CN104945377A

CN104945377A - Quinoline derivatives used as SMO inhibitors

Info

Publication number: CN104945377A
Application number: CN201410110890.1A
Authority: CN
Inventors: 吴颢; 林军; 李云辉; 韦昌青; 陈曙辉
Original assignee: NANJING MINGDE NEW DRUG RESEARCH AND DEVELOPMENT Co Ltd; Sichuan Kelun Pharmaceutical Co Ltd
Current assignee: NANJING MINGDE NEW DRUG RESEARCH AND DEVELOPMENT Co Ltd; Guangdong Zhongsheng Pharmaceutical Co Ltd
Priority date: 2014-03-24
Filing date: 2014-03-24
Publication date: 2015-09-30

Abstract

The invention discloses a type of quinoline derivatives. The quinoline derivatives are used as inhibitors for hedgehog channels, and in particular, used as SMO inhibitors. The compounds disclosed by the invention can be used for treating hedgehog channel-related diseases comprising cancers.

Description

Quinoline derivatives as SMO inhibitors

Technical Field

The invention relates to quinoline derivatives as inhibitors of the hedgehog pathway, particularly as inhibitors of SMO, which are useful in the treatment of hedgehog pathway related disorders, including cancer.

Background

Hedgehog proteins, originally secreted signaling proteins found in drosophila, are highly hydrophobic proteins that play a critical role in embryonic development. Three homologous hedgehog g proteins have been identified in humans, Sonic hedgehog (Shh), Indian hedgehog (Ihh) and Desert hedgehog (Dh). Not only is Shh important in embryonic development, but there is a lot of evidence that it also plays an important role in the carcinogenic mechanisms of several cancers including basal cell carcinoma (Caro, i.and j.a.low, Clin Cancer Res,2010.16(13): 3335-9). Shh synthesizes a precursor protein of 45kDa in vivo, and produces an N-terminal fragment of 20kDa by self-excision, which has all the biological activities known in vivo, including activation of the hedgehog signaling pathway in cells, the major members of which include Patched (PTCH), G-like protein coupled and receptor oncogene Smoothened (SMO), and transcription factor Gli, etc. (ball, A.E.and K.P.Yu, Hum Mol Genet,2001.10(7): 757-62). Analysis of the basal cell carcinoma hedgehog signaling pathway for variation showed that most of the variation occurred on PTCH-1 and SMO (Von Hoff, D.D., et al, N Engl J Med,2009.361(12): 1164-72). PTCH-1 is a membrane protein with a 12-pass transmembrane structure, and is a direct-acting receptor of Shh. In the absence of Shh, PTCH-1 interacts with SMO, a 7-transmembrane structural protein, inhibiting the biological activity of SMO. Binding of Shh to PTCH-1 results in the detachment of PTCH-1 from SMO, freeing SMO from the inhibited state. The Gli transcription factor, which is under the control of SMO, acts as a switch for gene transcription, the major members of which include Gli, Gli2 and Gli 3. The entire hedgehog pathway plays an important role in the normal development of embryos. Disruption of this information pathway can lead to serious malformations, such as the natural teratogenic compound cyclopamine, which is a hedgehog inhibitor. Under normal conditions, the concentration of hedgehog protein in adults is very low. In the case of very low hedgehog protein concentrations, PTCH-1 binds to SMO and inhibits its biological viability, and thus the entire pathway is in a non-viable, or very low-viable, state. When the cell secretes the hedgehog protein, the binding of the hedgehog protein to the PTCH-1 receptor causes it to be detached from the SMO, thereby losing the inhibitory effect on the SMO. SMO further activates the transcription factor Gli-1 to regulate gene transcription and cell growth. There is increasing evidence that the cause of most basal cell carcinomas is excessive hedgehog signaling pathway viability due to mutation or other causes. Therefore, the hedgehog signaling pathway activity is inhibited too much, and the growth of cancer cells can be inhibited so as to treat basal cell carcinoma or other cancers caused by the same mechanism. The demonstration that constitutive activation of SMO leads to cancer (e.g. BCC) and that release of Ptch's inhibition thereof could make SMO oncogenic is said to suggest the use of SMO antagonists as therapeutic agents in the treatment of such conditions (Stone et al, (1996) Nature384: 129). A series of scientific and clinical test results show that the hedgehog inhibitor can effectively treat various cancers. Recent clinical trial data show that hedgehog inhibitor GDC-0449 is effective in treating basal cell and medulloblast cancers (louusso pm. et al. clin Cancer res.2011; 17(8):2502-11) and is FDA-approved in 1 month 2012, or other cancers caused by the same mechanism, such as Basal Cell Nevus Syndrome (BCNS) (Goldberg lh. et al. arch department. 2011mar21.). The biochemical research shows that the inhibition point of GDC-0449 is on SMO, and the inhibition of the activity of SMO inhibits the activity of the whole hedgehog pathway, thereby achieving the aim of resisting cancer. In addition to both basal cell and medulloblastoma cancers, many other cancers are also associated with the superior viability of the hedgehog signaling pathway, including pancreatic, gastric, rectal, ovarian, and prostate cancers, as well as partial blood cancers, etc. (De Smele E.et al. curr Opin Invitro drugs.2010; 11(6): 707-18). Thus, the prospect of developing hedgehog inhibitors as novel anti-cancer drugs is very wide.

Although some SMO inhibitors already exist in the prior art, they are in need of improvement in terms of activity, solubility, pharmacokinetics, druggability, etc.

Disclosure of Invention

The invention aims to provide a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof,

wherein A is selected from

(R₂₀)₃C-E₁₃-；T_11-17Each independently selected from N, C (R)₁₃)；

E_11-13、L₁、L₂Are each independently selected from N (R)₁₄)、C(＝O)N(R₁₅)、S(＝O)₂N(R₁₆)、C＝N(R₁₇)、C(R₁₈)(R₁₉) S, C (═ O) O, C (═ O), C ═ S, S (═ O), or S (═ O)₂；

L₁、L₂Each may also be independently selected from single bonds;

R_11-13、R_18-19each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH₂Optionally with R₀₁Substituted C_1-6Alkyl or heteroalkyl, optionally substituted with R₀₂Substituted C_3-8A cyclic or heterocyclic group or a heterocyclic or heterocyclic group; preferably methyl, trifluoromethyl, trifluoromethoxy, F, Cl, Br, I, CN, methylaminocarbonyl, methylsulfonyl, trifluoromethylsulfonyl, trifluoromethoxy, cyclopropyl, morpholinosulfonyl, 2-imidazolyl, dimethylamino, n-, iso-or neo-propyl;

R_14-17each independently selected from H, optionally substituted by R₀₁Substituted C_1-6Alkyl or C_3-6A cycloalkyl group;

R₂₀selected from H, F, Cl, Br, I, CN, OH, SH, NH₂Methoxy, methylamino, dimethylamino;

Q_11-12each independently selected from phenyl, pyridyl, thienyl, furyl;

structural unitCan be replaced by

T_21-26Each independently selected from N, C (R)₂₅)；T₂₅May also be selected from N^⊕(R₂₅)；

R_21-25Each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH₂Optionally with R₀₁Substituted C_1-6Alkyl or heteroalkyl, optionally substituted with R₀₂Substituted C_3-8A cyclic or heterocyclic group or a heterocyclic or heterocyclic group; preferably F, Cl, Br, I, CN, OH, methyl, ethyl, methoxy, trifluoromethyl, difluoromethoxy, n-or iso-propoxy, cyclopropyl, carboxamido, methylsulfonylamino, dimethylamino, dimethylaminoethoxy, methylsulfonyl, methoxycarbonyl,

m_21-24each independently selected from 0, 1 or 2;

b is selected from

R₃Is selected fromH. Optionally substituted with R₀₁Substituted C_1-6Alkyl or heteroalkyl, optionally substituted with R₀₂Substituted C_3-8A cyclic or heterocyclic group or a heterocyclic or heterocyclic group;

E_31-38、L_3a、L_3bare each independently selected from N (R)₄₀)、C(＝O)N(R₄₁)、S(＝O)₂N(R₄₂)、C＝N(R₄₃)、C(R₄₄)(R₄₅) S, C (═ O) O, C (═ O), C ═ S, S (═ O), or S (═ O)₂；

L_3a、L_3bEach may also be independently selected from single bonds;

E₃₁、E₃₅may also each independently be selected from-T₃₉＝T₄₀-；

T_31-40Each independently selected from N, C (R)₄₆)；

R_40-43Each independently selected from H, optionally substituted by R₀₁Substituted C_1-6Alkyl or C_3-6Cycloalkyl, optionally substituted by R₀₁Substituted C_1-6Alkanoyl or C_3-6Cycloalkyl acyl, optionally substituted by R₀₁Substituted C_1-6Alkylsulfonyl or C_3-6A cycloalkanesulfonyl group;

R_31-39、R_44-46each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH₂C (═ O) OH, optionally with R₀₁Substituted C_1-6Alkyl or heteroalkyl, optionally substituted with R₀₂Substituted C_3-8A cyclic or heterocyclic group or a heterocyclic or heterocyclic group;

R₀₁、R₀₂each independently selected from F, Cl, Br, I, CN, OH, SH, NH₂、R₀₃；

R₀₃Is selected from C_1-6Alkylamino radical, di-C_1-6Alkylamino radical, C_1-6Alkoxy radical, C_3-8Cycloalkylamino radical, C_3-8Heterocycloalkylamino, C_3-8A cycloalkoxy group;

each heteroatom or heteroatom group is independently selected from C (═ O) NR₀₄、N(R₀₅)、C＝N(R₀₆)、O、S、C(＝O)O、C(＝O)、C＝S、S(＝O)、S(＝O)₂And/or S (═ O)₂N(R₀₇)；

R₀₄-₀₇Each independently selected from H, R₀₈；

R₀₈Is selected from C_1-6Alkyl or C_3-8A cycloalkyl group;

R₀₃、R₀₈optionally substituted by R₀₀₁Substituted, R₀₀₁Selected from OH, N (CH)₃)₂、NH(CH₃)、NH₂F, Cl, Br, I, CN, methyl and methoxy;

R₀₁、R₀₂、R₀₀₁the number of heteroatoms or heteroatom groups is independently selected from 0, 1,2 or 3;

m₃、m₄each independently selected from 0 or 1, when selected from 0, indicates that the corresponding structural unit represents a single bond that serves only as a link;

optionally, R₃₁And R₃₂、R₃₁And R₃₃、R₃₁And R₃₅、E₃₃And E₃₄Together form a connecting bond (CH)₂)_1-6Preferably (CH)₂)₂、(CH₂)₃、(CH₂)₄、(CH₂)₅；

Optionally, E₃₂And R₃₂Are connected with each other to form a five-membered carbocycle or heterocycle;

optionally, when E₃₂Is selected from N (R)₄₀) Or O is, R₃₁And R₃₄Forming an order relation; when E is₃₂Is selected from C (R)₄₃)(R₄₄) When R is₃₁And R₃₄Forming an inversion relation; when T is₃₄When selected from N, R₃₆And R₃₇Forming an order relation; when T is₃₄Is selected from C (R)₄₅)，R₃₆And R₃₇Forming an order relation;

preferably, C is as defined above_3-8The cyclic or heterocyclic group or the heterocyclic or heterocyclic group is selected from the group consisting of phenyl, pyridyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl.

Preferably, the above compound or a pharmaceutically acceptable salt thereof, wherein a is selected from

(CH₃)₃CC(＝O)NH。

Preferably, the above compound or a pharmaceutically acceptable salt thereof, wherein the structural unitIs selected fromIs selected fromStructural unitIs selected fromWherein,

R₂₀₁、R₂₀₂、R₂₀₃each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH₂Optionally with R₀₁Substituted C_1-6Alkyl or heteroalkyl, optionally substituted with R₀₂Substituted C_3-8A cyclic or heterocyclic group or a heterocyclic or heterocyclic group;

preferably, the first and second electrodes are formed of a metal,r is as defined above₂₀₁Selected from methyl, F, Cl, Br, I; r₂₀₂、R₂₀₃Selected from each independently C_1-6Alkoxy, more preferably methoxy.

Preferably, the above compound or a pharmaceutically acceptable salt thereof, wherein the structural unitSelected from:

structural unitSelected from:

preferably, the above compound or a pharmaceutically acceptable salt thereof, wherein B is selected fromWherein,

R_301-305are each independently selected fromH、OH、NH₂F, Cl, Br, I, CN, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or alkoxy or alkylamino or cyclopropyl;

R₃₀₀₁selected from OH, N (CH)₃)₂、NH(CH₃)、NH₂F, Cl, Br, I, CN, methyl, methoxy, R₃₀₀₁The number of (a) is selected from 1,2 or 3;

optionally, one of the above general structural formulasSubstitution to pyridyl, thienyl, furyl;

preferably, the first and second electrodes are formed of a metal,

R_301-305each independently selected from methyl, H, OH, NH₂、F、Cl、Br、I、CN；

It is further preferred that the first and second liquid crystal compositions,

b is selected from

Preferably, the above compound or a pharmaceutically acceptable salt thereof, wherein B is selected from

Wherein,

R_306-312h, OH and NH independently₂F, Cl, Br, I, CN, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or alkoxy or alkylamino or cyclopropyl;

L₃₁selected from single bond, R₃₀₀₂N(R₃₀₀₃)R₃₀₀₄、O、S、CO₂C (O), C (S, S) and/or S (O)₂，R₃₀₀₂Selected from a single bond or C (═ O);

R₃₀₀₃is selected from H or C_1-3Alkyl or cyclopropyl;

R₃₀₀₄is selected from (CH)₂)_0-3；

Optionally, R₃₀₈And R_309a、R₃₀₈And R₃₁₀Together form a connecting bond (CH)₂)_1-3；

Preferably, R is as defined above₃₀₈And R₃₁₀Together form a connecting bond CH₂、R₃₀₈And R_309aTogether form a connecting bond CH₂CH₂。

Preferably, R is as defined above_306-312Each independently selected from methyl, cyclopropyl, C (CH)₃)₂(OH)、CH₂CH₂OH、CH₂N(CH₃)₂、H、OH、NH₂、F、Cl、Br、I、CN。

Preferably, L is as defined above₂₁Selected from single bond, NHCH₂CH₂；

Preferably, B is selected from

R₃₁₃、R₃₁₅、R₃₁₆each independently selected from H, OH, NH₂F, Cl, Br, I, CN, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or alkoxy or alkylamino or cyclopropyl;

R₃₁₄selected from H, OH, NH₂F, Cl, Br, I, CN, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or alkoxy or alkylamino or cyclopropyl, (CH)₂)_0-3R₃₀₀₅、Wherein R is₃₀₀₅Optionally substituted by R₃₀₀₁Substituted;

R₃₀₀₅is selected from C_3-6Cycloalkyl, phenyl, pyridyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, optionally substituted with a phenyl ring;

optionally, one of the above general structural formulasSubstituted by pyridyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl.

Preferably, R is as defined above₃₁₃、R₃₁₅、R₃₁₆Each independently selected from H, methyl;

preferably, R is as defined above₃₁₄Selected from H, methyl, ethyl, phenylmethylene, cyclopropylmethylene, methoxyphenyl,

Preferably, B is selected from

Wherein,

R₃₁₇selected from the group consisting of CR₃₀₀₆Or N;

R₃₁₈、R₃₁₉、R_3006-3008each independently selected from H, OH, NH₂F, Cl, Br, I, CN, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or alkoxy or alkylamino or cyclopropyl;

R_320-321each independently selected from C (R)₃₀₀₇)(R₃₀₀₈)、O、CON(R₃₀₀₉)、N(R₃₀₁₀)、C＝N(R₃₀₁₁)、S、CO₂C (O), C (S, S) and/or S (O)₂；

R_3009-3011Each independently selected from H, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or cyclopropyl;

R₃₀₀₁selected from OH, N (CH)₃)₂、NH(CH₃)、NH₂F, Cl, Br, I, CN, methyl, AOxy radical, R₃₀₀₁The number of (a) is selected from 1,2 or 3;

Preferably, R is as defined above₃₁₇Selected from the group consisting of CR₃₀₀₆Or N; r₃₀₀₆、R₃₁₈、R₃₁₉Selected from methyl, trifluoromethyl; r_320-321Each independently selected from CH₂、O、C(＝O)。

Preferably, B is selected from

L₃₂is selected from C (R)₃₀₀₇)(R₃₀₀₈)、O、CON(R₃₀₀₉)、N(R₃₀₁₀)、C＝N(R₃₀₁₁)、S、CO₂C (O), C (S, S) and/or S (O)₂；

R₃₂₃Is selected from C_1-6Alkyl radical, C_3-6Cycloalkyl, phenyl, pyridyl, imidazolyl, thienyl, furyl, oxazolyl, thiazolyl, isothiazolyl, optionally substituted by R₃₀₁₂Substituted;

R₃₂₂、R₃₂₄、R₃₀₀₇、R₃₀₀₈、R₃₀₁₂each independently selected from H, OH,NH₂F, Cl, Br, I, CN, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or alkoxy or alkylamino or cyclopropyl;

R₃₀₀₁selected from OH, N (CH)₃)₂、NH(CH₃)、NH₂F, Cl, Br, I, CN, methyl and methoxy;

R₃₀₀₁、R₃₀₁₂the number of (a) is selected from 1,2 or 3.

Preferably, R is as defined above₃₂₂、R₃₂₄Each independently selected from H, methyl, phenyl, C (CH)₃)₂OH。

Preferably, L is as defined above₃₂Selected from C (═ O), S (═ O)₂；

Preferably, R is as defined above₃₂₃Selected from the group consisting of tert-butoxy, methyl, ethyl, ethoxy, propoxy, isopropyl, cyclopropyl, methylamino, phenyl, pyridyl, 3-methylpyridyl, imidazolyl, C (CH)₃)₂OH；

Preferably, B is selected from

R_325-3281 or 2 of (A) are selected from N, the remainder are selected from C (R)₃₀₁₃)；

R₃₂₉Is selected from N (R)₃₀₁₄)、O、C(R₃₀₁₅)(R₃₀₁₆)、CON(R₃₀₁₇)、N(R₃₀₁₈)、C＝N(R₃₀₁₉)、S、CO₂C (O), C (S, S) and/or S (O)₂；

R₃₀₁₄Is selected from C (═ O) R₃₀₂₀、S(＝O)₂R₃₀₂₀Thiazolyl, isothiazolyl, phenyl, pyridyl, imidazolyl, thienyl, furyl, oxazolyl;

R₃₀₂₀selected from the group consisting of₃₀₀₁Substituted C_1-3Alkyl or alkoxy;

R₃₀₁₃、R₃₀₁₅、R₃₀₁₆、R_330-331each independently selected from H, OH, NH₂F, Cl, Br, I, CN, C (═ O) OH, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or alkoxy or alkylamino or cyclopropyl;

R_3017-3019each independently selected from H, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or cyclopropyl;

optionally, R₃₃₀And R₃₃₁Together form a connecting bond(CH₂)_1-3；

Optionally, when R₃₂₉Is selected from N (R)₃₀₁₄) Or O is, R₃₃₀And R₃₃₁Forming an order relation; when R is₃₂₉Is selected from C (R)₃₀₁₅)(R₃₀₁₆) When R is₃₃₀And R₃₃₁Forming an inversion relation;

preferably, R is as defined above_325-3281 or 2 of them are selected from N, the others are selected from CH, CC (═ O) OH or CCH₃。

Preferably, R is as defined above₃₂₉Is selected from N (R)₃₀₁₄)、O。

Preferably, R is as defined above₃₀₁₄Is selected from C (═ O) R₃₀₂₀、

Preferably, R is as defined above₃₀₂₀Is selected from C (CH)₃)(F)₂、CH₂CH₃、CH₂CF₃、CH(F)(CH₃)、CH(OH)(CH₃)、CH₂(OH)、CH(NH₂)(CH₃) Methoxy, ethoxy, aminomethyl.

Preferably, R is as defined above_330-331Selected from methyl.

Preferably, B is selected from

Wherein,

R₃₃₂selected from S, N (R)₃₀₂₁)、O、C(R₃₀₂₂)(R₃₀₂₃)、CON(R₃₀₂₄)、N(R₃₀₂₅)、C＝N(R₃₀₂₆)、S、CO₂C (O), C (S, S) and/or S (O)₂；

L₃₃Selected from single bond, C (═ O), S, O, C (R)₃₀₂₂)(R₃₀₂₃)、CON(R₃₀₂₄)、N(R₃₀₂₅)、C＝N(R₃₀₂₆)、S、CO₂C ═ S, S (═ O) and/or S (═ O)₂；

R₃₃₃Selected from N, C (R)₃₀₂₇)；

R₃₀₂₇、R₃₃₄、R₃₃₅、R₃₀₂₂、R₃₀₂₃Each independently selected from H, OH, NH₂F, Cl, Br, I, CN, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or alkoxy or alkylamino or cyclopropyl;

R₃₀₂₁、R_3024-3026each independently selected from H, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or cyclopropyl;

R₃₀₀₁selected from OH, N (CH)₃)₂、NH(CH₃)、NH₂F, Cl, Br, I, CN, methyl, methoxy,

R₃₀₀₁the number of (a) is selected from 1,2 or 3;

preferably, R is as defined above₃₃₂Selected from S, R₃₃₃Is selected from N, L₃₃Selected from single bond, C (═ O), R₃₃₄、R₃₃₅Selected from methyl.

Preferably, B is selected from

Wherein,

R₃₃₆、R₃₃₇、R₃₄₂each independently selected from N or C (R)₃₀₂₈)；

R₃₃₈、R₃₃₉Is selected from C (R)₃₀₂₉)(R₃₀₃₀) Optionally R₃₃₈And R₃₃₉Are commonly connected to the same (CH)₂)_1-3Looping;

m₃₁、m₃₂each independently selected from 0 or 1;

R_342a、R_342b、R₃₄₃、L₃₄each independently selected from a single bond, C (═ O) N (R)₃₀₃₁)、C(＝O)C(R₃₀₃₂)(R₃₀₃₃)、C(R₃₀₃₄)(R₃₀₃₅)、CON(R₃₀₃₆)、N(R₃₀₃₇)、C＝N(R₃₀₃₈) O, S, CO2, C (O), C S, S (O) and/or S (O)₂；

L₃₄May also be selected from single bonds;

R₃₄₀、R₃₄₁、R₃₄₄、R₃₄₅、R₃₀₂₈、R₃₀₂₉、R₃₀₃₀、R_3032-3035each independently selected from H, OH, NH₂F, Cl, Br, I, CN, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or alkoxy or alkylamino or cyclopropyl;

R₃₀₃₁、R_3036-3038each independently selected from H, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or cyclicPropyl;

R₃₀₀₁the number of (a) is selected from 1,2 or 3;

preferably, R is as defined above₃₃₆、R₃₃₇、R₃₄₂Each independently selected from N or CH.

Preferably, R is as defined above₃₃₈、R₃₃₉Is selected from CH₂Optionally R₃₃₈And R₃₃₉Connected to the same CH at the same time₂CH₂And (4) looping.

Preferably, m is as defined above₃₁、m₃₂Each independently selected from 0 or 1.

Preferably, L is as defined above₃₄Each independently selected from the group consisting of a single bond, C (═ O) NH, C (═ O) N (CH)₃)、C(＝O)CH₂。

Preferably, R is as defined above₃₄₀、R₃₄₁、R₃₄₄、R₃₄₅Each independently selected from H or methyl.

