yield: 59%. MS m / z (ESI): 437.1 [M + 2]

Second step

6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methylpropyl) -1- (6-fluoropyridin-3-yl) -3-methyl -1,2,3,4-tetrahydrobenzofuran [2,3-c] pyridine 5c

Compound 5b (0.18g, 387.55umol) was dissolved in 14.4mL of a mixed solution of dioxane and water (V: V = 5: 1), and compound 1k (0.17g, 774.45umol) and potassium carbonate (0.16g) were added. , 1.15 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (0.03g, 38.35umol), protected by argon, stirred at 80 ° C in an oil bath for 16 hours, and stopped the reaction . The reaction was cooled, the reaction solution was concentrated, a saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing system B to obtain the title product 5c (170 mg), yield: 96%. MS m / z (ESI): 451.0 [M + 1]

third step

(2-((5- (6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methylpropyl) -3-methyl-1,2, Tert-butyl 3,4-tetrahydrobenzofuran [2,3-c] pyridin-1-yl) pyridin-2-yl) oxy) ethyl) carbamate 5d

Compound 5c (0.17g, 77.60umol) was dissolved in 1m (2.43g, 15.09mmol), sodium hydride (0.15g, 6.22mmol) was added, and the reaction was maintained at room temperature for 30 minutes. The reaction was stirred at 90 ° C in an oil bath for 16 hours and stopped. reaction. The reaction was cooled, the reaction solution was concentrated, a saturated sodium bicarbonate solution (25 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 2), washed with water (50 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed Concentrated, and the resulting residue was purified by thin layer chromatography with developing system B to give the title product 5d (214 mg), yield: 94%. MS m / z (ESI): 592.3 [M + 1]

the fourth step

2-((5- (6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methylpropyl) -3-methyl-1,2,3 , 4-tetrahydrobenzofuran [2,3-c] pyridin-1-yl) pyridin-2-yl) oxy) ethylamine 5e

Compound 5d (0.21g, 354.60umol) was dissolved in a dioxane solution (4N, 3mL) of hydrogen chloride, and the reaction was stirred for 2 hours to stop the reaction. The reaction solution was concentrated, and a saturated sodium bicarbonate solution (25 mL) was added to neutralize the reaction solution, followed by extraction with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 5e (150 mg). The product was directly subjected to the next reaction without purification. MS m / z (ESI): 492.3 [M + 1]

the fifth step

(E) -4-((2-((5- (6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methylpropyl) -3- Methyl-1,2,3,4-tetrahydrobenzofuran [2,3-c] pyridin-1-yl) pyridin-2-yl) oxy) ethyl) amino) -N, N-dimethyl Butyl-2-enamide 5

Crude compound 5e (0.15g, 305umol) was dissolved in N, N-dimethylformamide (5mL), diisopropylethylamine (0.12g, 913umol) was added, and 1p (0.06g, 286.38umol) of N, N-dimethylformamide (1 mL), and the reaction was stirred for 1 hour. A saturated sodium bicarbonate solution (20 mL) was added, extracted with ethyl acetate (50 mL × 2), and washed with saturated sodium chloride (50 mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing system A to give the title product 5 (25 mg), yield: 13.4%. MS m / z (ESI): 603.4 [M + 1]; ¹ H NMR (400MHz, DMSO-d ₆ ) 8.20 (s, 1H), 7.99 (s, 1H), 7.88 (s, 1H), 7.76 (s , 1H), 7.64-7.62 (d, 1H), 7.50-7.47 (m, 2H), 6.85-6.82 (d, 1H), 6.63-6.57 (m, 2H), 4.96 (s, 1H), 4.35-4.32 (m, 2H), 4.18-4.13 (m, 2H), 3.50-3.45 (m, 2H), 3.20-3.16 (m, 1H), 3.02 (s, 3H), 2.97-2.92 (m, 2H), 2.86 (s, 3H), 2.85-2.75 (m, 1H), 2.74-2.65 (m, 1H), 2.60-2.45 (m, 2H), 1.45-1.40 (m, 3H), 1.38-1.30 (d, 3H) , 1.30-1.20 (d, 3H), 1.13-1.08 (d, 3H).

Example 6

(E) -4-((2-((5-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9-tetra Hydrogen-1H-pyrido [3,4-b] indol-1-yl) pyridin-2-yl) oxy) ethyl) amino) -N, N-dimethylbut-2-enamide 6

first step

(R) -N- (1- (1H-Indol-3-yl) propyl-2-yl) -2-fluoro-2-methylpropyl-1-amine 6b

(2R) -1- (1H-Indol-3-yl) propyl-2-amine 6a (0.65 g, 3.73 mmol) was dissolved in dioxane (20 mL), and then compound 1e (1.13 g, 5.03 mmol), N, N-dimethylformamide (1.44 g, 11.18 mmol), and stirred in an oil bath at 90 ° C for 16 hours to stop the reaction. The reaction was cooled, the reaction solution was concentrated, and a saturated sodium bicarbonate solution (25 mL) was added. Extract with ethyl acetate (50 mL × 3), wash with saturated sodium chloride (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing system A to give the title product 6b (600 mg), yield: 64.7%. MS m / z (ESI): 249.2 [M + 1]

Second step

(1R, 3R) -2- (2-fluoro-2-methylpropyl) -1- (6-fluoropyridin-3-yl) -3-methyl-2,3,4,9-tetrahydro- 1H-pyrido [3,4-b] indole 6c

Compound 6b (0.39 g, 1.57 mmol) was dissolved in toluene (10 mL), then compound 1 h (0.29 g, 2.35 mmol), acetic acid (0.19 g, 3.13 mmol) were added, and the reaction was stirred at 90 ° C in an oil bath for 16 hours to stop the reaction. The reaction was cooled, the reaction solution was concentrated, a saturated sodium bicarbonate solution (25 mL) was added, and extracted with ethyl acetate (50 mL x 2), and the organic phases were combined. It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography with developing system B to obtain the title product 6c (400 mg), yield: 71.6%. MS m / z (ESI): 356.2 [M + 1]

third step

(2-((5-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9 tetrahydro-1H-pyrido [3 , 4-b] indol-1-yl) pyridin-2-yl) oxy) ethyl) carbamic acid tert-butyl 6d

Compound 6c (0.15g, 422.03umol) was dissolved in 1m (3.40g, 21.09mmol), sodium hydride (0.09g, 4.21mmol) was added, and after stirring for 30 minutes, the temperature was slowly raised to 100 ° C and the reaction was stirred for 8 hours to stop the reaction. . Cool the reaction, concentrate the reaction solution, add saturated sodium bicarbonate solution (25 mL), extract with ethyl acetate (50 mL x 2), wash with water (50 mL x 2), wash with saturated sodium chloride (50 mL x 2), combine the organic phases, Dry over anhydrous sodium sulfate and filter. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing system B to obtain the title product 6d (400 mg), yield: 38%. MS m / z (ESI): 497.3 [M + 1]

the fourth step

2-((5-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,4a, 9,9a-hexahydro-1H- Pyrido [3,4-b] indol-1-yl) pyridin-2-yl) oxy) ethylamine 6e

Compound 6d (0.08 g, 0.16 mmol) was dissolved in a hydrogen chloride solution (4N, 3 mL), and the reaction was stirred at room temperature for 1.5 hours to stop the reaction. The reaction solution was concentrated, a saturated sodium bicarbonate solution (25 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 3), washed with water (50 mL × 3), and washed with saturated sodium chloride (50 mL × 3), and the organic phases were combined. It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 6e (63 mg). The product was directly subjected to the next reaction without purification. MS m / z (ESI): 397.2 [M + 1]

the fifth step

(E) -4-((2-((5-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9-tetra Hydrogen-1H-pyrido [3,4-b] indol-1-yl) pyridin-2-yl) oxy) ethyl) amino) -N, N-dimethylbut-2-enamide 6

Crude compound 6e (0.06g, 158.89umol) was dissolved in N, N-dimethylformamide (3.5mL), then diisopropylethylamine (0.06g, 471umol) was added, and 1p (0.03g, 156.20umol) in 1 mL of N, N-dimethylformamide solution, and kept at room temperature for 2 hours. A saturated sodium bicarbonate solution (20 mL) was added, extracted with ethyl acetate (50 mL × 2), washed with saturated sodium chloride (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing system A to obtain the title product 6 (20 mg), yield: 24.7%. MS m / z (ESI): 508.3 [M + 1]; ¹ H NMR (400MHz, DMSO-d ₆ ) 10.79 (s, 1H), 7.59 (s, 1H), 7.55-7.53 (dd, 1H), 7.44 -7.42 (d, 1H), 7.28-7.26 (d, 1H), 7.05-7.03 (m, 1H), 6.99-6.96 (m, 1H), 6.79-6.77 (d, 1H), 6.66-6.59 (dt, 1H), 6.54-6.50 (d, 1H), 5.01 (s, 1H), 4.28-4.25 (m, 2H), 3.34-3.33 (d, 2H), 3.15-3.05 (m, 1H), 3.00 (s, 3H), 2.84 (s, 3H), 2.83-2.81 (m, 2H), 2.73-2.69 (m, 1H), 2.65-2.55 (m, 1H), 2.54-2.45 (m, 2H), 1.46-1.40 ( d, 3H), 1.31-1.25 (d, 3H), 1.07-1.05 (d, 3H).

Example 7

(E) -4-((2- (3,5-difluoro-4-((6S, 8R) -7- (2-fluoro-2-methylpropyl) -8-methyl-6,7 , 8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethyl) amino) -N, N-dimethylbut-2-ene Amide 7

first step

(2- (3,5-difluoro-4-((6S, 8R) -7- (2-fluoro-2-methylpropyl) -8-methyl-3- (tetrahydro-2H-pyran 2-yl) -6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethyl) carbamic acid tert-butyl ester 7b

(6S, 8R) -6- (4-bromo-2,6-difluorophenyl) -7- (2-fluoro-2-methylpropyl) -8-methyl-3- (tetrahydro- 2H-pyran-2-yl l) -6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinoline 7a (50 mg, 0.093 mmol, as disclosed in patent application US20170305909A1 Prepared by the method), N- (tert-butoxycarbonyl) ethanolamine (31 mg, 0.19 mmol) was suspended in toluene (5 mL), cesium carbonate (76 mg, 0.23 mmol) and RockPhos Pd G3 (8 mg, 0.0095 mmol, Aldrich-773905 ), Replaced by argon 3 times, heated to 95 ° C in an oil bath and stirred for 3 hours, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 7b (48 mg), yield : 83%. MS m / z (ESI): 617.0 [M + 1]

Second step

2- (3,5-difluoro-4-((6S, 8R) -7- (2-fluoro-2-methylpropyl) -8-methyl-6,7,8,9-tetrahydro- 3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethylamine hydrochloride 7c

Compound 7b (54 mg, 0.087 mmol) was dissolved in dichloromethane (4 mL), and a dioxane solution (4N, 0.43 mL) of hydrogen chloride was added dropwise, followed by stirring for 1.5 hours. Concentration under reduced pressure gave the crude title compound 7c (42 mg), which was used in the next reaction without purification. MS m / z (ESI): 433.0 [M + 1]

third step

(E) -4-((2- (3,5-difluoro-4-((6S, 8R) -7- (2-fluoro-2-methylpropyl) -8-methyl-6,7 , 8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethyl) amino) -N, N-dimethylbut-2-ene Amide 7

The crude compound 7c (42 mg, 0.089 mmol) was dissolved in N, N-dimethylformamide (3 mL), and N, N-diisopropylethylamine (46 mg, 0.35 mmol) was added. Compound 1p (14 mg, 0.073) mmol), stirred for 1.5 hours, quenched by adding 10 mL of ice water, and extracted with ethyl acetate (15 mL × 3). The organic layers were combined, washed once with 10 mL of a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and prepared using high performance liquid phase (Waters 2767-SQ Detecor2, elution system: NH ₄ HCO ₃ , water, acetonitrile) to give the title compound 7 (4 mg), yield: 8%. MS m / z (ESI): 544.3 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.06 (s, 1H), 7.20 (d, 1H), 680-6.67 (m, 3H), 6.57 ( d, 2H), 5.22 (s, 1H), 4.16-4.13 (m, 2H), 3.81-3.74 (m, 1H), 3.63 (d, 2H), 3.45-3.40 (m, 1H), 3.17-3.14 ( m, 2H), 3.13 (s, 3H), 2.99 (s, 3H), 2.96-2.93 (m, 2H), 2.40-2.29 (m, 1H), 1.13 (q, 6H), 1.04 (d, 3H) .

Example 8

(E) -4-((2- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3 , 4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) amino) -N, N-dimethylbut-2-enamide 8

first step

Tert-butyl (2- (3,5-difluoro-4formylphenoxy) ethyl) carbamate 8b

The raw material 2,6-difluoro-4-hydroxybenzaldehyde 8a (1.00 g, 6.32 mmol) was dissolved in dichloromethane (30 mL), and intermediate 1 m (1.52 g, 9.48 mmol) and triphenylphosphine (2.48 g) were added. , 9.48 mmol), diisopropyl azodicarboxylate (1.91 g, 9.48 mmol) was added under cooling in an ice water bath, and the reaction was stirred for 16 hours to stop the reaction. The reaction solution was washed with water (50 mL × 2), saturated sodium chloride solution (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography using developing system B to obtain the title product 8b (1.20 g), yield: 82%. MS m / z (ESI): 246.1 [M-56 + 1]

Second step

(2- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9-tetrahydro -1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) carbamic acid tert-butyl ester 8c

Compound 8b (0.28g, 945.94umol) and compound 6b (0.25g, 998.63umol) were dissolved in toluene (25mL), acetic acid (0.36g, 6.00mmol) was added, and the reaction was stirred at 80 ° C in an oil bath for 16 hours to stop the reaction. The reaction was cooled, and a saturated sodium bicarbonate solution (25 mL) was added, followed by extraction with ethyl acetate (50 mL × 2). It was washed with saturated sodium chloride (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography using developing system B to obtain the title product 8c (200 mg), yield: 37%. MS m / z (ESI): 532.2 [M + 1]

third step

2- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9-tetrahydro- 1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethylamine 8d

The starting material 8c (0.12 g, 225.73 mmol) was dissolved in a dioxane solution (4N, 3 mL) of hydrogen chloride, and the reaction was stirred at room temperature for 2 hours to stop the reaction. The reaction solution was concentrated, a saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined. It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 8d (83 mg). The product was directly subjected to the next reaction without purification. MS m / z (ESI): 432.2 [M + 1]

the fourth step

(E) -4-((2- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3 , 4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) amino) -N, N-dimethylbut-2-enamide 8

Crude compound 8d (0.08g, 192.35umol) was dissolved in N, N-dimethylformamide (6mL), then diisopropylethylamine (0.07g, 572.56umol) was added, and 1p (0.03g, 171.82) was added. umol) in 1 mL of N, N-dimethylformamide solution and kept stirring for 2 hours. A saturated sodium bicarbonate solution (20 mL) was added, extracted with ethyl acetate (50 mL × 3), washed with saturated sodium chloride (50 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography with developing system A to give the title product 8 (45 mg), yield: 63%. MS m / z (ESI): 543.3 [M + 1]; ¹ H NMR (400MHz, DMSO-d ₆ ) 10.53 (s, 1H), 7.40-7.38 (d, 1H), 7.19-7.17 (d, 1H) , 7.00-6.97 (m, 1H), 6.96-6.93 (m, 1H), 6.69 (s, 1H), 6.63 (s, 1H), 6.62-6.60 (m, 2H), 5.12 (s, 1H), 4.10 -4.02 (m, 2H), 3.52-3.45 (m, 1H), 3.44-3.40 (m, 2H), 3.02 (s, 3H), 2.93-2.89 (m, 2H), 2.86 (s, 3H), 2.85 -2.79 (m, 2H), 2.56-2.50 (m, 1H), 2.40-2.25 (m, 1H), 1.20-1.20 (d, 3H), 1.19-1.15 (d, 3H), 1.07-1.05 (d, 3H).

Example 9

(E) -4-((S) -3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl- 2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) pyrrolidin-1-yl) -N, N-dimethylbutyl- 2-enamide 9

first step

(S) -3- (3,5-Difluoro-4-formylphenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester 9b

Compound (3R) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl 9a (1.24 g, 6.63 mmol) and compound 8a (0.70 g, 4.42 mmol), triphenylphosphine (1.74 g, 4.42 mmol) were dissolved in After dichloromethane (50 mL), diisopropyl azodicarboxylate (1.34 g, 6.63 mmol) was added. The reaction was stirred at room temperature for 16 hours, and the reaction was stopped. Saturated sodium bicarbonate solution was added to wash (50 mL × 2), saturated sodium chloride was washed (50 mL × 2), and the organic phases were combined. Dry over anhydrous sodium sulfate and filter. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography using developing system B to obtain the title product 9b (1.20 g), yield: 82%. MS m / z (ESI): 272.1 [M-56 + 1]

Second step

(S) -3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9 -Tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester 9c

The raw material 6b (0.15g, 604.001umol) was dissolved in toluene (20mL), compound 9b (0.19g, 601umol) and acetic acid (0.22g, 3.61mmol) were added, and the reaction was stirred at 85 ° C in an oil bath for 16 hours to stop the reaction. The reaction was cooled, a saturated sodium bicarbonate solution (50 mL) was added, and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing system B to obtain the title product 9c (54 mg), yield: 16%. MS m / z (ESI): 558.3 [M + 1]

third step

(1R, 3R) -1- (2,6-difluoro-4-(((S) -pyrrolidin-3yl) oxy) phenyl) -2- (2-fluoro-2-methylpropyl ) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole 9d

Compound 9c (0.05g, 96.83umol) was dissolved in a dioxane solution (4N, 3mL) of hydrogen chloride, and the reaction was stirred for 2 hours. A saturated sodium bicarbonate solution (25 mL) was directly added to neutralize the reaction solution, and then extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 9d ( 44 mg), the product was directly reacted without purification. MS m / z (ESI): 458.3 [M + 1]

the fourth step

(E) -4-((S) -3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl- 2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) pyrrolidin-1-yl) -N, N-dimethylbutyl- 2-enamide 9

The crude compound 9d (0.04g, 96.16umol) was dissolved in N, N-dimethylformamide (5mL), and diisopropylethylamine (0.03g, 286.28umol), 1p (0.02g, 104.13umol) was added. N, N-dimethylformamide (1 mL), and the reaction was stirred for 1 hour. Add saturated sodium bicarbonate solution (20 mL), extract with ethyl acetate (50 mL x 2), wash with saturated sodium chloride (50 mL x 4), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by thin-layer chromatography with developing system A to give the title product 9 (35 mg), yield: 63%.