Preferably, R is as defined above_342a、R_342bIs selected from C (═ O) or CH₂。

Preferably, B is selected from

L₃₅each independently selected from the group consisting of a single bond, C (═ O) N (R)₃₀₃₁)、C(＝O)C(R₃₀₃₂)(R₃₀₃₃)、C(R₃₀₃₄)(R₃₀₃₅)、CON(R₃₀₃₆)、N(R₃₀₃₇)、C＝N(R₃₀₃₈)、O、S、CO₂C (O), C (S, S) and/or S (O)₂；

L₃₅May also be selected from single bonds;

R_3032-3035each independently selected from H, OH, NH₂F, Cl, Br, I, CN, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or alkoxy or alkylamino or cyclopropyl;

R₃₄₆、R_346a、R_346beach independently selected from H, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or alkoxy or alkanoyl or alkylsulfonyl or alkylamino or cyclopropyl, optionally substituted by R₃₀₀₁A substituted cyclopropyl acyl group or a cyclopropyl sulfone group;

R₃₄₆can also be selected from phenyl, pyridyl, imidazolyl, thienyl, furyl, oxazolyl, thiazolyl, isothiazolyl;

R₃₀₃₁、R_3036-3038each independently selected from H, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or cyclopropyl;

R₃₀₀₁the number of (a) is selected from 1,2 or 3;

preferably, L is as defined above₃₅Selected from single bond, C (═ O), CH₂；

Preferably, R is as defined above₃₄₆Selected from H, methyl, phenyl, C (CH)₃)₂(OH)、CH₂C(CH₃)₂(OH), cyclopropanoyl, isopropylsulfone;

preferably, B is selected from

R_347a、R_347beach independently selected from N or C (R)₃₀₂₈)；

R_348-3500, 1 or 2 of (A) are selected from N, the remainder are selected from C (R)₃₀₃₉)；

R₃₅₂、L₃₆Each independently selected from a single bond, -C (═ O) N (R)₃₀₃₁)-、-C(＝O)C(R₃₀₃₂)(R₃₀₃₃)-、C(R₃₀₃₄)(R₃₀₃₅)、CON(R₃₀₃₆)、N(R₃₀₃₇)、C＝N(R₃₀₃₈)、O、S、CO₂C (O), C (S, S) and/or S (O)₂；

L₃₆May also be selected from single bonds;

R₃₀₂₈、R_3032-3035、R₃₀₃₉、R_351a、R_351beach independently selected from H, OH, NH₂F, Cl, Br, I, CN, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or alkoxy or alkylamino or cyclopropyl;

R₃₀₀₁selected from OH, N (CH)₃)₂、NH(CH₃)、NH₂F, Cl, Br, I, CN, methyl, methoxy, R₃₀₀₁The number of (a) is selected from 1,2 or 3; preferably, L is as defined above₃₆Selected from single bond, C (═ O) NH, C (═ O) CH₂。

Preferably, R is as defined above_347a、R_347bEach independently selected from N, CH or C (OH).

Preferably, R is as defined above_348-3500, 1 or 2 of (A) are selected from N, the remainder are selected from C (R)₃₀₃₉)。

Preferably, R is as defined above₃₀₃₉Selected from H, methyl, trifluoromethyl, C (CH)₃)₂(OH)。

Preferably, R is as defined above_351a、R_351bEach independently selected from H, methyl, trifluoromethyl.

Preferably, R is as defined above₃₅₂Selected from C (═ O), C (CH)₃)(OH)。

Preferably, B is selected from

Preferably, the above compound or a pharmaceutically acceptable salt thereof, wherein B is selected from:

preferably, the above compound or a pharmaceutically acceptable salt thereof is selected from:

the term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; also included are Salts of amino acids (e.g., arginine, etc.), and Salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science66:1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt.

Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.

As used herein, "pharmaceutically acceptable salts" belong to derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a salt with a base. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, for example, salts formed with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic or organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous form.

Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.

Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, including variations of deuterium and hydrogen, so long as the valency of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., ═ O), it means that two hydrogen atoms are substituted. The keto substitution does not occur on the aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemical realizability.

When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent, unless otherwise specified. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, when a bond of a group or substituent may cross-link two atoms on a ring, such group or substituent may be bonded to any atom on the ring. When no atom through which a group or substituent is attached to a compound included in the general chemical structure formula but not specifically mentioned is specified in the listed group or substituent, such group or substituent may be bonded through any atom thereof. Combinations of groups or substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, the term "hydrocarbyl" or a subset thereof (e.g., alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means a straight, branched, or cyclic hydrocarbon radical, or combination thereof, that may be fully saturated, mono-, di-, or poly-unsaturated, that may be mono-, di-, or poly-substituted, that may include divalent or polyvalent radicals, that has the specified number of carbon atoms (e.g., C)₁-C₁₀Representing 1to 10 carbons). The alkyl group includes aliphatic alkyl groups including chain and cyclic, specifically including but not limited to alkyl, alkenyl, alkynyl, and aromatic alkyl groups including but not limited to 6-12 membered aromatic alkyl groups such as benzene, naphthalene, etc. In some embodiments, the term "alkyl" denotes a linear or branched or cyclic atomic group or a combination thereof, which may be fully saturated, mono or polyunsaturated, and may include both divalent and polyvalent atomic groups. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, and homologs or isomers of radicals such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl groups have one or more double or triple bonds, examples of which include, but are not limited to, ethenyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl, and higher homologs and isomers.

Unless otherwise specified, the term "heterocarbyl, heterocyclyl, hydrocarbacy, cycloheteroalkyl, heterocarbylheteroaryl, heterocyclylheteroaryl" means that the specified group contains a heteroatom or heteroatom group, heteroAtoms or heteroatom groups include, but are not limited to N, NH, substituted or protected NH, O, S (═ O)₂C (═ O), C (═ O) O, for the ring system, the heteroatom or group of heteroatoms may be located within or outside the ring system (e.g. cyclopropylsulfonyl, cyclopropylacyl), where the so-called heterohydrocarbyl, heterocyclyl group is attached to the rest of the molecule through a carbon atom, i.e. the heteroatom may be located anywhere on the group (except where the group is attached to the rest of the molecule); the term hydrocarbohetero, cyclohetero, is taken to mean attached to the remainder of the molecule through a heteroatom, i.e., a heteroatom is positioned at a position where the group is attached to the remainder of the molecule; the term heterocarbyl, heterocyclylheteroaryl is intended to mean a group attached to the remainder of the molecule through a heteroatom, which heteroatom may be located anywhere within the group (including where the group is attached to the remainder of the molecule).

Unless otherwise specified, the term "heterohydrocarbyl" or a subset thereof (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and the like) by itself or in combination with another term means a stable straight-chain, branched, or cyclic hydrocarbon radical, or combination thereof, consisting of a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heterocarbyl" or subset thereof (e.g., heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in combination with another term means a stable straight-chain, branched-chain hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom. In one exemplary embodiment, the heteroatoms are selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatoms B, O, N and S can be located at any internal position of the heterohydrocarbyl group (except where the hydrocarbyl group is attached to the rest of the molecule). Examples include, but are not limited to-CH₂-CH₂-O-CH₃、-CH₂-CH₂-NH-CH₃、-CH₂-CH₂-N(CH₃)-CH₃、-CH₂-S-CH₂-CH₃、-CH₂-CH₂、-S(O)-CH₃、-CH₂-CH₂-S(O)₂-CH₃、-CH＝CH-O-CH₃、-CH₂-CH＝N-OCH₃and-CH ═ CH-N (CH)₃)-CH₃. Up to two heteroatoms may be consecutive, e.g. -CH₂-NH-OCH₃。

Unless otherwise specified, the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in the conventional expression to refer to those alkyl groups attached to the rest of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.

Unless otherwise specified, the terms "cycloalkyl", "heterocycloalkyl", "cyclohydrocarbacyl" or their derivatives (such as aryl, heteroaryl, heteroaromato, cycloalkyl, heterocycloalkyl, cycloheteroalkenyl, cycloalkenyl, heterocycloalkenyl, cycloheteroalkenyl, cycloalkynyl, heterocycloalkynyl, cycloheteroalkynyl, and the like) by themselves or in combination with other terms mean cyclized "alkyl", "heteroalkyl" or "hydrocarbacyl", respectively. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclyl groups include 1- (1,2,5, 6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran indol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, and 2-piperazinyl.

Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. Furthermore, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C)₁-C₄) Alkyl "is intended to include, but not be limited to, trifluoromethyl, 2,2, 2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl, and the like.

Unless otherwise specified, the term "aryl" means a polyunsaturated aromatic hydrocarbon substituent, which may be mono-, di-or poly-substituted, which may be monocyclic or polycyclic (preferably 1to 3 rings), fused together or covalently linked. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In one illustrative example, the heteroatom is selected from B, N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroaryl group may be attached to the rest of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-oxazolyl, 2-thiazolyl, 2-pyridyl, 4-pyridyl, and the like, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalyl, 5-quinoxalyl, 3-quinolyl, and 6-quinolyl. The substituents for any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

Unless otherwise specified, for the sake of simplicity, aryl when used in combination with other terms (e.g., aryloxy, arylthio, aralkyl) includes aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like), including those alkyl groups in which a carbon atom (e.g., methylene) has been replaced by, for example, an oxygen atom, such as phenoxymethyl, 2-pyridyloxymethyl 3- (1-naphthyloxy) propyl and the like.

Unless otherwise specified, "ring" means a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. The so-called ring includes fused rings. The number of atoms in the ring is generally defined as the number of ring members, for example, "5 to 7 membered ring" means 5 to 7 atoms arranged around the ring. Unless otherwise specified, the ring optionally contains 1-3 heteroatoms. Thus, "5 to 7 membered ring" includes, for example, phenylpyridine and piperidinyl; in another aspect, the term "5-to 7-membered heterocycloalkyl ring" includes pyridyl and piperidyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.

The term "heteroatom" as used herein, unless otherwise specified, includes atoms other than carbon (C) and hydrogen (H), including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), and the like.

Unless otherwise specified, the term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate and the like; acyloxy groups such as acetoxy, trifluoroacetyloxy, and the like.

Unless otherwise specified, the term "protecting group" includes, but is not limited to, an "amino protecting group," a "hydroxyl protecting group," or a "thiol protecting group. The term "amino protecting group" refers to a protecting group suitable for use in preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: a formyl group; acyl, for example alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), 1-bis- (4' -methoxyphenyl) methyl; silyl groups, such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing side reactions of a hydroxy group. Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups, such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl groups, such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like.

Unless otherwise specified, examples of haloalkyl include, but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "alkoxy" represents the above alkyl group having the specified number of carbon atoms attached through an oxygen bridge. C_1-6Alkoxy radicals comprising C₁、C₂、C₃、C₄、C₅And C₆Alkoxy group of (2). Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and S-pentoxy. "cycloalkyl" includes saturated cyclic groups such as cyclopropyl, cyclobutyl, or cyclopentyl. 3-7 cycloalkyl radicals including C₃、C₄、C₅、C₆And C₇A cycloalkyl group. "alkenyl" includes hydrocarbon chains in either a straight or branched configuration, wherein one or more carbon-carbon double bonds, such as ethenyl and propenyl, are present at any stable site along the chain.

The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo, unless otherwise specified.

Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic or bicyclic heterocyclic ring which may be saturated, partially unsaturated or unsaturated (aromatic), which contains carbon atoms and 1,2,3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocyclic rings may be fused to a benzene ring to form a bicyclic ring.

Unless otherwise specified, examples of heterocyclic compounds include, but are not limited to: acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromene, cinnolinyl decahydroquinolinyl, 2H,6H-1,5, 2-dithiazinyl, dihydrofuro [2,3-b ] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatino, isobenzofuranyl, pyran, isoindolyl, indolyl, etc, Isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, isoxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazine, phenothiazine, benzoxanthine, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, Pyrazolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, isothiazolylthiothienyl, thienyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl, and xanthenyl. Fused ring and spiro compounds are also included. Unless otherwise specified, the compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof well known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present invention.

Unless otherwise specified, the structure of a compound is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass spectrometry (LCMS). NMR shift () at 10^-6The units in (ppm) are given. NMR was measured using a Brukeravence-400 nuclear magnetic spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) DeuteriumChloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

Unless otherwise specified, the determination of the absolute configuration is carried out by the conventional method of single crystal X-Ray diffraction, taking the determination of the absolute configuration of the compounds 1to 16 as an example, using a Bruker APEX-II CCD, a temperature of 296K, a radiation wavelength of 1.54178 and a radiation pattern of Cu-Ka.

Unless otherwise specified, the measurement liquid portion of the liquid mass spectrum LCMS was performed using Agilent 1200 (Xitinate C182.1X 30mm column) and the mass spectrum portion was performed using Agilent 6110 (ion source: ESI).

Unless otherwise specified, HPLC measurements were performed using shimadzu LC10AD high pressure liquid chromatograph (Xtimate C182.1 × 30mm column).

Unless otherwise specified, the silica gel plate for Thin Layer Chromatography (TLC) is HSGF254 silica gel plate of tobacco yellow sea or GF254 silica gel plate of Qingdao, the silica gel plate for Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification for separating and purifying products for thin layer chromatography is 0.4 mm-0.5 mm.

Unless otherwise specified, the column chromatography generally uses 200-300 mesh silica gel of Futai Huanghai silica gel as a carrier.

Unless otherwise specified, known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, TCI, Alfa, Shaoyuan Chemicals (Accela ChemBio Inc), Beijing couplings, and the like.

Unless otherwise specified, the reactions can be carried out in an argon atmosphere or a nitrogen atmosphere without specific mention in the examples. An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

Unless otherwise specified, hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1L volume.

Unless otherwise specified, the pressure hydrogenation reaction used a Parr3916EKX model hydrogenator and a Qinglan QL-500 model hydrogen generator or HC2-SS model hydrogenator. The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

Microwave reactions, unless otherwise specified, used either CEM Discover-S908860 or Biotage Initiator60 microwave reactors.

Unless otherwise specified, the solutions refer to aqueous solutions without specific mention in the examples.

Unless otherwise stated, the reaction temperature is room temperature and is 20 ℃ to 30 ℃ unless otherwise specified in the examples.

Unless otherwise specified, the progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC), using a system of developing reagents: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: the volume ratio of acetone and solvent is adjusted according to the polarity of the compound.

Unless otherwise specified, the system of eluents for column chromatography and developer system for thin layer chromatography used for purifying compounds include: a: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, C: the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

The present invention will be specifically described below by way of examples, which are not intended to limit the present invention in any way.

Unless otherwise specified, all solvents used in the present invention are commercially available and can be used without further purification.

Unless otherwise specified, the following abbreviations are used in the present invention: aq represents water; HATU represents O-7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; EDC stands for N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq representsEquivalent and equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc for ethyl acetate; EtOH stands for ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, an amine protecting group; BOC represents tert-butylcarbonyl as an amine protecting group; HOAc represents acetic acid; NaCNBH₃Represents sodium cyanoborohydride; r.t. represents room temperature; O/N stands for overnight; THF represents tetrahydrofuran; boc₂O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl₂Represents thionyl chloride; CS₂Represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N- (phenylsulfonyl) benzenesulfonamide; NCS represents 1-chloropyrrolidine-2, 5-dione; n-Bu₄NF represents tetrabutyl ammonium fluoride; iPrOH represents 2-propanol; mp represents the melting point.

Unless otherwise specified, the compounds are either by hand orThe software names, and the commercial compounds are under the supplier catalog name.

Compared with the prior art, the compound has high efficiency and low toxicity, makes remarkable and even unexpected progress in the aspects of activity, half-life period, solubility, pharmacokinetics and the like, and is more suitable for pharmacy.

Detailed Description

The present invention is described in detail below by way of examples, but is not meant to be limited to any of the disadvantages of the present invention. Having described the invention in detail and having disclosed specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Example 1

4- (2- (4- ((3R,5R) -3, 5-dimethylpiperidin-1-yl) phenyl) -4-methyl-1-oxo-1, 2-dihydroisoquinolin-5-yl) benzonitrile

Step 1: compound 1-1(60g,0.36mol) was dissolved in ice water (900mL), acetone (300mL) and aqueous HCl (180mL,2.23mol), and slowly added dropwise to an aqueous solution (360mL) of sodium nitrite (50g,0.72mol) at a temperature of 0-10 ℃. After stirring for 2 hours, solid potassium iodide (120g,0.72mol) was added directly and the temperature was maintained at 7-10 ℃ for 30 minutes, and then the reaction solution was heated to 80-90 ℃ until the purple gas disappeared and cooled to room temperature. The mixture was filtered to give compound 1-2(85g, yield 85%) as a yellow solid. MS ESI calculated value C₈H₇IO₃[M+H]⁺279, found 279.

Step 2: compound 1-2(34.5g,0.12mol) was dissolved in DCM (300mL), DMF (0.1mL) was added, then Compound 1-3(12mL,0.135mol) was added dropwise, and the reaction was stirred for 1 hour to give Compound 1-4 as a yellow oil. The crude product was used directly in the next step. MS ESI calculated value C₈H₆ClIO₂[M+H]⁺297, found 297.

And step 3: compound 1-5(15g,0.12mol) was dissolved in DCM (150mL), DIPEA (77g,0.6mol) was added, the reaction was stirred at room temperature for 5 minutes, then Compound 1-4(46g,0.12mol) was dissolved in DCM (300mL) and added dropwise at 0 ℃. After 3 hours of reaction, TLC (PE: EtOAc ═ 3:1) checked for completion, and the mixture was poured into water and extracted with DCM. The organic phase was washed with brine and dried over sodium sulfateAnd concentrated under reduced pressure. The crude product was purified by column chromatography (PE: EtOAc ═ 3:1) to give compounds 1-6(38g, 75% yield) as yellow solids. MS ESI calculated value C₁₃H₉ClINO₂[M+H]⁺374, found value 374.

And 4, step 4: to a solution of compounds 1-6(38g,0.1mol) in DMF (400mL) was added NaH (4.8g,0.2mol), the reaction solution, then compounds 1-7(24g,0.2mol) was added and stirred at 0 ℃ for 2 hours. And (4) detecting the reaction completion by LC-MS, slowly pouring the reaction liquid into water, and extracting by using ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (PE: EtOAc ═ 5:1) to give compounds 1-8(29g, 69% yield) as a yellow oil. MS ESI calculated value C₁₇H₁₅ClINO₂[M+H]⁺428, found value 428.

And 5: compounds 1-8(28g,66mmol), tetrabutylammonium bromide (53g,165mmol), KOAc (9.7g,0.1mol) and Pd (OAc)₂(1.48g,6.6mmol) was dissolved in DMF (250mL) and the reaction was stirred at 100 ℃ for 16 h. The reaction was complete by TLC (PE: EtOAc: 3: 1). The reaction was quenched with water, extracted with ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by recrystallization to afford compounds 1-9 as white solids (16g, 81% yield). MS ESI calculated value C₁₇H₁₄ClNO₂[M+H]⁺300, found 300.

Step 6: to a solution of compounds 1-9(16g,0.054mol) in DCM (150mL) was added BBr dropwise at 0deg.C₃(12.5mL,0.134mol), the reaction was stirred at room temperature for 16 h. The reaction was checked by TLC (PE: EtOAc: 3: 1). The reaction was quenched with saturated sodium carbonate solution and filtered to give compound as a white solid 1-10(13g, 84% yield). MS ESI calculated value C₁₆H₁₂ClNO₂[M+H]⁺286, found 286.

And 7: to a solution of compounds 1-10(5g,17.5mmol) in THF (50mL) were added DIPEA (4.5g,35mmol) and compounds 1-11(9.4g,26mmol), and the reaction was stirred at room temperature for 16 h. TLC (P) was used for the reaction solutionE: EtOAc 2: 1). The mixture was poured into water, extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (PE: EtOAc ═ 5:1) to afford compounds 1-12 as yellow oils (3.6g, 50% yield). MS ESI calculated value C₁₇H₁₁ClF₃NO₄S[M+H]⁺418, found 418.

And 8: compounds 1-12(3.6g,8.6mmol), compounds 1-13(1.7g,12mmol), Pd (dppf) Cl₂(630mg,0.86mmol) and sodium carbonate (2.1g,19.8mmol) were dissolved in dioxane/H₂O (48mL), the mixture was stirred at 110 ℃ and refluxed for 16 hours. The reaction was detected by TLC (PE: EtOAc: 3: 1). The mixture was poured into water, the residue was collected by filtration, and the crude product was purified by column chromatography (PE: EtOAc ═ 5:1) to afford compounds 1-14 as white solids (1.5g, 50% yield). MS ESI calculated value C₂₃H₁₅ClN₂O[M+H]⁺371, found 371.

And step 9: under the protection of nitrogen, compounds 1-14(100mg,0.27mmol), compounds 1-15(46mg,0.40mmol), Pd₂(dba)₃(25mg,0.03mmol), Xantphos (26mg,0.06mmol) and potassium tert-butoxide (61mg,0.54mmol) were dissolved in toluene (10mL) and the mixture was refluxed at 120 ℃ for 2h. After that, the mixture was filtered through celite, and the filtrate was spin-dried, extracted with ethyl acetate (50mL) and water (20mL), washed with brine, and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was purified by preparative HPLC to give the title compound as a white solid.¹H NMR (400MHz, CDCl3)8.65(d, J ═ 7.2Hz,1H),7.69(d, J ═ 8.0Hz,2H),7.50-7.35(m,4H),7.23(d, J ═ 8.4Hz,2H),6.93(t, J ═ 8.8Hz,3H),3.20(dd, J ═ 3.2Hz, J ═ 12.0Hz,2H),2.85(dd, J ═ 2.4Hz, J ═ 11.6Hz,2H),2.02(dd, J ═ 5.6Hz, J ═ 9.2Hz,2H),1.56(s,3H),1.45(t, J ═ 6.0Hz,2H),1.01(d, J ═ 6.8, 6H), 6C, 1H), calculated values₃₀H₂₉N₃O[M+H]⁺448, found 448.

The compounds shown in Table 1 can be synthesized from compounds 1-14 and the corresponding amines

Example 14

4- (2- (4- ((3R,5R) -4-benzoyl-3, 5-dimethylpiperazin-1-yl) phenyl) -4-methyl-1-oxo-1, 2-dihydroisoquinolin-5-yl) benzonitrile

Step 1 Compound 14-1(75g,0.4mol) and triethylamine (60mL,0.45mol) were dissolved in a solution of THF (500mL) and cooled to-30 deg.C, a solution of isobutyl chloroformate (54mL,0.42mol) in THF (100mL) was added dropwise and the reaction was stirred at-30 deg.C for 0.5h, then warmed to room temperature and stirred for an additional 5 h. The reaction mass was cooled again to 0 ℃ and Bn was added₂NH (88mL,0.43mol) and TEA (70mL,500mmol) were dissolved in THF (100mL) and added dropwise, and the reaction was stirred at room temperature for 10 hours. The reaction mixture was checked by LC-MS. The mixture was poured into water and extracted with ethyl acetate, and the organic layer was separatedWashed with brine, dried over sodium sulfate and concentrated under reduced pressure to give compound 14-2 as a white solid (84g, 60% yield). MS ESI calculated value C₂₂H₂₈N₂O₃[M+H]⁺369, found 369.

Step 2: to a solution of compound 14-2(53g,0.15mol) in DCM (450mL) was added TFA (120mL) and the reaction was stirred at room temperature for 5 h. The reaction mixture was checked by TLC (PE: EtOAc ═ 5: 1). The mixture was poured into water and sodium bicarbonate was added to adjust the pH>7, extracted with DCM, the organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give compound 14-3 as a yellow oil (38g, 98% yield). MS ESI calculated value C₁₇H₂₀N₂O[M+H]⁺269, found 269.