MS m / z (ESI): 569.3 [M + 1]

Chiral HPLC analysis: retention time 10.339 minutes, chiral purity: 99.8% (chromatographic column: OZ Phenomenex Lux Cellulose-2 150 * 4.6mm, 5um; mobile phase: ethanol / n-hexane = 20/80 (v / v)) .

¹ H NMR (400MHz, DMSO-d ₆ ) 10.53 (s, 1H), 7.40-7.38 (d, 1H), 7.19-7.17 (d, 1H), 7.00-6.97 (m, 1H), 6.96-6.93 (m , 1H), 6.63 (s, 1H), 6.60-6.55 (m, 3H), 5.12 (s, 1H), 4.92-4.85 (m, 1H), 3.52-3.45 (m, 1H), 3.23-3.20 (m , 2H), 3.02 (s, 3H), 2.86 (s, 3H), 2.84-2.81 (m, 1H), 2.80-2.72 (m, 2H), 2.66-2.64 (m, 1H), 2.43-2.36 (m , 1H), 2.35-2.31 (m, 2H), 2.30-2.26 (m, 1H), 1.78-1.74 (m, 2H), 1.21-1.15 (d, 3H), 1.14-1.08 (d, 3H), 1.04 -1.03 (d, 3H).

Example 10

(E) -4-((3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3 , 4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) propyl) amino) -N, N-dimethylbut-2-enamide 10

first step

3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9-tetrahydro-1H-pyridine Benzo [3,4-b] indol-1-yl) phenol 10a

Compound 6b (1.4 g, 5.44 mmol) was dissolved in toluene (100 mL), and 8a (945 mg, 5.98 mmol) and acetic acid (1.87 mL, 32.63 mmol) were added. After the addition was completed, the reaction was stirred at 90 ° C in an oil bath for 16 hours. Cool the reaction to room temperature, add ethyl acetate (100 mL), adjust the pH to 7-8 with saturated sodium bicarbonate solution, separate the aqueous phase, extract with ethyl acetate (100 mL × 2), combine the organic phases and dry over anhydrous sodium sulfate ,filter. The filtrate was concentrated, and the resulting residue was purified by thin layer chromatography with developing system B to obtain the title compound 10a (597 mg), yield: 28%. MS m / z (ESI): 389.2 [M + 1]

Second step

(3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9-tetrahydro -1H-pyrido [3,4-b] indol-1-yl) phenoxy) propyl) carbamic acid tert-butyl ester 10b

Compound 10a (110mg, 0.28mmol) was dissolved in 1.5mL of a mixed solution of N, N-dimethylformamide and acetone (V: V = 1: 2), and tert-butyl (3-bromopropyl) carbamate was added. Ester (81 mg, 0.34 mmol), potassium carbonate (117 mg, 0.85 mmol), and stirred in an oil bath at 100 ° C for 5 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), stirred for 10 minutes, and filtered. The filtrate was collected, washed with ethyl acetate (100 mL × 2), and the organic phase was concentrated, and the resulting residue was purified by thin layer chromatography using developing system B to obtain the title compound 10b (148 mg), yield: 96%. MS m / z (ESI): 546.3 [M + 1]

third step

3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9-tetrahydro- 1H-pyrido [3,4-b] indol-1-yl) phenoxy) propyl-1-amine 10c

Compound 10b (148 mg, 0.27 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.2 mL) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (50 mL) was added, and the reaction solution was adjusted to pH ~ 7 with a saturated sodium bicarbonate solution (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound 10c (101 mg), yield: 84%. MS m / z (ESI): 446.2 [M + 1]

the fourth step

(E) -4-((3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3 , 4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) propyl) amino) -N, N-dimethylbut-2-enamide 10

Compound 10c (60 mg, 0.14 mmol) was dissolved in N, N-dimethylformamide (5 mL), and diisopropylethylamine (52 mg, 0.40 mmol) was added. Compound 1 p (18 mg, 0.09 mmol) in 1 mL N, N-dimethylformamide solution, react at room temperature for 2 hours. The reaction was monitored by LC-MS. It was added dropwise to a 50 mL aqueous solution, extracted with ethyl acetate (50 mL × 2), and the organic phase was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The obtained residue was purified by thin layer chromatography with developing system B to obtain the title compound 10 (5 mg), yield: 7%. MS m / z (ESI): 557.3 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 7.40 (d, 1H), 7.18 (d, 1H), 7.02-6.92 (m, 2H), 6.83 6.74 (m, 1H), 6.64-6.57 (m, 1H), 6.51 (s, 1H), 6.54 (s, 1H), 5.19 (s, 1H), 4.06 (t, 2H), 3.67 (br, 1H) , 3.47 (d, 2H), 3.12 (s, 3H), 3.04 (d, 1H), 2.98 (s, 3H), 2.96-2.85 (m, 1H), 2.82 (t, 2H), 2.59 (dd, 1H ), 2.47-2.33 (m, 1H), 2.00 (m, 2H), 1.19 (d, 3H), 1.14 (d, 3H), 1.10 (d, 3H).

Example 11

(E) -4-((3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3 , 4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) cyclobutyl) amino) -N, N-dimethylbut-2-enamide 11

first step

3-((tert-butoxycarbonyl) amino) cyclobutyl mesylate 11b

Dissolve tert-butyl (3-hydroxycyclobutyl) carbamate 11a (100 mg, 0.53 mmol) in dichloromethane (5 mL), add triethylamine (162 mg, 1.60 mmol), cool to -20 ° C, and stir for 10 In minutes, methanesulfonyl chloride (67 mg, 0.59 mmol) was slowly added dropwise. After stirring for 5 minutes, the mixture was warmed to room temperature and stirred for 0.5 hours. The reaction was monitored by TLC until the starting material disappeared, and the reaction was stopped. Water (50 mL) was added, extracted with dichloromethane (50 mL x 2), and the organic phases were combined. It was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound 11b (132 mg), yield: 93%.

Second step

(3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9-tetrahydro -1H-pyrido [3,4-b] indol-1-yl) phenoxy) cyclobutyl) carbamic acid tert-butyl ester 11c

Compound 10a (100 mg, 0.26 mmol) was dissolved in N, N-dimethylformamide (2.5 mL), cesium carbonate (168 mg, 0.51 mmol) and compound 11b (89 mg, 0.33 mmol) were added. The reaction was stirred at 70 ° C in an oil bath for 16 hours. The reaction was monitored by LC-MS until the starting material disappeared and the reaction was stopped. After cooling the reaction, the reaction solution was filtered, and the filtrate was concentrated. The obtained residue was purified by thin-layer chromatography using developing system B to obtain the title compound 11c (136 mg), yield: 95%. MS m / z (ESI): 558.2 [M + 1]

third step

3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9-tetrahydro- 1H-pyrido [3,4-b] indol-1-yl) phenoxy) cyclobut-1-amine 11d

Compound 11c (68 mg, 0.12 mmol) was dissolved in dichloromethane (1 mL), stirred for 10 minutes in an ice bath, and a 1,4-dioxane solution of hydrogen chloride (4N, 1.5 mL) was slowly added dropwise, and the ice bath The reaction was stirred for 10 minutes and allowed to stir to room temperature for 1 hour. The reaction was monitored by LC-MS until the starting material disappeared and the reaction was stopped. Dichloromethane (50mL) was added, and the reaction solution was adjusted to pH ~ 7 with a saturated sodium bicarbonate solution (50mL), and extracted with dichloromethane (50mL × 2). The organic phases were combined, and the organic phases were washed with a saturated sodium chloride solution. It was then dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave the title compound 11d (44 mg) in a yield of 79%. MS m / z (ESI): 458.3 [M + 1]

the fourth step

(E) -4-((3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3 , 4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) cyclobutyl) amino) -N, N-dimethylbut-2-enamide 11

Compound 11d (40 mg, 0.09 mmol) was dissolved in N, N-dimethylformamide (5 mL), and diisopropylethylamine (39 mg, 0.31 mmol) was added. Compound 1 p (12 mg, 0.06 mmol) in 1 mL N, N-dimethylformamide solution. The reaction was continued for 1 hour. The reaction was monitored by LC-MS. The reaction solution was added dropwise to a 50 mL aqueous solution, and extracted with ethyl acetate (50 mL × 2). The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by thin layer chromatography with a developing system B. The residue was obtained as the title compound 11 (11 mg), yield: 22%. MS m / z (ESI): 569.3 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 7.40 (d, 1H), 7.18 (d, 1H), 7.04-6.92 (m, 2H), 6.84- 6.73 (m, 1H), 6.57 (d, 1H), 6.48-6.36 (m, 2H), 5.18 (s, 1H), 4.48-4.38 (m, 1H), 3.72-3.61 (m, 1H), 3.57- 3.47 (m, 1H), 3.38-3.33 (m, 2H), 3.13 (s, 3H), 2.99 (s, 4H), 2.82 (s, 3H), 2.59 (dd, 1H), 2.46-2.31 (m, 2H), 2.03 (q, 2H), 1.96-1.85 (m, 1H), 1.19 (d, 3H), 1.13 (d, 3H), 1.09 (d, 3H).

Example 12

N-((1S, 3R) -3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) cyclopentyl) acrylamide 12

first step

(1S, 3S) -3-((tert-butoxycarbonyl) amino) cyclopentyl mesylate 12b

Dissolve tert-butyl N-[(1S, 3S) -3-hydroxycyclopentyl] carbamate 12a (105mg, 0.52mmol, Shuya) in methylene chloride (5mL), and add triethylamine (158mg, 1.56 mmol), cooled to -20 ° C, and stirred for 10 minutes. Methanesulfonyl chloride (66 mg, 0.57 mmol) was slowly added dropwise, and the mixture was stirred for 5 minutes after the addition, and the reaction was transferred to room temperature and stirred for 1 hour. The reaction was monitored by TLC until the starting material disappeared, and the reaction was stopped. Water (50 mL) was added and extracted with dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound 12b (145 mg), yield: 99%.

Second step

((1S, 3R) -3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3, Tert-butyl 4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) cyclopentyl) carbamate 12c

Compound 12b (140 mg, 0.50 mmol) was dissolved in N, N-dimethylformamide (4 mL), and cesium carbonate (251 mg, 0.77 mmol) and compound 10a (150 mg, 0.39 mmol) were added. The reaction was stirred at 70 ° C in an oil bath for 16 hours. After cooling the reaction, the reaction solution was filtered, and the filtrate was concentrated. The obtained residue was purified by thin layer chromatography with developing system B to obtain the title compound 12c (200 mg), yield: 90%. MS m / z (ESI): 572.3 [M + 1]

third step

(1S, 3R) -3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4 , 9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) cyclopentane-1-amine 12d

Compound 12c (150 mg, 0.26 mmol) was dissolved in dichloromethane (1.5 mL), and stirred in an ice bath for 10 minutes, and then a solution of hydrogen chloride in dioxane (4N, 2 mL) was slowly added dropwise, and the reaction was stirred in the ice bath for 10 minutes. , Warm to room temperature and stir for 1 hour. The reaction was monitored by LC-MS until the starting material disappeared and the reaction was stopped. Dichloromethane (50 mL) was added, and the reaction solution was adjusted to pH ~ 7 with a saturated sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound 12d (120 mg), yield: 97%. MS m / z (ESI): 472.3 [M + 1]

the fourth step

N-((1S, 3R) -3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) cyclopentyl) acrylamide 12

Compound 12d (50 mg, 0.11 mmol) was dissolved in tetrahydrofuran (5 mL), and diisopropylethylamine (45 mg, 0.35 mmol) was added at -60 ° C, followed by stirring for 10 minutes, and acrylic acid chloride (11 mg, 0.12 mmol) was added dropwise. After the addition, the temperature was raised to -20 ° C and the reaction was stirred for 1 hour, and then the temperature was raised to room temperature. The reaction was monitored by LC-MS until the starting material disappeared and the reaction was stopped. Water (50 mL) was added and stirred for 10 minutes. Extract with dichloromethane (50 mL x 2) and combine the organic phases. It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the resulting residue was purified by thin layer chromatography with developing system B to obtain the title compound 12 (15 mg), yield: 27%. MS m / z (ESI): 526.3 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 7.40 (d, 1H), 7.17 (d, 1H), 7.03-6.92 (m, 2H), 6.48 ( s, 1H), 6.51 (s, 1H), 6.24-6.18 (m, 2H), 5.62 (dd, 1H), 5.18 (s, 1H), 4.86-4.79 (m, 1H), 4.28 (m, 1H) , 3.68 (m, 1H), 3.50-3.41 (m, 1H), 3.08-2.98 (m, 1H), 2.95-2.84 (m, 1H), 2.83 (s, 1H), 2.59 (dd, 1H), 2.52 -2.42 (m, 1H), 2.42-2.32 (m, 1H), 2.12-2.03 (m, 1H), 2.03-1.95 (m, 2H), 1.80-1.69 (m, 2H), 1.18 (d, 3H) , 1.13 (d, 3H), 1.10 (d, 3H).

Example 13

(E) -4- (3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3, 4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) azetidin-1-yl) -N, N-dimethylbutyl- 2-enamide 13

first step

3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9-tetrahydro- 1H-pyrido [3,4-b] indol-1-yl) phenoxy) azetidine-1-carboxylic acid tert-butyl 13b

Compound 10a (0.10g, 25umol) was dissolved in acetonitrile (5mL), tert-butyl 3-iodoazetane-1-carboxylic acid 13a (0.15g, 512.17umol), and cesium carbonate (0.25g, 770.36umol) were added. The reaction was stirred overnight at 80 ° C in an oil bath for 16 hours. The reaction was cooled, a saturated sodium bicarbonate solution (20 mL) was added, and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing system B to obtain the title product 13b (125 mg), yield: 89%. MS m / z (ESI): 544.3 [M + 1]

Second step

(1R, 3R) -1- (4- (azetidin-3-yloxy) -2,6-difluorophenyl) -2- (2-fluoro-2-methylpropyl)- 3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole 13c

Compound 13b (0.12g, 220.74umol) was added to a hydrogen chloride solution (4N, 3mL) under cooling in an ice water bath, and the reaction was stirred for 1 hour. The reaction was stopped, the reaction was cooled, and a saturated sodium bicarbonate solution (25 mL) was added. Extracted with dichloromethane (50 mL x 3), combined the organic phases, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title product 13c (97 mg) as a crude product, which was directly subjected to the next reaction without purification. MS m / z (ESI): 444.3 [M + 1]

third step

(E) -4- (3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3, 4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) azetidin-1-yl) -N, N-dimethylbut-2 -Enamide 13

Crude compound 13c (0.05g, 112.73umol) was dissolved in N, N-dimethylformamide (5mL), then diisopropylethylamine (0.04g, 332.70umol) was added, and then 1p (0.02g, 130.17) was added. umol) N, N-dimethylformamide solution (1 mL), and the reaction was stirred for 1 hour to stop the reaction. The reaction was cooled, a saturated sodium bicarbonate solution (20 mL) was added, extracted with ethyl acetate (50 mL × 2), and the saturated sodium chloride solution was washed (50 mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography with developing system A to obtain the title product 13 (35 mg), yield: 55%. MS m / z (ESI): 555.3 [M + 1]; ¹ H NMR (400MHz, CDCl ₃ ) 7.55-7.50 (d, 1H), 7.43 (s, 1H), 7.25-7.21 (d, 1H), 7.10 -7.08 (m, 2H), 6.80-6.72 (dt, 1H), 6.45-6.35 (d, 1H), 6.29 (s, 1H), 6.26 (s, 1H), 5.20 (s, 1H), 4.80-4.70 (m, 1H), 3.90-3.80 (m, 2H), 3.70-3.60 (m, 1H), 3.35-3.30 (d, 2H), 3.20-3.15 (m, 2H), 3.09 (s, 3H), 3.08 -3.04 (m, 1H), 3.01 (s, 3H), 2.90-2.80 (m, 1H), 2.65-2.55 (m, 1H), 2.45-2.30 (m, 1H), 1.30-1.20 (d, 3H) , 1.19-1.15 (d, 3H), 1.12-1.07 (d, 3H).

Example 14

(E) -4-((R) -3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl- 2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) pyrrolidin-1-yl) -N, N-dimethylbutyl- 2-enamide 14

first step

(S) -3-((Methanesulfonyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester 14b

The raw material (S) tert-butyl 3-hydroxypyrrolidine-1-carboxylic acid 14a (187mg, 998.74umol, Shaoyuan) was dissolved in dichloromethane (8mL), and triethylamine (151.59mg, 1.49mmol) was added, and ice Methanesulfonyl chloride (137.28 mg, 1.19 mmol) was added under cooling in a water bath. The reaction was stopped for 1 hour. A saturated sodium bicarbonate solution (25 mL) was directly added, and extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 14b (264 mg). Purify and proceed directly to the next reaction.

Second step

(R) -3- (3,5difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9- Tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester 14c

Compound 10a (100mg, 257.44umol) was dissolved in N, N-dimethylformamide (8mL), and crude compound 14b (102.46mg, 386.17umol), cesium carbonate (209.70mg, 643.62umol), and sodium iodide ( 7.71 mg, 51.49 umol), and stirred at 75 ° C in an oil bath for 16 hours. A saturated sodium bicarbonate solution (20 mL) was added, extracted with ethyl acetate (50 mL × 2), washed with a saturated sodium chloride solution (50 mL × 4), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing system B to obtain the title product 14c (117 mg), yield: 87%. MS m / z (ESI): 558.3 [M + 1]

third step

(1R, 3R) -1- (2,6-fluoro-4-(((R) -pyrrolidin-3-yl) oxy) phenyl) -2- (2-fluoro-2-methylpropyl ) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole 14d

Compound 14c (117mg, 209.81umol) was dissolved in a dioxane solution (4N, 3mL) of hydrogen chloride, and the reaction was stirred for 2 hours. The reaction solution was neutralized by directly adding a saturated sodium bicarbonate solution (25 mL), and then extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title product 14d (60 mg), yield: 62%. Take the next step directly. MS m / z (ESI): 458.3 [M + 1]

the fourth step

(E) -4-((R) -3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl- 2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) pyrrolidin-1-yl) -N, N-dimethylbutyl- 2-enamide 14

Compound 14d (0.06g, 131.16umol) was dissolved in N, N-dimethylformamide (5mL), diisopropylethylamine (0.05g, 386.28umol), 1p (0.02g, 130.13umol) of N was added N-dimethylformamide (1 mL), and the reaction was stirred for 1 hour. A saturated sodium bicarbonate solution (20 mL) was added, extracted with ethyl acetate (50 mL × 2), washed with saturated sodium chloride (50 mL × 4), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing system A to obtain the title product 14 (15 mg), yield: 20%.

MS m / z (ESI): 569.3 [M + 1]

Chiral HPLC analysis: retention time 12.398 minutes, chiral purity: 97.5% (chromatographic column: OZ Phenomenex Lux Cellulose-2 150 * 4.6mm, 5um; mobile phase: ethanol / n-hexane = 20/80 (v / v)) .

¹ H NMR (400MHz, DMSO-d ₆ ) 10.53 (s, 1H), 7.40-7.38 (d, 1H), 7.19-7.17 (d, 1H), 7.00-6.97 (m, 1H), 6.96-6.93 (m , 1H), 6.63 (s, 1H), 6.60-6.55 (m, 3H), 5.12 (s, 1H), 4.92-4.85 (m, 1H), 3.52-3.45 (m, 1H), 3.23-3.20 (m , 2H), 3.02 (s, 3H), 2.86 (s, 3H), 2.84-2.81 (m, 1H), 2.80-2.72 (m, 2H), 2.66-2.64 (m, 1H), 2.43-2.36 (m , 1H), 2.35-2.31 (m, 2H), 2.30-2.26 (m, 1H), 1.78-1.74 (m, 2H), 1.21-1.15 (d, 3H), 1.14-1.08 (d, 3H), 1.04 -1.03 (d, 3H).

Example 15

(E) -4-((S) -3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl- 2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) piperidin-1-yl) -N, N-dimethylbutyl -2-enamide 15

first step

(S) -3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9 -Tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) piperidine-1-carboxylic acid tert-butyl ester 15a

Compound 10a (105mg, 0.27mmol), (3R) -3- (methylsulfonyloxy) piperidine-1-carboxylic acid tert-butyl ester (98mg, 0.35mmol, prepared by the method disclosed in patent application US2007135479A1) were suspended To toluene (8 mL), cesium carbonate (177 mg, 0.54 mmol) was added, the oil bath was heated to 80 ° C. and stirred for 48 hours, filtered and dried, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title product 15a (25 mg), yield: 17%.

MS m / z (ESI): 572.0 [M + 1]

Second step

(1R, 3R) -1- (2,6-difluoro-4-(((S) -piperidin-3-yl) oxy) phenyl) -2- (2-fluoro-2-methylpropane ) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole hydrochloride 15b

Compound 15a (25 mg, 0.043 mmol) was dissolved in dichloromethane (4 mL), and a solution of hydrogen chloride dioxane (4N, 0.21 mL) was added dropwise. Stir for 1.5 hours and spin dry to give the crude title compound 15b (22 mg). The product was used in the next reaction without purification.

MS m / z (ESI): 472.0 [M + 1]

third step

(E) -4-((S) -3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl- 2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) piperidin-1-yl) -N, N-dimethylbutyl- 2-enamide 15

The crude compound 15b (22 mg, 0.016 mmol) was dissolved in N, N-dimethylformamide (3 mL), and N, N-diisopropylethylamine (7 mg, 0.054 mmol) was added. Compound 1p (4 mg, 0.021) mmol), stirred at 40 ° C for 1.5 hours, and quenched by adding 10 mL of ice water. Extracted with ethyl acetate (15mL × 3), collected the organic layer, washed once with 10mL saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated, and prepared using high-performance liquid phase (Waters 2767-SQ Detecor2, elution system: NH ₄ HCO _3, water, acetonitrile) to give the title compound (8mg), yield of 15: 30%. MS m / z (ESI): 583.1 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 7.40 (d, 1H), 7.18 (d, 1H), 7.01-6.93 (m, 2H), 6.76- 6.70 (m, 1H), 6.60-6.52 (m, 3H), 5.18 (s, 1H), 4.45-4.40 (m, 1H), 3.69-3.65 (m, 1H), 3.23 (d, 2H), 3.11- 2.86 (m, 3H), 3.06 (s, 3H), 2.92 (s, 3H), 2.68-2.65 (m, 1H), 2.61-2.58 (m, 1H), 2.45-2.34 (m, 3H), 2.00- 1.96 (m, 1H), 1.89-1.82 (m, 1H), 1.69-1.52 (m, 2H), 1.20-1.09 (m, 9H).

Example 16

(E) -4-(((1S, 3R) -3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3- Methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) cyclopentyl) amino) -N, N-dimethyl But-2-enamide 16

Compound 12d (50 mg, 0.11 mmol) was dissolved in N, N-dimethylformamide (5 mL), and a solution of compound 1 p (14 mg, 0.07 mmol) in 1 mL of N, N-dimethylformamide was added, and the reaction was maintained at room temperature. At 1 hour, the reaction was monitored by LC-MS. The reaction solution was added dropwise to a 50 mL aqueous solution, and 50 mL of ethyl acetate was added for extraction. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the resulting residue was purified by thin layer chromatography with a developing system B to obtain the title compound. 16 (2 mg), yield: 4%. MS m / z (ESI): 583.4 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 7.40 (d, 1H), 7.18 (d, 1H), 7.03-6.93 (m, 2H), 6.78- 6.66 (m, 2H), 6.50 (s, 1H), 6.53 (s, 1H), 5.20 (s, 1H), 4.83 (m, 1H), 3.70-3.59 (m, 4H), 3.46-3.40 (m, 1H), 3.10 (s, 3H), 3.06-3.00 (m, 1H), 3.00-2.97 (m, 3H), 2.95-2.85 (m, 1H), 2.60 (dd, 1H), 2.54-2.46 (m, 1H), 2.45-2.35 (m, 1H), 2.21 (dt, 1H), 2.01 (d, 2H), 1.95 (s, 1H), 1.84-1.75 (m, 2H), 1.20 (d, 3H), 1.14 (d, 3H), 1.10 (d, 3H).

Example 17

N- (2- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9- Tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) acrylamide 17

first step

(2- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9-tetrahydro -1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) carbamic acid tert-butyl ester 17a

Compound 10a (100 mg, 0.26 mmol) was dissolved in 1.5 mL of a mixed solution of N, N-dimethylformamide and acetone (V: V = 1: 2), and (2-bromoethyl) carbamic acid tert-butyl was added Esters (69 mg, 0.31 mmol, Shuya), potassium carbonate (107 mg, 0.77 mmol), and the reaction was stirred at reflux for 17 hours. The reaction was monitored by LC-MS until the starting material disappeared and the reaction was stopped. The reaction was quenched with a saturated sodium chloride solution (20 mL), and water (100 mL) was added, followed by stirring for 10 minutes. The filtrate (100 mL x 2) was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing system B to obtain the title compound 17a (136 mg), yield: 99%. MS m / z (ESI): 532.2 [M + 1]

Second step

2- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9-tetrahydro- 1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl-1-amine 17b

Compound 17a (130 mg, 0.24 mmol) was dissolved in dichloromethane (2 mL), stirred for 10 minutes in an ice bath, and a 1,4-dioxane solution of hydrogen chloride (4N, 1.5 mL) was slowly added dropwise. The ice bath The reaction was stirred for 1 hour and then allowed to stir to room temperature for 1 hour. The reaction was monitored by LC-MS until the starting material disappeared and the reaction was stopped. The reaction solution was concentrated under reduced pressure, dichloromethane (50 mL) was added, and the reaction solution was adjusted to pH ~ 7 with a saturated sodium bicarbonate solution (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound 17b (100 mg), yield: 95%. MS m / z (ESI): 432.2 [M + 1]

third step

N- (2- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9- Tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) acrylamide 17

Compound 17b (50 mg, 0.12 mmol) was dissolved in tetrahydrofuran (5 mL), and diisopropylethylamine (49 mg, 0.38 mmol) was added at -60 ° C, followed by stirring for 10 minutes, and acrylic acid chloride (12 mg, 0.13 mmol) was added dropwise. After the addition was completed, the temperature was raised to -20 ° C and the reaction was stirred for 1 hour, and then the temperature was raised to room temperature and continued to be stirred. The reaction was monitored by LC-MS until the starting material disappeared and the reaction was stopped. Water (50 mL) was added and stirred for 10 minutes. The filtrate (50 mL x 2) was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the resulting residue was purified by thin layer chromatography to develop the solvent system B to obtain the title compound 17 (48 mg) Yield: 85%. MS m / z (ESI): 486.2 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 7.40 (d, 1H), 7.17 (d, 1H), 7.04-6.92 (m, 2H), 6.54 ( s, 1H), 6.57 (s, 1H), 6.33-6.20 (m, 2H), 5.67 (dd, 1H), 5.19 (s, 1H), 4.07 (t, 2H), 3.68 (m, 1H), 3.64 (t, 2H), 3.04 (dd, 1H), 2.96-2.84 (m, 1H), 2.59 (dd, 1H), 2.47-2.32 (m, 1H), 1.19 (d, 3H), 1.13 (d, 3H ), 1.10 (d, 3H).

Example 18

1- (3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9- Tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) azetidin-1-yl) prop-2-en-1-one 18

Compound 13c (50 mg, 0.11 mmol) was dissolved in tetrahydrofuran (5 mL). N, N-diisopropylethylamine (48 mg, 0.37 mmol) was added at -60 ° C, and the mixture was stirred for 10 minutes. Acryloyl chloride (12 mg, 0.13 mmol) was added dropwise. ). After the addition, the temperature was raised to -20 ° C and the reaction was stirred for 1 hour, and then the temperature was raised to room temperature. The reaction was monitored by LC-MS until the starting material disappeared and the reaction was stopped. Water (50 mL) was added and stirred for 10 minutes. Extracted with dichloromethane (50 mL x 2), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate, and the resulting residue was purified by thin layer chromatography using developing system B to give the title compound 18 (17 mg). Rate: 30%. MS m / z (ESI): 498.2 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 7.40 (d, 1H), 7.18 (d, 1H), 7.03-6.92 (m, 2H), 6.47 ( s, 1H), 6.49 (s, 1H), 6.41-6.22 (m, 2H), 5.76 (d, 1H), 5.21 (s, 1H), 5.11-5.03 (m, 1H), 4.76-4.67 (m, 1H), 4.47 (dt, 1H), 4.27 (dd, 1H), 4.01 (dd, 1H), 3.67 (m, 1H), 3.03 (d, 1H), 2.96-2.84 (m, 1H), 2.60 (dd , 1H), 2.48-2.33 (m, 1H), 1.20 (d, 3H), 1.14 (d, 3H), 1.10 (d, 3H).

Example 19

N- (3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3,4,9- Tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) propyl) acrylamide 19

Compound 10c (60 mg, 0.134 mmol) was dissolved in 6 mL of a mixed solution of tetrahydrofuran and N-methylpyrrolidone (V: V = 5: 1), and N, N-diisopropylethylamine (57.4 mg, 444.4umol), stirred for 10 minutes, and acryloyl chloride (14mg, 0.155mmol) was added dropwise. After the addition was completed, the temperature was raised to -20 ° C with stirring for 1 hour, and then the temperature was raised to room temperature. The reaction was monitored by LC-MS until the starting material disappeared and the reaction was stopped. Water (50 mL) was added and stirred for 10 minutes. Extracted with dichloromethane (50 mL x 2), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate. The resulting residue was purified by thin layer chromatography with developing system A to give the title compound 19 (10 mg). Rate: 10%. MS m / z (ESI): 500.2 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 7.40 (d, 1H), 7.18 (d, 1H), 7.03-6.92 (m, 2H), 6.51 ( s, 1H), 6.54 (s, 1H), 6.29-6.16 (m, 2H), 5.65 (dd, 1H), 5.19 (s, 1H), 4.02 (t, 2H), 3.68 (m, 1H), 3.43 (t, 2H), 3.09-2.99 (m, 1H), 2.96-2.85 (m, 1H), 2.64-2.55 (m, 1H), 2.47-2.33 (m, 1H), 2.00 (q, 2H), 1.19 (d, 3H), 1.14 (d, 3H), 1.10 (d, 3H).

Example 20

(E) -4-((S) -3- (3,5-difluoro-4-((6S, 8R) -7- (2-fluoro-2-methylpropyl) -8-methyl- 6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) pyrrolidin-1-yl) -N, N-dimethyl But-2-enamide 20

first step

(3S) -3- (3,5-difluoro-4-((6S, 8R) -7- (2-fluoro-2-methylpropyl) -8-methyl-3- (tetrahydro-2H -Pyran-2-yl) -6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) pyrrolidine-1-carboxylic acid Tert-butyl ester 20a

Compound 7a (100 mg, 0.19 mmol) and compound 14a (70 mg, 0.37 mmol) were suspended in toluene (5 mL), cesium carbonate (152 mg, 0.47 mmol), RockPhos Pd G3 (16 mg, 0.019 mmol) were added, and argon was substituted for 3 Next, the oil bath was heated to 90 ° C. and stirred for 3 hours, filtered and dried, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title product 20a (28 mg), yield: 23%. MS m / z (ESI): 643.1 [M + 1];

Second step

(6S, 8R) -6- (2,6-difluoro-4-(((S) -pyrrolidin-3-yl) oxy) phenyl) -7- (2-fluoro-2-methylpropane ) -8-methyl-6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinoline hydrochloride 20b

Compound 20a (28mg, 0.044mmol) was dissolved in dichloromethane (4mL), and a solution of hydrogen chloride dioxane (4N, 0.22mL) was added dropwise, stirred for 1.5 hours, and spin-dried to obtain the crude title compound 20b (22mg). The product It was used in the next reaction without purification. MS m / z (ESI): 459.0 [M + 1];

third step

(E) -4-((S) -3- (3,5-difluoro-4-((6S, 8R) -7- (2-fluoro-2-methylpropyl) -8-methyl- 6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) pyrrolidin-1-yl) -N, N-dimethyl But-2-enamide 20

The crude compound 20b (22 mg, 0.044 mmol) was dissolved in N, N-dimethylformamide (3 mL), and N, N-diisopropylethylamine (46 mg, 0.35 mmol) was added. Compound 1p (36 mg, 0.18 mmol), stirred for 1.5 hours, quenched by adding 10 mL of ice water, extracted with ethyl acetate (15 mL × 3), collected the organic layer, washed once with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by filtration to obtain a crude product. High performance liquid phase preparation (Waters 2767-SQ Detecor2, elution system: NH ₄ HCO ₃ , water, acetonitrile) gave the title compound 20 (8 mg), yield: 30%. MS m / z (ESI): 570.0 [M + 1]; ¹ H NMR (400MHz, DMSO-d ₆ ) 13.00 (s, 1H), 8.06 (s, 1H), 7.20 (d, 1H), 6.66 (d , 1H), 6.63-6.52 (m, 4H), 5.12 (s, 1H), 4.90-4.84 (m, 1H), 3.63-3.59 (m, 1H), 3.28-3.18 (m, 3H), 3.01 (s , 3H), 2.93-2.89 (m, 2H), 2.85 (s, 3H), 2.81-2.62 (m, 3H), 2.42-2.21 (m, 3H), 1.79-1.70 (m, 1H), 1.13 (t , 6H), 0.98 (d, 3H).

Example 21

(E) -4- (3- (3,5-difluoro-4-((6S, 8R) -7- (2-fluoro-2-methylpropyl) -8-methyl-6,7, 8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) azetidin-1-yl) -N, N-dimethylbutane -2-enamide 21

first step

3- (3,5-difluoro-4-((6S, 8R) -7- (2-fluoro-2-methylpropyl) -8-methyl-3- (tetrahydro-2H-pyran- 2-yl) -6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) azetidine-1-carboxylic acid tert Butyl 21a

Compound 7a (50 mg, 0.093 mmol), N-tert-butoxycarbonyl-3-hydroxyazetidine (33 mg, 0.19 mmol) was suspended in toluene (5 mL), and cesium carbonate (76 mg, 0.23 mmol) was added. RockPhos Pd G3 (8mg, 0.0095mmol), replaced with argon 3 times, heated to 95 ° C in an oil bath and stirred for 3 hours, filtered and spin-dried, and purified the obtained residue by silica gel column chromatography with eluent system B to give the title product 21a ( 50 mg), yield: 85%. MS m / z (ESI): 629.0 [M + 1].

Second step

(6S, 8R) -6- (4- (azetidin-3-yloxy) -2,6-difluorophenyl) -7- (2-fluoro-2-methylpropyl)- 8-methyl-6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinoline hydrochloride 21b

Compound 21a (62 mg, 0.098 mmol) was dissolved in dichloromethane (4 mL), and a dioxane solution (4N, 0.49 mL) of hydrogen chloride was added dropwise, followed by stirring for 1.5 hours. Spin-drying gave the crude title compound 21b (48 mg), which was used in the next reaction without purification. MS m / z (ESI): 445.0 [M + 1]

third step

(E) -4- (3- (3,5-difluoro-4-((6S, 8R) -7- (2-fluoro-2-methylpropyl) -8-methyl-6,7, 8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) azetidin-1-yl) -N, N-dimethylbutane -2-enamide 21

The crude compound 21b (48 mg, 0.098 mmol) was dissolved in N, N-dimethylformamide (3 mL), and N, N-diisopropylethylamine (52 mg, 0.40 mmol) was added. Compound 1p (29 mg, 0.15 mmol), stirred for 1.5 hours, quenched by adding 10 mL of ice water, extracted with ethyl acetate (15 mL × 3), collected the organic layer, washed once with 10 m saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by filtration. preparation phase (Waters 2767-SQ Detecor2, eluent system: NH ₄ HCO _3, water, acetonitrile) to give the title compound 21 (25mg), yield: 45%. MS m / z (ESI): 556.0 [M + 1]; ¹ H NMR (400MHz, DMSO-d ₆ ) 12.99 (s, 1H), 8.06 (s, 1H), 7.20 (d, 1H), 6.65 (d , 1H), 6.55-6.49 (m, 4H), 5.13 (s, 1H), 4.85-4.80 (m, 1H), 3.78-3.74 (m, 2H), 3.62-3.58 (m, 1H), 3.27-3.23 (m, 3H), 3.02 (s, 3H), 3.00-2.98 (m, 2H), 2.93-2.89 (m, 2H), 2.85 (s, 3H), 2.31-2.22 (m, 1H), 1.13 (t , 6H), 0.98 (d, 3H).