And step 3: to a solution of compound 14-3(38g,0.14mol) in THF (400mL) was added borane dimethylsulfide (98mL,0.98mol), and the reaction was stirred at room temperature for 48 hours. The reaction mixture was checked by LC-MS. The reaction is quenched with hydrochloric acid and adjusted to pH with aqueous NaOH>KOH (100g) was then added and the mixture was heated and refluxed for 24 hours. Extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM: MeOH ═ 10:1) to give compound 14-4 as a white solid (25g, 69% yield). MS ESI calculated value C₁₇H₂₂N₂[M+H]⁺255, found 255.

And 4, step 4: to a solution of methyl 2-trifluoromethanesulfonyloxypropionate (27.9g,118.1mmol) in DCM (100mL) at 0deg.C was added a solution of compound 14-4(25g,98.4mmol) and triethylamine (15.9g,157.44mmol) in DCM (150mL), and the reaction was stirred at 0deg.C for 2h and room temperature for 2h. The reaction mixture was checked by LC-MS and poured into DCM and NaHCO₃In (1). Extracted with DCM and the organic layer washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc) to afford compound 14-5 as a yellow oil (13.5g, 40% yield). MS ESI calculated value C₂₁H₂₈N₂O₂[M+H]⁺341, found value 341.

And 5: compound 14-5(12g,35.2mmol), hydrochloric acid (36%) (5mL) and Pd/C (2.5g) were dissolved in EtOH (100mL) and the mixture was reacted at 40psi for 2h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in EtOH (100mL), p-toluenesulfonic acid (2g) was added, and the reaction mixture was stirred and refluxed for 16 hours at 90 ℃. The reaction mixture was checked by LC-MS, the mixture was concentrated under reduced pressure, DCM and NaHCO were added₃. Extraction with DCM and organic layer washed with brine, dried over sodium sulfate and concentrated under reduced pressure gave compound 14-6 as a yellow solid (6g, 78% yield). MS ESI calculated value C₁₃H₁₈N₂O[M+H]⁺219, found value 219.

Step 6: to a solution of LAH (2.9g,75.6mmol) in THF (50mL) was added compound 14-6(5.5g,25.2mmol) in portions and the reaction mixture was stirred at room temperature for 0.5h, then heated to 70 ℃ for 6 h. The reaction mixture was checked by LC-MS. The reaction was quenched with water (2.9mL), 15% NaOH (2.9mL) and water (8.8mL), the mixture was stirred for 0.5h, the solid was filtered off and washed with THF. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to give compound 14-7 as a yellow solid (4.9g, 96%). MS ESI calculated value C₁₃H₂₀N₂[M+H]⁺205, found value 205.

And 7: mixing compound 14-7(2g,9.8mmol) and Pd (OH)₂the/C (0.9g) was dissolved in MeOH (20mL) and the mixture reacted at 35psi for 24 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 14-8 as a colorless oil (1g, 91% yield). MS ESI calculated value C₆H₁₄N₂[M+H]⁺115, found 115.

And 8: compound 14-10 was prepared by the foregoing method as a yellow solid (600mg, yield 84%). MS ESI calculated value C₂₉H₂₈N₄O[M+H]⁺449, found 449.

And step 9: to a solution of compound 14-10(150mg,0.33mmol) and triethylamine (100mg,0.99mmol) in DCM (5mL) was added compound 14-11(93mg,0.66mmol), and the reaction was stirred at room temperature for 5 hours. Mixing the reaction mixtureDetection was by LC-MS. The crude product was purified by preparative HPLC to give the title compound as a white solid.¹H NMR (400MHz, CDCl3)8.68(d, J ═ 7.6Hz,1H),7.72(d, J ═ 7.2Hz,2H),7.67-7.39(m,8H),7.28(t, J ═ 8.0Hz,3H),6.96(s,1H),6.74(d, J ═ 8.4Hz,2H),4.25(brs,2H),3.85(d, J ═ 10.4Hz,2H),3.40(d, J ═ 11.2Hz,2H),1.61(s,3H),1.31(brs,6H). MS calculated value C₃₆H₃₂N₄O₂[M+H]⁺553, found 553.

The compounds shown in Table 2 can be synthesized from compounds 14-10 and the corresponding acid chlorides and sulfonyl chlorides

Example 33

4- (4-methyl-1-oxo-2- (4- (3,4, 5-trimethylpiperazin-1-yl) phenyl) -1, 2-dihydroisoquinolin-5-yl) benzonitrile

Compound 33-1(200mg,0.45mmol), formaldehyde (41mg,1.35mmol) and NaBH₃CN (43mg,0.675mmol) was dissolved in THF (5mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was checked by LC-MS. The crude product was purified by preparative HPLC to give the title compound as a white solid.¹H NMR (400MHz, DMSO-d6)8.43(d, J ═ 8.0Hz,1H),7.91(d, J ═ 8.0Hz,2H),7.61-7.54(m,4H),7.35(d, J ═ 8.8Hz,2H),7.19(s,1H),7.14(d, J ═ 8.4Hz,2H),4.01(d, J ═ 12.8Hz,2H),3.35(d, J ═ 6.4Hz,2H),2.85(t, J ═ 12.4Hz,2H),1.52(s,3H),1.34(d, J ═ 6.4Hz,6H),1.19(t, J ═ 6.4Hz,3H), MS ESI C calculated values₃₀H₃₀N₄O[M+H]⁺463, found 463.

The compounds shown in Table 3 can be synthesized from compound 33-1 and the corresponding aldehyde

Example 39

4- (2- (4- (4-hydroxy-3, 3,5, 5-tetramethylpiperidin-1-yl) phenyl) -4-methyl-1-oxo-1, 2-dihydroisoquinolin-5-yl) benzonitrile

Step 1: compound 39-1(4g,20mmol) was dissolved in THF (50mL), cooled to 0deg.C, NaH (6.4g,160mmol) was added, the reaction mixture was then stirred at room temperature for 0.5h, the reaction mixture was cooled to 0deg.C again, methyl iodide (10mL,160mmol) was added dropwise, followed by warming to room temperature and stirring for 2h. The reaction was checked by TLC, the mixture was quenched with water, extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give compound 39-2 as a yellow solid (4.5g, 88% yield). MS ESI calculated value C₁₄H₂₅NO₃[M+H]⁺256, found 256.

Step 2: compound 39-2(410mg,1.6mmol) was dissolved in hydrochloric acid/methanol (10mL) and stirred at room temperature for 2 hours, the reaction was completed, and concentrated under reduced pressure to give compound 39-3 as a yellow oil (330mg, yield 86%). MS ESI calculated value C₉H₁₇NO[M+H]⁺156, measured value 156.

And step 3: compound 39-5 was prepared by the foregoing method as a yellow solid (300mg, yield 75%). MS ESI calculated value C₃₂H₃₁N₃O₂[M+H]⁺490, found 490.

And 4, step 4: compound 39-5(490mg,1mmol) was dissolved in THF (10mL) and NaBH was added₄(57mg,1.5mmol), followed by stirring at room temperature for 0.5 h. The reaction mixture was checked by LC-MS, the residue was poured into water and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the crude product. The crude product was purified by preparative HPLC to give the title compound as a white solid (64mg, 13% yield).¹HNMR (400MHz, CDCl3)8.69(d, J ═ 7.2Hz,1H),7.74(d, J ═ 7.6Hz,2H),7.60-7.45(m,4H),7.27(d, J ═ 6.4Hz,2H),7.00-6.90(m,3H),3.39(d, J ═ 12.0Hz,2H),3.12(s,1H),2.60(d, J ═ 12.0Hz,2H),1.62(s,3H),1.09(s,6H),1.04(s,6H). MS ESI calculated C₃₂H₃₃N₃O₂[M+H]⁺492, measured actuallyThe value 492.

Example 40

(S) -4- (4-methyl-1-oxo-2- (4- (6-oxo-hexahydro [1,2-a ] pyrazin-2 (1H) -yl) phenyl) -1, 2-dihydroisoquinolin-5-yl) benzonitrile

Step 1: a solution of compound 40-1(10g,4.20mmol) and DIEA (10.8g,84mmol) dissolved in toluene (200mL) was cooled to 0deg.C, ethyl 2, 3-dibromopropionate (13.1g,50.4mmol) was added, and the reaction mixture was stirred at 100 deg.C overnight. The reaction was checked by TLC. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and purified by concentration column chromatography under reduced pressure (PE/EtOAc ═ 10/1) to give compound 40-2 as a yellow oil (8.5g, 61% yield). MS ESI calculated value C₂₁H₂₆N₂O₂[M+H]⁺339, found 339.

Step 2: DIBAL-H (45mL,45mmol) was added to a solution of compound 40-2(8.4g,24.85mmol) in toluene (100mL) at-78 deg.C under nitrogen and stirred for 1H at-78 deg.C. After completion of the reaction, 20% sodium hydroxide (30.7mL) was added, followed by warming to room temperature and addition of 20% aqueous sodium hydroxide (76.8 mL). The solution was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give compound 40-3 as a yellow oil (7.4g crude). MS ESI calculated value C₁₉H₂₂N₂O[M+H]⁺295, found 295.

And step 3: compound 40-3(7.3g,24.75mmol) was dissolved in toluene (100) under nitrogen protectionmL), compound 40-4(17.2g,49.50mmol) was added thereto and stirred at 80 ℃ overnight. The reaction mixture was checked by LC-MS. The residue was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and purified by concentration under reduced pressure via column chromatography (PE/EtOAc 10/1to4/1) to give compound 40-5 as a yellow oil (5.6g, 62% yield). MS ESI calculated value C₂₃H₂₈N₂O₂[M+H]⁺365, found 365.

And 4, step 4: to a solution of compound 40-5(5.6g,15.34mmol) in ethanol (100mL) was added Pd/C (2.8g, 10%) and the reaction was heated to 70 ℃ at 55psi and stirred overnight. The reaction was checked by TLC, filtered through celite, and the filtrate was concentrated to give compound 40-6 as a yellow oil (2g, 71% yield). MS ESI calculated value C₇H₁₂N₂O[M+H]⁺141, found value 141.

And 5: the title compound was prepared by the preceding method as a white solid (30mg, 12% yield).¹H NMR (400MHz, CDCl3)8.66(d, J ═ 7.6Hz,1H),7.72(d, J ═ 8.0Hz,2H),7.42-7.58(m,4H),7.34(d, J ═ 8.8Hz,2H),7.04(d, J ═ 8.8Hz,2H),6.94(s,1H),4.13-4.18(m,1H),3.76-3.90(m,2H),2.69(d, J ═ 12.0Hz,1H),3.05-3.18(m,1H),2.75-2.85(m,1H),2.52-2.63(m,3H),2.25-2.35(m,1H),1.65-1.78(m,1H),1.61 (MS, 3H), calculated values of C (C, C), 1H), and 7.72(d, J ═ 8.8.8 Hz,1H)₃₀H₂₆N₄O₂[M+H]⁺475, found 475.

EXAMPLE 41

4- (4-methyl-2- (4- (5-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) phenyl) -1-oxo-1, 2-dihydroisoquinolin-5-yl) benzonitrile

Step 1: compound 41-1(2.9g,22.75mmol) was added to hydrazine hydrate (15mL), and the reaction mixture was immersed in a preheated oil bath (50 ℃) and then heated to above 100 ℃ for 30 minutes. After cooling to room temperature, the mixture was cooled to 0 ℃ and held for 1 hour. The residue was collected by filtration and dried to give compound 41-2 as a white solid (1.6g, 58% yield). MS ESI calculated value C₅H₈N₄[M+H]⁺125, measured value 125.

Step 2: TFAA (35mL) was added dropwise to compound 41-2(1.6g,13.2mmol) at 0deg.C, and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give a yellow solid. To this was added PPA (40mL) and the reaction was heated to 120 ℃ and stirred for 18 hours. The hot PPA solution was added to ice water and neutralized by adding ammonia. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (PE: EtOAc ═ 1:1) to afford compounds 41-3 as yellow solids (2g, 77% yield). MS ESI calculated value C₇H₅F₃N₄[M+H]⁺203, found value 203.

And step 3: compound 41-3(2g,10mmol) and Pd/C (1.1g) were dissolved in EtOH (30mL) and THF (15mL), and the reaction was stirred at room temperature for 18 hours under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated to give compound 41-4 as a yellow oil (1.9g, 90% yield). MS ESI calculated value C₇H₉F₃N₄[M+H]⁺207, found 207.

And 4, step 4: the title compound was prepared by the preceding method as a white solid (25mg, 6.8% yield).¹H NMR (400MHz, CDCl3)8.66(d, J ═ 7.6Hz,1H),7.71(d, J ═ 8.4Hz,2H),7.54(t, J ═ 8.0Hz,1H),7.45(dd, J ═ 23.2Hz, J ═ 8.0Hz5H),7.06(d, J ═ 8.8Hz,2H),6.92(s,1H), 4.91(d, J ═ 16.0Hz,1H),4.70(brs,1H),4.44(d, J ═ 16.0Hz,1H),3.83(d, J ═ 13.2Hz,1H),3.53(d, J ═ 10.8Hz,1H),1.68(d, J ═ 6.0, 3H), 3.59 (MS, s,3H), calculated values (C, 1H), 1H, and ESI₃₀H₂₃F₃N₆O[M+H]⁺541, found value 541.

Example 42

4- (4-methyl-1-oxo-2- (4- (3-oxotetrahydro-1H-oxazolo [3,4-a ] pyrazin-7 (3H) -yl) phenyl) -1, 2-dihydroisoquinolin-5-yl) benzonitrile

Step 1: compound 42-1(17g,84mmol) was dissolved in dioxane (340mL) and water (210mL) and the solution was adjusted to pH with aqueous sodium hydroxide (50%)>CbzCl (24mL,168mmol) was added and the mixture was stirred for 2 hours and then poured into 1L of water. The aqueous phase was extracted with DCM and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give compound 42-2 as a colorless viscous oil (18g, 51%). MS ESI calculated value C₂₁H₂₂N₂O₆[M+H]⁺399, measured value 399.

Step 2: compound 42-2(14g,35mmol) was dissolved in THF (150mL) and BH was added dropwise₃THF (70mL,70mmol), which was stirred at 50 ℃ for 3h. LC-MS showed the reaction was complete and the reaction was slowly quenched by addition of MeOH, after gas evolution ceased it was heated to 50 ℃ and stirred for 1 hour then it was reduced in pressure to give compound 42-3 as a colorless oil (4g, 30%). MS ESI calculated value C₂₁H₂₄N₂O₅[M+H]⁺385, measured value 385.

And step 3: compound 42-3(4g,10.4mmol) and potassium carbonate (1.7g,12.5mmol) were dissolved in EtOH (40mL) and the reaction was stirred at 70 ℃ overnight. LC-MS showed the reaction was complete, which was then removedFiltration to remove remaining potassium carbonate. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE: EtOAc ═ 1:1) to give compound 42-4 as a yellow solid (2.2g, 78%). MS ESI calculated value C₁₄H₁₆N₂O₄[M+H]⁺277, found 277.

And 4, step 4: to a solution of compound 42-4(500mg,1.8mmol) in MeOH (50mL) was added Pd/C (100mg) and the reaction was stirred under hydrogen (40psi) at room temperature for 12 h. Pd/C was removed by filtration, and the filtrate was reduced in pressure to give compound 42-5 as a yellow oil (240mg, 95%). MS ESI calculated value C₆H₁₀N₂O₂[M+H]⁺143, found 143.

And 5: the title compound was prepared by the preceding method as a white solid (55mg, yield 20%).¹H NMR (400MHz, CDCl3)8.67(d, J ═ 6.8Hz,1H),7.72(d, J ═ 8.0Hz,2H),7.55(t, J ═ 8.0Hz,1H),7.48(d, J ═ 7.6Hz,3H),7.35(d, J ═ 8.4Hz,2H),7.02(d, J ═ 8.4Hz,2H),6.92(s,1H),4.51(t, J ═ 10.4Hz,1H),4.04(d, J ═ 5.6Hz,2H),3.96(d, J ═ 2.4Hz,1H),3.71(d, J ═ 12.0Hz,1H),3.61(d, J ═ 12.0, 1H), 3.37H, 3.76(t, 1H), 1H, 3.94, 1H, 3.76(m ═ 10, 1H), calculated values of C, 1H₂₉H₂₄N₄O₃[M+H]⁺477, measured 477.

Example 43

2- (4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) -5- (furan-3-yl) -4-methylisoquinolin-1 (2H) -one

Step 1: to compound 43-1(9.7g,34.9mmol) at 0deg.CHATU (5.5g,40.86mmol) was added to a DMF (100mL) solution, and after stirring at room temperature for 30 minutes, DIEA (18g,69.8mmol) and compound 43-2(7.2g,34.9mmol) were added at 0deg.C, and the mixture was reacted at room temperature overnight. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give compound 43-3(13g, yield 80%) as a white solid. MS (ESI) M/z (M + H)⁺467.

Step 2: at 0 ℃ N₂To a solution of compound 43-3(13g,27.9mmol) in DMF (100mL) was added NaH (1.34g,33.5mmol), 3-bromo-1-propene (6.8g,55.8mmol) under protection, then reacted at room temperature overnight, the reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated by filtration, and the residue was purified by crude column chromatography to give compound 43-4(12g, 85.7% yield). MS (ESI) M/z (M + H)⁺507.

And step 3: compound 43-4(11.1g,21.74mmol), TBAB (17.50g,54.35mmol), potassium acetate (3.2g,32.61mmol), palladium acetate (487mg,2.17mmol) were added to DMF (700mL), followed by heating to 100 ℃ and stirring overnight, water was added to the reaction solution, extraction was performed with ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated by filtration, and the residue was purified by column chromatography to give compound 43-5(4.5g, yield 50%). MS (ESI) M/z (M + H)⁺379.

And 4, step 4: boron tribromide (12.6g,4.7mL) was added to a solution of compound 43-5(3.8g,10.05mmol) in dichloromethane (40mL) at 0 ℃, stirred at room temperature overnight, then quenched with a saturated sodium carbonate solution to give compound 43-6(1.9g, yield 53%) after filtration of the mixture. MS (ESI) M/z (M + H)⁺365.

And 5: to a solution of compound 43-6 (1.5g,4.12mmol) in DMF (60mL) were added DIPEA (1.1g,8.24mmol) and compound 43-7(2.2g,6.18mmol), reacted at room temperature overnight, then the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give compound 43-8(1.5g, yield 75%). MS (ESI) M/z (M + H)⁺497.

Step 6: to a solution of compound 43-8(496mg,1.0mmol) in 1, 4-dioxane was added compound 43-9(508mg,2.0mmol), Pd (dppf) Cl₂(73mg,0.10mmol) and potassium acetate (196mg,2.0mmol). reaction at 110 ℃ under nitrogen overnight, then the solvent was evaporated and the residue was purified by column chromatography to give compounds 43-10(270mg, 60% yield). MS (ESI) M/z (M + H)⁺475.

And 7: to a solution of compound 43-10(70mg,0.14mmol) in DMF and water (6mL,5:1) were added 3-furanboronic acid (24mg,1.5eq) potassium phosphate (59mg,0.28mmol) and Pd (dppf) Cl₂(10mg) and then refluxed overnight, water was added to the reaction solution, extracted three times with dichloromethane, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC to give the title compound as a pale yellow solid.¹H NMR (400MHz, Methanol-d4)8.57-8.59(d, J ═ 8.0Hz,1H)7.55-7.60(m,4H)7.33-7.35(mz,2H)7.16-7.18(d, J ═ 8.4Hz,2H)7.13(s,1H)6.52(s,1H)3.79-3.83(d, J ═ 14.4Hz2H)3.60-3.63(t, J ═ 11.2Hz,2H)2.50-2.56(t, J ═ 22.4Hz,2H)1.97(s,3H)1.24-1.25(d, J ═ 6.4Hz,6H) MS ESI C calculated₂₆H₂₆N₂O₃[M+H]⁺416, found 416.

Synthesis of the Compounds shown in Table 4 from Compounds 43-10 and the corresponding boronic acids

Example 69

5- (4-Cyclopropylphenyl) -2- (4- ((2R,6S) -2, 6-dimethylmorpholinyl) phenyl) -4-methylisoquinolin-1 (2H) -one

Mixing compound 69-1(106mg,0.20mmol), compound 69-2(52mg,0.60mmol), n-BuPAd₂(6.5mg,0.02mmol), palladium acetate (2.7mg,0.01mmol) and cesium carbonate (197mg,0.6mmol) were added to toluene/water (5:1, 3mL) and stirred under nitrogen at 110 ℃ for 2h. The mixture was poured into water and extracted with ethyl acetate (10mL), and the extract was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to giveThe title compound (20mg, yield 15%) was a yellow solid.¹H NMR (400MHz, CDCl3)8.60-8.62(t, J ═ 9.6Hz,1H)7.55-7.56(d, J ═ 3.6Hz,2H)7.46-7.48(d, J ═ 8.4Hz,2H),7.27-7.32(m,2H)7.20-7.22(d, J ═ 8.0Hz,2H),7.09-7.11(d, J ═ 8.0Hz,2H),6.89(s,1H),4.00-4.04(t, J ═ 14.4Hz2H)3.57-3.60(t, J ═ 11.2Hz,2H)2.68-2.73(t, J ═ 22.4Hz,2H),1.96-1.98(m, 1.66H), 1.0, 1.79 (d, J ═ 8.0Hz,2H), 1.79 (m,1H), 1.7.7.7.7, 7.7, 2H), calculated values (d, J ═ 8.0Hz,2H),6.89 (t, 1H), 1H, 1₃₁H₃₂N₂O₂[M+H]⁺465, found 465.

Example 70

4- (2- (6- (2, 6-dimethyl-morpholin-4-yl) -pyridin-3-yl) -1-oxo-1, 2-dihydro-isoquinolin-5-yl) -benzonitrile

Step 1: to a solution of compound 70-2 in dry dichloromethane (20mL) was added a solution of trimethylaluminum (2mol/L,3.85mL) in toluene at 0deg.C, and the mixture was stirred at room temperature for 15 minutes. Then a solution of compound 70-1(0.7g,3.1mmol) in dichloromethane (5mL) was added dropwise and the resulting solution was stirred at room temperature for 3 hours. LCMS showed reaction completion and addition of Rochelle salt solution. The resulting mixture was extracted with dichloromethane, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate ═ 5:1) gave compound 70-3(1.1g, 85%) as a yellow solid. MS ESI calculated value C₂₀H₂₄BrN₃O₃[M+H]⁺435, measurement 435.

Step 2: to compound 70-3(434mg,1mmol) in dry dichloromethane was added(20mL) to the solution was added dess-martin periodinane (507mg,1.2mmol) at 0 ℃. The mixture was stirred at room temperature overnight. The reaction was then quenched with saturated aqueous sodium thiosulfate and extracted with dichloromethane, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate ═ 5:1) gave compound 70-4(320mg, 77%) as a yellow solid. MS ESI calculated value C₂₀H₂₀BrN₃O₂[M+H]⁺415, and measuring the value 415.

And step 3: to a solution of compound 70-4(0.10g,0.24mmol) in 1, 4-dioxane (5mL) and water (1mL) under a nitrogen atmosphere was added compound 70-5(53mg,0.36mmol), sodium carbonate (51mg,0.48mmol) and Pd (dppf) Cl2(18mg,0.024 mmol). The reaction mixture was then heated to reflux and stirred overnight. When the reaction was complete, purification by preparative HPLC gave the title compound (56mg, 53%) as a white solid.¹HNMR (400MHz, CDCl3)8.43(d, J ═ 8.0Hz,1H),8.18(d, J ═ 2.0Hz,1H),7.90-7.82(m,3H),7.75-7.61(m,4H),7.32(d, J ═ 8.0Hz,1H),7.16(d, J ═ 8.8Hz,1H),6.60(d, J ═ 7.6Hz,1H),4.13(d, J ═ 12.8Hz,2H),3.75-3.71(m,2H),2.68(t, J ═ 12.0Hz,2H),1.24(d, J ═ 5.6Hz,6H), MS esic calculated value₂₇H₂₄N₄O₂[M+H]⁺437, found 437.