Example 22

1-((S) -3- (3,5-difluoro-4-((1R, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2,3, 4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) pyrrolidin-1-yl) but-2-yn-1-one 22

Compound 9d (109 mg, 0.24 mmol) was dissolved in N, N-dimethylformamide (5 mL), and 2-butynyl acid 22a (25 mg, 0.29 mmol) and diisopropylethylamine (166 mg, 1.29 mmol) were added. ), And then 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (73 mg, 0.38 mmol) and 1-hydroxybenzotriazole (58 mg, 0.38 mmol) were added. The reaction was stirred at room temperature for 3 hours. Water (50 mL) was added and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title product 22 (62 mg). Yield: 50%. MS m / z (ESI): 524.2 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 7.43-7.37 (dd, 1H), 7.18 (d, 1H), 7.03-6.93 (m, 2H), 6.61-6.53 (m, 2H), 5.20 (s, 1H), 5.05 (s, 1H), 3.93-3.85 (m, 1H), 3.71-3.62 (m, 3H), 3.54-3.45 (m, 1H), 3.03 (dd, 1H), 2.93 (d, 1H), 2.60 (dd, 1H), 2.48-2.34 (m, 1H), 2.28-2.18 (m, 2H), 2.04 (d, 3H), 1.23-1.12 ( m, 6H), 1.10 (d, 3H).

Example 23

(E) -4-((2- (3,5-difluoro-4-((1S, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-6- ( 1-methyl-1H-pyrazol-4-yl) -1,2,3,4-tetrahydroisoquinolin-1-yl) phenoxy) ethyl) amino) -N, N-dimethyl But-2-enamide 23

first step

(1S, 3R) -1- (4-bromo-2,6-difluorophenyl) -2- (2-fluoro-2-methylpropyl) -3-methyl-1,2,3,4 -Tetrahydroisoquinoline-6-phenol 23b

Compound 1 g (1.00 g, 4.44 mmol) was dissolved in toluene (10 mL), and 2,6-difluoro-4-bromobenzaldehyde 23a (1.18 g, 5.34 mmol) and acetic acid (2.13 g, 35.45 mmol) were added. After the addition was completed, the reaction was stirred in an oil bath at 85 ° C for 16 hours to stop the reaction. It was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with developing system B to obtain the title product 23b (1.35 g). Yield: 71%. MS m / z (ESI): 428.1 [M + 1];

Second step

(1S, 3R) -6- (benzyloxy) -1- (4-bromo-2,6-difluorophenyl) -2- (2-fluoro-2-methylpropyl) -3-methyl -1,2,3,4-tetrahydroisoquinoline 23d

Compound 23b (1.3 g, 3.0 mmol) was dissolved in acetone (20 mL), and benzyl bromide 23c (0.8 mg, 4.5 mmol) and potassium carbonate (1.3 g, 9.0 mmol) were added. The reaction was refluxed in an oil bath at 70 ° C for 3 hours to stop the reaction. It was filtered, washed with acetone (20 mL), and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained residue was purified by column chromatography with developing system B to obtain the title product 23d (1.0 g). Yield: 64%. MS m / z (ESI): 518.1 [M + 1];

third step

(2- (4-((1S, 3R) -6- (benzyloxy) -2- (2-fluoro-2-methylpropyl) -3-methyl-1,2,3,4-tetra Hydroisoquinolin-1-yl) -3,5-difluorophenoxy) ethyl) carbamic acid tert-butyl 23e

Compound 23d (500mg, 1.0mmol), compound 1m (310mg, 1.9mmol) and toluene (15mL) were added to the reaction bottle in sequence, protected by argon, and then [(2-di-tert-butylphosphino-3-methyl) Oxy-6-methyl-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl) -2- (2-aminobiphenyl)] palladium (II) methanesulfonic acid Methyl ester (80 mg, 0.09 mmol), cesium carbonate (785 mg, 2.4 mmol), argon was pumped 3 times, and the temperature was raised to 90 ° C and stirred for 3 hours. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with developing system B to obtain the title product 23e (480 mg). Yield: 83%. MS m / z (ESI): 599.3 [M + 1];

the fourth step

(2- (3,5-difluoro-4-((1S, 3R) -2- (2-fluoro-2-methylpropyl) -6-hydroxy-3-methyl-1,2,3, 4-tetrahydroisoquinolin-1-yl) phenoxy) ethyl) carbamic acid tert-butyl 23f

Compound 23e (500 mg, 0.8 mmol) was dissolved in methanol (15 mL), 20% palladium hydroxide carbon (58 mg, 0.08 umol) was added, and hydrogen was substituted 3 times. The reaction was hydrogenated at 30 ° C for 4 hours to stop the reaction. Filtration and spin-drying gave compound 23f (400 mg), yield: 94%. Used directly in the next reaction. MS m / z (ESI): 509.3 [M + 1];

the fifth step

(1S, 3R) -1- (4- (2-((tert-butoxycarbonyl) amino) ethoxy) -2,6-difluorophenyl) -2- (2-fluoro-2-methylpropane (Methyl) -3-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl trifluoromethanesulfonate 23g

Compound 23f (450 mg, 0.9 mmol) was dissolved in dichloromethane (20 mL), and 4-dimethylaminopyridine (10 mg, 0.08 umol), triethylamine (180 mg, 1.8 mmol) were added under an ice bath, and then N-benzene was added. Bis (trifluoromethanesulfonic acid imine) (506 mg, 1.4 mmol), reacted at room temperature overnight, and concentrated under reduced pressure to obtain a crude product. The obtained residue was purified by column chromatography with developing system B to obtain the title product 23 g (566 mg), yield: 100%.

Step Six

(2- (3,5-difluoro-4-((1S, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-6- (1-methyl-1H- Pyrazole-4-yl) -1,2,3,4-tetrahydroisoquinolin-1-yl) phenoxy) ethyl) carbamic acid tert-butyl ester 23i

Compound 23g (140mg, 0.2mmol), 1-methylpyrazole-4-boronic acid pinacol ester 23h (90mg, 0.4mmol, using the well-known method "Organic Process Research & Development, 2010, 14 (4), 849-858 "Prepared" and 1,4-dioxane (6 mL), water (1.5 mL) were added to the reaction flask, and then 1,1'-bisdiphenylphosphine ferrocene dichloride palladium (15 mg, 0.02 mmol), anhydrous sodium carbonate (54 mg, 0.5 mmol), protected by argon replacement three times, and heated to 90 ° C. and stirred for 4 hours. The reaction was cooled to room temperature, 20 mL of water was added, and extracted with ethyl acetate (15 mL × 3). The organic layer was washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The resulting residue was purified by column chromatography with developing system B to give the title product 23i (108 mg), yield: 86%. MS m / z (ESI): 573.3 [M + 1];

Step Seven

2- (3,5-difluoro-4-((1S, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-6- (1-methyl-1H-pyridine Azole-4-yl) -1,2,3,4-tetrahydroisoquinolin-1-yl) phenoxy) ethane-1-amine 23j

Compound 23i (105mg, 0.2mmol) was dissolved in dichloromethane (4mL), and a solution of hydrogen chloride in dioxane (5M, 0.4mL) was added dropwise at room temperature, stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain crude 23j. Yield : 99%. Used directly in the next reaction.

Step eight

(E) -4-((2- (3,5-difluoro-4-((1S, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-6- ( 1-methyl-1H-pyrazol-4-yl) -1,2,3,4-tetrahydroisoquinolin-1-yl) phenoxy) ethyl) amino) -N, N-dimethyl But-2-enamide 23

Compound 1p (84mg, 0.2umol) was dissolved in N, N-dimethylformamide (4mL), diisopropylethylamine (46mg, 0.4umol) was added at room temperature, and then compound 23j (84mg, 0.2umol) was added. And stirred at room temperature for 1.5 hours. 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layer was washed with a saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and filtered to obtain a crude product. The obtained residue was purified by thin layer chromatography with developing system A to give the title product 23 (32 mg), yield: 31%. MS m / z (ESI): 584.3 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 7.87 (s, 1H), 7.75 (s, 1H), 7.28 (s, 1H), 7.18 (d, 1H), 6.76 (t, 1H), 6.68 (d, 2H), 6.57 (d, 2H), 5.10 (s, 1H), 4.13 (t, 2H), 3.90 (s, 3H), 3.72-3.60 (m , 1H), 3.59 (d, 2H), 3.40-3.30 (m, 1H), 3.20-3.05 (m, 5H), 3.00-2.85 (m, 4H), 2.60 (dd, 1H), 2.25 (dd, 1H ), 1.14 (d, 3H), 1.07 (d, 3H), 0.98 (d, 3H).

Example 24

(E) -4-((2- (4-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methylpropane Yl) -3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) -3,5-difluorophenoxy) ethyl) amino) -N, N-dimethyl But-2-enamide 24

first step

4-((tert-butyldiphenylsilyl) oxy) -2,6-difluorobenzaldehyde 24b

Compound 24a (2g, 12.7mmol) was dissolved in dichloromethane (50mL), and imidazole (2.2g, 31.6mmol) was added at 0 ° C. The reaction was stirred at room temperature for 1 hour, and then tert-butyldiphenylchlorosilane (3.8 g, 13.9 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction was washed with a saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate. The resulting residue was purified by column chromatography with developing system B to give the title product 24b (3.4 g), yield: 68%.

Second step

(1S, 3R) -1- (4-((tert-butyldiphenylsilyl) oxy) -2,6-difluorophenyl) -2- (2-fluoro-2-methylpropyl) -3-methyl-1,2,3,4-tetrahydroisoquinoline-6-phenol 24c

Compound 1 g (1.1 g, 4.9 mmol) was dissolved in toluene (20 mL), compound 24b (2.3 g, 5.9 mmol) was added, and acetic acid (1.5 g, 24.4 mmol) was added. After the addition was complete, the reaction was stirred overnight in an oil bath at 85 ° C. Cool the reaction to room temperature, add ethyl acetate (50 mL), adjust the pH to 7-8 with saturated sodium bicarbonate solution, separate the aqueous phase, extract with ethyl acetate (20 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate The filtrate was purified by column chromatography using developing system B to obtain the title product 24c (1.0 g). Yield: 34%.

third step

(1S, 3R) -1- (4-((tert-butyldiphenylsilyl) oxy) -2,6-difluorophenyl) -2- (2-fluoro-2-methylpropyl) -3-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl trifluoromethanesulfonate 24d

Compound 24c (1 g, 1.7 mmol) was dissolved in dichloromethane (15 mL), and 4-dimethylaminopyridine (20 mg, 0.2 mmol) and triethylamine (335 mg, 3.3 mmol) were added under an ice bath, followed by N-benzene Bis (trifluoromethanesulfonic acid imine) (1.1 g, 3.0 mmol), stirred overnight at room temperature, and concentrated under reduced pressure to give the crude title compound 24d (1.2 g), yield: 98%.

the fourth step

(1S, 3R) -1- (4-((tert-butyldiphenylsilyl) oxy) -2,6-difluorophenyl) -6- (1-ethyl-1H-pyrazole-4 -Yl) -2- (2-fluoro-2-methylpropyl) -3-methyl-1,2,3,4-tetrahydroisoquinoline 24e

Add compound 24d (1.2g, 1.6mmol), compound 1k (90mg, 0.4mmol) and 1,4-dioxane (8mL), water (2mL) to the reaction flask and then add 1,1'-bisdiphenyl Phosphonoferrocene palladium dichloride (119 mg, 0.2 mmol), anhydrous sodium carbonate (432 mg, 4.1 mmol), replaced with argon three times, and heated to 90 ° C. and stirred for 5 hours. 20 mL of water was added, extracted with ethyl acetate (15 mL × 3), and the organic layer was washed with a saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, and concentrated by filtration. The obtained residue was purified by column chromatography with developing system B to obtain the title product 24e (1.1 g), yield: 99%.

the fifth step

4-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methylpropyl) -3-methyl-1,2 , 3,4-tetrahydroisoquinolin-1-yl) -3,5-difluorophenol 24f

Compound 24e (1.1 g, 1.6 mmol) was dissolved in methanol (10 mL). Dilute hydrochloric acid (2M, 1 mL) was added under an ice bath, and the mixture was stirred at room temperature for 16 hours. Dilute hydrochloric acid (2M, 1.5 mL) was added and stirred at 45 ° C for 3 hours. 15 mL of water was added to the reaction, and the mixture was extracted with ethyl acetate (15 mL × 3), washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified by column chromatography with a developing agent system B to obtain the title. Product 24f (0.71 g), yield: 99%. MS m / z (ESI): 444.2 [M + 1];

Step Six

(2- (4-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methylpropyl) -3-methyl -1,2,3,4-tetrahydroisoquinolin-1-yl) -3,5-difluorophenoxy) ethyl) carbamic acid tert-butyl ester 24h

Compound 24g (98mg, 0.4mmol) was dissolved in N, N-dimethylformamide (5mL), cesium carbonate (177mg, 0.5mmol) was added, compound 24f (120mg, 0.3mmol) was added, and the reaction was stirred at 70 ° C in an oil bath 2 hour. Added 15 mL of water, extracted with ethyl acetate (15 mL × 3), washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, and concentrated by filtration. The resulting residue was purified by column chromatography with developing system A to give the title product for 24 h (140 mg), yield: 88%. MS m / z (ESI): 587.2 [M + 1];

Step Seven

2- (4-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methylpropyl) -3-methyl- 1,2,3,4-tetrahydroisoquinolin-1-yl) -3,5-difluorophenoxy) ethane-1-amine 24i

Compound 24h (140mg, 0.2mmol) was dissolved in dichloromethane (3mL), and a solution of hydrogen chloride in dioxane (5M, 0.5mL) was added dropwise under an ice bath. After the dropwise addition, the mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain The title compound 24i (125 mg), yield: 100%. Used directly in the next reaction.

Step eight

(E) -4-((2- (4-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methylpropane Yl) -3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) -3,5-difluorophenoxy) ethyl) amino) -N, N-dimethyl But-2-enamide 24

Compound 24i (125 mg, 0.2 mmol) was dissolved in N, N-dimethylformamide (4 mL), and diisopropylethylamine (155 mg, 1.2 mmol) was added at room temperature, followed by compound 1p (30 mg, 0.2 mmol). Stir at 30 ° C overnight. 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layer was washed with a saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and filtered to obtain a crude product. The obtained residue was purified by thin layer chromatography with developing system A to obtain the title product 24 (29 mg), yield: 20%. MS m / z (ESI): 598.2 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 7.93 (s, 1H), 7.77 (s, 1H), 7.28 (s, 1H), 7.18 (d, 1H), 6.78 (t, 1H), 6.67 (d, 1H), 6.63 (d, 1H), 6.56 (t, 2H), 5.10 (s, 1H), 4.20 (t, 2H), 4.08 (t, 2H) ), 3.72-3.62 (m, 1H), 3.49 (d, 2H), 3.40-3.30 (m, 1H), 3.13 (s, 3H), 3.03-3.00 (m, 2H), 2.98 (s, 3H), 2.97-2.88 (m, 1H), 2.62 (dd, 1H), 2.25 (dd, 1H), 1.30 (t, 3H), 1.14 (d, 3H), 1.09 (d, 3H), 1.00 (d, 3H) .

Example 25

(E) -4-((2- (3,5-difluoro-4-((1S, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-6- ( 1-methyl-1H-pyrazol-4-yl) -1,2,3,4-tetrahydroisoquinolin-1-yl) phenoxy) ethyl) amino) -1-morpholinylbutyl- 2-en-1-one 25

first step

(E) -4-bromo-1-morpholinylbut-2-en-1-one 25c

Compound 25a (500 mg, 3.0 mmol) was dissolved in dichloromethane (30 mL), and 2- (7-benzobenzotriazole) -N, N, N ', N'-tetramethylurea was added under cooling in an ice water bath. Hexafluorophosphate (856 mg, 3.6 mmol) and triethylamine (368 mg, 3.6 mmol). Morphine (314 mg, 3.6 mmol) was slowly added dropwise. After the dropwise addition was completed, the ice-water bath was kept in the cooled state for 1 hour, and then the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into ice water, and extracted with dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography with developing system B to obtain the title product 25c (271 mg), yield: 38%.

Second step

(E) -4-((2- (3,5-difluoro-4-((1S, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-6- ( 1-methyl-1H-pyrazol-4-yl) -1,2,3,4-tetrahydroisoquinolin-1-yl) phenoxy) ethyl) amino) -1-morpholinylbutyl- 2-en-1-one 25

Compound 25c (303 mg, 1.3 mmol) was dissolved in N, N-dimethylformamide (8 mL), and diisopropylethylamine (393 mg, 3.0 mmol) was added at room temperature, followed by compound 23j (720 mg, 1.5 mmol). And stirred at room temperature for 1.5 hours. Water (15 mL) was added, and ethyl acetate was extracted (20 mL × 3). The organic layer was washed with a saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated by filtration to obtain a crude product. The resulting residue was purified by thin layer chromatography with developing system A to give the title product 25 (230 mg), yield: 24%. MS m / z (ESI): 626.1 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 7.88 (s, 1H), 7.76 (s, 1H), 7.28 (s, 1H), 7.18 (d, 1H), 6.90-6.74 (dt, 1H), 6.70-6.59 (m, 2H), 6.56 (d, 2H), 5.10 (s, 1H), 4.11 (t, 2H), 3.90 (s, 3H), 3.74 -3.60 (m, 9H), 3.55 (d, 2H), 3.40-3.30 (m, 1H), 3.06 (t, 2H), 2.94 (t, 1H), 2.61 (dd, 1H), 2.30 (dd, 1H) ), 1.14 (d, 3H), 1.09 (d, 3H), 1.00 (d, 3H).