The compounds shown in Table 5 were synthesized from compound 70-4 and the corresponding boronic acid

Example 76

4- (4-chloro-2- (3-chloro-4- ((2S,6R) -2, 6-dimethylmorpholine) phenyl) -1-oxa-1, 2-dihydroisoquinolin-5-yl) benzonitrile

Add NCS (48mg,0.36mmol) to a solution of compound 76-1(100mg,0.24mmol) in dry DCM (10 mL). The reaction was then stirred at room temperature overnight. When the reaction was complete, purification by preparative HPLC gave the title compound as a white solid.¹H NMR (400MHz, CDCl3)8.65(d, J ═ 8.0Hz,1H),7.70(d, J ═ 8.4Hz,2H),7.50-7.68(m,2H),7.40-7.49(m,3H),7.27-7.35(m,2H),7.12(d, J ═ 8.0Hz,1H),3.85-4.00(m,2H),3.20-3.35(m,2H),2.40-2.55(m,2H),1.25(s,3H),1.24(s,3H) · MS ESI C calculated value₂₈H₂₇N₅O[M+H]⁺450, found 450.

Examples 77 and 78

4- (2- (3-chloro-4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) -1-oxo-1, 2-dihydroisoquinolin-5-yl) benzonitrile

4- (4-chloro-2- (3-chloro-4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) -1-oxo-1, 2-dihydroisoquinolin-5-yl) benzonitrile

To a solution of compound 77-1(100mg,0.24mmol) in dichloromethane (10mL) was added NCS (48mg,0.36mmol) in portions, the solvent was evaporated after stirring overnight at room temperature, and the residue was purified by preparative HPLC to give the title compound of example 77 as a yellow solid.¹H NMR (400MHz, CDCl3)8.57-8.59(d, J ═ 8.0Hz,1H)7.80-7.82(d, J ═ 8.0Hz,2H)7.63-7.64(t, J ═ 6.4Hz,2H),7.56-7.58(t, J ═ 8.0Hz,2H),7.46(s,1H)7.29-7.34(m,1H)7.12-7.14(d, J ═ 8.4Hz,2H),6.52-6.54(d, J ═ 8.0Hz,1H),3.93-3.95(t, J ═ 14.4Hz2H)3.27-3.30(t, J ═ 10.8, 2H)2.47-2.53(t, J ═ 14.4Hz, 24H, 23.26H), calculated values of t, J ═ 10.8, 2H, 23, 24.26H, 1H, C₂₈H₂₄ClN₃O₂[M+H]⁺471, found 471 the title compound of example 78 was isolated simultaneously as a yellow solid.¹H NMR (400MHz, Methanol-d4)8.64-8.66(d, J ═ 7.2Hz,1H)7.57-7.71(m,4H),7.44-7.47(dd, J ═ 8.0Hz,3H)7.31(s,1H),7.11-7.13(d, J ═ 8.0Hz,1H),3.89-3.93(t, J ═ 14.4Hz2H),3.26-3.29(t, J ═ 11.6Hz,2H)2.44-2.50(t, J ═ 21.6Hz,2H),1.24-1.26(d, J ═ 6.0Hz,6H) MS ESI₂₈H₂₃Cl₂N₃O₂[M+H]⁺505, measured value 505.

Example 79

4- (2- (3-bromo-4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) -1-oxo-1, 2-dihydroisoquinolin-5-yl) benzonitrile

NBS (43mg,0.24mmol) was added portionwise to a solution of compound 79-1(100mg,0.24mmol) in dichloromethane (10mL), the solvent was evaporated after stirring overnight at room temperature, and the residue was purified by preparativePurification by HPLC gave the title compound (20mg, 25% yield) as a white solid.¹H NMR (400MHz, Methanol-d4)8.43-8.45(d, J ═ 7.6Hz,1H)7.87-7.89(d, J ═ 8.4Hz,2H),7.64-7.71(m,5H),7.24-7.40(m,3H),6.58-6.60(d, J ═ 7.6Hz,2H),3.87-3.91(t, J ═ 14.4Hz2H),2.42-2.47(t, J ═ 22.4Hz,2H),1.18-1.20(d, J ═ 6.4Hz,6H), MS calculated value C ESI₂₈H₂₄BrN₃O₂[M+H]⁺515, found 515.

Example 80

4- (2- (3-cyclopropyl-4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) -1-oxo-1, 2-dihydroisoquinolin-5-yl) benzonitrile

Mixing compound 80-1(100mg,0.19mmol), compound 80-2(49mg,0.57mmol), n-BuPAd₂(7.2mg,0.02mmol), palladium acetate (3mg,0.01mmol) and cesium carbonate (187mg,0.57mmol) were added to toluene/water (5:1, 3mL) and stirred at 110 ℃ for 2h under nitrogen. The mixture was poured into water and extracted with ethyl acetate (10mL), and the extract was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (250mg, 20% yield) as a yellow solid.¹H NMR (400MHz, CDCl3)8.57-8.59(t, J ═ 9.2Hz,1H)7.80-7.82(d, J ═ 8.0Hz,2H)7.57-7.63(m,4H),7.11-7.18(m,3H)6.83-6.84(d, J ═ 1.6Hz,1H),6.50-6.52(d, J ═ 7.6Hz,1H),3.94-3.98(t, J ═ 14.4Hz2H)3.27-3.30(t, J ═ 10.8Hz,2H)2.55-2.60(t, J ═ 21.6Hz,2H),2.29-2.34(m,2H),1.24-1.26(d, J ═ 6H), 1.03-1.76 (m, 1.05H), MS-0.75 (m,3H), calculated values (m,3H), 1.5H, 1.6Hz,1, 2H, 1₃₁H₂₉N₃O₂[M+H]⁺476, found 476.

Example 81

4- (6- (4- ((2S,6R) -2, 6-dimethylmorpholine) phenyl) -8-methyl-5-oxa-5, 6-dihydro-2, 6-naphthyridin-1-yl) benzonitrile

Step 1: LDA (60mL,0.12mol) was added dropwise to a THF solution (200mL) of Compound 81-1(20g,0.1mol) at-78 deg.C, and the reaction was stirred at-78 deg.C for 2 hours. The mixture was poured quickly into dry ice. The mixture was then stirred at room temperature for 30 minutes and finally quenched by addition of water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and Na₂SO₄Drying and concentration under reduced pressure gave compound 81-2 as an off-white solid (10g, 43% yield). MS ESI calculated value C₆H₃BrClNO₂[M+H]⁺236, found value 236.

Step 2: a mixture of 81-3(5g,24.3mmol), allyl bromide (2.1g,17mmol) and K₂CO₃(6.7g,48.6mmol) was added to DMF (50mL) and stirred at 80 ℃ for 5 h. The reaction was poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (PE: EtOAc ═ 15:1) to give compound 81-4(2.5g, 42% yield) as a brown solid. MS ESI calculated value C₁₅H₂₂N₂O[M+H]⁺247, found value 247.

And step 3: add previous compound 81-2(2.1g,8.9mmol), compound 81-4(2.2g,8.9mmol) and DIEA (2.3g, 1)7.8mmol) in acetonitrile (20mL) was added CMPI (2.2g,8.9 mmol). The reaction was stirred at room temperature for 16 hours. The crude product was used directly in the next step. MS ESI calculated value C₂₁H₂₃BrClN₃O₂[M+H]⁺464, found 464.

And 4, step 4: compound 81-5(4.1g,8.9mmol), tetrabutylammonium bromide (7.2g,22.3mmol), palladium acetate (200mg,0.89mmol) and TEA (2.7g,26.7mmol) were heated to reflux in acetonitrile (40mL) and stirred for 48 h. The mixture was poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Finally, purification by silica gel chromatography (PE: EtOAc ═ 2:1) gave compound 81-6(1g, 30% yield) as a brown solid. MS ESI calculated value C₂₁H₂₂ClN₃O₂[M+H]⁺384, found 384.

And 5: compound 81-6(100mg,0.26mmol), 4-cyanophenylboronic acid (45.6mg,0.31mmol), Pd₂(dba)₃(24mg,0.026mmol), Xantphos (25mg,0.052mmol) and cesium carbonate (171mg,0.52mmol) were added to dioxane (5mL) and the mixture was heated to reflux and stirred for 16 h. The crude product was purified by preparative HPLC to give the title compound as a white solid.¹H NMR(400MHz,DMSO-d₆)8.79(d, J ═ 5.6Hz,1H),7.77(d, J ═ 8.0Hz,2H),7.67(d, J ═ 5.2Hz,1H),7.61(s,1H),7.54(d, J ═ 8.0Hz,2H),7.17(d, J ═ 8.4Hz,2H),6.97(d, J ═ 8.8Hz,2H),3.45-3.52(m,4H),2.15-2.30(m,4H),1.13(s,3H),1.11(s,3H), MS ESI C calculated value₂₈H₂₆N₄O₂[M+H]⁺451, found value 451.

The compounds shown in Table 6 were synthesized from compound 81-6 and the corresponding boronic acid

Example 85

4- (7- (4- ((2S,6R) -2, 6-dimethylmorpholine) phenyl) -5-methyl-8-oxa-7, 8-dihydro-1, 7-naphthyridin-4-yl) benzonitrile

Step 1: compound 85-1(4.3g,35mmol), DMF (0.5mL) and thionyl chloride (13mL,181mmol) were stirred at 80 ℃ for 12 h. The reaction mixture was concentrated to dryness under reduced pressure to give compound 85-2(6.1g, yield 100%) as a brown solid. MS ESI calculated value C₆H₃Cl₂NO[M+H]⁺176, found 176.

Step 2: to a solution of compound 85-3(6g,29.1mmol) in DCM (60mL) at 0deg.C was added compound 85-2(6.1g,35 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The reaction was poured into water (200mL) and the resulting precipitate was collected by filtration. The filter cake was dissolved in ethyl acetate and taken up with Na₂SO₄Dried, then filtered and concentrated to dryness. Final purification by silica gel chromatography (PE: EtOAc ═ 2:1) afforded compound 85-4(5.6g, 56% yield) as a white solid. MS ESI calculated value C₁₈H₂₀ClN₃O₂ [M+H]⁺346, found 346.

And step 3: at-78 ℃ N₂LDA (22mL,43.5mmol) was added to a solution of compound 85-4(5g,14.5mmol) in THF (20mL) under atmosphere. After 30 minutes, add I₂A solution of (5.5g,22.7mmol) in THF (20mL) was added to the above solution. The reaction mass obtained is subjected to a temperature of-78 DEG.CStirring was continued for 2 hours. It was then poured into water and extracted with ethyl acetate, the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EtOAc ═ 2:1) to give compound 85-5(5g, 74% yield) as a yellow solid. MS ESI calculated value C₁₈H₁₉ClIN₃O₂[M+H]⁺472, found 472.

And 4, step 4: add NaH (848mg,21.2mmol, 40% mineral oil) to a solution of compound 85-5(5g,10.6mmol) in DMF at 0 deg.C. The mixture was stirred under nitrogen atmosphere for 10 minutes. Then compound 85-6(2.56g,21.2mmol) was added to the above solution and the resulting mixture was stirred at 0 ℃ for an additional 2 hours. It was then poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 85-7(5.3g, 99% yield) as a white solid. MS ESI calculated value C₂₁H₂₃ClIN₃O₂[M+H]⁺512, found 512.

And 5: compound 85-7(5.4g,10.6mmol), palladium acetate (237mg,1.06mmol), TEA (2.1g,21.2mmol) and POT (322mg,1.06mmol) were added to DMF (40mL) and the mixture was stirred at 120 ℃ for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and finally purified by silica gel chromatography (PE: EtOAc ═ 1:1) to afford compounds 85-8(3g, 75% yield) as off-white solids. MS ESI calculated value C₂₁H₂₂ClN₃O₂[M+H]⁺384, found 384.

Step 6: mixing compound 85-8(300mg,0.78mmol), compound 85-9(160mg,1.09mmol), K₃PO₄(413mg,1.95mmol),Pd(dppf)Cl₂(57mg,0.078mmol) was added to DMF (5mL) and the mixture was stirred at 120 ℃ under a nitrogen atmosphere for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentratedAnd purified by preparative HPLC to give the title compound (75mg, 21% yield) as a white solid. MS ESI calculated value C₂₈H₂₆N₄O₂[M+H]⁺451, found value 451.

Example 86

4- (7- (4- ((2S,6R) -2, 6-dimethylmorpholine) phenyl) -5-methyl-8-oxa-7, 8-dihydro-2, 7-naphthyridin-4-yl) benzonitrile

Step 1: to a solution of 2,2,6, 6-tetramethylpiperidine (0.81mL,4.8mmol) in THF (10mL) at-50 ℃ under a nitrogen atmosphere was added dropwise n-butyllithium (1.8mL,4.4 mmol.5 minutes, then to the above solution was added 5-bromonicotinic acid (0.40g,2.0mmol), and after further 30 minutes, I was added dropwise at-50 ℃₂(0.61g,2.4mmol) in THF (5 mL). The resulting reaction mixture was stirred at-50 ℃ for 2 hours. The reaction mixture was quenched with water (10mL), the aqueous layer separated and Et₂O (10mL) was extracted, and the aqueous layer was acidified with 1M hydrochloric acid to pH 3. The precipitate was filtered and the filter cake was dried to give compound 86-2 as a beige powder. MS ESI calculated value C₆H₃BrINO₂[M+H]⁺328, found 328.

Step 2: compound 86-2(650mg,25mmol), compound 86-3(500mg,2mmol), HATU (770mg,2mmol) and DIEA (2mL) were added to DMF (10mL) and stirred at 20 ℃ for 4 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with Na₂SO₄And (5) drying. After concentration, purification by silica gel chromatography gave compound 86-4 (yield 70%) as an off-white solid. MS ESI calculated value C₂₁H₂₃BrIN₃O₂[M+H]⁺556, found 556.

And step 3: synthesis of compound 86-5 was as previously described. As a white solid. MS ESI calculated value C₂₁H₂₂BrN₃O₂[M+H]⁺428, found value 428.

And 4, step 4: the title compound (48% yield) was synthesized as a white solid as described previously.¹H NMR (400MHz, CDCl3)9.66(s,1H),8.56(s,1H),7.72(d, J ═ 8.4Hz,2H),7.44(d, J ═ 8.4Hz,2H),7.23(d, J ═ 8.4Hz,2H),6.95(d, J ═ 8.8Hz,2H),3.55-3.75(m,3H),3.40-3.50(m,2H), 2.35-2.50(m,2H),1.57(s,3H),1.22(s,3H),1.21(s,3H) · MS ESI calcd C₂₈H₂₆N₄O₂[M+H]⁺451, found value 451.

Example 87

4- (2- (4- ((2S,6R) -2, 6-dimethylmorpholine) phenyl) -4-methyl-1-oxa-1, 2,3, 4-tetrahydroisoquinolin-5-yl) benzonitrile

Step 1: to a solution of compound 87-1(500mg,1.37mmol) in MeOH (50mL) was added 10% Pd/C (50mg, 50% wet). The reaction mixture was then brought to 55psi H₂The mixture was stirred at 40 ℃ for 48 hours. After completion of the reaction, the reaction mixture was filtered with celite, and the filtrate was concentrated under reduced pressure to give compound 87-2(400mg, yield 80%) as a white solid. MS ESI calculated value C₂₂H₂₆N₂O₃[M+H]⁺367, found 367.

Step 2: transformingCompound 87-3(150mg, 30% yield) was synthesized as an off-white solid as described above. MS ESI calculated value C₂₂H₂₆N₂O₃[M+H]⁺499, found 499.

And step 3: the title compound was synthesized as a white solid as described previously.¹H NMR (400MHz, CDCl3)8.25(d, J ═ 7.6Hz,1H),7.78(d, J ═ 8.4Hz,2H),7.35-7.56(m,8H),4.33(dd, J ═ 8.4,3.6Hz,1H),4.06-4.16(m,2H),3.50-3.57(m,3H),3.07-3.16(m,1H),2.75-2.85(m,2H),1.31(s,3H),1.30(s,3H),1.24(d, J ═ 6.8Hz,1H). MS ESI calculated value C₂₉H₂₉N₃O₂[M+H]⁺452, found 452.

Example 88

4- (3- (4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: compound 88-1(50g,350mmol) was added to compound 88-2(170mL,1mol) and the system was then heated to reflux for 3h. After the reaction system was cooled to room temperature, compound 88-3(48g,280mmol) was added to the system, stirred for 12h and monitored by LC-MS until the reaction was complete. The system was then concentrated and the residue was washed with MeOH and dried to afford 88-4(80g, 90%) as a pale yellow compound. MS ESI calculated value C₁₃H₁₂BrNO₄[M+H]⁺326, found 326.

Step 2: compound 88-4(80g,245mmol) was dissolved in Ph₂O (560mL), the mixture was then heated to reflux for 1h, and after monitoring by LC-MS to completion of the reaction, 560mL of n-hexane was added in portionsIn this solution, the product was obtained. The product was washed with n-hexane and dried under reduced pressure to give 88-5(48g, 87%) as a gray solid. MS ESI calculated value C₉H₆BrNO[M+H]⁺225, found value 225.

And step 3: mixing 88-5(20g,89mmol), 88-6(14.4g,98mmol), Pd (dppf) Cl₂(6.5g,8.9mmol) and Na₂CO₃(18.8g,178mmol) was dissolved in DMF (200mL) and 40mL of water was added to the solution. The reaction was allowed to react at 90 ℃ overnight. LC-MS monitors until the reaction is completed. It was poured into 500mL of water and filtered to give a brown solid (19g, 87%). MS ESI calculated value C₁₆H₁₀N₂O [M+H]⁺247, found value 247.

And 4, step 4: NIS (17.4g,77.2mmol) was added portionwise to a solution of compound 88-7(19g,77.2mmol) in DMF (200 mL). The reaction was stirred at room temperature for 3h. LC-MS and TLC monitored until the reaction was complete. The solution was poured into water (500 mL). Filtration gave a brown residue. The residue was washed with MeOH and recrystallized from PE: EtOAc ═ 1: 1to give the title compound 88-8(25g, 87%) as a brown solid. MS ESI calculated value C₁₆H₉IN₂O[M+H]⁺373, found 373.

And 5: mixing 88-8(15g,40.3mmol) and Ag₂CO₃(25g,80.6mmol) was dissolved in DMF (150 mL). MeI (3.8mL,60.5mmol) was then added to the system. The reaction was stirred at 80 ℃ for 3h.lc-MS monitored to completion, the mixture was added to water and extracted with ethyl acetate, the organic layers were combined, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was purified by column chromatography (PE: EtOAc 10:1) to afford 88-9(3g, 19%) as a white compound. MS ESI calculated value C₁₇H₁₁IN₂O[M+H]⁺387, found 387.

And 5: mixing 88-9(200mg,0.52mmol), 88-13(246mg,1.04mmol), Pd (dppf) Cl₂(38mg,0.052mmol) and Na₂CO₃110mg,1.04mmol) was dissolved in THF (5mL) and H₂O (1 mL). MixingThe mixture was stirred at 60 ℃ overnight. LC-MS monitors until the reaction is complete. The reaction was extracted with ethyl acetate, the organic layers were combined, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was isolated by preparative chromatography to give the title compound as a pale yellow solid (23mg, 10% yield).¹H NMR(400MHz,CDCl₃)8.89(s,1H),8.33-8.31(m,1H),7.84-7.56(m,8H),7.04(d, J ═ 8.8Hz,2H),3.86-3.82(m,2H),3.70(s,3H),3.57(d, J ═ 11.2Hz,2H),2.51(t, J ═ 11.2Hz,2H),1.30(d, J ═ 6.0Hz,6H), MS ESI calculated value C₂₉H₂₇N₃O₂[M+H]⁺450, found 450.

Example 89

(2R,6S) -4- (4- (4-methoxy-8- (4- (trifluoromethyl) phenyl) quinolin-3-yl) phenyl) -2, 6-dimethylmorpholine

Step 1: to a solution of compound 89-1(4.9g,22mmol) in DMF (40mL) was added NIS (3.8g,22mmol) in portions. The reaction was stirred at room temperature for 2 hours. After completion of the LC-MS detection reaction, it was poured into water (500 mL). Product 2(5.5g, 71%) was obtained by filtration as a brown solid. MS ESI calculated value C₉H₅BrINO[M+H]⁺350, found 350.

Step 2: to compound 89-2(2.0g,5.8mmol) and Ag₂CO₃(2.4g,8.7mmol) in DMF (20mL) was added CH₃I (1.2g,8.7 mmol). The reaction mixture was stirred at 60 ℃ for 2 hours. After completion of the reaction was checked by LC-MS, the reaction was poured into water, followed by extraction with ethyl acetate (80X 3mL), and the organic phase was dried over sodium sulfate. After concentrationThe crude product was further purified by elution column PE: EtOAc ═ 5: 1to give compound 89-3(464mg, 22%) as a white solid. MS ESI calculated value C₁₀H₇BrINO[M+H]⁺364, measured value 364.

And step 3: mixing 89-3(1089mg,3mmol), 89-4(1050mg,3.3mmol), Pd (dppf) Cl₂(110mg,0.15mmol) and Na₂CO₃(636mg,6mmol) was added to THF (20mL)/H₂O (2mL), stirred overnight at 60 ℃ under nitrogen. After the reaction was complete, the mixture was filtered, the filtrate was extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product 4(140mg, 11%) as a white solid calculated as MS ESI C₂₂H₂₃BrN₂O₂[M+H]⁺427, found 427.

And 4, step 4: adding Pd (dppf) Cl into 89-5(70mg,0.16mmol) and 89-6(46mg,0.24mmol) compounds₂(15mg,0.02mmol),Na₂CO₃(34mg,0.32mmol) in THF (10mL)/H₂O (1mL) solution was stirred at 80 ℃ under nitrogen overnight. After the reaction was complete, the mixture was filtered, the filtrate was extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound (35mg, 45%) as a pale yellow solid.¹H NMR(400MHz,CDCl₃)8.91(s,1H),8.32-8.30(m,1H),7.83-7.57(m,8H),7.04(d, J ═ 8.8Hz,2H),3.84-3.83(m,2H),3.71(s,3H),3.57(d, J ═ 11.2Hz,2H),2.51(t, J ═ 11.2Hz,2H),1.30(d, J ═ 6.0Hz,6H), MS ESI calculated value C₂₉H₂₇F₃N₂O₂[M+H]⁺493, found 493.

The compounds shown in Table 7 were synthesized from compounds 89-5 and the corresponding boronic acids

Example 114

(2S,6R) -4- (4- (8- (1H-benzo [ d ] imidazol-2-yl) -4-methoxyquinolin-3-yl) phenyl) -2, 6-dimethylmorpholine

Compound 114-1(100mg,0.61mmol), Pd (dppf) Cl₂(23.1mg,0.061mmol), Compound 114-2(263.5mg,0.61mmol) and Na₂CO₃(161mg,1.53mmol) of the mixture was added to dioxane (2mL)The mixture was heated to 120 ℃ under nitrogen and stirred for 16 hours. The reaction was poured into water and extracted with ethyl acetate. The combined extracts were washed with brine, Na₂SO₄Dried and concentrated to dryness. Finally, column chromatography (PE: EtOAc ═ 3:1) was used to purify the title compound (15mg, yield 5.4%) as a white solid.¹H NMR (400MHz, CDCl3)9.10-9.20(m,1H),9.02(s,1H),8.37(d, J ═ 8.0Hz,1H),7.65-7.80(m,1H),7.62(d, J ═ 8.4Hz,2H),7.20-7.35(m,5H),7.08(d, J ═ 8.4Hz,1H),3.80-3.92(m,2H),3.74(s,3H),3.55-3.62(m,2H),2.50-2.60(m,2H),1.20-1.40(m,6H). MS ESI calcd C₂₉H₂₈N₄O₂[M+H]⁺465, found 465.