Example 26

(E) -4-((1-((4-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methyl (Propyl) -3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) -3,5-difluorophenoxy) methyl) cyclopropyl) amino) -1- Morpholinobut-2-en-1-one 26

first step

(1-((4-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methylpropyl) -3-form -1,2,3,4-tetrahydroisoquinolin-1-yl) -3,5-difluorophenoxy) methyl) cyclopropyl) carbamic acid tert-butyl 26b

Compound 24f (230 mg, 0.5 mmol) was dissolved in N, N-dimethylformamide (3 mL), and compound 26a (155 mg, 0.6 mmol) was added. The well-known method "Bioorganic & Medical Chemistry Letters, 2008, 18 (6), 2188 -2193 "), potassium carbonate (215 mg, 1.6 mmol), and the reaction was stirred at 70 ° C under reflux for 24 hours. The reaction was quenched with a saturated sodium chloride solution (20 mL), and water (100 mL) was added, followed by stirring for 10 minutes. The filtrate (100 mL × 2) was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography with developing system B to give the title product 26b (230 mg), yield: 72%. MS m / z (ESI): 613.4 [M + 1];

Second step

1-((4-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methylpropyl) -3-methyl -1,2,3,4-tetrahydroisoquinolin-1-yl) -3,5-difluorophenoxy) methyl) cyclopropane-1-amine 26c

Compound 26b (230 mg, 0.4 mmol) was dissolved in dichloromethane (8 mL), and a solution of hydrogen chloride in dioxane (5 M, 0.5 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 2 hours. Yield: 94%. Used directly in the next reaction.

third step

(E) -4-((1-((4-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methyl (Propyl) -3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) -3,5-difluorophenoxy) methyl) cyclopropyl) amino) -1- Morpholinobut-2-en-1-one 26

Compound 25c (26mg, 0.1umol) was dissolved in N, N-dimethylformamide (3mL), diisopropylethylamine (68mg, 0.5mmol) was added at room temperature, and then compound 26c (90mg, 0.2umol) was added. And stirred at room temperature for 1.5 hours. Water (15 mL) was added, and ethyl acetate was extracted (20 mL × 3). The organic layer was washed with a saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated by filtration to obtain a crude product. The resulting residue was purified by thin layer chromatography with developing system A to give the title product 26 (52 mg), yield: 38%. MS m / z (ESI): 666.4 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.05 (s, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.45 (d, 1H), 7.02 (d, 1H), 6.87 (d, 1H), 6.83-6.72 (m, 2H), 6.71-6.60 (m, 1H), 6.08 (s, 1H), 4.29 (s, 2H), 4.22 (q, 2H), 4.12-4.08 (m, 1H), 4.07 (d, 2H), 3.72-3.58 (m, 9H), 3.42-3.34 (m, 1H), 3.25-3.08 (m, 2H), 1.75 -1.45 (m, 12H), 1.29 (t, 2H), 1.16 (t, 2H).

Example 27

(E) -4-((2- (3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7 , 8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethyl) amino) -1-morpholinylbut-2-ene-1 -Ketone 27

first step

(6S, 8R) -6- (4-bromo-2,6-difluorophenyl) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7,8,9 -Tetrahydro-3H-pyrazolo [4,3-f] isoquinoline 27b

Compound 27a (5.7 g, 22.2 mmol, prepared by the method disclosed in Example 49 of page 160 of the specification in Patent Application WO2017182493) was dissolved in toluene (80 mL), and compound 23a (9.8 g, 44.3 mmol) was added, and trifluoroacetic acid was added. (6 mL), the reaction was stirred in an oil bath at 95 ° C for 48 hours, raised to 110 ° C and continued to stir for 12 hours. The reaction was cooled, saturated sodium bicarbonate solution (50 mL) was added, and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography with developing system B to give the title product 27b (8.0 g), yield: 78%. MS m / z (ESI): 460.1 [M + 1];

Second step

(6S, 8R) -6- (4-bromo-2,6-difluorophenyl) -8-methyl-3- (tetrahydro-2H-pyran-2-yl) -7- (2,2 , 2-trifluoroethyl) -6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinoline 27c

Compound 27b (8.0 g, 17.4 mmol) was dissolved in dichloromethane (50 mL), and dihydropyran (7.3 g, 86.9 mmol) and p-toluenesulfonic acid (165 mg, 0.9 mmol) were added. The reaction was stirred at room temperature for 48 hours. The reaction was terminated, the reaction solution was concentrated, a saturated sodium bicarbonate solution (100 mL) was added, and extracted with dichloromethane (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography with developing system B to give the title product 27c (7.8 g), yield: 82%.

third step

(2- (3,5-difluoro-4-((6S, 8R) -8-methyl-3- (tetrahydro-2H-pyran-2-yl) -7- (2,2,2- Trifluoroethyl) -6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethyl) carbamic acid tert-butyl ester 27d

Compound 27c (500 mg, 0.9 mmol) was dissolved in toluene (8 mL), and then compound 1 m (444 mg, 2.8 mmol) was added, [(2-di-tert-butylphosphino-3-methoxy-6-methyl- 2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl) -2- (2-aminobiphenyl)] palladium (II) methyl methanesulfonate (54mg, 0.06mmol) , Cesium carbonate (746 mg, 2.3 mmol), replaced with argon three times. The reaction was then stirred at 80 ° C in an oil bath for 17 hours. The reaction was cooled, the reaction solution was concentrated, a saturated sodium bicarbonate solution (15 mL) was added, and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography with developing system B to give the title product 27d (496 mg), yield: 86%. MS m / z (ESI): 625.3 [M + 1];

the fourth step

2- (3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7,8,9-tetrahydro- 3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethane-1-amine 27e

Compound 27d (496mg, 0.8mmol) was dissolved in methanol (3mL), and a 1,4-dioxane solution of hydrogen chloride (5M, 2.0mL) was slowly added dropwise under cooling in an ice-water bath, and the reaction was stirred for 0.5 hours under ice-bath, and room temperature The reaction took 18 hours. A saturated sodium bicarbonate solution (15 mL) was added and extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 27e (349 mg). Yield: 100%.

the fifth step

(E) -4-((2- (3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7 , 8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethyl) amino) -1-morpholinylbut-2-ene-1 -Ketone 27

Compound 27e (350 mg, 0.8 mmol) was dissolved in N, N-dimethylformamide (5 mL), diisopropylethylamine (308 mg, 2.4 mmol) and compound 25c (186 mg, 0.8 mmol) were added. The reaction was stirred at room temperature for 1 hour. The resulting residue was purified by thin-layer chromatography with developing system A to give the title product 27 (150 mg), yield: 32%. MS m / z (ESI): 594.2 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.07 (s, 1H), 7.23 (d, 1H), 6.88-6.75 (m, 2H), 6.69 ( d, 1H), 6.59 (d, 2H), 5.35 (s, 1H), 4.15 (t, 2H), 3.70-3.55 (m, 9H), 3.45-3.32 (m, 2H), 3.23-3.10 (m, 2H), 3.05-2.86 (m, 2H), 1.95 (s, 2H), 1.12 (s, 3H).

Example 28

(E) -4-((2- (3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7 , 8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethyl) amino) -1- (pyrrolidin-1-yl) but- 2-en-1-one 28

first step

(E) -4-bromo-1- (pyrrolidin-1-yl) but-2-en-1-one 28b

Compound 25a (500 mg, 3.0 mmol) was dissolved in dichloromethane (30 mL), and 2- (7-benzobenzotriazole) -N, N, N ', N'-tetramethylurea was added under cooling in an ice water bath. Hexafluorophosphate (855 mg, 3.6 mmol) and triethylamine (368 mg, 3.6 mmol). Tetrahydropyrrole 28a (226 mg, 3.2 mmol) was slowly added dropwise. After the dropwise addition was completed, the reaction was continued in an ice bath for 1 hour and at room temperature for 12 hours. The reaction solution was poured into ice water, and extracted with dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography with developing system B to give the title product 28b (300 mg), yield: 45%.

Second step

(E) -4-((2- (3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7 , 8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethyl) amino) -1- (pyrrolidin-1-yl) but- 2-en-1-one 28

Compound 27e (105 mg, 0.2 mmol) was dissolved in N, N-dimethylformamide (3.5 mL), diisopropylethylamine (92 mg, 0.7 mmol) was added, and compound 28b (36 mg, 0.2 mmol) was added. The reaction was stirred at room temperature for 1 hour. The obtained residue was purified by thin layer chromatography with developing system A to give the title product 28 (40 mg), yield: 29%. MS m / z (ESI): 578.2 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.07 (s, 1H), 7.23 (d, 1H), 6.90-6.75 (m, 2H), 6.69- 6.45 (m, 3H), 5.35 (s, 1H), 4.25-4.06 (m, 2H), 3.70-3.52 (m, 5H), 3.47 (t, 2H), 3.45-3.27 (m, 2H), 3.14 ( s, 2H), 3.05-2.85 (m, 2H), 2.05-1.80 (m, 4H), 1.24 (d, 3H).

Example 29

(E) -4-((1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6, 7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclopropyl) amino) -1- (pyrroline-1 -Yl) but-2-en-1-one 29

first step

3,5-difluoro-4-((6S, 8R) -8-methyl-3- (tetrahydro-2H-pyran-2-yl) -7- (2,2,2-trifluoroethyl ) -6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenol 29b

Compound 27c (1.5 g, 2.8 mmol) was dissolved in N, N-dimethylformamide (10 mL), benzaldehyde oxime 29a (0.5 g, 4.0 mmol), [(2-di-tert-butylphosphino- 3-methoxy-6-methyl-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl) -2- (2-aminobiphenyl)] palladium (II) Methane mesylate (115 mg, 0.1 mmol), cesium carbonate (2.2 g, 6.9 mmol). Argon was replaced three times, and the reaction was stirred in an oil bath at 90 ° C-95 ° C for 16 hours. Cool the reaction, concentrate the reaction solution, add saturated sodium bicarbonate solution (50 mL), extract with ethyl acetate (50 mL × 3), wash with saturated sodium chloride solution (50 mL × 3), combine the organic phases, and dry over anhydrous sodium sulfate, It was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography with developing system B to obtain the title product 29b (1.30 g), yield: 98%. MS m / z (ESI): 482.2 [M + 1];

Second step

(1-((3,5-difluoro-4-((6S, 8R) -8-methyl-3- (tetrahydro-2H-pyran-2-yl) -7- (2,2,2 -Trifluoroethyl) -6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclopropyl) amino Tert-butyl formate 29c

Compound 29b (250 mg, 0.5 mmol) was dissolved in 15 mL of a mixed solvent of acetone and N, N-dimethylformamide (V: V = 2: 1), and compound 26a (207 mg, 0.8 mmol) and potassium carbonate (214 mg) were added. , 1.56 mmol), and the reaction was stirred in an oil bath at 70 ° C for 72 hours. Cool the reaction, add saturated sodium bicarbonate solution (30mL), extract with ethyl acetate (50mL × 2), wash with saturated sodium chloride solution (50mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and reduce the filtrate. Pressure concentrated. The obtained residue was purified by column chromatography with developing system B to give the title product 29c (0.250 g), yield: 74%. MS m / z (ESI): 651.3 [M + 1];

third step

1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7,8,9-tetrahydro -3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclopropane-1-amine 29d

Compound 29c (250 mg, 0.4 mmol) was dissolved in 1,4-dioxane (5 mL), and concentrated sulfuric acid (376 mg, 3.8 mmol) was added under ice-water bath cooling. The reaction was naturally warmed to room temperature and stirred for 16 hours. Cool the reaction, concentrate the reaction solution, add saturated sodium bicarbonate solution (25 mL), extract with ethyl acetate (50 mL x 2), wash with saturated sodium chloride solution (50 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, The filtrate was concentrated under reduced pressure to obtain the target product crude product 29d (179 mg). Yield: 100%, which was directly used in the next reaction.

the fourth step

(E) -4-((1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6, 7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclopropyl) amino) -1- (pyrrolidine-1 -Yl) but-2-en-1-one 29

Compound 29d (80 mg, 0.2 mmol) was dissolved in N, N-dimethylformamide (5 mL), and diisopropylethylamine (66 mg, 0.5 mmol) and compound 28b (33 mg, 0.2 mmol) were added. The reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated, a saturated sodium bicarbonate solution (25 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography with developing system A to give the title product 29 (31 mg), yield: 30%. MS m / z (ESI): 604.3 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.09 (s, 1H), 7.25 (d, 1H), 6.94-6.82 (m, 1H), 6.79 ( d, 1H), 6.57 (d, 2H), 6.43 (d, 1H), 5.36 (s, 1H), 3.97 (s, 2H), 3.70-3.61 (m, 1H), 3.60-3.50 (m, 4H) , 3.45 (t, 3H), 3.40-3.33 (m, 1H), 3.10-2.90 (m, 2H), 2.05-1.80 (m, 4H), 1.14 (d, 3H), 0.78 (t, 2H), 0.70 (t, 2H):

Example 30

(E) -4-((1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6, 7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclopropyl) amino) -1-morpholinylbutan- 2-en-1-one 30

Using the synthetic route of Example 29, and replacing the starting material 28b with 25c in the fourth step, the title compound 30 (25 mg) was obtained with a yield of 27%. MS m / z (ESI): 620.3 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.06 (s, 1H), 7.23 (d, 1H), 6.88-6.72 (m, 2H), 6.60- 6.48 (m, 3H), 5.34 (s, 1H), 3.94 (s, 2H), 3.70-3.52 (m, 11H), 3.48-3.36 (m, 2H), 3.08-2.92 (m, 2H), 1.13 ( d, 3H), 0.76 (t, 2H), 0.69 (t, 2H).

Example 31

(E) -4-((1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6, 7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclohexyl) amino) -1-morpholinylbut-2 -En-1-one 31

first step

1-((3,5-difluoro-4-((6S, 8R) -8-methyl-3- (tetrahydro-2H-pyran-2-yl) -7- (2,2,2- Trifluoroethyl) -6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclohexane-1- Methyl formate 31b

Compound 29b (500 mg, 1.0 mmol) was dissolved in N, N-dimethylformamide (5 mL), and cesium carbonate (677 mg, 2.1 mmol), methyl 1- (iodomethyl) cyclohexylcarboxylate 31a (439 mg, 1.6 mmol, prepared by a known method "Bioorganic & Medical Chemistry, 2010, 18 (5), 1854-1865"), and the reaction was stirred at 60 ° C for 18 hours. The reaction was cooled, water (50 mL) was added, and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography with developing system B to give the title product 31b (421 mg), yield: 64%. MS m / z (ESI): 636.3 [M + 1];

Second step

1-((3,5-difluoro-4-((6S, 8R) -8-methyl-3- (tetrahydro-2H-pyran-2-yl) -7- (2,2,2- Trifluoroethyl) -6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclohexane-1- Formic acid 31c

Compound 31b (421 mg, 0.7 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL), lithium hydroxide monohydrate (167 mg, 4.0 mmol) was added, and the reaction was stirred at 60 ° C. for 18 hours. Cool to room temperature, adjust the pH to 3-4 with 10% citric acid solution, add ethyl acetate (100mL) and water (100mL), extract with ethyl acetate (100mL × 2), combine the organic phases, anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure to give the title compound 31c (410 mg) in 100% yield. Used directly in the next reaction.

third step

(6S, 8R) -6- (2,6-difluoro-4-((1-isocyanoxycyclohexyl) methoxy) phenyl) -8-methyl-3- (tetrahydro-2H- Pyran-2-yl) -7- (2,2,2-trifluoroethyl) -6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinoline 31d

Compound 31c (410 mg, 0.7 mmol) was dissolved in toluene (5 mL), and triethylamine (87 mg, 0.9 mmol) and diphenyl azide phosphate (200 mg, 0.7 mmol) were added and protected by argon. The reaction was stirred in a 90 ° C oil bath for 17 hours. The reaction was cooled, ethyl acetate (100 mL) and water (100 mL) were added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography with developing system B to obtain the title product 31d (281 mg), yield: 69%.

the fourth step

1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7,8,9-tetrahydro -3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclohexane-1-amine 31e

Compound 31d (281 mg, 0.5 mmol) was dissolved in tetrahydrofuran (5 mL), concentrated hydrochloric acid (0.5 mL) was added under an ice bath, and the reaction was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (200 mL) was added, and the reaction solution was adjusted to pH about 7 with a saturated sodium bicarbonate solution (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 31e (230 mg), yield 100%. MS m / z (ESI): 509.3 [M + 1];

the fifth step

(E) -4-((1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6, 7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclohexyl) amino) -1-morpholinylbut-2 -En-1-one 31

Compound 25c (26mg, 0.1mmol) was dissolved in N, N-dimethylformamide (3mL), and diisopropylethylamine (61mg, 0.5mmol) was added at room temperature, followed by compound 31e (115mg, 0.2umol). And stirred at room temperature overnight. The obtained residue was purified by thin layer chromatography with developing system A to give the title product 31 (17 mg), yield: 16%. MS m / z (ESI): 662.3 [M + 1]; ¹ H NMR (400MHz, CDCl ₃ ) 8.08 (s, 1H), 7.20 (d, 1H), 7.00-6.88 (m, 1H), 6.83 (d , 1H), 6.46 (d, 1H), 6.40 (d, 2H), 5.34 (s, 1H), 3.75 (s, 2H), 3.68 (s, 7H), 3.59-3.40 (m, 3H), 3.34 ( d, 2H), 3.30-3.16 (m, 1H), 3.05-2.86 (m, 2H), 1.72-1.57 (m, 4H), 1.56-1.20 (m, 7H), 1.13 (d, 3H).

Example 32

(E) -4-((1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6, 7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclopentyl) amino) -N, N-dimethyl But-2-enamide 32

first step

3-oxa-2-thia-1-azaspiro [4.4] nonane-1-carboxylic acid tert-butyl 2-oxide 32b

Imidazole (1.7g, 24.4mmol) was dissolved in dichloromethane (60mL), and the reaction was cooled to -70 ° C. Triethylamine (1.4g, 13.7mmol) and sulfoxide (0.8g, 6.9mmol) were added and the reaction After stirring for 1 hour, the raw material (1- (hydroxymethyl) cyclopentyl) carbamic acid tert-butyl 32a (1.3 g, 6.0 mmol) was added at -70 ° C, using a well-known method "Bioorganic & Medical Chemistry, Letters, 2009, 19 (4) , 1110-1114 "prepared in) methylene chloride (20 mL) solution. After 30 minutes, the reaction was warmed to room temperature and stirred overnight. Under ice-cooling, water (15 mL) was added to quench the reaction, and the layers were allowed to stand. The organic phase was washed with water (30 mL), saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound. 32b (1.6 g), 99% yield, used directly in the next reaction.