Example 115

2- (3- (4- ((2S,6R) -2, 6-dimethylmorpholine) phenyl) -4-methoxyquinolin-8-yl) thiazole-4-carbonitrile

Step 1: to a solution of compound 115-1(200mg,0.46mmol) in THF (10mL) was added dropwise under nitrogen at-65 deg.CⁿBuLi (0.22mL,0.552mmol), after the addition was complete, stirring was continued at that temperature for 1 hour. Then SnBu₃Cl (150mg,0.46mmol) was added to the above solution. The reaction mixture was stirred for 4 hours at-65 ℃ and saturated NH was added after the reaction₄And (4) quenching the Cl solution. Extraction was performed with ethyl acetate. The combined extracts were washed with brine, Na₂SO₄Dried and concentrated to dryness. Finally, column chromatography (PE: EtOAc ═ 1:1) was performed to give compound 115-2(120mg, yield 41%) as a white solid. MS ESI calculated value C₃₄H₅₀N₂O₂Sn[M+H]⁺639 measurement ofA value of 639.

Step 2: mixing compound 115-1(100mg,0.16mmol.), compound 115-2(30mg,0.16mmol), and Na₂CO₃(43mg,0.4mmol) and Pd (dppf) Cl₂(10mg,0.016mmol) was added to dioxane (2 mL). The mixture was heated to 120 ℃ under nitrogen blanket and stirred for 16 hours. The reaction was poured into water and extracted with ethyl acetate. The combined extracts were washed with brine, Na₂SO₄Dried and concentrated to dryness. Finally, column chromatography (PE: EtOAc ═ 1:1) was used to obtain the title compound (25 m)_gYield 34%) as a white solid.¹H NMR (400MHz, CDCl3)8.95(s,1H),8.85(d, J ═ 2.0Hz,1H),8.33(d, J ═ 2.0Hz,1H),8.10(s,1H),7.60-7.70(m,1H),7.56(d, J ═ 8.4Hz,2H),7.02(d, J ═ 8.4Hz,2H),3.75-3.85(m,2H),3.57(s,3H),3.52-3.60(m,2H),3.40-3.50(m,2H),1.29(s,3H),1.27(s,3H), MS ESI calcd C₂₆H₂₄N₄O₂S[M+H]⁺457, found 457.

Example 116

4- (3- (4- ((2S,6R) -2, 6-dimethylmorpholine) phenyl) -4-methoxyquinolin-8-yl) cyclohexanecarbonitrile

Step 1: to compound 116-1(10g,64mmol) and TosMIC (17.6g,90.27mmol) in DME (10mL) at 0deg.C was added t-BuOK (18.5g,165.2 mmol). The reaction mixture was stirred at 0 ℃ for 2 hours. After the reaction is finished, saturated NH is used₄And (4) quenching the Cl solution. Extraction was performed with ethyl acetate. The combined extracts were washed with brine, Na₂SO₄Dried and concentrated to dryness. Finally, column chromatography (PE: EtOAc ═ 1:1) was used to obtain 2(6.7g, yield50%) as a colorless oil.

Step 2: compound 116-1(3g,18mmol) in concentrated HCl/H₂A mixture solution of O (v/v ═ 1:1,20mL) was stirred at room temperature for 2 hours. The pH was adjusted to8 with NaOH and extracted with ethyl acetate. The combined extracts were washed with brine, Na₂SO₄Dried and concentrated to dryness. Finally, column chromatography (PE: EtOAc ═ 1:1) afforded compound 116-3(1.5g, 68% yield) as a colorless oil.

And step 3: LiHMDS (9.5mL,9.5mmol) was added dropwise to a solution of compound 116-3(1g,8mmol) in THF (20mL) at 0deg.C, stirring was continued for 30min after the addition was complete, and PhN (SO)₂CF₃) (3.6g,8.6mmol) was added to the above solution and the resulting mixture was stirred at 25 ℃ for 6 hours. Finally, water was added to quench and extraction was performed with ethyl acetate. The combined extracts were washed with brine, Na₂SO₄Drying and concentrating to dryness to obtain the sulfonate as yellow oil. The resulting sulfonate, Pd (dppf) Cl₂(80.4mg,0.11mmol), pinacol borate (0.67g,2.6mmol) and KOAc (0.65g,6.6mmol) were added to dioxane (15mL), heated to 100 ℃ under nitrogen and stirred for 18 hours. The reaction was poured into water and extracted with ethyl acetate. The combined extracts were washed with brine, Na₂SO₄Dried and concentrated to dryness. Finally, column chromatography (PE: EtOAc ═ 5:1) afforded compound 116-4(0.5g, 28% yield) as a white solid.

And 4, step 4: pd (dppf) Cl₂(180.8mg,0.23mmol), Compound 116-4(500mg,2.1mmol), Compound 116-5(1g,2.3mmol.) and Na₂CO₃(556mg,5.25mmol) of the mixture was added to dioxane (20 mL). The resulting suspension was heated to 80 ℃ under nitrogen and stirred for 4 hours. The reaction was poured into water and extracted with ethyl acetate. The combined extracts were washed with brine, Na₂SO₄Dried and concentrated to dryness. Finally, column chromatography (PE: EtOAc ═ 5:1) afforded compound 116-9(400mg, 42% yield) as a white solid. MSESI calculated value C₂₉H₃₁N₃O₂[M+H]⁺454, found 454.

And 5: Pd/C (100mg, 10%) and compound 116-6(100mg,0.22mmol) were added to EtOAc (20 mL). The mixture was stirred at room temperature for 50 hours under a hydrogen atmosphere of a hydrogen balloon. The reaction mixture was filtered and the filtrate was concentrated to dryness. Finally, separation and purification by preparative HPLC gave the title compound (50mg, 46% yield) as a white solid.¹H NMR (400MHz, CDCl3)8.90(s,1H),8.14(d, J ═ 8.4Hz,1H),7.50-7.65(m,6H),7.06(d, J ═ 8.8Hz,2H),4.00-4.15(m,1H),3.80-3.95(m,2H),3.69(s,3H),3.55-3.65(m,2H),3.15-3.20(m,1H),2.45-2.55(m,2H),1.90-2.25(m,7H),1.55-1.65(m,1H),1.33(s,3H),1.31(s,3H). MS ESI calculated value C₂₉H₃₃N₃O₂[M+H]⁺456, found 456.

Example 117

N- (3- (6- ((2S,6R) -2, 6-dimethylmorpholin) pyridin-3-yl) -4-methoxyquinolin-8-yl) pivaloamide

Step 1: mixing Na₂CO₃(430mg,4mmol), Compound 117-1(730mg,2mmol), Compound 117-2(480mg,2mmol) and Pd (dppf) Cl₂(150mg,0.2mmol) of the mixture was added THF/DMF/H₂O in a mixture solution of three solvents. Then heated to 80 ℃ and stirred for 4 hours. The reaction was poured into water and extracted with ethyl acetate. The combined extracts were washed with Na₂SO₄Dried and concentrated to dryness. Finally, column chromatography (PE: EtOAc ═ 5:1) was used to afford compound 117-3(430mg, 50% yield) as a brown solid, calculated as MS ESI C₂₁H₂₂BrN₃O₂[M+H]⁺428, found value 428.

Step 2:compound 117-3(130mg,0.3mmol), pivaloamide (60mg,0.6mmol), Cs₂CO₃(190mg,0.6mmol),Pd₂(dba)₃A mixture of (30mg,0.03mmol) and Xantphos (36mg,0.06mmol) was added to dioxane (5 mL). The mixture was heated to 120 ℃ and stirred under nitrogen for 4 hours. The reaction was poured into water and extracted with ethyl acetate. The combined extracts were washed with Na₂SO₄Dried and concentrated to dryness. Finally, separation and purification by preparative HPLC gave the title compound (30mg, 21% yield) as a white solid.¹H NMR (400MHz, CDCl3)10.23(brs,1H),8.77(d, J ═ 7.6Hz,1H),8.74(s,1H),8.47(d, J ═ 2.0Hz,1H),7.90-7.95(m,2H),7.69-7.80(m,1H),6.78(d, J ═ 8.4Hz,1H),4.05-4.10(m,2H),3.35-3.46(m,5H),2.26-2.85(m,2H),1.42(s,9H),1.31(s,9H),1.29(s,3H), MS ESI calcd for C₂₆H₃₂N₄O₃[M+H]⁺449, found 449.

Example 118

4- (4-chloro-3- (4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) quinolin-8-yl) benzonitrile

Step 1: to a suspension of compound 118-1(10g,44.64mmol), p-cyanophenylboronic acid (7.2g,49.11mmol) was added Pd (dppf) Cl₂(1.6g,0.1mmol), sodium carbonate (9.5g,89.23mmol) and DMF/H₂O (100:20, 120 mL). Reaction mixture in N₂Stirring was carried out overnight at 90 ℃ under protection. After completion of the LC-MS detection reaction, it was poured into water (500 mL). After filtration, product 2(10.8g, 98%) was obtained as a brown solid calculated by MS ESI C₁₆H₁₀N₂O[M+H]⁺247, found value 247.

Step 2: NIS (11.96g,53.17mmol) was added portionwise to a solution of compound 118-2(10.9g,44.31mmol) in DMF (110 mL). The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction was checked by LC-MS and TLC, it was poured into water (500 mL). After filtration the product was obtained as a brown residue (14g and 85%). MS ESI calculated value C₁₆H₉IN₂O[M+H]⁺373, found 373.

And step 3: to compound 118-3(5g,13.4mmol) was added phosphorus oxychloride (20 mL). The reaction mixture was stirred at reflux for 3 hours. After the reaction was complete, it was then poured into water (500mL) using LC-MS. After filtration and drying in vacuo, product 4(5.2g, 99%) was obtained as a brown solid calculated by MS ESI C₁₆H₈ClIN₂ [M+H]⁺391, found 391.

And 4, step 4: a mixture of compound 118-1(200mg,0.5mmol), compound 118-5(176mg,0.75mmol) was added Pd (dppf) Cl2(18mg,0.03mmol), sodium carbonate (106mg,1.0mmol) and suspended in THF/H2O (10:1,11mL) under protection of N2 at 90.deg.C and stirred overnight. The reaction was complete as detected by LC-MS. The mixture was purified by preparative HPLC to give the desired product as a brown solid (40mg, 33%).¹H NMR (400MHz, CDCl3)8.84(s,1H),8.38-8.49(m,1H),7.37-7.62(m,6H),7.54(d,2H, J ═ 8.0Hz),7.25(d,2H, J ═ 8.4Hz),3.97(t,2H, J ═ 7.6Hz),3.61(d,2H, J ═ 11.6Hz),2.67(t,2H, J ═ 11.6Hz),1.28(d,6H, J ═ 6.4Hz), MS esic calculated₂₈H₂₄ClN₃O[M+H]⁺454, found 454.

Example 119

4- (4- (dimethylamino) -3- (4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) quinolin-8-yl) benzonitrile

Step 1: compound 119-2(1.1g,13mmol) was added to a solution of compound 119-1(500mg,1.3mmol) in DMF (5 mL). DIEA (5g,39mmol) was then added. The reaction mixture was stirred at 120.deg.c for 10 hours. Then, it was poured into water (50mL) and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give the desired product as a white solid concentrated (100mg, 20%). calculated for MS ESI C₁₈H₁₄IN₃[M+H]⁺400, found value 400.

Step 2: compound 119-3(18mg,0.03mmol), sodium carbonate (100mg,0.25mmol), compound 119-4(88mg,0.37mmol), Pd (dppf) Cl2(53mg,0.5mmol) in THF/H₂O (11mL, 10:1) was stirred overnight under 90. deg.C. After completion of the LC-MS detection reaction, the mixture was purified by preparative HPLC to give the title compound as a white solid (20mg, 20%).¹H NMR (400MHz, CDCl3)8.37(s,1H),8.26(t,1H, J ═ 4.8Hz),7.80(d,2H, J ═ 6.8Hz),7.74(d,2H, J ═ 4.4Hz), 7.59(d,2H, J ═ 7.2Hz),7.19(d,2H, J ═ 7.2Hz),7.05(d,2H, J ═ 8.0Hz),3.85(t,2H, J ═ 7.2Hz),3.12(s,6H),2.53(t,2H, J ═ 11.2Hz),1.28(d,6H, J ═ 10.0Hz), MS ESI, calculated value C₃₀H₃₀N₄O[M+H]⁺463, found 463.

Example 120

4- (3- (4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) -4- (methylsulfonyl) quinolin-8-yl) benzonitrile

Step 1: NaSCH3(31mg,0.44mmol) was added to a solution of compound 120-1(200mg,0.44mmol) in DMF (5 mL). The mixture was then stirred at a temperature of 60 ℃ for 3 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate by LC-MS. The organic phase was dried over sodium sulfate and concentrated in vacuo to give the desired product (200mg, 97.6%) as a white solid. MS ESI calculated value C₂₉H₂₇N₃OS[M+H]⁺466, found 466.

Step 2: to a solution of compound 120-2(200mg,0.43mmol) in DCM (20mL) was added m-chloroperoxybenzoic acid (186mg,1.08 mmol, 80%). The mixture was then stirred at reflux overnight. After completion of the reaction, LC-MS detection was performed, poured into water and extracted with DCM. The organic phase was dried over sodium sulfate, concentrated in vacuo, and purified by preparative HPLC to give the desired product (120mg, 55%) as a white solid.¹H NMR (400MHz, CDCl3)9.36(d,1H, J ═ 8.0Hz),8.77(s,1H),7.99(d,2H, J ═ 8.4Hz),7.68 to 7.88(m,6H),7.62(d,2H, J ═ 8.4Hz),4.67(s,2H),4.19(d,2H, J ═ 14.0Hz),3.48(dd,2H, J ═ 10.0Hz,22.0Hz),3.06(s,3H),1.22 to 1.42(m,6H), MS esic calculated values₂₉H₂₇N₃O₃S[M+H]⁺498, found 498.

Example 121

4- (4-cyclopropyl-3- (4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) quinolin-8-yl) benzonitrile

Compound 121-1(100mg,0.22mmol), Palladium acetate (4.5mg,0.02mmol), n-BuPAd₂(4.7mg,0.01mmol), cesium carbonate (143mg,0.44mmol) in tolumen/H₂O (10:1,11mL) was stirred overnight at 120deg.C under protection of N2. After completion of the LC-MS detection reaction, purification by preparative HPLC gave the desired product (50mg, 42%) as a white solid.¹H NMR (400MHz, CDCl3)8.80(s,1H),8.70(d,1H, J ═ 8.4Hz),7.77(t,2H, J ═ 8.4Hz),7.65-7.75(m,3H),7.50(d,2H, J ═ 8.0Hz),7.38(d,2H, J ═ 8.4Hz),7.04-7.13(m,2H),3.85(dd,2H, J ═ 6.0Hz, J ═ 8.0Hz),3.50(d,2H, J ═ 11.2Hz),2.56(t,2H, J ═ 11.2Hz),2.34(t,1H, J ═ 6.4Hz),1.18(d,6H, J ═ 6.0), 1.08(d, 8H, J ═ 8.08, J ═ 8H, J ═ 8.5 Hz), calculated values of d, 8H, J ═ 8.5 (d, J ═ 8.0Hz), C, J ═ 6H, J ═ 8.0Hz, J ═ 8.0, 8.5 Hz, J ═₃₁H₂₉N₃O[M+H]⁺460, measured value 460.

Synthesis of the Compounds shown in Table 8 from Compound 121-1 and the corresponding boronic acid

Example 126

4- (4- (azetidin-1-yl) -3- (4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) quinolin-8-yl) benzonitrile

Step 1: PBr₃(26.0g,97mmol) solution was added dropwise to a solution of compound 126-1(24.0g,65mmol) in DMF (320 mL). Will be provided withThe mixture was stirred at room temperature for 1 hour. This was filtered and the product compound 126-5(26.0g, yield 93%) was given as a white solid. MS ESI calculated value C₁₆H₈BrIN₂[M+H]⁺434, found 434.

Step 2: to a solution of compound 126-2(11g, 25mmol), compound 126-3(9g,28mmol) and sodium carbonate (5.3g,50mmol) were dissolved in THF/H₂Pd (dppf) Cl was added to an O (5:1, 180mL) solution₂(1.83g,2.5 mmol). The mixture was stirred at 66 ℃ for 12 hours. The reaction mixture was complete and checked by LCMS. Then, it was poured into water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Crude compound 126-purification by column chromatography gave compound 126-4(9.3g, 74% yield) as a yellow solid calculated by MS ESI C₂₈H₂₄BrN₃O[M+H]⁺498, found 498.

And step 3: to a solution of compound 126-4(100mg,0.2mmol), compound 126-5(37.6mg,0.4mmol) and potassium tert-butoxide (112mg,1mmol) were added to PhCH₃(5mL) to the solution Pd was added₂(dba)₃(18.3mg,0.02mmol) and Xantphos (19.1mg,0.04 mmol). The reaction mixture was heated to reflux for 12 hours. LCMS indicated it was intact. It was then poured into water, extracted with diethyl ether (3X 3mL) and the organic phase was dried over anhydrous sodium sulfate. After concentration, the residue was purified by preparative HPLC to give the title compound (yield 21%) as a white solid.¹H NMR (400MHz, CDCl3)8.30(brs,1H),8.00(d,1H, J ═ 8.0Hz),7.70-7.80(m,3H),7.50-7.65(m,5H),6.92(d,2H, J ═ 5.6Hz),3.79(t,3H, J ═ 8.0Hz),3.45-3.53(m,4H),2.30-2.50(m,5H),1.27(d,6H, J ═ 6.0Hz), MS calculated value C ESI₃₁H₃₀N₄O[M+H]⁺475, found 475.

Example 127

4- (3- (4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) quinolin-8-yl) benzonitrile

A solution of compound 127-1(150mg,0.3mmol) in THF was added n-BuLi (0.5 mmol, 0.2mL) at-70 ℃. The mixture was poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were taken up in saturated aqueous solution. Sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative-HPLC to give the product (50mg, yield: 50%) as a white solid. MS ESI calculated value C₂₈H₂₅N₃O[M+H]⁺420, found value 420.

Example 128

Methyl 8- (4-cyanophenyl) -3- (4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) quinoline-4-carboxylic acid ethyl ester

To a solution of compound 128-1(150mg,0.3mmol) in methanol/DMF/THF (25/5/5mL) was added Pd (PPh)₃)Cl₂(21mg,0.03mmol) and TEA (303mg,3mmol) were reacted at 70 ℃ under a CO atmosphere with stirring at 50psi for 48 hours. After completion of the reaction by LC-MS, the crude product was purified by preparative HPLC to give the title compound as a white solid.¹H NMR(400MHz,CDCl3)9.00(s,1H),7.95(d,1H,J＝7.6Hz),7.68-7.85(m,6H),7.50(d,2H,J＝8.8Hz),7.27(d,2H,J＝8.8Hz),3.98(d,2H,J＝6.4Hz),3.86(s,3H),3.62(d,2H,J＝11.6Hz),2.62-2.73(m,2H),1.30(d,6H,J ＝6.0Hz) MS ESI calculated value C₃₀H₂₇N₃O₃[M+H]⁺478, found 478.

Example 129

N- (8- (4-cyanophenyl) -3- (4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) quinolin-4-yl) acetamide

To compound 129-1(50mg,0.1mmol) and NH₂Ac (30mg,0.5mmol) in dioxane (5mL) was added cesium carbonate (100mg,0.3mmol), Pd₂dba₃(9mg,0.01mmol) and Xantphos (12mg,0.02 mmol). The mixture was heated to reflux for 12 hours. After completion of the reaction was checked by LCMS, it was then poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and dissolved with DMF. The crude compound was purified by preparative HPLC to give the title compound (21mg, 44% yield) as a yellow solid.¹H NMR (400MHz, CDCl3)8.93(s,1H),8.00(d,1H, J ═ 8.4Hz),7.65-7.80(m,6H),7.37(d,2H, J ═ 8.8Hz),7.10(d,2H, J ═ 8.8Hz),3.87(t,2H, J ═ 7.6Hz),3.58(d,2H, J ═ 11.6Hz),3.56(t,2H, J ═ 11.6Hz),2.22(brs,2H),1.93(s,3H),1.18(d,6H, J ═ 6.0Hz), MS ESI calculated value C₃₀H₂₈N₄O₂[M+H]⁺477 measured value 477.

Synthesis of the Compounds shown in Table 9 from Compound 129-1 and the corresponding amide

Example 132

4- (3- (6- ((2S,6R) -2, 6-dimethylmorpholinyl) pyridin-3-yl) -4-methylquinolin-8-yl) benzonitrile

To compound 132-1(100mg,0.2mmol) and CH₃B(OH)₂(120mg,2mmol) in Toluene/H₂Adding n-BuPAd into solution of O (3mL/1mL)₂A mixture of (20mg,0.04mmol), palladium acetate (5mg,0.02mmol) and cesium carbonate (130mg,0.4mmol) was stirred at 110 deg.C overnight. After pouring into water, the mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated to give the crude product, which was purified by preparative HPLC to give the title compound (30mg, 30% yield) as a yellow solid. MS ESI calculated value C₂₈H₂₆N₄O[M+H]⁺435 found value 435.

Synthesis of the Compound shown in Table 10 from Compound 132-1 with the corresponding boronic acid

Example 135

4- (6-chloro-3- (4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: a mixture of 2, 2-dimethyl-1, 3-dioxane-4, 6-dione (19.2g,133mmol) and trimethoxymethane (70mL, 680mmol) was refluxed for 2.5 hours, then a mixture solution of compound 135-1(20g,97mmol) at 100 deg.C was added overnight, after filtration, the solid was collected to give compound 135-2(35.6g, yield 98%) as a yellow solid MS ESI calcd C₁₃H₁₃BrClNO₄[M+H]⁺362, measured value 362.

Step 2: compound 135-2(35.6g,100mmol) and compound 135-Ph₂Mixture of O (170g,1mol) was heated to 250 ℃ for 0.5h, then cooled to room temperature, after filtration, the solid was collected to give the product as a brown solid (12.2g, yield 48%). calculated MS ESI C₉H₅BrClNO[M+H]⁺258, found 258.

And step 3: to a solution of compound 135-3(3.56g,14mmol) and NIS (3.1g,14mmol) in DMF (10mL) was stirred at room temperature for 2 hours, after filtration the solid was collected to give 4.2g of the product as a yellow solid (yield 80%). calculation of MS ESI C₉H₄BrClINO[M+H]⁺384, found 384.

And 4, step 4: to a solution of compound 135-4 (4.5g,12mmol) in DMF (20mL) was added MeI (2.0g,14mmol) and Ag₂CO₃(6.6g,24mmol) which is stirred at 70 deg.CAfter stirring for 2 hours, then filtration, the mixture was extracted with ethyl acetate, dried over sodium sulfate, concentrated to give 4.8g of crude product, which was a purified column to give 2.2g of product as a red solid (yield 47%). calcd C by MS ESI₁₀H₆BrClINO[M+H]⁺397, found 397.

And 5: to a mixture of 135-5(200mg,0.5mmol) and2, 6-dimethyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) morpholine (160mg,0.5mmol) in THF/H₂Pd (dppf) Cl was added to an O (6mL,5:1) solution₂(40mg,0.05mmol) and sodium carbonate (107mg,1.0 mmol). The mixture was stirred at 70 ℃ overnight, then poured into water, the mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated to give compound 135-6 as a yellow solid (200mg, yield 40%). calcd by MS ESI₂₂H₂₂BrClN₂O₂[M+H]⁺461, measured value 461.

Step 6: to a solution of compound 135-6(200mg,0.43mmol) and (4-cyanophenyl) boronic acid (63.7mg,0.43mmol) in THF/H2O (6mL,5:1) was added Pd (dppf) Cl₂(37mg,0.05mmol) and sodium carbonate (92mg,0.86 mmol). After stirring the mixture at 70 ℃ for 3h, poured into water, the mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated to give the crude product, which was purified by preparative HPLC to give the title compound (55mg, yield 26%) as a yellow solid.¹H NMR (400MHz, CDCl3)8.84(s,1H),8.27(d,1H, J ═ 2.4Hz),7.78(dd,4H, J ═ 8.4Hz, J ═ 10.8Hz),7.63(d,1H, J ═ 2.0Hz),7.54(d,2H, J ═ 8.8Hz),7.02(d,2H, J ═ 8.4Hz),3.75-3.85(m,2H),3.68(s,3H),3.56(d,2H, J ═ 10.8Hz),2.50(t,2H, J ═ 11.2Hz),1.28(d,6H, J ═ 6.4Hz), MS ESI C calculated value₂₉H₂₆ClN₃O₂[M+H]⁺484, measured value 484.

Example 136

4- (3- (4- (2, 6-dimethylmorpholinyl) phenyl) -6-fluoro-4-methoxyquinolin-8-yl) benzonitrile

To a solution of compound 136-1(200mg,0.45mmol) and (4-cyanophenyl) boronic acid (66mg,0.45mmol) in THF/H2O (6mL,5:1) was added Pd (dppf) Cl₂(33mg,0.045mmol) and sodium carbonate (96mg,0.9 mmol). The mixture was stirred at 70 ℃ overnight, then poured into water, the mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated to give the crude product, which was purified by preparative HPLC to give the title compound (45mg, 21.4% yield) as a yellow solid.¹H NMR (400MHz, CDCl3)8.82(s,1H),7.65-7.70(m,1H),7.70-7.80(m,4H),7.50-7.60(m,2H),7.47(dd,1H, J ═ 2.8Hz, J ═ 8.8Hz),7.03(brs,2H),3.85(brs,2H),3.68(s,3H),3.56(d,2H, J ═ 10.8Hz),2.53(t,2H, J ═ 10.4Hz),1.29(d,6H, J ═ 6.4Hz), esims calculated value C₂₉H₂₆FN₃O₂[M+H]⁺468 measured value 468.

The compounds shown in Table 11 were synthesized from compound 136-1 and the corresponding boronic acid

Example 139

4- (4- (azetidin-1-yl) -3- (6- ((2S,6R) -2, 6-dimethylmorpholinyl) pyridin-3-yl) quinolin-8-yl) benzonitrile

Step 1: to a solution of compound 139-1(19.2g,0.1mol) in DMF (200mL) was added 2, 6-dimethylmorpholine (18g,0.15mol) and K₂CO₃(27.6g,0.2mol) and the reaction mixture was stirred at 120 ℃ for 4 h. After pouring in water, the mixture was extracted with ethyl acetate, dried over sodium sulfate and concentrated to give the crude product. Purification by column chromatography (EtOAc: PE ═ 1:5 to 1:1) gave compound 139-2(15.4g, 57% yield) as a yellow solid. MS ESI calculated value C₁₁H₁₅BrN₂O[M+H]⁺271, found value 271.

Step 2: to a solution (100mL) of the resulting 1, 4-dioxane compound 139-2(5.4g,20mmol) and pinacol borate (7.6g,30mmol) was added Pd (dppf) Cl₂(732mg,1mmol) and AcOK (4.0g,40mmol), and stirred at 120 ℃ for 6 hours. The solvent was then removed and purified with a column (EtOAc: PE ═ 1:10 to 1:2) to give compound 139-3(5.0g, yield 98%) as a white solid. MS ESI calculated value C₁₁H₁₇BN₂O₃[M+H]⁺237, found 237.

And step 3: to compound 139-3(236mg,0.7mmol) and compound 139-4(300mg,2mmol) in DMF/H₂A solution of O/THF (14: 1:5mL) was added to a mixture of sodium carbonate (214mg,4mmol) and stirred at-80 deg.C for 2 hours. After pouring into water, the mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated to give the crude product, which was purified by column chromatography (PE: EtOAc ═ 5:1) to give compound 139-5(200mg, yield 57%) as a white solid. MS ESI calculated value C₂₇H₂₃BrN₄O[M+H]⁺499, found 499.

And 4, step 4: to the compound139-2(1.5g,3mmol) and azetidine (560mg,6mmol) in toluene (20mL) was added Xantphos (350mg,0.6mmol), Pd₂(dba)₃(275mg,0.3mmol) and potassium tert-butoxide (1.3g,12mmol), the mixture was stirred at 110 ℃ for 3 hours. After pouring into water, the mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated to give the crude product, which was purified by column chromatography to give the desired product compound 139-6 as a yellow solid (500mg, yield 30%). MS ESI calculated value C₃₀H₃₁N₅O₂[M+H]⁺494, found 494.

And 5: to a solution of compound 139-6(1.5g,3mmol) in DCM (20mL) was added TFAA (4mL) and DIPEA (4mL), the mixture was stirred at room temperature for 30 minutes, then poured into water, the mixture was extracted with ethyl acetate, dried over sodium sulfate, concentrated to give the crude product, which was transferred to preparative HPLC for purification to give the title compound as a yellow solid (500mg, 30% yield).¹H NMR (400MHz, CDCl3)8.29(s,1H),8.19(s,1H),8.05(d,1H, J ═ 8.0Hz),7.93(brs,1H),7.80(d,2H, J ═ 7.6Hz),7.50-7.70(m,4H),6.98(brs,1H),4.70(brs,3H),4.17(d,3H, J ═ 12.4Hz),3.65-3.80(m,2H),2.78(t,2H, J ═ 11.6Hz),2.47(brs,2H),1.30(d,6H, J ═ 6.0Hz), esi₃₀H₂₉N₅O[M+H]⁺476 measured value 476.

Example 140

4- (3- (6- ((3S,5R) -3, 5-dimethyl-4-propionylpiperazin-1-yl) pyridin-3-yl) -4-hydroxyquinolin-8-yl) benzonitrile

Solution to Compound 140-1(100mg,0.2mmol) in DCM (5mL) was added CF₃COOH (114mg,1 mmol). The reaction mixture was stirred at 50 ℃ for 2 hours and then examined by LC-MS, showing that it was intact. The mixture is poured into H₂O, then extracted with ethyl acetate (30X 3mL) and the organic phase dried over sodium sulfate. After concentration, the residue was purified by preparative HPLC to give the title compound (30mg) as a white solid product. MS ESI calculated value C₃₀H₂₉N₅O₂[M+H]⁺492 measured values 492.

Example 141

4- (3- (4- ((2S,6R) -2, 6-dimethylmorpholine) phenyl) -4-methoxy-2- (trifluoromethyl) quinolin-8-yl) benzonitrile

Step 1: to a mixture of compound 140-2(10.7g,58.5mmol) and PPA (40g) was added dropwise compound 140-1(10g,58.5mmol) at 100 deg.C over 15 minutes. After the addition was complete, the reaction was heated to 150 ℃ and stirred for 12 hours, after cooling, the reaction was diluted with 160mL of 10% by weight sodium hydroxide. The resulting precipitate was filtered and the filtrate was acidified with concentrated hydrochloric acid. The resulting precipitate was filtered and recrystallized from ethanol to give compound 140-3(10.5g, yield 62%) as a white solid. MS ESI calculated value C₁₀H₅BrF₃NO[M+H]⁺292, found 292.

Step 2: add NIS (8.1g,36mmol) in portions to a solution of compound 140-3(10.5g,36mmol) in DMF (100 mL). The reaction mixture was stirred at room temperature for 1 hour, then poured into water (1L) and filtered, the resulting filter cake was washed with ethyl acetateDissolving the ester in Na₂SO₄Drying and concentration gave compound 140-4(14.3g, 95% yield) as a yellow solid. MS ESI calculated value C₁₀H₄BrF₃INO[M+H]⁺418, found 418.

And step 3: add previous compound 140-4(1g,2.4mmol) and Ag₂CO₃To a suspension of (1.5g,4.8mmol) in toluene (10mL) was added MeI (0.22mL,3.6mmol) dropwise, followed by stirring at 70 ℃ for 2h. The reaction was poured into water and extracted with ethyl acetate. The combined extracts were washed with brine, Na₂SO₄Dried and concentrated to dryness. Finally, purification by column chromatography (PE: EtOAc ═ 10:1) afforded compound 140-5(550mg, 55% yield) as a yellow-brown solid. MS ESI calculated value C₁₁H₆BrF₃INO[M+H]⁺432, found 432.

And 4, step 4: mixing 140-5(550mg,1.27mmol), 140-6(299mg,1.27mmol), Pd (dppf) Cl₂(93mg,0.127mmol) and Na₂CO₃(269mg,2.54mmol) was added to a mixed solution of THF (5mL) and water (1mL) and the reaction was heated to 60 ℃ under nitrogen and stirred overnight. The reaction was poured into water and extracted with ethyl acetate. The combined extracts were washed with brine, Na₂SO₄Dried and concentrated to dryness to give compound 140-7(170mg, 27% yield) as a yellow-brown solid. MS ESI calculated value C₂₃H₂₂BrF₃N₂O₂[M+H]⁺495, found value 495.

And 5: compounds 140-7(170mg,0.34mmol), 140-8(60.6mg,0.41mmol), Pd (dppf) Cl₂(25mg,0.034mmol) and Na₂CO₃(72mg,0.68mmol) was added to a mixed solution of THF (10mL), DMF (2mL) and water (2mL) and the reaction was heated to 110 ℃ under nitrogen and stirred overnight. The organic phase was separated and washed with brine, over Na₂SO₄Dried and concentrated to dryness. Finally, isolation and purification by preparative HPLC gave the title compound (60mg, 34% yield) as a white solid.¹H NMR(400MHz,CDCl3)8.26(d,J＝8.0Hz,1H),7.82-7.95(m,3H),7.70-7.80(m,3H),7.35-7.50(m,4H),3.95-4.20(m,3H),3.65-3.80(m,2H),3.63(s,3H),2.76-2.90(m,2H),1.33(s,3H),1.32(s,3H). MS ESI calcd for C₃₀H₂₆F₃N₃O₂[M+H]⁺518, measured value 518.

Example 142

4- (2- (4- ((2R,6S) -2, 6-dimethylmorpholine) phenyl) -4-methoxyquinolin-5-yl) benzonitrile

Step 1: compound 142-1(3.0g,17.4mmol) and compound 142-2(1.4g,8.7mmol) were heated to 180 ℃ under microwave irradiation and stirred for 3 hours. After cooling, the resulting solid was washed with ethyl acetate to give compound 142-3(2.4g, yield 22.2%) as a yellow-brown solid. MS ESI calculated value C₁₅H₁₂Br₂N₂O₂[M+H]⁺411, found 411.

Step 2: the compound 142-3(3.5g,8.46mmol) and P₂O₅(2.4g,16.9mmol) of CH₃SO₃The H (15mL) solution was heated to 160 ℃ and stirred for 3 hours. The reaction was poured into ice. The resulting solid was filtered and washed with water. The solid was then dissolved in 1M NaOH solution. Insoluble matter was filtered. The aqueous phase was adjusted to pH 3 with concentrated brine, the precipitate was filtered and washed with a small amount of water, and finally dried under reduced pressure to give compound 142-4(1.85g, 91% yield) as a white solid. MS ESI calculated value C₉H₆BrNO₂[M+H]⁺240, measured value 240.

And step 3: the compound 142-4(1.84g,7.62mmol) and K₂CO₃(2.11g,15.24mmol) ofThis was added to acetone (300 mL). Dimethyl sulfate (1.152g,9.15mmol) was added dropwise with stirring at room temperature. After the addition was complete, the reaction was heated to 50 ℃ and stirred for 2 hours. The reaction was concentrated to dryness. The pH was then adjusted to4 with 1M aqueous hydrochloric acid. The precipitate was filtered and washed with n-hexane to give a mixture of compound 142-5(0.84g, 43% yield). the mixture was purified by preparative HPLC to give compound 142-5(420mg) as a white solid. MS ESI calculated value C₁₀H₈BrNO₂[M+H]⁺254, found 254.

And 4, step 4: mixing compound 142-5(300mg,1.18mmol), compound 142-6(208mg,1.41mmol), Na₂CO₃(313mg,2.95mmol) and Pd (dppf) Cl₂(86mg,0.118mmol) of the mixture was added CH₃CN (5mL) and H₂O (1 mL). Then heated to 80 ℃ under nitrogen and stirred for 8 hours. The reaction was filtered and the filtrate was concentrated to dryness. Finally, purification was performed by column chromatography to give compound 142-7(223mg, yield 69%) as a yellowish brown solid. MS ESI calculated value C₁₇H₁₂N₂O₂[M+H]⁺277, found 277.

And 5: add trifluoromethanesulfonic anhydride (644mg,2.28mmol) dropwise to a solution of compound 142-7(350mg,1.27mmol) and pyridine (201mg,2.54mmol) in dichloromethane (15 mL). And the reaction was stirred overnight at room temperature. The reaction was concentrated to dryness, and finally purified by column chromatography to give compound 142-8(254mg, yield 49%) as a white solid. MS ESI calculated value C₁₈H₁₁F₃N₂O₄S[M+H]⁺409, measured value 409.

Step 6: mixing compound 142-8(100mg,0.245mmol), compound 142-9(116mg,0.367mmol), and Na₂CO₃(78mg,0.735mmol) and Pd (dppf) Cl₂(36mg,0.049mmol) of the mixture was added CH₃CN (5mL) and H₂O (1 mL). The reaction was heated to 80 ℃ under nitrogen and stirred for 3 hours. The reaction was filtered and the filtrate was concentrated to dryness. Finally, purification by preparative TLC gave the title compound (95mg, 86% yield) as a white solid.¹H NMR(400MHz, CDCl3)8.18(d, J ═ 7.6Hz,1H),8.09(d, J ═ 8.8Hz,2H),7.62-7.72(m,3H),7.40-7.50(m,2H),7.19(d, J ═ 6.4Hz,1H),7.09(s,1H),7.03(d, J ═ 8.8Hz,2H),3.75-3.83(m,2H),3.65(s,3H),3.55-3.64(m,2H),2.45-2.57(m,2H),1.25-1.30(m,6H), MS ESI calcd for C₂₉H₂₇N₃O₂[M+H]⁺450, found 450.

Example 143

4- (3- (4- ((2S,6R) -2, 6-dimethylmorpholine) -phenyl) -4-ethoxyquinolin-8-yl) benzonitrile

Step 1: to a solution of compound 143-1 in DMF (20mL) was added potassium carbonate (745mg,5.4mmol) and ethyl iodide, the mixture was stirred at 90 ℃ for 2h, after the reaction was complete water was added, then ethyl acetate was extracted, the combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the desired product 2(0.9g, 83%) as a solid. MS ESI calculated value C₁₈H₁₃IN₂O[M+H]⁺401, found value 401.

Step 2: compound 143-2(200mg,0.5mmol), compound 143-3(176mg,0.74mmol), Pd (dppf) Cl₂(36mg,0.05mmol) and sodium carbonate (106mg,1mmol) were suspended in THF/H₂O (10:1,11mL) was added to the mixed solution, followed by stirring at 90 ℃ for 12 hours under a nitrogen atmosphere. After the reaction was cooled, diluted with ethyl acetate then washed with salt, dried over sodium sulfate, concentrated under reduced pressure and the residue was purified by reverse phase HPLC (acetonitrile/water with 0.05% ammonium hydroxide modifier) to give the title compound (150mg, 70%) as a white solid.¹H NMR(400MHz,CDCl3)8.89(s,1H),8.51-8.49(m,1H),7.82(s,4H),7.64(d, J ═ 8.0Hz,2H), 7.49(d, J ═ 7.6Hz,2H), 7.08(d, J ═ 7.6Hz,2H), 4.08-4.03(m,2H),3.86(br.s.,2H),3.58(d, J ═ 12Hz,2H), 2.56(t, J ═ 11.2Hz,2H),1.37(t, J ═ 7.2Hz,3H),1.0(d, J ═ 6.4Hz,6H), MS ESI calculated value C calculated for MS ESI₃₀H₂₉N₃O₂[M+H]⁺464, found 464.

Synthesis of the Compound shown in Table 12 from Compound 143-1 and the corresponding alkyl halide

Example 147

4- (7- (4- ((2S,6R) -2, 6-dimethylmorpholine) phenyl) -8-methoxy-1, 5-naphthyridin-4-yl) benzonitrile

Step 1: to HC (OMe)₃2,2,6, 6-tetramethyl-2H-pyran-3, 5(4H,6H) -dione (13.8g,96mmol) was added (50mL,288mmol), and the mixture was stirred at 80 ℃ for 3 hours, then compound 147-1(10g,76.9mmol) was added, and stirring was continued for 5 hours. After LC-MS detection, the mixture was concentrated under reduced pressure and the crude product was washed with MeOH to give compound 147-2(15g, yield 57%). MS ESI calculated value C₁₅H₁₇ClN₂O₃[M+H]⁺309, found value 309.

Step 2: to preheated Ph₂O (250 ℃ C.) (500mL)) was added in portions to compound 147-2(13g,46mmol), the mixture was stirred for 5 minutes, LC-MS detection was carried out, and the reaction solution was cooledAfter cooling to room temperature, petroleum ether was added thereto and the mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 147-3(4g, yield 48%). MS ESI calculated value C₈H₅ClN₂O[M+H]⁺309, found value 309.

And step 3: a solution of compound 147-3(3g,16.7mmol) and NIS (4.1g,18.3mmol) in DMF (20mL) was stirred at room temperature for 16 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 147-4(2.5g, yield 49%). MS ESI calculated value C₈H₄ClIN₂O[M+H]⁺307, found 307.

And 4, step 4: compound 147-4(2.5g,8.2mmol), MeI (1.75g,12.3mmol) and Ag₂CO₃A solution of (4.5g,16.4mmol) in DMF (20mL) was stirred at 90 ℃ for 3 hours. The reaction mixture was checked by LC-MS. The mixture was poured into water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE: EtOAc ═ 10:1) to give compound 147-5(300mg, 12% yield). MS ESI calculated value C₉H₆ClIN₂O[M+H]⁺321, found value 321.

And 5: compound 147-5(320mg,1mmol), compound 147-6(350mg,1.1mmol), Pd (dppf) Cl₂(74mg,0.1mmol) and sodium carbonate (212mg,2mmol) in THF/H₂O (10:2mL) and stirred at 70 ℃ for 16 hours. The reaction mixture was checked by LC-MS. The mixture was poured into water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (using PE: EtOAc ═ 2:1) to give compound 147-7(200mg, 52% yield). MS ESI calculated value C₂₁H₂₂ClN₃O₂[M+H]⁺384, found 384.

Step 6: mixing compound 147-7(200mg,0.52mmol), compound 147-8(84mg,0.57mmol), Pd (dppf) Cl₂(38mg,0.052mmol) and sodium carbonate (110mg,1.04mmol) in THF/H₂O/DMF (10:2:2mL) and stirred at 90 ℃ for 4 hours. The reaction mixture was checked by LC-MSAnd (6) measuring. The mixture was poured into water and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the title compound (80mg, yield 34%) as a white solid.¹H NMR (400MHz, CDCl3)9.05(d, J ═ 4.8Hz,1H),8.95(s,1H),7.89-7.81(m,4H),7.59(t, J ═ 4.4Hz, 3H),7.04(d, J ═ 8.8Hz,2H), 4.09(s,3H),3.85-3.82(m,2H),3.58(d, J ═ 11.2Hz,2H),2.51(t, J ═ 11.2Hz,2H),1.30-1.25(m,6H), MS ESI calcd C₂₈H₂₆N₄O₂[M+H]⁺451, found value 451.

Example 148

4- (3- (4- ((2S,6R) -2, 6-dimethylmorpholine) phenyl) -4-methoxy-1, 7-naphthyridin-8-yl) benzonitrile

The title compound was synthesized as a white solid as described above.¹H NMR (400MHz, CDCl3)9.05(s,1H),8.82(d, J ═ 5.2Hz,1H),8.32(d, J ═ 5.6Hz,1H),8.14(d, J ═ 7.6Hz,2H),7.87(d, J ═ 8Hz,2H),7.62(d, J ═ 8Hz,2H),7.16(d, J ═ 8Hz,2H),3.89(s,2H),3.77(s, 3H),3.62(d, J ═ 12Hz,2H),2.61(d, J ═ 10.8Hz,2H),1.31(d, J ═ 6Hz,6H), MS ESI C calculated value₂₈H₂₆N₄O₂[M+H]⁺451, found value 451.

Example 149

4- (3- (6- ((3S,5R) -3, 5-dimethyl-4-propionylpiperazin-1-yl) pyridin-3-yl) -4-methoxy-1, 7-naphthyridin-8-yl) benzonitrile

The title compound was synthesized as a white solid as described above.¹H NMR(400MHz,METHANOL-d₄)8.96(s,1H),8.69(d, J ═ 5.6Hz,1H),8.46(d, J ═ 2.4Hz,1H),8.18(dd, J ═ 11.6,8.4Hz,3H),7.95(dd, J ═ 8.8,2.4Hz,2H),7.87(d, J ═ 8.4Hz,2H),7.06(d, J ═ 8.8Hz,1H),4.31-4.42(m,3H),3.81(s, 3H),3.16(d, J ═ 11.6Hz,2H),2.50(m,2H),1.31(s,6H),1.15(t, J ═ 7.6Hz,3H), MS ESI calculated value C₃₀H₃₀N₆O₂[M+H]⁺507, found value 507.

Example 150

8- (4-Benzenecarbonyl) -3- (4- ((2R,6S) -2, 6-dimethylmorphine) phenyl) -2-methylcinnolin-2-ammonium-4-ol salt

Step 1: to a solution of compound 150-1(2.3g,6.84mmol) in DMF (20mL) was added potassium carbonate (1.9g,13.7mmol) and methyl iodide. The mixture was then stirred at 90 degrees celsius for 4 hours. When the reaction was complete (according to LC-MS), water was added, followed by extraction with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (using PE/EtOAc ═ 3:1) to give the desired product 2(1.5g, 68%) as a solid. MS ESI calculated value C₉H₆ClIN₂O[M+H]⁺321, found value 321.

Step 2: compound 150-2(321mg,1mmol)Compound 150-3(282mg,1.2mmol), Pd (dppf) Cl₂(73.2mg,0.1mmol) and sodium carbonate (212mg,2mmol) were suspended in THF/H₂O (10:1mL) and stirred at 90 deg.C under nitrogen overnight. When the reaction was complete (according to LC-MS), water was added, followed by extraction with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give crude 4(320mg, 83.6%). MS ESI calculated value C₂₁H₂₂ClN₃O₂[M+H]⁺384, found 384.