Second step

3-oxa-2-thia-1-azaspiro [4.4] nonane-1-carboxylic acid tert-butyl 2,2-dioxide 32c

Compound 32b (1.6 g, 6.0 mmol) was dissolved in water (12 mL) and acetonitrile (24 mL), and ruthenium trichloride trihydrate (4 mg, 0.02 mmol) and sodium periodate (1.5 g, 6.8) were added under ice-cooling. mmol). The reaction was carried out in an ice bath for 0.5 hours and at room temperature overnight. Cool the reaction, add water (50 mL), extract with ethyl acetate (50 mL x 3), combine the organic phases, wash with water (50 mL), wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce the pressure of the filtrate Concentrated to give the crude product. The obtained residue was purified by column chromatography with developing system B to obtain the title product 32c (1.4 g), yield: 85%.

third step

(1-((3,5-difluoro-4-((6S, 8R) -8-methyl-3- (tetrahydro-2H-pyran-2-yl) -7- (2,2,2 -Trifluoroethyl) -6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclopentyl) amino Tert-butyl formate 32d

Compound 29b (190 mg, 0.4 mmol) was dissolved in N, N-dimethylformamide (10 mL), compound 32c (328 mg, 1.2 mmol) and cesium carbonate (386 mg, 1.2 mmol) were added, and the reaction was stirred in an oil bath at 130 ° C 3 hours. Cool the reaction, concentrate the reaction solution, add saturated sodium bicarbonate solution (25 mL), extract with ethyl acetate (50 mL x 2), combine the organic phases, wash with saturated sodium chloride solution (50 mL x 3), and dry over anhydrous sodium sulfate , Filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography with developing system B to obtain the title product 32d (250 mg), yield: 93%. MS m / z (ESI): 679.3 [M + 1];

the fourth step

1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7,8,9-tetrahydro -3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclopentane-1-amine 32e

Compound 32d (250 mg, 0.4 mmol) was dissolved in methanol (2 mL), and a 1,4-dioxane solution (4 M, 2 mL) of hydrogen chloride was added, and the reaction was stirred at room temperature for 6 hours. The reaction was cooled, and the reaction solution was concentrated. A saturated sodium bicarbonate solution (25 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound of the crude product 32e (160 mg), yield 88%. Used directly in the next reaction.

the fifth step

(E) -4-((1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6, 7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclopentyl) amino) -N, N-dimethyl But-2-enamide 32

Compound 32e (80 mg, 0.2 mmol) was dissolved in N, N-dimethylformamide (3 mL), diisopropylethylamine (63 mg, 0.5 mmol) was added, and compound 1p (34 mg, 0.2 mmol) was added. The reaction was stirred at room temperature for 48 hours. Water (15 mL) was added and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated by filtration to obtain a crude product. The resulting residue was purified by thin-layer chromatography with developing system A to give the title product 32 (52 mg), yield: 53%. MS m / z (ESI): 606.3 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.08 (s, 1H), 7.24 (d, 1H), 6.85-6.68 (m, 3H), 6.64 ( d, 2H), 5.36 (s, 1H), 4.01 (s, 2H), 3.70-3.56 (m, 3H), 3.46-3.35 (m, 2H), 3.22 (s, 3H), 3.05-2.90 (m, 5H), 1.88-1.66 (m, 8H), 1.14 (d, 3H).

Example 33

(E) -4-((1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6, 7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclopentyl) amino) -1-morpholinylbutan- 2-en-1-one 33

Using the synthetic route of Example 32, replacing the raw material 1p in the fifth step with 25c, the title compound 33 (30 mg) was obtained with a yield of 29%. MS m / z (ESI): 648.3 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.08 (s, 1H), 7.25 (d, 1H), 6.90-6.66 (m, 2H), 6.64 ( t, 3H), 5.37 (s, 1H), 3.97 (s, 2H), 3.75-3.60 (m, 9H), 3.52 (d, 2H), 3.45-3.35 (m, 2H), 3.07-2.86 (m, 2H), 1.90-1.55 (m, 8H), 1.15 (d, 3H).

Example 34

(E) -4-((2- (3,5-difluoro-4-((1S, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-6- ( 1H-pyrazol-4-yl) -1,2,3,4-tetrahydroisoquinolin-1-yl) phenoxy) ethyl) amino) -N, N-dimethylbut-2-ene Amide 34

first step

(2- (3,5-difluoro-4-((1S, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-6- (1H-pyrazole-4- T-butyl) -1,2,3,4-tetrahydroisoquinolin-1-yl) phenoxy) ethyl) carbamate 34b

Compound 23g (160mg, 0.2umol) and pyrazole-4-boronic acid pinacol ester 34a (147mg, 0.5mmol, prepared by the well-known method "Journal of American Chemical Society, 2014, 136 (11), 4287-4299" And), 1,4-dioxane (6 mL), water (1.5 mL) were sequentially added to the reaction flask, and then 1,1'-bisdiphenylphosphine ferrocene dichloride (18 mg, 0.02 mmol), anhydrous sodium carbonate (61 mg, 0.6 mmol), protected by argon, warmed to 90 ° C. and stirred overnight. The reaction was cooled to room temperature, 20 mL of water was added, and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography with developing system B to give the title product 34b (139 mg), yield: 75%.

Second step

2- (3,5-difluoro-4-((1S, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-6- (1H-pyrazol-4-yl ) -1,2,3,4-tetrahydroisoquinolin-1-yl) phenoxy) ethane-1-amine 34c

Compound 34b (105 mg, 0.2 mmol) was dissolved in dichloromethane (4 mL), and a 1,4-dioxane solution (5 M, 0.4 mL) of hydrogen chloride was added dropwise at room temperature, and the mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain a crude product. 34c (85 mg), yield: 99%. Used directly in the next reaction.

third step

(E) -4-((2- (3,5-difluoro-4-((1S, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-6- ( 1H-pyrazol-4-yl) -1,2,3,4-tetrahydroisoquinolin-1-yl) phenoxy) ethyl) amino) -N, N-dimethylbut-2-ene Amide 34

Compound 1p (24 mg, 0.1 mmol) was dissolved in N, N-dimethylformamide (3 mL), diisopropylethylamine (48 mg, 0.4 mmol) was added at room temperature, and then compound 34c (85 mg, 0.2 mmol) was added. And stirred at room temperature for 1.5 hours. 15 mL of water was added and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated by filtration to obtain a crude product. The resulting residue was purified by thin layer chromatography with developing system A to give the title product 34 (35 mg), yield: 33%. MS m / z (ESI): 570.3 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 7.92-7.88 (m, 2H), 7.31 (s, 1H), 7.22 (d, 1H), 6.85- 6.60 (m, 3H), 6.57 (d, 2H), 5.11 (s, 1H), 4.12 (t, 2H), 3.72-3.60 (m, 1H), 3.57 (d, 2H), 3.43-3.35 (m, 1H), 3.25-3.08 (m, 5H), 3.05-2.86 (m, 4H), 2.62 (dd, 1H), 2.28 (dd, 1H), 1.14 (d, 3H), 1.09 (d, 3H), 1.00 (d, 3H).

Example 35

(E) -4-((2-((4-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methyl (Propyl) -3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) -3,5-difluorophenoxy) ethyl) amino) -1-morpholinylbutyl -2-en-1-one 35

Using the synthetic route of Example 24, replacing the raw material 1p in the eighth step with 25c, the title compound 35 (40 mg) was obtained with a yield of 22%. MS m / z (ESI): 640.4 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.03 (s, 1H), 7.84 (s, 1H), 7.48 (s, 1H), 7.39 (d, 1H), 6.96 (d, 1H), 6.89 (d, 1H), 6.82-6.60 (m, 3H), 5.91 (s, 1H), 4.34 (s, 2H), 4.22 (q, 2H), 3.98 (s , 1H), 3.94 (d, 2H), 3.75-3.55 (m, 8H), 3.56-3.42 (m, 2H), 3.41-3.30 (m, 2H), 3.02 (s, 2H), 1.62-1.32 (m , 9H), 0.88 (t, 3H).

Example 36

(E) -4-((2- (4-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -3-methyl-2- (2,2, 2-trifluoroethyl) -1,2,3,4-tetrahydroisoquinolin-1-yl) -3,5-difluorophenoxy) ethyl) amino) -1-morpholinylbutyl- 2-en-1-one 36

first step

(1S, 3R) -1- (4-bromo-2,6-difluorophenyl) -3-methyl-2- (2,2,2-trifluoroethyl) -1,2,3,4 -Tetrahydroisoquinoline-6-phenol 36b

Compound 36a (340 mg, 1.5 mmol, prepared by the method disclosed in Example 131 on page 100 of the specification of WO2017174757) was dissolved in acetic acid (4 mL), and 2,6-difluoro-4-bromobenzaldehyde 23a was added. (418 mg, 1.9 mmol), trifluoroacetic acid (813 mg, 7.3 mmol). After the addition was complete, the reaction was stirred in an oil bath at 85 ° C for 16 hours to stop the reaction. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with developing system B to obtain the title product 36b (600 mg). Yield: 94%. MS m / z (ESI): 437.1 [M + 1];

Second step

(1S, 3R) -6- (benzyloxy) -1- (4-bromo-2,6-difluorophenyl) -3-methyl-2- (2,2,2-trifluoroethyl) -1,2,3,4-tetrahydroisoquinoline 36c

Compound 36b (685 mg, 1.6 mmol) was dissolved in acetone (15 mL), and benzyl bromide 23c (402 mg, 2.4 mmol) and potassium carbonate (650 mg, 4.7 mmol) were added. The reaction was refluxed in an oil bath at 70 ° C for 3 hours to stop the reaction. It was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with developing system B to give the title product 36c (780 mg), yield: 94%.

third step

(2- (4-((1S, 3R) -6- (benzyloxy) -3-methyl-2- (2,2,2-trifluoroethyl) -1,2,3,4-tetra Hydroisoquinolin-1-yl) -3,5-difluorophenoxy) ethyl) carbamic acid tert-butyl 36d

Compound 36c (260mg, 0.5mmol), compound 1m (159mg, 1.0mmol) and toluene (10mL) were sequentially added to the reaction flask, protected by argon, and then [(2-di-tert-butylphosphon-3-methyl Oxy-6-methyl-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl) -2- (2-aminobiphenyl)] palladium (II) methanesulfonic acid Methyl ester (41 mg, 0.05 mmol), cesium carbonate (402 mg, 1.2 mmol), argon was pumped 3 times, and the temperature was raised to 90 ° C. and stirred for 3 hours. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with developing system B to obtain the title product 36d (270 mg). Yield: 90%. MS m / z (ESI): 607.1 [M + 1];

the fourth step

(2- (3,5-difluoro-4-((1S, 3R) -6-hydroxy-3-methyl-2- (2,2,2-trifluoroethyl) -1,2,3, 4-tetrahydroisoquinolin-1-yl) phenoxy) ethyl) carbamic acid tert-butyl 36e

Compound 36d (270 mg, 0.4 mmol) was dissolved in methanol (8 mL), 20% palladium hydroxide carbon (15 mg, 0.02 mmol) was added, and hydrogen was substituted three times. The reaction was hydrogenated at 30 ° C for 4 hours to stop the reaction. Concentrated under reduced pressure to obtain compound 36e (210 mg), yield: 91%. The product was used in the next reaction without purification.

the fifth step

(1S, 3R) -1- (4- (2-((tert-butoxycarbonyl) amino) ethoxy) -2,6-difluorophenyl) -3-methyl-2- (2,2, 2-trifluoroethyl) -1,2,3,4-tetrahydroisoquinoline-6-yl trifluoromethanesulfonate 36f

Compound 36e (210 mg, 0.4 mmol) was dissolved in dichloromethane (6 mL), cooled to -40 ° C under argon protection, and 2,6-lutidine (5 mg, 0.05 mmol) and triethylamine (82 mg, 0.8) were added. mmol), 1,1,1-trifluoro-N-phenyl-N- (trifluoromethanesulfonyl) methanesulfonamide (232 mg, 0.6 mmol) was slowly added dropwise. The reaction was naturally warmed to room temperature and stirred for 1 hour. The reaction was cooled, a saturated sodium bicarbonate solution (20 mL) was added, and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Thin layer chromatography was used to develop the solvent system. B The resulting residue was purified to give the title product 36f (263 mg), yield: 99%.

Step Six

(2- (4-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -3-methyl-2- (2,2,2-trifluoroethyl) -1,2,3,4-Tetrahydroisoquinolin-1-yl) -3,5-difluorophenoxy) ethyl) carbamic acid tert-butyl 36g

Compound 36f (263 mg, 0.4 mmol) was dissolved in 7.5 mL of a mixed solvent of 1,4-dioxane and water (V: V = 4: 1). Compound 1k (180 mg, 0.8 mmol) and sodium carbonate ( 98 mg, 0.1 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (29 mg, 0.04 mmol), protected by argon. The reaction was stirred in an 80 ° C oil bath for 16 hours. Stop reaction. The reaction solution was cooled, and concentrated under reduced pressure. The residue was added with a saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by layer chromatography with developing system B to obtain the title product 36 g (200 mg), yield: 83%. MS m / z (ESI): 595.1 [M + 1];

Step Seven

2- (4-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -3-methyl-2- (2,2,2-trifluoroethyl)- 1,2,3,4-tetrahydroisoquinolin-1-yl) -3,5-difluorophenoxy) ethane-1-amine 36h

36 g (200 mg, 0.3 mmol) of the compound was dissolved in dichloromethane (4 mL), and a 1,4-dioxane solution (5 M, 0.3 mL) of hydrogen chloride was added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 36 h (150 mg), yield: 90%.

Step eight

(E) -4-((2- (4-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -3-methyl-2- (2,2, 2-trifluoroethyl) -1,2,3,4-tetrahydroisoquinolin-1-yl) -3,5-difluorophenoxy) ethyl) amino) -1-morpholinylbutyl- 2-en-1-one 36

Compound 36h (150mg, 0.3mmol) was dissolved in N, N-dimethylformamide (5mL), diisopropylethylamine (78mg, 0.6mmol) was added at room temperature, and then compound 25c (50mg, 0.2mmol) was added. The reaction was stirred for 2 hours. Stop the reaction, add water (50 mL), extract with ethyl acetate (50 mL x 2), wash with saturated sodium chloride solution (50 mL x 4), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by thin-layer chromatography with developing system B to give the title product 36 (25 mg), yield: 18%. MS m / z (ESI): 648.1 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 7.94 (s, 1H), 7.78 (s, 1H), 7.31 (s, 1H), 7.22 (d, 1H), 6.90-6.77 (m, 1H), 6.75-6.63 (m, 2H), 6.60 (d, 2H), 5.25 (s, 1H), 4.30-4.10 (m, 4H), 3.75-3.60 (m, 10H), 3.59-3.50 (m, 1H), 3.42-3.30 (m, 2H), 3.16 (t, 2H), 2.98-2.80 (m, 1H), 2.75-2.60 (dd, 1H), 1.48 (t, 3H), 1.09 (d, 3H).

Example 37

(E) -4-((1-((4-((1S, 3R) -6- (1-ethyl-1H-pyrazol-4-yl) -2- (2-fluoro-2-methyl Propyl) -3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) -3,5-difluorophenoxy) methyl) cyclopropyl) amino) -N, N-dimethylbut-2-enamide 37

Using the synthetic route of Example 26, replacing the raw material 25c in the third step with 1 p, the title compound 37 (50 mg) was obtained with a yield of 39%. MS m / z (ESI): 624.2 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.05 (s, 1H), 7.85 (s, 1H), 7.51 (s, 1H), 7.43 (d, 1H), 7.00 (d, 1H), 6.88 (d, 1H), 6.85-6.72 (m, 2H), 6.71-6.58 (m, 1H), 6.02 (s, 1H), 4.29 (s, 2H), 4.24 (q, 2H), 4.16-4.00 (m, 3H), 3.74-3.56 (m, 1H), 3.42-3.30 (m, 1H), 3.25-3.04 (m, 5H), 2.99 (s, 3H), 1.57 (d, 3H), 1.54-1.40 (m, 9H), 1.28 (t, 2H), 1.18 (t, 2H).

Example 38

(E) -4-((2- (3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7 , 8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethyl) amino) -1- (4-methylpiperazine-1- Butyl) -2-en-1-one 38

first step

(E) -4-((2- (3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7 , 8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethyl) amino) but-2-enoic acid 38b

Compound 27e (250 mg, 0.57 mmol) was dissolved in N, N-dimethylformamide (3 mL), diisopropylethylamine (293 mg, 2.27 mmol) was added at room temperature, and then (E) -4-bromobutane was added. The 2-enoic acid 38a (75 mg, 0.45 mmol) was stirred for 24 hours. Stop and cool the reaction, add water (50 mL), extract with ethyl acetate (50 mL x 2), combine the organic phases, wash with saturated sodium chloride solution (50 mL x 4), dry over anhydrous sodium sulfate, filter, and reduce the pressure of the filtrate Concentrated to give the title product 38b (296 mg), yield: 99%. The product was used in the next reaction without purification.

Second step

(E) -4-((tert-butoxycarbonyl) (2- (3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl Yl) -6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethyl) amino) but-2-enoic acid 38c

Compound 38b (296 mg, 0.57 mmol) was dissolved in N, N-dimethylformamide (3 mL), and diisopropylethylamine (293 mg, 2.27 mmol) was added at room temperature, followed by di-tert-butyl dicarbonate (496 mg , 2.27 mmol), and the reaction was stirred for 24 hours. Stop and cool the reaction, add water (50 mL), extract with ethyl acetate (50 mL x 2), combine the organic phases, wash with saturated sodium chloride solution (50 mL x 4), dry over anhydrous sodium sulfate, filter, and reduce the pressure of the filtrate Concentrated, and the resulting residue was purified by thin layer chromatography with developing system A to give the title product 38c (120 mg), yield: 34%. MS m / z (ESI): 625.3 [M + 1];

third step

(2- (3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7,8,9-tetrahydro -3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethyl) ((E) -4- (4-methylpiperazin-1-yl) -4- Tert-butyl oxobut-2-en-1-yl) carbamate 38d

Compound 38c (120 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), N-methylpiperazine (25 mg, 0.25 mmol) and triethylamine (23 mg, 0.23 mmol) were added, and 2- (7- Benzotriazole oxide) -N, N, N ', N'-tetramethylurea hexafluorophosphate (54 mg, 0.23 mmol). The reaction was stirred at room temperature for 3 hours. Water (50 mL) was added and extracted with dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to give the title product 38d (94 mg), yield: 69%.

the fourth step

(E) -4-((2- (3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7 , 8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethyl) amino) -1- (4-methylpiperazine-1- Butyl) -2-en-1-one 38

Compound 38d (94 mg, 0.13 mmol) was dissolved in methanol (3 mL), and a 1,4-dioxane solution (4 M, 2 mL) of hydrogen chloride was added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 38 (30 mg). Yield: 31%. MS m / z (ESI): 607.3 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.09 (s, 1H), 7.23 (d, 1H), 6.92 (d, 1H), 6.85-6.68 ( m, 2H), 6.65 (d, 2H), 5.37 (s, 1H), 4.29 (t, 2H), 3.96 (d, 2H), 3.53-3.25 (m, 14H), 3.05-2.95 (m, 1H) , 2.98 (s, 3H), 1.13 (d, 3H).

Example 39

(E) -4-((1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6, 7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclopropyl) amino) -1- (4-methyl Piperazin-1-yl) but-2-en-1-one 39

first step

(E) -4-((1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6, 7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclopropyl) amino) but-2-enoic acid 39a

Compound 29d (120 mg, 0.26 mmol) was dissolved in N, N-dimethylformamide (6 mL), diisopropylethylamine (100 mg, 0.78 mmol) was added at room temperature, and then (E) -4-bromobutane The 2-enoic acid 38a (43 mg, 0.26 mmol) was stirred for 24 hours. Stop and cool the reaction, add water (50 mL), extract with ethyl acetate (50 mL x 2), combine the organic phases, wash with saturated sodium chloride solution (50 mL x 4), dry over anhydrous sodium sulfate, filter, and decompress the filtrate Concentrated, and the resulting residue was purified by thin layer chromatography with developing system A to give the title product 39a (135 mg), yield: 95%. MS m / z (ESI): 551.2 [M + 1];

Second step

(E) -4-((1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6, 7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclopropyl) amino) -1- (4-methyl Piperazin-1-yl) but-2-en-1-one 39

Compound 39a (135 mg, 0.25 mmol) was dissolved in N, N-dimethylformamide (5 mL), and N-methylpiperazine (147 mg, 1.47 mmol) and diisopropylethylamine (95 mg, 0.74 mmol) were added. ), And 2- (7-benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate (205 mg, 0.54 mmol) was added. The reaction was stirred at room temperature for 3 hours. Water (50 mL) was added and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 39 (15 mg), yield: 10%. MS m / z (ESI): 633.3 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.09 (s, 1H), 7.25 (d, 1H), 6.90-6.75 (m, 2H), 6.58 ( t, 3H), 5.36 (s, 1H), 3.97 (s, 2H), 3.75-3.60 (m, 4H), 3.57 (d, 2H), 3.45-3.35 (m, 2H), 3.08-2.80 (m, 3H), 2.57-2.43 (m, 4H), 2.33 (s, 3H), 1.14 (d, 3H), 0.80 (t, 2H), 0.72 (t, 2H).

Example 40

(E) -4-((1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6, 7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclohexyl) amino) -N, N-dimethylbutane -2-enamide 40

Using the synthetic route of Example 31, replacing the raw material 25c in the fifth step with 1 p, the title compound 40 (3 mg) was obtained with a yield of 18%. MS m / z (ESI): 620.3 [M + 1]; ¹ H NMR (400MHz, CDCl ₃ ) 8.10 (s, 1H), 7.23 (d, 1H), 7.00-6.80 (m, 2H), 6.52 (d , 1H), 6.43 (d, 2H), 5.36 (s, 1H), 3.77 (s, 2H), 3.73-3.62 (m, 1H), 3.58-3.44 (m, 1H), 3.40-3.30 (m, 2H ), 3.27-3.20 (m, 1H), 3.09 (s, 3H), 3.02 (s, 3H), 3.00-2.88 (m, 1H), 2.23 (t, 1H), 2.10-2.00 (m, 1H), 1.80-1.38 (m, 9H), 1.15 (d, 3H).

Example 41

(E) -4-((1- (3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7 , 8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) -2-methylpropane-2-yl) amino) -N, N- Dimethylbut-2-enamide 41

first step

(1- (3,5-difluoro-4-((6S, 8R) -8-methyl-3- (tetrahydro-2H-pyran-2-yl) -7- (2,2,2- Trifluoroethyl) -6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) -2-methylpropane-2- Propyl) tert-butyl carbamate 41b

Compound 29b (100 mg, 0.2 mmol) was dissolved in N, N-dimethylformamide (5 mL), compound 41a (104 mg, 0.4 mmol) was added, and the well-known method "Journal of Organic Chemistry, 2002, 67 (15), 5164-5169 "), cesium carbonate (203 mg, 0.6 mmol). The reaction was stirred in an oil bath at 80 ° C for 3 hours to stop the reaction. Cool the reaction, concentrate, add water (25 mL), extract with ethyl acetate (50 mL x 2), add saturated sodium bicarbonate solution (20 mL) to the aqueous phase, extract with ethyl acetate (50 mL x 2), combine all organic phases, It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography using developing system B to obtain the title product 41b (100 mg), yield: 74%. MS m / z (ESI): 653.3 [M + 1];

Second step

1- (3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7,8,9-tetrahydro- 3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) -2-methylpropane-2-yl) -2-amine 41c

Compound 41b (55 mg, 0.08 mmol) was dissolved in 1,4-dioxane (3 mL), concentrated sulfuric acid (82 mg, 0.8 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (5 mL) was added. After extraction with ethyl acetate (10 mL × 2), the aqueous phase was added with a saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (10 mL × 2). All organic phases were combined and dried over anhydrous sodium sulfate. , Filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing system A to give the title product 41c (30 mg), yield: 76%. MS m / z (ESI): 469.2 [M + 1];

third step

(E) -4-((1- (3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7 , 8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) -2-methylpropane-2-yl) amino) -N, N- Dimethylbut-2-enamide 41

Compound 41c (90mg, 0.19mmol) was dissolved in N, N-dimethylformamide (3mL), diisopropylethylamine (74mg, 0.57mmol) was added at room temperature, and then compound 1p (37mg, 0.19mmol) was added. The reaction was stirred for 24 hours. Stop and cool the reaction, add water (50 mL), extract with ethyl acetate (50 mL x 2), wash with saturated sodium chloride solution (50 mL x 4), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure The obtained residue was purified by thin layer chromatography with developing system B to obtain the title product 41 (30 mg), yield: 27%. MS m / z (ESI): 580.3 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.08 (s, 1H), 7.24 (d, 1H), 6.76 (t, 3H), 6.65 (d, 2H), 5.37 (s, 1H), 4.01 (s, 2H), 3.78-3.56 (m, 3H), 3.40-3.30 (m, 2H), 3.12 (s, 3H), 3.05-2.85 (m, 5H) , 1.40 (s, 6H), 1.13 (d, 3H).

Example 42

(E) -4-((2- (3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7 , 8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethyl) amino) -N, N-dimethylbut-2-ene Amide 42

Using the synthetic route of Example 27, replacing the raw material 25c in the fifth step with 1 p, the title compound 42 (330 mg) was obtained with a yield of 24%. MS m / z (ESI): 552.2 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.07 (s, 1H), 7.23 (d, 1H), 6.85-6.78 (m, 2H), 6.76 ( d, 1H), 6.59 (d, 2H), 5.36 (s, 1H), 4.15 (t, 2H), 3.62 (d, 3H), 3.45-3.30 (m, 2H), 3.24-3.08 (m, 5H) , 3.04-2.88 (m, 5H), 1.13 (d, 3H).

Example 43

(E) -4-((1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6, 7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclopropyl) amino) -N, N-dimethyl But-2-enamide 43

Using the synthetic route of Example 29, replacing the starting material 28b with 1p in the fourth step, the title compound 43 (180 mg) was obtained with a yield of 22%. MS m / z (ESI): 578.3 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.07 (s, 1H), 7.23 (d, 1H), 6.85-6.74 (m, 2H), 6.63- 6.48 (m, 3H), 5.34 (s, 1H), 3.88 (s, 2H), 3.56-3.50 (m, 3H), 3.44-3.33 (m, 2H), 3.13 (s, 3H), 3.05-2.88 ( m, 5H), 1.13 (d, 3H), 0.76 (t, 2H), 0.69 (t, 2H).

Example 44

(E) -4-((1-((3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6, 7,8,9-tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) methyl) cyclohexyl) amino) -1- (pyrrolidine-1- ) But-2-en-1-one 44

Using the synthetic route of Example 31, replacing the starting material 25c in the fifth step with 28b, the title compound 44 (50 mg) was obtained with a yield of 49%. MS m / z (ESI): 646.4 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.06 (s, 1H), 7.21 (d, 1H), 6.92-6.77 (m, 2H), 6.48- 6.32 (m, 3H), 5.34 (s, 1H), 4.10 (s, 2H), 3.75-3.56 (m, 2H), 3.53-3.38 (m, 4H), 3.35-3.23 (m, 1H), 3.05- 2.85 (m, 2H), 2.05-1.70 (m, 10H), 1.45-1.20 (m, 6H), 1.13 (d, 3H).

Example 45

4-((2- (3,5-difluoro-4-((1S, 3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-6- (1-methyl -1H-pyrazol-4-yl) -1,2,3,4-tetrahydroisoquinolin-1-yl) phenoxy) ethyl) amino) -1-morpholinylbutan-1-one 45

Compound 25 (62 mg, 0.1 mmol) was dissolved in methanol (5 mL), 20% wet palladium on carbon (12 mg) was added, and the reaction was stirred for 3 hours to replace the reaction with hydrogen for 3 times to stop the reaction. Filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography with developing system A to give the title product 45 (21 mg), yield: 33%. MS m / z (ESI): 628.2 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.00 (s, 1H), 7.84 (s, 1H), 7.51 (s, 1H), 7.43 (d, 1H), 7.03 (d, 1H), 6.81-6.79 (m, 2H), 6.07 (s, 1H), 4.35-4.34 (m, 2H), 4.09-3.97 (m, 1H), 3.66 (s, 3H) , 3.65-3.50 (m, 12H), 3.31-3.16 (m, 4H), 2.61-2.58 (m, 2H), 2.02-1.99 (m, 2H), 1.63-1.29 (m, 9H).

Example 46

4-((2- (3,5-difluoro-4-((6S, 8R) -8-methyl-7- (2,2,2-trifluoroethyl) -6,7,8,9 -Tetrahydro-3H-pyrazolo [4,3-f] isoquinolin-6-yl) phenoxy) ethyl) amino) -1-morpholinylbut-1-one 46

Using the synthetic route of Example 45, replacing the starting material 25 with 27 as the first step, the title compound 46 (15 mg) was obtained with a yield of 37%. MS m / z (ESI): 596.2 [M + 1]; ¹ H NMR (400MHz, CD ₃ OD) 8.11 (s, 1H), 7.24 (d, 1H), 6.78 (d, 1H), 6.65-6.62 ( m, 2H), 5.37 (s, 1H), 4.27 (br, 2H), 3.64-3.50 (m, 13H), 3.15-3.14 (m, 2H), 3.01-2.97 (m, 2H), 2.61-2.58 ( m, 2H), 2.01-1.98 (m, 2H), 1.13 (d, 3H).

Biological evaluation

The present invention is further described below in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.

Test Example 1 Inhibitory effect of compounds of the present invention on estrogen receptor reporter gene activity

1.Experimental purpose

Purpose of this experiment is to test the compounds of the present invention, inhibition of the estrogen receptor reporter gene activity, evaluated in vitro activity of compounds according to the size of the IC _50.

2.Experimental methods

MCF7 cells (ATCC, HTB-22) expressing the luciferase reporter gene ERE-luc (synthesized by Jinweizhi Biotechnology Co., Ltd.) controlled by estrogen receptor response elements. MCF7 / ERE-luc was used containing 10% fetal bovine serum and 500 μg. / ml G418 in MEM (GE Healthcare, SH30024.01) medium. On the first day of the experiment, MCF7 / ERE-luc cells were seeded at a density of 30,000 cells / well in 96-well plates using MEM incomplete medium containing 10% activated carbon-treated fetal calf serum (BioSun, BS-0004-500). 100 μl of cell suspension was placed in a cell incubator at 37 ° C. and 5% CO ₂ overnight. On the second day, 10 μl of β-estradiol prepared with incomplete medium and different concentrations of the test compound were added to each well. The final β-estradiol concentration was 0.1 nM, and the final concentration of the compound was 10 times from 10 μM. Nine concentration points of gradient dilution, a blank control containing 0.5% DMSO was set, and the cells were incubated at 37 ° C and 5% CO ₂ for 20 hours. On the third day, remove the 96-well plate, and add 100 μl of ONE-Glo ^™ Luciferase Assay system (Promega, E6110) to each well to detect the luciferase activity. Leave at room temperature for 3 minutes until the cells are fully lysed. instrument (PerkinElmer, VICTOR 3) signal values of the read light emission using Graphpad Prism software to calculate IC ₅₀ values of compounds to inhibit the activity depending on the concentration of the compound and the emission signal values.

3. Test results

Compound Inhibition of estrogen receptor reporter gene activity was measured by the above test the present invention, with Graghpad Prism chemiluminescence signal values plotted against log concentration of compound, the measured IC ₅₀ values are shown in Table 1.

Table 1 Inhibitory effect of compounds of the present invention on estrogen receptor reporter gene activity IC ₅₀

Example number	IC 50 (nM)
1	20
2	20
3	57

4	33
6	twenty two
7	2
8	2
9	2
10	8
11	4
12	2
13	2
14	9
15	6
16	6
17	4
18	10
19	3
20	1
twenty one	1
twenty two	3
twenty three	2
twenty four	3
25	2
26	twenty three
27	0.6
28	0.7
29	3
30	3
31	4
32	4
33	3
34	2

35	3
36	7.7
37	26
38	4
39	8
40	3.5
41	1
42	2.5
43	2
44	6

Conclusion: The compound of the present invention has a significant inhibitory effect on the estrogen receptor reporter gene.

Test Example 2 Inhibitory effect of the compound of the present invention on MCF7 cell proliferation

1.Experimental purpose

Purpose of this experiment was to determine compounds of the invention inhibit the activity of MCF7 cell proliferation in vitro evaluation of the activity of compound ₅₀ according to the size of the IC.

2.Experimental methods

MCF7 cells (ATCC, HTB-22) were cultured in MEM (GE Healthcare, SH30024.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, MCF7 cells were seeded in a 96-well plate at a density of 3,000 cells / well using a complete medium, and 100 μl of cell suspension was placed in a cell incubator at 37 ° C. and 5% CO ₂ overnight. The next day, the medium was aspirated, and each well was replaced with 135 μl of MEM incomplete medium containing 2% fetal bovine serum. At the same time, 15 μl of each concentration of the test compound prepared with the incomplete medium was added to each well. The final concentration of the compound was Nine concentration points were diluted 4-fold from 100 nM, a blank control containing 0.5% DMSO was set, and the cells were incubated at 37 ° C and 5% CO ₂ for 144 hours. On the eighth day, remove the 96-well cell culture plate and add 150 μl to each well.

Luminescent Cell Viability Assay (Promega, G7573). After standing at room temperature for 10 minutes, use a multi-label microplate reader (PerkinElmer, VICTOR 3) to read the luminescence signal value, and use Graphpad Prism software to calculate the compound concentration and luminescence signal value. IC ₅₀ values for compound inhibitory activity.

3.Data analysis

Graghpad Prism using logarithmic values chemiluminescent signal plotted against the concentration of the compound, the compound obtained IC ₅₀ values. The results are shown in Table 2.

Table IC ₅₀ of the inhibitory effect of compounds of the invention on MCF7 cell proliferation 2

Example number

IC 50 (nM)

Max inhibition

		(%)
1	2	100
2	10	94
3	2	115
4	8	94
5	7	120
6	3	97
7	0.06	99
8	0.19	102
9	0.07	100
10	0.52	96
11	0.26	103
12	0.14	100
13	0.23	92
14	0.31	94
15	0.64	85
16	0.45	100
17	0.16	98
18	3	91
19	0.36	97
20	0.24	101
twenty one	0.16	103
twenty two	0.24	102
twenty three	0.55	103
twenty four	0.63	101
25	0.18	97
26	1.09	96
27	0.27	100
28	0.05	105
29	0.22	99

30	0.16	99
31	0.78	104
32	0.26	103
33	0.25	98
34	0.2	92
35	0.73	93
36	0.37	100
37	1	100
38	0.37	97
39	0.34	106
40	0.42	95
41	0.17	93
42	0.09	99
43	0.15	98
44	0.55	104

Conclusion: The compound of the present invention has obvious inhibitory effect on MCF7 cell proliferation.

Test Example 3 Evaluation of Experimental Proliferation Inhibition of ERα Mutant MCF7 Cells

1.Experimental purpose

The purpose of this experiment was to determine the inhibitory activity of the compounds of the present invention on the proliferation of MCF7 cells expressing ERa mutants.

2.Experimental methods

Site-directed mutations and cell line construction

Human estrogen receptor α (ERα) protein mutants ERα Y537S and ERα D538G were obtained by site-directed mutagenesis using the cDNA of the wild-type ESR1 gene (Accession No. NM000125) as a template using a double primer PCR method. The primer sequence used for the mutation is as follows (the underlined nucleotides are the mutation sites): Y537S: F-AAG AAC GTG GTG CCC CTC T C T GAC CTG CTG CTG GAG ATG; R-CAT CTC CAG CAG CAG GTC A G A GAG GGG CAC CAC GTT CTT; D538G: F-AAC GTG GTG CCC CTC TAT G G C CTG CTG CTG CTG GAG ATG CTG; R-CAG CAT CTC CAG CAG CAG G C C ATA GAG GGG CAC CAC GTT. The cDNA of the mutant ESR1 was cloned into the target lentiviral vector pCDH-CMV-MCS-EF1-Puro. The lentiviral plasmid carrying the mutant ESR1 gene sequence and the lentiviral packaging plasmid were then transfected into HEK-293T cells (ATCC, CRL-3216) by Lipofectamine 3000 Transfection Reagent (ThermoFisher Scientific, Cat # L3000075). 48 hours after transfection, the supernatant of the virus-containing medium was filtered and ultracentrifuged to obtain the virus precipitate. After resuspending and lysing with an appropriate amount of medium, it was added to MCF7 cells (ATCC, HTB-22) and added to the final concentration. Polybrene was incubated at 8 μg / ml overnight. Two days after transfection, 1 μg / ml puromycin was added to the cell culture medium for resistance screening. About two weeks later, an MCF7 cell line capable of stably expressing ERαY537S and ERαD538G mutants was obtained.