And step 3: mixing compound 150-4(320mg,0.84mmol), compound 150-5(184mg,1.25mmol), Pd₂(dba)₃(77mg,0.08mmol), Xantphos (86mg,0.16mmol) and sodium carbonate (178mg,1.68mmol) were suspended in 1.4-dioxane/H₂O (10:1mL) and heated at 120 ℃ under reflux for 3 hours under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered through celite, and the filtrate was evaporated and extracted with ethyl acetate. The combined EtOAc layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (80mg, 20%).¹H NMR (400MHz, CDCl3)8.48(d, J ═ 8Hz,1H),7.80-7.69(m,6H),7.89-7.81(m,4H),7.36(d, J ═ 8.8Hz,2H), 7.15(d, J ═ 8.4Hz,2H), 4.19(s,3H),3.90-3.86(m,2H),3.60(d, J ═ 11.6Hz,2H),2.61(t, J ═ 10.8Hz,2H),1.29(d, J ═ 6.4Hz,6H), MS ESI calcd C₂₈H₂₆N₄O₂[M+H]⁺451, found value 451.

Example 151

4- (3- (6- (3, 5-dimethyl-4-propionylpiperazin-1-yl) -pyridin-3-yl) -4-methoxycinnolin-8-yl) -benzonitrile

Step 1: after heating and refluxing compound 151-1(51g,0.3mol), thionyl chloride (200mL) for two hours, thionyl chloride was evaporated, the residue was dissolved in dichloromethane, a solution of compound 151-2(42.3g,0.45mol), DIPEA (116g,0.9mol) in dichloromethane was added, the mixture was reacted at room temperature for 1 hour, then poured into water, washed with water, brine, the organic phase was dried and concentrated, and the residue was purified by column chromatography to give compound 151-3(26g, yield 40%) as a yellow oily liquid. MS ESI calculated value C₉H₁₁ClN₂O₂[M+H]⁺215, measured value 215.

Step 2: compound 151-3(26g,0.12mol) was dissolved in THF (300mL), MeMgBr (120mL,3M in Et2O) was slowly added to the solution at 0 ℃ and allowed to react at 0 ℃ for 2 hours, then the reaction solution was poured into aqueous ammonium chloride solution and extracted with ethyl acetate, and the extract was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give compound 151-4(10.5g, yield 51.4%) as a yellow solid. MS ESI calculated value C₈H₈ClNO[M+H]⁺169, found 169.

And step 3: compound 151-4(1.69g,10mmol) was added to water (10mL), concentrated hydrochloric acid (17mL) was added at 0 ℃, then sodium nitrite (2.1g,30mmol) was dissolved in water (10mL) dropwise to the reaction solution maintaining-5-0 ℃, after completion of the dropwise addition, reaction was carried out at 0 ℃ for 1 hour, then reaction was carried out at 80 ℃ for 6 hours, then cooling in an ice-water bath, the mixture was filtered and dried to give 1.2g of compound 151-5 in 67% yield as a yellow solid. MS ESI calculated value C₈H₅ClN₂O[M+H]⁺181, found value 181.

And 4, step 4: NIS (1.5g,0.67mmol) was added portionwise to a solution of compound 151-5(1.2g,0.67mmol) in DMF (10mL) and stirred at room temperature for 2 hours, then the solution was poured into water, filtered and the filter cake was dried to give 1.5g of compound 151-6 in 75% yield as a yellow solid. Calculated MS ESIC₈H₄ClIN₂O[M+H]⁺307, found 307.

And 5: compound 151-6(1.2g,0.67mmol), phosphorus oxychloride (5mL) were heated to 120 ℃, stirred for 2 hours, the reaction was cooled, poured slowly into methanol, water and ethyl acetate were added, the organic phase was separated, dried and concentrated to give 1.0g of compound 151-7 in 62.5% yield as a yellow solid. MS ESI calculated value C₉H₆ClIN₂O[M+H]⁺321, found value 321.

Step 6: mixing compound 151-7(320mg,1.0mmol), compound 151-8(292mg,1.0mmol), Pd (dppf) Cl₂(73mg,0.1mmol) and sodium carbonate (212mg,2.0mmol) were added to THF/H₂O/DMF (10: 1:1, 12mL) was stirred overnight at 80 ℃ under nitrogen. The mixture was filtered through celite, the filtrate was washed with water (10mL) and extracted with ethyl acetate (20mL), and the extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give compound 151-9(200mg, yield 68%) as a yellow solid. MS ESI calculated value C₂₃H₂₆ClN₅O₂[M+H]⁺441, measured value 441.

And 7: the title compound (10mg, yield 9%) was prepared as a white solid by the foregoing method.¹H NMR (400MHz, CDCl3)9.04-9.05(d, J ═ 2.0Hz,1H), 8.42-8.43(d, J ═ 6.8Hz,1H), 8.28-8.30(d, J ═ 8.8Hz,1H), 7.91-7.93(d, J ═ 8.4Hz,2H), 7.55-7.85(m,4H)6.86-6.88(d, J ═ 8.8Hz,1H)4.08-4.13(m,2H),3.90(s,3H)3.17-3.21(d d, J ═ 4.0Hz2H),2.25-2.28(m,2H)2.03-2.06(m,1H)1.19-1.28(m,9H ═ 0.98, 99.52 (d, J ═ 4Hz,2H) 2C 2H (m,1H) calculated values₃₀H₃₀N₆O₂[M+H]⁺507, found value 507.

Example 152

4- (3- (4- ((2R,6S) -2, 6-dimethylmorpholine) phenyl) -4-methoxycinnolin-8-yl) benzonitrile

Step 1: compound 152-1(1.2g,4mmol), sodium carbonate (4.3g,40.2mmol), Pd (dppf) Cl₂(200mg,02mmol) of 4- ((2R,6S) -2, 6-dimethylmorpholinyl) phenylboronic acid (1.15g,5mmol) was dissolved in a mixed solution of THF/water (20:4mL) and heated at 70 ℃ overnight. When (after completion of the reaction according to LC-MS), water was added, followed by extraction with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EtOAc ═ 5:1-2:1) to give compound 152-2(0.62g, yield 44%). MS ESI calculated value C₂₀H₂₀ClN₃O₂[M+H]⁺370, found 370.

Step 2: compound 152-2(3.7g,10mmol) in POCl₃(35mL) the solution was heated at 110 ℃ for 6 hours. The solvent was removed under vacuum. The residue was quenched by addition of water. The solution was separated between EtOAc and water and the organic layer, combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EtOAc ═ 2:1) to give compound 152-3(0.78g, yield 21%). MS ESI calculated value C₂₀H₁₉Cl₂N₃O[M+H]⁺389, found 389.

And step 3: to a solution of compound 152-3(0.19g,0.5mmol) in MeOH (10mL) was added NaOMe (0.055g,1mmol) portionwise at-10 deg.C over 10 minutes. The reaction mixture was stirred at 20 ℃ for 1 hour, then 50 ℃ for 3 hours. When the reaction was complete, water (100mL) was added, followed by extraction with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford compound 152-4(0.11g, 58%) as a brown solid, which was used directly in the next step. MS ESI calculated value C₂₁H₂₂ClN₃O₂[M+H]⁺384, found 384.

And 4, step 4: compound 152-4(40mg,0.1mmol), (4-cyanophenyl) boronic acid (30mg,0.2mmol), Pd₂(dba)₃(9mg,0.01mmol), Xantphos (10mg,0.02mmol) and sodium carbonate (4.3g,40.2mmol) were dissolved in a mixed solution of dioxane/water (5:1mL) and stirred at 110 ℃ for 6 hours under a nitrogen atmosphere. The mixture was diluted with water (10mL) and extracted with EtOAc. The combined layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound as a white solid (yield 32%).¹H NMR (400MHz, CDCl3)8.23(d, J ═ 8Hz,1H),8.06(d, J ═ 8.4Hz,2H),7.85(d, J ═ 8Hz,2H),7.77-7.69(m,4H),6.99(d, J ═ 8.8Hz,2H), 3.74(s,5H),3.57(d, J ═ 12Hz,2H),2.47(t, J ═ 10.8Hz,2H),1.23(d, J ═ 6.4Hz,6H), MS ESI C calculated value₂₈H₂₆N₄O₂[M+H]⁺451, found value 451.

Example 153

4- (4-chloro-3- (4- ((2S,6R) -2, 6-dimethylmorpholine) phenyl) -1, 6-naphthyridin-8-yl) benzonitrile

Step 1: mixing compound 153-2(21g,0.146mol) in CH (OMe)₃The solution (50mL) was stirred at 60 ℃ for 0.5 h. The reaction mixture was cooled to room temperature, and compound 153-1(21.05g,0.122mol) was added. The mixture was refluxed at 100 ℃ for 2 hours. TLC (PE: EtOAc ═ 1:1) showed complete consumption of starting material. The reaction mixture was cooled to 0 ℃ and filtered. The filter cake was triturated with MeOH to afford the compoundMaterial 153-2(24g, 62%) as a dark yellow solid.¹H NMR (400MHz, DMSO-d6) 11.48(brs,1H),8.96-8.81(m,1H),8.77(s,1H),8.51(d, J ═ 5.29Hz,1H),7.90(d, J ═ 5.29Hz,1H),7.37(t, J ═ 7.9Hz,1H),7.15-6.90(m,1H),1.68(s,6H). MS ESI calcd for C₁₂H₁₁BrN₂O₄[M+H]⁺326,328, found 326, 328.

Step 2: the pH of 153-2(0.4g,1.223mol) was adjusted₂The O (3mL) solution was refluxed at 220 ℃ for 0.5 hour. TLC detection showed complete consumption of starting material. The reaction mixture was cooled to room temperature and hexane was added. The mixture was filtered and the filter cake was washed with hexanes to give compound 153-4(200mg, 72%) as a dark yellow solid. MS ESI calculated value C₈H₅BrN₂O[M+H]⁺224and226, found 224and 226.

And step 3: to compound 153-4(550mg,2.455mmol) and compound 153-5(397mg,2.701mmol) (397mg,2.701mmol) in DMF (5mL) and H at room temperature₂To the mixed solution of O (1mL) was added sodium carbonate (780mg,7.365 mmol). The reaction mixture was purged with nitrogen three times and PdCl was added₂(dppf) (90mg,0.123 mmol). The reaction mixture was then sparged with nitrogen three more times and refluxed overnight. TLC (ethyl acetate) showed complete consumption of the starting material. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to dryness to give the crude product, which was purified by silica gel chromatography (EtOAc: MeOH ═ 100:4) to give compound 153-6(310mg, 35%) as a beige solid. MS ESI calculated value C₁₅H₉N₃O[M+H]⁺248, found value 248.

And 4, step 4: to a solution of compound 153-6(210mg,0.85mmol) in DMF (2mL) at 0deg.C was added NIS (200mg,0.887mmol) in portions. The reaction mixture was stirred at room temperature overnight. Tlc (etoac) showed most of the starting material was consumed. The reaction mixture was filtered, and the filtrate was concentrated to give compound 153-7(250mg, 79%) as a white solid. MS ESI calculated value C₁₅H₈IN₃O[M+H]⁺374, found value 374.

Step (ii) of5: 153-7(310mg,0.831mmol) in POCl₃The solution was refluxed (10mL) for 4 hours. TLC showed complete consumption of starting material. The reaction mixture was concentrated to dryness and diluted with ethyl acetate. The resulting solution was treated with NaHCO at 0deg.C₃(aq) basification. The mixture was partitioned between EtOAc and water. The organic layer was concentrated to dryness to give the crude product, which was purified by silica gel chromatography (PE: EtOAc ═ 1:1) to give compound 153-8(290mg, 90%) as a white solid. MS ESI calculated value C₁₅H₇ClIN₃[M+H]⁺392, found 392.

Step 6: compound 153-8(27mg,0.691mmol) and compound 153-9(262mg,0.828mmol) were dissolved in dioxane (3mL) and H₂O (0.6mL), and sodium bicarbonate (145mg,1.727mmol) was added. The reaction mixture was purged with nitrogen three times and Pd (dppf) Cl was added₂(50mg,0.069mmol), the reaction mixture was then sparged with nitrogen three more times and stirred at 80 ℃ for 2 hours. TLC (PE: EtOAc ═ 3:1) showed complete consumption of starting material. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to dryness to give the crude product, which was purified by chromatography on silica gel (PE: EtOAc ═ 2:1) to give the title compound (120mg, 30%) as a yellow solid.¹H NMR (400MHz, CDCl3)9.85(s,1H),9.08(s,1H),8.87(s,1H),7.90-7.83(m,5H),7.52(d, J ═ 8.53Hz,2H),7.09(d, J ═ 7.78Hz,2H),3.87(br.s.,2H),3.62(d, J ═ 11.29Hz,2H),2.57(t, J ═ 11.17Hz,2H),1.32(d, J ═ 6.27Hz,6H), MS ESI C calculated value₂₇H₂₃ClN₄O[M+H]⁺455 measured value 455

Example 154

4- (3- (4- ((2S,6R) -2, 6-dimethylmorpholine) phenyl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: sodium methoxide (32mg,6mmol) was added to a solution of compound 154-1(120mg,3mmol) in MeOH (15mL) and the mixture was stirred at 45 ℃ for 16 hours. While LC-MS showed complete consumption of the starting material, the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 154-2(0.1g, 83%) as a white solid. MS ESI calculated value C₁₆H₁₀IN₃O[M+H]⁺387, found 387.

Step 2: mixing compound 154-2(100mg,0.28mmol), compound 154-3(91mg,0.39mmol), Pd (dppf) Cl₂(22mg,0.032mmol) and sodium carbonate (45mg,0.52mmol) in THF (20mL) and H₂O (3mL), and the mixture was stirred at 80 ℃ overnight. While LC-MS showed complete consumption of the starting material, the solution was partitioned between EtOAc and water. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (30mg, 25%).¹H NMR (400MHz, CDCl3)9.71(s,1H),9.03(s,1H),8.76(s,1H),7.87(d, J ═ 8Hz,2H),7.81(d, J ═ 8Hz,2H),7.53(d, J ═ 8.4Hz,2H),7.04(d, J ═ 8.8Hz,2H),3.86-3.82(m, 5H),3.59(d, J ═ 10.8Hz,2H), 2.52(t, J ═ 11.2Hz,2H),1.30(d, J ═ 6.4Hz,6H), MS esic calculated value₂₈H₂₆N₄O₂[M+H]⁺451, found value 451.

Example 155

4- (4- (dimethylamino) -3- (4- ((2S,6R) -2, 6-dimethylmorpholine) phenyl) -1, 6-naphthyridin-8-yl) benzonitrile

To a solution of compound 155-1(80mg,0.176mmol) in DMF (2mL) was added compound 155-2(146mg,1.79mmol) and DIPEA (282mg,2.186 mmol). The mixture was stirred at 120 ℃ overnight. TLC (PE: EtOAc ═ 1:1) showed complete consumption of starting material. The mixture was concentrated to give the crude product, which was purified by chromatography on silica gel (PE: EtOAc ═ 1:1) to give the title compound (35mg, 43%) as a yellow solid.¹H NMR (400MHz, CDCl3)9.62(br.s.,1H),8.77(s,1H),8.61(s,1H),7.91(d, J ═ 7.06Hz,2H),7.84-7.69(m,5H),7.40(d, J ═ 7.06Hz,2H),4.58(br.s.,2H),3.51(d, J ═ 11.47Hz,2H),3.01(s,6H),2.91(t, J ═ 11.25Hz,2H),2.55(s,1H),1.94(s,1H),1.25(d, J ═ 6.62Hz,6H), MS ESI₂₉H₂₉N₅O[M+H]⁺464, found 464.

Example 156

4- (3- (4- ((2S,6R) -2, 6-dimethylmorpholine) phenyl) -8-hydroxy-4-methoxy-5, 6,7, 8-tetrahydroquinolin-8-yl) benzonitrile

Step 1: to a solution of compound 156-1(14.62g,0.101mol) in DMF (150mL) was added Ag2CO3(55.55g,0.201 mol). The mixture was purged with nitrogen and MeI (12.88g,0.091mol) was added. The reaction mixture was then stirred at 80 ℃ overnight. Tlc (etoac) showed complete consumption of starting material. The mixture was filtered and the filtrate was separated between EtOAc and water. Concentrating the organic layer to obtain crude product, and using the crude productChromatography on silica gel (PE: EtOAc ═ 2:1) gave compound 156-2(10g, 56%) as a colorless oil.¹H NMR (400MHz, CDCl3)8.72(d, J ═ 3.53Hz,1H),8.17(d, J ═ 7.94Hz,1H),8.02(d, J ═ 8.38Hz,1H),7.71-7.62(m,1H),7.52-7.42(m,1H),6.75-6.59(m,1H),3.99(d, J ═ 1.76Hz,4H), MS ESI calcd C₁₀H₉NO[M+H]⁺160, found 160.

Step 2: to a solution of compound 156-2(5g,0.031mol) in TFA (45mL) under nitrogen was added PtO₂(1g) of (1). The mixture was stirred at room temperature under 50psi of hydrogen. TLC (PE: EtOAc ═ 1:1) showed complete consumption of starting material. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in water and basified to pH 9 at 0 ℃ the aqueous layer was extracted with DCM with 8N NaOH (aq), the organic layer was washed with brine, dried over sodium sulfate and concentrated to give compound 156-3(4g, 80%) as a yellow oil which was used directly in the next step.¹H NMR (400MHz, CDCl3)8.18(d, J ═ 5.73Hz,1H),6.50(d, J ═ 5.73Hz,1H),3.75(s,3H),2.78(t, J ═ 6.17Hz,2H),2.53(t, J ═ 6.17Hz,2H),1.79-1.62(m,5H) · MS esic calcd₁₀H₁₃NO[M+H]⁺164, measured value 164.

And step 3: NIS (9.6g,0.043mol) was added portionwise to a solution of compound 156-3(5.8g,0.0356mol) in sulfuric acid (30mL) at 0deg.C, and the mixture was stirred at room temperature for 0.5 hour and heated to 60 deg.C for 2 hours. TLC (PE: EtOAc ═ 1:1) showed complete consumption of starting material. The mixture was poured into ice water and basified to pH 9 with 8N NaOH (aq). The aqueous layer was then extracted with DCM. Nahco the organic layer was washed with sat₃(aq), washed with brine and concentrated to give the crude product which is purified by chromatography on silica gel (PE: EtOAc 15:1) to give compound 156-4sat₃(aq) as a brown solid.¹H NMR (400MHz, CDCl3)8.55(brs,1H),3.80-3.73(m,2H),2.84-2.77(m,2H),2.76-2.70(m,2H),1.85-1.69(m,4H). MS ESI calcd for C₁₀H₁₂INO[M+H]⁺290, found value 290.

And 4, step 4: to compound 156-4(1.44g,0.005mol) in CHCl at 0deg.C₃(10mL)m-CPBA (2.6g,0.015mol) was added in portions to the solution and the mixture was stirred at 40 ℃ for 2 hours. The mixture was quenched with water and the pH adjusted to 14 by addition of 8N NaOH (aq). The aqueous layer was then extracted with DCM. Nahco the organic layer was washed with sat₃(aq), washed with brine and concentrated to give compound 156-5(1.3g, 88%) as a yellow solid which was used directly in the next step. MS ESI calculated value C₁₀H₁₂INO₂[M+H]⁺306, found value 306.

And 5: ac of compound 156-5(1.3g,0.0043mmol)₂The O (6mL) solution was stirred at 90 ℃ for 2 hours. The mixture was concentrated and 4N NaOH (aq) (4.3mL,0.017mol) was added. The mixture was stirred at 80 ℃ for 2 hours. The aqueous layer was then extracted with DCM. The organic layer was concentrated to give the crude product, which was purified by silica gel chromatography (PE: EtOAc ═ 3:1) to give compound 156-6(0.82g, 33%) as a yellow solid.¹HNMR (400MHz, CDCl3) 8.61(s,1H),4.59(brs,1H),3.79(s,3H),3.67(br.s.,1H),2.77(br.s.,2H),2.19(br.s.,1H),1.94(br.s.,1H),1.71(br.s.,2H). MS ESI C₁₀H₁₂INO₂[M+H]⁺306, found value 306.

Step 6: to dioxane (8mL) of compound 156-6(0.8g,0.0026mol) and compound 156-7 and H₂To the O (2mL) mixed solution was added sodium carbonate (0.69g,0.0065 mol). The mixture was purged with nitrogen and Pd (dppf) Cl was added₂(0.19g,0.26 mmol). The mixture was then refluxed at 100 ℃ for 2 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to give the crude product which was purified by silica gel chromatography (PE: EtOAc ═ 1:2) to give compound 156-8(0.66g, 68%) as a yellow solid.¹H NMR (400MHz, CDCl3)8.28(s,1H),7.37(d, J ═ 8.82Hz,2H),6.91(d, J ═ 8.82Hz,2H),4.65(t, J ═ 6.84Hz,1H),3.88(s,1H),3.79-3.68(m,2H),3.47(d, J ═ 11.03Hz,2H),3.39(s,3H),2.82-2.63(m,2H),2.41 (t, J ═ 11.03Hz,2H),2.27-2.14(m,1H),2.01-1.91(m,1H),1.73(t, J ═ 8.16Hz,2H),1.22(d, J ═ 6.17, ESI ═ 7H), MS, ESI, C, calculated values₂₂H₂₈N₂O₃[M+H]⁺369, found 369.

Step (ii) of7: to compound 156-8(0.66g,0.0018mol) in CHCl₃(10mL) solution added MnO₂(1.56g,0.018 mol). The mixture was refluxed overnight. The mixture was filtered through a pad of celite and the filtrate was concentrated to give the crude product which was purified by silica gel chromatography (PE: EtOAc ═ 1:2) to give compound 156-9(0.57g, 86%) as a yellow solid. MS ESI calculated value C₂₂H₂₆N₂O₃[M+H]⁺367, found 367.

And 8: to a solution of compound 156-10(124mg,0.682mmol) in THF (2mL) was added n-BuLi (0.3mL,0.75mmol) dropwise at-65 deg.C under a nitrogen atmosphere. The mixture was stirred at-65 ℃ for 0.5h, then compound 156-9(200mg,0.546mmol) in THF (1mL) was added dropwise. The mixture was stirred at-65 ℃ for 1 hour and at 0 ℃ for another 1 hour. TLC showed complete consumption of substrate. Nahco reacting mixture with sat₃(aq) quench and dilute with ethyl acetate. The organic layer was concentrated to give the crude product, which was purified by chromatography on silica gel (PE: EtOAc ═ 3:1) to give the title compound (65mg, 30%) as a yellow solid.¹H NMR (400MHz, CDCl3)8.28(s,1H),7.51(d, J ═ 8.38Hz,2H),7.39(d, J ═ 8.82Hz,2H),7.27(d, J ═ 8.38Hz,2H),6.92(d, J ═ 8.82Hz,2H),4.08(s,1H),3.76(ddd, J ═ 10.14,6.17,2.21Hz,2H),3.49(s,1H),3.46(s,4H),2.91-2.74(m,2H),2.42(t, J ═ 11.25Hz,2H),2.21-2.11(m,2H),1.85(brs,1H),1.55(brs,1H),1.22(d, 6.17H), 6.17, 6H, 17C, calculated values₂₉H₃₁N₃O₃[M+H]⁺470, found 470.