Cell Proliferation Inhibition Experiment

MCF7 cells expressing the ERa mutant were cultured in MEM (GE Healthcare, SH30024.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, cells were seeded in a 96-well plate at a density of 3,000 cells / well using a complete medium. 100 μl of cell suspension per well was placed in a 37 ° C, 5% CO ₂ cell incubator and cultured overnight. The next day, the medium was aspirated, and each well was replaced with 135 μl of MEM incomplete medium containing 2% fetal bovine serum. At the same time, 15 μl of different concentrations of the test compound prepared with incomplete medium were added to each well. The final concentration of the compound was Nine concentration points were diluted 4-fold from 100 nM, a blank control containing 0.5% DMSO was set, and the cells were incubated at 37 ° C and 5% CO ₂ for 144 hours. On the eighth day, remove the 96-well cell culture plate and add 150 μl to each well.

Luminescent Cell Viability Assay (Promega, G7573). After standing at room temperature for 10 minutes, use a multi-label microplate reader (PerkinElmer, VICTOR 3) to read the luminescence signal value, and use Graphpad Prism software to calculate the compound concentration and luminescence signal value. IC ₅₀ values for compound inhibitory activity.

TABLE 3 Compound IC invention inhibitory effect on the expression of the mutant ERα of MCF7 cell proliferation ₅₀

Conclusion: The compound of the present invention has a significant inhibitory effect on the proliferation of ERF mutant MCF7 cells.

Pharmacokinetic evaluation

Test Example 4. BALB / C Pharmacokinetic Test of Nude Mice in Example Compounds of the Invention

1.Abstract

Using BALB / C nude mice as test animals, the LC / MS / MS method was used to determine whether BALB / C nude mice were orally administered with the compound of Example 9, the compound of Example 12, the compound of Example 20, the compound of Example 24, or Example Drug concentration in the plasma at different times after the 25 compound, the compound of Example 27, the compound of Example 28, and the compound of Example 43. The pharmacokinetic behavior of the compound of the present invention in nude mice of BALB / C was studied, and its pharmacokinetic characteristics were evaluated.

2. Test plan

2.1 Test drugs

Example 9 compound, Example 12 compound, Example 20 compound, Example 24 compound, Example 25 compound, Example 27 compound, Example 28 compound, and Example 43 compound.

2.2 Test animals

Seventy-two BALB / C nude mice were female, and were divided into eight groups on average. Nine mice were in one group. They were purchased from Jiesijie Experimental Animal Co., Ltd., animal production license number SCXK (Shanghai) 2013-0006.

2.3 Drug Formulation

Weigh an appropriate amount of sample, add 5% by volume of DMSO, 5% by volume of Tween 80, and 90% by volume of physiological saline to prepare a colorless, clear, transparent liquid at 0.1 mg / mL.

2.4 Administration

After fasting overnight, they were administered orally, with a volume of 0.2ml / 10g. The compound of Example 9 and Example 12 were administered at a dose of 2mg / kg. The compound of Example 20, Example 24, Example 25, The compound of Example 27, the compound of Example 28 and the compound of Example 43 were administered at a dose of 30 mg / kg.

3.Operation

Seventy Balb / C nude mice were female; they were administered by gavage after an overnight fast. Blood was collected at 0.1, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 h (3 animals at each time point), placed in a heparinized test tube, and centrifuged at 3500 rpm for 10 min to separate the plasma. save. Determining the content of test compounds in nude mice's plasma after oral administration of drugs at different concentrations: Take 25 μL of nude mice's plasma at each time after administration, add 40 μL of internal standard solution camptothecin (100 ng / mL), 200 μL of acetonitrile, and vortex Spin and mix for 5 minutes, centrifuge for 10 minutes (4000 rpm), and take 0.5 μL of the supernatant from the plasma sample for LC / MS / MS analysis.

4. Results of Pharmacokinetic Parameters of BALB / C Nude Mice

The pharmacokinetic parameters of the compounds of the examples of the present invention are as follows:

"-" Means not tested.

Conclusion: The compound of the present invention has good pharmacokinetic absorption, and has obvious pharmacokinetic absorption effect.

Test Example 5, Rat Pharmacokinetic Test of Compounds of Examples 9, 12, and 13 of the Invention

1.Abstract

Using rats as test animals, LC / MS / MS methods were used to determine the drug concentrations in plasma of rats at different time points after administration of the compound of Example 9, the compound of Example 12, and the compound of Example 13. The pharmacokinetic behavior of the compound of the present invention in rats was studied, and its pharmacokinetic characteristics were evaluated.

2. Test plan

2.1 Test drugs

The compound of Example 9, the compound of Example 12, and the compound of Example 13.

2.2 Test animals

Twelve healthy adult SD rats, half male and four females, were divided into three groups on average, and were purchased from Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2013-0006.

2.3 Drug Formulation

Weigh a certain amount of drug, add 5% volume of DMSO, 5% volume of Tween 80, and 90% volume of normal saline to prepare a 0.2 mg / mL colorless clear transparent liquid.

2.4 Administration

SD rats were fasted orally after fasting overnight. The doses were all 2.0 mg / kg, and the volume was 10.0 mL / kg.

3. operation

The compound of Example 9, the compound of Example 12, and the compound of Example 13 were administered orally to rats. 0.5 mL, 1.0 mL, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours of blood were collected from the orbits before and after the administration. Plasma was placed in a heparinized test tube, centrifuged at 4 ° C, 3500 rpm for 10 minutes to separate plasma, stored at -20 ° C, and eaten 2 hours after administration.

Determine the content of test compounds in rat plasma after oral administration of drugs with different concentrations: Take 25 μL of rat plasma at each time after administration, add 40 μL of internal standard solution camptothecin (100 ng / mL), 200 μL of acetonitrile, vortex Spin-mix for 5 minutes, centrifuge for 10 minutes (4000 rpm), and take 8.0 μL of the supernatant from the plasma sample for LC / MS / MS analysis.

4. Results of pharmacokinetic parameters

The pharmacokinetic parameters of the compounds of the invention are as follows:

Conclusion: The compounds of the present invention have good pharmacokinetic absorption and have pharmacokinetic advantages.

Test Example 6 Biological evaluation of covalent modification of estrogen receptor ERα wild type and ERα Y537S mutant

1.Experimental purpose

The purpose of this experiment was to determine the covalent modification effect of the compounds of the present invention on the estrogen receptor ERα wild type and ERα Y537S mutant type.

2.Experimental methods

The ligand binding domains (LBD, ligand binding domain, aa296-554) of estrogen receptor ERα wild type and ERα Y537S mutant were expressed and purified. Add 2 μM ERα wild type or ERα Y537S mutant protein and 10 μM compound to a buffer containing 50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM TCEP, 5% glycerol, and incubate at 4 ° C for 24 hours. Perform high resolution mass spectrometry detection. Or add 1μM of ERα wild type or ERαY537S mutant protein and 3μM compound to a buffer containing 50mM Tris-HCl, pH7.5, 150mM NaCl, 1mM TCEP, 5% glycerol, and incubate at 37 ° C for 15 minutes For high resolution mass spectrometry. In the mass spectrum detection result spectrum, the peak whose molecular weight is the sum of the protein and the compound is the covalent modification product. The percentage of covalent modification is calculated by calculating the ratio of the unbound compound protein to the total protein.

Covalent modification ratio after 24 hours of covalent modification

Conclusion: The test compounds (except 45 and 46) have good covalent modification effect on ERα wild type or ERα Y537S mutant protein.

Covalent modification ratio after 15 minutes of covalent modification

"-" Means not tested.

Conclusion: The test compound has a faster covalent modification effect on ERa wild type or ERa Y537S mutant protein.

Claims (27)

1. A compound represented by the general formula (I):

   

   Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

   among them:

   Ring A is selected from

   

   Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

   W is selected from O, NH or S;

   G is CH or N;

   Z is selected from CR ⁵ R ⁶ , O and NR ⁷ ;

   Y is selected from cycloalkyl, heterocyclyl, alkylene and

   

   R ^{a is} selected from -CH ₂ CH = CHC (O) NR ⁸ R ⁹ , -C (O) CH = CR ¹⁰ R ¹¹ and -C (O) C≡CR ¹² ;

   R ^c and ^{Rd are the} same or different, and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl;

   Or R ^c and ^Rd together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group;

   R ^{1 is} selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl Optionally selected from one or more substituents selected from alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl Replaced by

   R ^{2 is} selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, amino, cyano, nitro, carboxy, aldehyde, hydroxy, hydroxyalkyl, cycloalkyl, aryl, and heteroaryl;

   R ^{3 is the} same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, and cycloalkyl , Heterocyclyl, aryl, and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of alkyl, halogen, cyano, amino, and nitro Substituted with one or more of the hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups;

   R ^{b is the} same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, and cycloalkyl , Heterocyclyl, aryl and heteroaryl;

   R ^{4 is the} same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl;

   R ⁵ and R ^{6 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cyclic Alkyl, heterocyclyl, aryl and heteroaryl;

   R ^{7 is} selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

   R ⁸ and R ^{9 are the} same or different and each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

   Alternatively, the R ⁸ and R ⁹ form a heterocyclic group together with a nitrogen atom connected thereto, wherein the heterocyclic group optionally contains 1 to 2 nitrogen atoms, and optionally contains 1 to 2 same or different Heteroatoms of N, O and S, and said heterocyclic group is optionally selected from alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic Substituted with one or more substituents of aryl, aryl and heteroaryl;

   R ¹⁰ and R ^{11 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cyclic Alkyl, heterocyclyl, aryl and heteroaryl;

   R ^{12 is} selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

   m is 0 or 1;

   n is 0, 1, 2, 3, or 4;

   p is 0, 1, or 2;

   s is 0, 1, 2 or 3 and

   t is an integer from 1 to 6.
2. The compound represented by the general formula (I) according to claim 1, or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof. , Or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II):

   

   Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

   among them:

   Ring ^{A, G, R a, Z} , Y, R 1, R 2, R 4, m and s are as defined in claim 1 and claim.
3. The compound represented by the general formula (I) according to claim 1, or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof. , Or a pharmaceutically acceptable salt thereof, which is optionally a compound represented by general formula (III), general formula (IV) or general formula (V):

   

   Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

   among them:

   Ring B is heteroaryl; preferably 5-membered heteroaryl, more preferably pyrazolyl;

   R ^a , G, Z, Y, W, R ¹ to R ⁴ , R ^b , m, n, p and s are as defined in claim 1.
4. The compound represented by the general formula (I) according to any one of claims 1 to 3 or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer A structure or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is selected from a C _3-6 cycloalkyl group, a 3 to 6 membered heterocyclic group,-(CH ₂ ) _k -and

   

   The heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S; k is an integer from 1 to 6; t is an integer from 1 to 6; R ^c and ^Rd are alkyl groups, or R ^c And R ^d together with the carbon atom to which they are attached form a cycloalkyl group.
5. The compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer according to any one of claims 1 to 4. Structure or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of -CH ₂ CH _2- , -CH ₂ CH ₂ CH _2- ,

   

   
6. The compound represented by the general formula (I) according to claim 1, or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof. , Or a pharmaceutically acceptable salt thereof, which is optionally a compound represented by general formula (VI), general formula (VII), general formula (VIII) or general formula (IX):

   

   Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

   among them:

   R ^c and ^{Rd are the} same or different, and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl;

   Or R ^c and ^Rd together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group;

   t is an integer from 1 to 6; q is 1, 2 or 3;

   k is an integer from 1 to 6;

   Ring ^{A, G, R a, Z} , R 1, R 2, R 4 and s are as defined in claim 1 and claim.
7. The compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer according to any one of claims 1 to 6. As a structure or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is an alkyl group, preferably a methyl group.
8. The compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer according to any one of claims 1 to 7. A conformation or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z is O or NH.
9. A compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof according to claim 3 A form, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the general formula (III) or the general formula (V) is a compound represented by the general formula (III-C) or the general formula (VC):

   

   Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

   among them:

   Ring B is heteroaryl; preferably 5-membered heteroaryl, more preferably pyrazolyl;

   k is an integer from 1 to 6;

   ^{G, R a, R 1,} R 3, R 4, R b, n, s and p are as defined in claim 3 as claimed.
10. A compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof according to claim 3 Form, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the general formula (IV) is a compound represented by the general formula (IV-A), (IV-B), or (IV-C):

    

    Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

    among them:

    q is 1, 2 or 3;

    k is an integer from 1 to 6;

    ^{G, W, R a, R} 1, R 3, R 4, n and s are defined as claimed in claim 3.
11. A compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof according to claim 10 Form, or a pharmaceutically acceptable salt thereof, wherein the general formula (IV-

    A) The compound represented by general formula (IV-B) or (IV-C) is a compound represented by general formula (IV-a), general formula (IV-b) or general formula (IV-c) :

    

    Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

    among them:

    q is 1, 2 or 3;

    k is an integer from 1 to 6;

    ^{G, W, R a, R} 1, R 3, R 4, n and s are defined as claimed in claim 10.
12. The compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer according to any one of claims 1 to 11. Or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from the group consisting of alkyl, haloalkyl, cycloalkyl, and aryl, and the alkyl, cycloalkyl, and aryl are optionally selected from Is substituted with one or more substituents of the group, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, and heterocyclic.
13. The compound represented by the general formula (I) according to any one of claims 1 to 12 or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a pharmaceutically acceptable salt thereof, wherein R ^{3 is the} same or different, and each is independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, or a heteroaryl group, wherein the heteroaryl group is further One or more alkyl substitutions.
14. The compound represented by the general formula (I) according to any one of claims 1 to 13 or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a pharmaceutically acceptable salt thereof, wherein R ^{4 is the} same or different, and each is independently selected from a hydrogen atom, a halogen, an alkyl group, and an alkoxy group.
15. The compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer according to any one of claims 1 to 14. A structure or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{a is} selected from -CH ₂ CH = CHC (O) NR ⁸ R ⁹ , -C (O) CH = CR ¹⁰ R ¹¹ and -C (O) C≡CR ¹² ; R ¹⁰ to R ^{12 are the} same or different and each is independently a hydrogen atom or an alkyl group; R ⁸ and R ^{9 are the} same or different and each is independently selected from a hydrogen atom or an alkyl group; or R ⁸ and R ⁹ forms a heterocyclic group together with the nitrogen atom to which it is connected, wherein the heterocyclic group optionally contains 1 to 2 nitrogen atoms, and optionally contains 1 or 2 heteroatoms selected from N, O, and S And the heterocyclic group is optionally selected from alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl With one or more substituents.
16. The compound represented by the general formula (I) according to any one of claims 1 to 15 or a tautomer, meso, racemate, enantiomer, diastereomer Structure or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{a is} selected from -CH ₂ CH = CHC (O) N (CH ₃ ) ₂ , -C (O) CH = CH ₂ , -C (O) C≡CCH ₃ ,

    

    
17. The compound represented by the general formula (I) according to any one of claims 1 to 16 or a tautomer, meso, racemate, enantiomer, diastereomer A conformation or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is selected from any one of the following compounds:

    

    

    
18. A compound represented by the general formula (IA),

    

    Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

    among them:

    Ring A is selected from

    

    Ring B is cycloalkyl, heterocyclyl, aryl or heteroaryl;

    W is selected from O, NH or S;

    G is CH or N;

    Z is selected from CR ⁵ R ⁶ , O and NR ⁷ ;

    Y is selected from cycloalkyl, alkylene and

    

    R ^c and ^{Rd are the} same or different, and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl;

    Or R ^c and ^Rd together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group;

    R ^{1 is} selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl Optionally selected from one or more substituents selected from alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl Replaced by

    R ^{2 is} selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, amino, cyano, nitro, carboxy, aldehyde, hydroxy, hydroxyalkyl, cycloalkyl, aryl, and heteroaryl;

    R ^{3 is the} same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, and cycloalkyl , Heterocyclyl, aryl, and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of alkyl, halogen, cyano, amino, and nitro Substituted with one or more of the hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups;

    R ^{b is the} same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, and cycloalkyl , Heterocyclyl, aryl and heteroaryl;

    R ^{4 is the} same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl;

    R ⁵ and R ^{6 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cyclic Alkyl, heterocyclyl, aryl and heteroaryl;

    R ^{7 is} selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

    m is 1;

    n is 0, 1, 2, 3, or 4;

    p is 0, 1, or 2;

    s is 0, 1, 2 or 3 and

    t is an integer from 1 to 6.
19. The compound represented by the general formula (IA) according to claim 18, or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof. , Or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VIIA), the general formula (VIIIA), or the general formula (IXA):

    

    Or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

    among them:

    R ^c and ^{Rd are the} same or different, and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl;

    Or R ^c and ^Rd together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group;

    t is an integer from 1 to 6;

    q is 1, 2 or 3;

    k is an integer from 1 to 6;

    Ring ^{A, G, Z, R 1} , R 2, R 4 and s are as defined in claim 18 as required.
20. The compound represented by the general formula (IA) according to claim 18 or 19, or a tautomer, meso, racemate, enantiomer, diastereomer, or A mixture, or a pharmaceutically acceptable salt thereof, selected from:

    

    

    
21. A compound selected from:

    
22. Preparation of a compound of general formula (I) according to any one of claims 1 to 17 or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Method, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

    

    Formula (IA) compound is reacted with R ^a -X, to give compounds of general formula (the I);

    among them:

    m is 1;

    X is halogen;

    Ring A, G, Z, Y, R a, R 1, R 2, R 4 and s are as defined in claim 1 and claim.
23. A method for preparing a compound of general formula (VII), general formula (VIII) or general formula (IX) according to any one of claims 18 to 20, or a tautomer, meso, or racemate thereof , Enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

    

    Formula (VIIA), compounds of formula (VIIIA of) or the general formula (IXA) is reacted with R ^a -X, to give formula (VII) or a compound of formula (VIII) or a compound of formula (IX);

    among them:

    m is 1;

    X is halogen;

    Rings A, G, Z, Ra, R ¹ , R ² , R ⁴ and s are as defined in claim 6.
24. A pharmaceutical composition containing a therapeutically effective amount of a compound represented by the general formula (I) according to any one of claims 1 to 17 or a tautomer, a meso, or a racemate thereof , Enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers, diluents or excipients.
25. The compound represented by the general formula (I) according to any one of claims 1 to 17 or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24 for use in the preparation of an estrogen receptor modulator.
26. The compound represented by the general formula (I) according to any one of claims 1 to 17 or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24 in the manufacture of a medicament for the prevention and / or treatment of an estrogen receptor-mediated or dependent disease or disorder .
27. The use according to claim 26, wherein the estrogen receptor-mediated or dependent disease or disorder is cancer, preferably breast cancer, ovarian cancer, endometrial cancer, prostate cancer or uterine cancer; more preferably Breast cancer.