Example 157

4- (3- (4- ((2S,6R) -2, 6-dimethylmorpholine) phenyl) -4, 8-dimethoxy-5, 6,7, 8-tetrahydroquinolin-8-yl) benzonitrile

To a solution of compound 157-1 (80mg,0.171mmol) in THF (3mL) at 0deg.C was added NaH (27.3mg,0.682mmol) and the suspension was stirred at 0deg.C for 10 min. A solution of MeI (29mg,0.204mmol) in THF (1mL) was added. The mixture was stirred at room temperature overnight. TLC showed complete consumption of compound 157-1. The mixture was concentrated to give the crude product, which was purified by pre-TLC (PE: EtOAc ═ 3:1) to give the title compound (40mg, 40%) as a white solid.¹H NMR (400MHz, CDCl3)8.43(s,1H),7.63(d, J ═ 8.28Hz,2H),7.56-7.49(m,2H),7.41(d, J ═ 8.28Hz,2H),7.02(d, J ═ 8.78Hz,2H),3.90-3.79(m,2H),3.59(br.s.,1H),3.57-3.51(m,4H),3.27(s,3H),3.10-3.00(m,1H),2.87-2.76(m,1H),2.51(t, J ═ 11.17Hz,2H),2.33(dd, J ═ 13.30,4.02, 1H),2.14(br.s.,1H), 1H, 84(m, 1H), 1.84H, 6H, 1H, 6H, 1H, d,6H, 1H, C ═ 6, 1H₃₀H₃₃N₃O₃[M+H]⁺484, measured value 484.

Example 158

4- (3- (6- ((2S, 6R-yl) -2, 6-dimethylmorpholinyl) pyridin-3-yl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: to a solution of 5-bromo-2-chloro-pyridine (5.0g,26.2mmol) in DMF (18mL) was added (2S,6R) -2, 6-dimethylmorpholine (4.0g,34.8mmol) and potassium carbonate (8.0g,58 mmol). The reaction solution was stirred at 90 ℃ for 6 hours, then filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated, and the crude product was purified by silica gel column to give compound 158-2(6g, productRate 84.9%) as a yellow oil. MS ESI calculated value C₁₁H₁₅BrN₂O[M+H]⁺271, found value 271.

Step 2: to a solution of compound 158-2(3.7g,13.7mmol) in tetrahydrofuran (30mL) was added n-butyllithium (8.3mL,20.6mmol), and the mixture was stirred at-78 ℃ under nitrogen for 30 minutes. Triisopropyl borate (7.8g,41.2mmol) was added to the reaction mixture and stirred at-78 ℃ for 3 hours. The mixture was poured into water, extracted with ethyl acetate, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column to give compound 158-3(1.3g, yield 40.2%) as a brown solid. MS ESI calculated value C₁₁H₁₇BN₂O₃[M+H]⁺237, found 237.

And step 3: to a mixed solution of 8-bromo-3-iodo-4-methoxyquinoline (500mg,1.37mmol) in tetrahydrofuran (4mL), water (1mL) and DMF (1mL) was added compound 158-3(324mg,1.37mmol), Pd (dppf) Cl₂(100.3mg, 1.37mmol) and sodium carbonate (290mg,2.74mmol), and the reaction was stirred at 60 ℃ for 3 hours. The reaction was then poured into water, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude compound 158-4(400mg, yield 68.4%) as a brown solid. MS ESI calculated value C₂₁H₂₂BrN₃O₂[M+H]⁺428, found value 428.

And 4, step 4: to a mixed solution of compound 158-4(200mg,0.466mmol) in tetrahydrofuran (3mL), water (0.5mL) and DMF (0.5mL) was added (4-cyanophenyl) boronic acid (206mg, 1.4mmol), Pd (dppf) Cl₂(34mg,0.0466mmol) and sodium carbonate (100mg,0.932 mmol). The reaction solution was stirred at 70 ℃ for 4 hours. Then poured into water and extracted with ethyl acetate, the organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by preparative HPLC to give the title compound (100mg, yield 47.8%) as a white solid.¹H NMR (400MHz, CDCl3)8.89(s,1H),8.50(s,1H),8.31(d, J ═ 7.2Hz,1H),7.78-7.87(m,5H),7.66-7.71(m,2H),6.78(d, J ═ 8.8Hz,1H),4.15(d, J ═ 12Hz,2H),3.76(s,5H),2.63(t, J ═ 11.6Hz,2H),1.31(d, J ═ 6.4Hz,7H), MS ESI calcd C₂₈H₂₆N₄O₂[M+H]⁺451, found value 451.

Synthesis of the Compounds shown in Table 13 from Compound 158-4 with the corresponding boronic acid

Example 166

4- (3- (6- ((2S,6R) -2, 6-dimethylmorpholine) -2-methylpyridin-3-yl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: to a solution of 2-bromo-6-methylpyridine (3g,17.4mmol) in toluene (50mL) were added Xantphos (1.7g,3.48mmol), (2S,6R) -2, 6-dimethylmorpholine (6g,52.2mmol), potassium tert-butoxide (3.9g,34.8mmol), Pd₂(dba)₃(1.6g,1.74 mmol). The reaction mixture was stirred at 110 ℃ for 2 hours, then poured into water, extracted with ethyl acetate (50mL × 3), and the organic layer was washed with brine, filtered, and dried over sodium sulfate. After concentration, purification by a silica gel column gave compound 166-2(2.4g, yield 66.7%) as a white solid. MSESI calculated value C₁₂H₁₈N₂O[M+H]⁺207, found 207.

Step 2: to a solution of compound 166-2(2.4g,11.6mmol) in DMF (30mL) was added NBS (1.65g,9.3 mmol). The reaction solution was stirred at room temperature for 6 hours, poured into water, and then extracted with ethyl acetate (30 × 3mL), the organic phase was dried over sodium sulfate, and after concentration, the crude product was purified by a silica gel column to obtain compound 166-3(0.86g, yield 25.9%) as a white solid. MS ESI calculated value C₁₂H₁₇BrN₂O[M+H]⁺285, found value 285.

And step 3: to a solution of compound 166-3(0.86g,3mmol) in tetrahydrofuran (20mL) at-78 deg.C was added a solution of n-butyllithium (1.8mL,4.5 mmol). The reaction solution was stirred at-78 ℃ for 30 minutes. Triisopropyl borate (846mg,4.5mmol) was then added. The reaction was then poured into water, extracted with ethyl acetate (50mL × 3), and the organic phase was dried over sodium sulfate, filtered and concentrated to give crude compound 166-4(375mg) as a white solid. MS ESI calculated value C₁₂H₁₉BN₂O₃[M+H]⁺251, found value 251.

And 4, step 4: (6- ((2S,6R) -2, 6-dimethylmorpholine) -2-methylpyridin-3-yl) boronic acid (375mg,1.5mmol),4- (3-bromo-4-methoxyquinolin-8-yl) benzonitrile (340mg,1mmol) and sodium carbonate (212mg,2mmol) were dissolved in DMF (3mL), water (3mL) and tetrahydrofuran (15mL), and Pd (dppf) Cl was added to the solution₂(73mg,0.1mmol) and the reaction was then stirred at 70 ℃ for 2h. Then poured into water, extracted with ethyl acetate, the organic layer washed with brine and dried over sodium sulfate. The crude product was purified by preparative HPLC to give the title compound (55mg, 8% yield) as a white solid.¹H NMR (400MHz, CDCl3)8.64(s,1H),8.29(d, J ═ 8.0Hz,1H),7.93-7.95(m,2H),7.84-7.89(m,3H),7.52-7.54(m,1H),7.45-7.50(m,1H),6.82(d, J ═ 8.4Hz,1H),4.23(d, J ═ 12Hz,2H),3.63-3.65(m,5H),2.62-2.66(m,2H),2.22(s,2H),1.19(d, J ═ 6.0Hz,7H), MS ESI₂₉H₂₈N₄O₂[M+H]⁺465, found 465.

Synthesis of the Compounds shown in Table 14 from the corresponding aryl halides

Example 168

4- (3- (4- ((2S,6R) -2, 6-dimethylmorpholine) -2-fluorophenyl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: to compound 168-1(1.8g,5mmol) in THF/H₂To a solution in O/DMF (15/3/3mL) was added (4-chloro-2-fluorophenyl) boronic acid (0.87g,5mmol) and Pd (dppf) Cl₂(350mg,0.5mmol) and sodium carbonate (1.1g,10mmol) were carried out at room temperature. The reaction mixture was stirred at 70 ℃ for 4 hours. The reaction mixture was poured into water, extracted with EtOAc, the organic layer was dried over sodium sulfate and concentrated. The residue was purified by PE/EtOAc (15/1) eluting with silica gel chromatography column to give compound 168-2(1.158g, 63.3% yield) as a brown solid. MS ESI calculated value C₁₆H₁₀BrClFNO[M+H]⁺366, found value 366.

Step 2: to compound 168-2(0.4g,1mmol) in THF/H₂To a solution in O/DMF (5/1/1mL) was added (4-cyanophenyl) boronic acid (0.2g,1.4mmol) and Pd (dppf) Cl₂(73mg,0.1mmol) and sodium carbonate (0.4g) were carried out at room temperature. The reaction mixture was stirred at 70 ℃ for 5 hours. The reaction mixture was poured into water, extracted with EtOAc, and the organic phase was dried over sodium sulfate and concentrated. Eluting the residue with silica gel chromatography columnPurification of PE/EtOAc (10/1) afforded compound 168-3(158mg, 43.2% yield) as a brown solid. MS ESI calculated value C₂₃H₁₄ClFN₂O[M+H]⁺389, found 389.

And step 3: the title compound (100mg, yield 55.6%) was prepared as a white solid by the preceding method.¹H NMR (400MHz, CDCl3)8.78(s,1H),8.34(d, J ═ 6.8Hz,1H), 7.85-7.60(m, 6H),7.37(t, J ═ 6.4Hz,1H), 6.82-6.71(m,2H),3.90-3.75(m, 2H),3.75(s,3H),2.53(t, J ═ 11.2Hz,2H), 1.31(d, J ═ 6.8Hz,6H), MS ESI calculated values C₂₉H₂₆FN₃O₂[M+H]⁺468, measured value 468.

The compounds shown in Table 15 were synthesized from compound 168-1 and the corresponding boronic acids

Example 175

4- (3- (6- ((2S,6R) -2, 6-dimethylmorpholine) pyridazin-3-yl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: to a solution of compound 175-1(40g,270mmol) and diethyl malonate (61mL,410mmol) in DMSO (80mL) was added cesium carbonate (176g,540mmol) at room temperature. The reaction was stirred at 110 ℃ for 1 hour. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE: EtOAc ═ 10:1) to give compound 175-2(52g, 71% yield) as a colorless oil. MS ESI calculated value C₁₁H₁₃ClN₂O₄[M+H]⁺273, found 273.

Step 2: a mixture of 2(52g,190mmol), sodium chloride (45g,760mmol) and H₂O (5mL) was added to DMSO (300mL) and the reaction mixture was stirred at 150 ℃ and 160 ℃ for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE: EtOAc ═ 5:1) to give compound 175-3(30g, 79% yield) as a colorless oil. MS ESI calculated value C₈H₉ClN₂O₂[M+H]⁺201, measured value 201.

And step 3: to compound 175-3(20g,100mmol) in HCO under a nitrogen atmosphere at 0deg.C₂To a solution in Et (200mL) was added NaH (8.4g,350 mmol). The reaction was stirred at room temperature for 2 hours. The mixture was poured into 5% aqueous hydrochloric acid and extracted with EtOAc. The organic layer was washed with aqueous Na2CO3 solution and with Na₂SO₄And (5) drying. The crude product was purified by silica gel chromatography (PE: EtOAc ═ 8:1) to give compound 175-4(6g, 26% yield) as a colorless oil. MS ESI calculated value C₉H₉ClN₂O₃[M+H]⁺229, found 229.

And 4, step 4: a solution of compound 175-4(5g,22mmol) and 2-bromoaniline (3.8g,22mmol) in EtOH (100mL) was stirred at 70 ℃ for 20 h. The reaction mixture was cooled to room temperature. The crude product was collected by filtration to give compound 175-5(5g, 57% yield) as a yellow solid. MS ESI calculated value C₁₅H₁₃BrClN₃O₂ [M+H]⁺382, measured value 382.

And 5: compound 175-5(4.4g,11.5mmol) was dissolved in PPA (50 mL). The mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water. The product was collected by filtration to give compound 175-6(3g, 77% yield) as a yellow solid. MS ESI calculated value C₁₃H₇BrClN₃O[M+H]⁺335, measured value 335.

Step 6: solution of Compound 175-6 (1.4g,4.2mmol), CH₃I (887mg,6.2mmol) and Ag₂CO₃(2.3g,8.4mmol) in DMF (20mL) was stirred at 70 ℃ for 4 h. The reaction mixture was poured into water and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE: EtOAc ═ 1:1) to give compound 175-7(540mg, yield 37%) as a yellow solid. MS ESI calculated value C₁₄H₉BrClN₃O[M+H]⁺350, found 350.

And 7: a solution of compound 175-7(540mg,1.55mmol) in (2S,6R) -2, 6-dimethylmorpholine (1mL) was stirred at 120deg.C for 2h. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine and Na₂SO₄Dried and concentrated under reduced pressure to give compound 175-8(663mg, 100%) as a yellow solid. The crude product was used directly in the next step without further purification. MS ESI calculated value C₂₀H₂₁BrN₄O₂[M+H]⁺429, found 429.

And 8: a solution of compound 175-8(663mg, 1.55mmol), (4-cyanophenyl) boronic acid (251mg,1.7mmol) was added Pd (dppf) Cl₂(117mg,0.16mmol) and sodium carbonate (329mg,3.1mmol) in THF/H₂The O/DMF (10/2/2) solution was stirred at 90 deg.C for 3 hours. The reaction mixture was filtered and partitioned between EtOAc and water, the organic layer was dried and concentrated. The crude product was purified by preparative HPLC to give the title compound (90mg, yield 13%) as a yellow solid.¹H NMR(400MHz,Methanol-d4)8.96(s,1H),8.65(d, J ═ 9.6Hz,1H), 8.56(d, J ═ 10.0Hz, 1H),8.06(d, J ═ 8.4Hz,1H), 7.92(d, J ═ 8.4Hz,1H), 7.81-7.61(m, 6H),4.29(d, J ═ 12.8Hz,2H), 3.81-3.71(m,2H),3.30(s, 3H),2.81(t, J ═ 12.0Hz,2H), 1.28(d, J ═ 5.6Hz,6H), MS ESI₂₇H₂₅N₅O₂[M+H]⁺452, found 452.

Example 176

4- (3- (2- ((2S,6R) -2, 6-dimethylmorpholinyl) pyrimidin-5-yl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: compound 1(3g,15.5mmol) was dissolved in compound 176-2(1.8g,15.5mmol) and then stirred for 2 hours at 100 ℃. The solution was separated between EtOAc and water and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 176-3(3.1g, 74%) as a white solid. MS ESI calculated value C₁₀H₁₄BrN₃O[M+H]⁺272, found value 272.

Step 2: compound 176-3(4.2g,15.4mmol) was dissolved in THF (40mL), n-BuLi (9.2mL,23.1mmol) was added, then added dropwise to the solution at-78 deg.C. This was added with stirring for 30 minutes. Then B (OME)₃(4.8g,46.2mmol) was added dropwise. It was then warmed to 0 ℃ and stirred for 3 hours. The reaction mixture was taken up in EtOAc and water, the organic layers were separated, combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 176-4(2.6g, 72%) as a brown solid. MS ESI calculated value C₁₀H₁₆BN₃O₃[M+H]⁺237, found 237.

And step 3: the title compound was prepared by the preceding method (23mg, 10%) as a brown solid.¹H NMR (400MHz, CDCl3)8.83(s,1H),8.65(s, 2H),8.27(d, J ═ 7.2Hz,1H), 7.85-7.60(m, 6H),4.63(d, J ═ 12.8Hz,2H), 3.80(s,3H), 3.75-3.61(m,2H),2.68(t, J ═ 12.0Hz,2H), 1.27(d, J ═ 6.0Hz,6H). MS ESI calculated value C₂₇H₂₅N₅O₂[M+H]⁺452, found 452.

Synthesis of the Compounds shown in Table 16 from the corresponding aryl halides

Example 178

4- (3- (5- ((2S,6R) -2, 6-dimethylmorpholine-4-carbonyl) thiophen-2-yl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: to a solution of compound 178-1 (500mg,1.4mmol), (5-formylthiophen-2-yl) boronic acid (270mg,1.7mmol) and sodium carbonate (300mg,2.8mmol) in DMF (2mL) in H₂To a solution of O (2mL)/THF (10mL) was added Pd (dppf) Cl₂(102mg,0.14 mmol). The mixture was stirred at 70 ℃ for 2 hours. The mixture was poured into water, extracted with EtOAc, and the organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (PE/EtOAc ═ 5:1) to give compound 178-2(438mg, 91.6%) to give a brown solidAnd (3) a body. MS ESI calculated value C₁₅H₁₀BrNO₂S[M+H]⁺348, found value 348.

Step 2: to a solution of compound 178-2(438mg,1.25mmol) and potassium permanganate (200mg,1.25mmol) in acetone (15mL) was added sodium dihydrogen phosphate (300mg,2.5 mmol). The mixture was stirred at room temperature for 4 hours. Brown MnO₂The precipitate was filtered, the acetone removed in vacuo, the mixture acidified with 1N HCl and extracted with EtOAc. The organic phase was dried over sodium sulfate and concentrated to give compound 178-3(350mg, 76.4%) as a brown solid. MS ESI calculated value C₁₅H₁₀BrNO₃S[M+H]⁺364, measured value 364.

And step 3: to a solution of compound 178-3(350mg,1mmol) was added HATU (384mg,1mmol) and (2S,6R) -2, 6-dimethylmorpholine (138mg,1.2mmol) in DMF (10mL) and DIPA (387mg,3mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was poured into H2O, extracted with EtOAc, and the organic phase was dried over sodium sulfate and concentrated. The residue was purified with petroleum ether/ethyl acetate 2: 1to give 178-4(265mg, 59.8%) as a brown solid column. MS ESI calculated value C₂₁H₂₁BrN₂O₃S[M+H]⁺461, measured value 461.

And 4, step 4: to compound 178-4(265mg,0.6mmol), (4-cyanophenyl) boronic acid (106mg,0.72mmol) and sodium carbonate (127mg,1.2mmol) in DMF (2mL)/H₂To a solution of O (solution 2mL)/THF (10mL) was added Pd (dppf) Cl₂(45mg,0.06 mmol). The mixture was stirred at 70 ℃ for 2 hours. The reaction mixture was poured into water, extracted with EtOAc, and the organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC to give the title compound (32mg, yield 11%) as a white solid.¹H NMR (400MHz, CDCl3)9.20(s,1H),8.26-8.24(m,1H),7.83-7.78(m,4H),7.74-7.68(m,2H),7.56-7.55(m,1H),7.35-7.34(m,1H),4.03(s,3H),3.67(s,1H),1.24(d,6H). MSESI calcd C₂₈H₂₅N₃O₃S[M+H]⁺484, measured value 484.

Example 179

4- (3- (2- (26-dimethyl-morpholin-4-yl) -thiazol-4-yl) -4-methoxy-quinolin-8-yl) -benzonitrile

Step 1: to a solution of compound 179-1(5.0g,20.5mmol) and (2S,6R) -2, 6-dimethylmorpholine (3.55g,30.9mmol) in DMF (60mL) was added K₂CO₃(5.7g,41 mmol). The mixture was stirred at 70 ℃ overnight. The reaction mixture was cooled to room temperature, then poured into water, the mixture was extracted with EtOAc, dried over sodium sulfate and concentrated. The residue was purified by column to give 179-2 cases (5.56g, yield 99%) of the compound as a yellow oil. MS ESI calculated value C₉H₁₃BrN₂OS[M+H]⁺277, found 277.

Step 2: to a solution of compound 179-2(500mg,1.8mmol) in THF (10mL) was added n-BuLi (0.8mL,2.5M in THF), the mixture was stirred at-78 deg.C for 1 hour, then SnBu3Cl (650mg,2mmol) was added and stirred at-78 deg.C for 1 hour. The reaction mixture was poured into water, extracted with EtOAc, dried over sodium sulfate and concentrated to give compound 179-3(0.7g, 79% yield) as a colorless oil. MS ESI calculated value C₂₁H₄₀N₂OSSn[M+H]⁺489, found 489.

And step 3: to a solution of compound 179-3(500mg,1.2mmol) and 8-bromo-3-iodo-4-methoxyquinoline (230mg,0.6mmol) in toluene (10mL) was added palladium tetratriphenylphosphine (80mg,0.08 mmol). The mixture was stirred at 110 degrees celsius overnight. The reaction mixture is mixed with water andpartitioned between EtOAc. The organic layer was dried over sodium sulfate and concentrated to give compound 179-4(50mg, 12% yield) as a yellow solid. MS ESI calculated value C₁₉H₂₀BrN₃O₂S[M+H]⁺433, found 433.

And 4, step 4: to a solution of compound 179-4(50mg,0.14mmol) and (4-cyanophenyl) boronic acid (48mg,0.14mmol) in THF/H2O/DMF (42mL,5 point 01 min 01 sec) was added Pd (dppf) Cl₂(25mg,0.03mmol) and sodium carbonate (50mg,0.5 mmol). The mixture was stirred at 70 ℃ overnight. The reaction mixture was poured into water, extracted with EtOAc, the organic layer was dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to give the title compound (6mg, yield 10%) as a yellow solid.¹H NMR (400MHz, CDCl3)9.45(s,1H),8.15-8.10(m, 1H),7.75-7.50(m, 6H),7.20(s, 1H),3.85(s, 3H),3.75-3.60(m,4H),2.68(t, J ═ 10.8Hz,2H), 1.15(d, J ═ 6.4Hz,6H). MS ESI calcd for C₂₆H₂₄N₄O₂S[M+H]⁺457, found 457.

Example 180

4- (3- (4- ((3S,5R) -3, 5-dimethyl-4-propionylpiperazin-1-yl) phenyl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: to a solution of compound 180-1(2.0g,5.4mmol) and (2S,6R) -2, 6-dimethylpiperazine (0.8g,7mmol) in toluene (30mL) was added Pd₂(dba)₃(330m g,0.3mmol), Xantphos (350m g,0.7mmol) and KO^tBu (1.6g,15 mmol). The reaction mixture was stirred at 120 ℃ for 5 hours under nitrogen and then poured inIn water. The mixture was extracted with ether (3X 30mL) and the organic phase was dried over sodium sulfate. The residue was purified by column chromatography to give compound 180-2(1.7g, yield 70%) as a yellow solid. MS ESI calculated value C₂₉H₂₈N₄O[M+H]⁺449, found 449.

Step 2: to a solution of compound 180-2(90m g,0.2mmol) and triethylamine (200m g,2mmol) in dichloromethane (10mL) was added propionyl chloride (130m g,0.1mmol) at room temperature. The reaction mixture was stirred for 1 hour, poured into water, extracted with dichloromethane (2X 10mL) and the organic phase was dried over sodium sulfate. The residue was purified by preparative HPLC to give the title compound (50mg, 40% yield) as a white solid.¹H NMR (400MHz, CDCl3)8.89(s,1H),8.47-8.45(m,2H),7.97-7.81(m,4H),7.62(d, J ═ 3.6Hz,2H),7.46(d, J ═ 4.8Hz,2H),7.02(d, J ═ 8.8Hz,2H),3.89(s,3H),3.56(d, J ═ 12.4Hz,2H),3.00(d, J ═ 9.6Hz,2H),2.51-2.38(m,2H),1.49-1.36(m,6H),1.19(t, J ═ 7.6Hz,3H), MS ESI C calculated value₃₂H₃₂N₄O₂[M+H]⁺505, measured value 505.

The compounds in Table 17 were synthesized from compound 180-2 and the corresponding acid chloride

Example 188

4- (3- (6- (4-methanesulfonyl-3, 5-dimethylpiperazin-1-yl) -pyridin-3-yl) -4-methoxy-quinolin-8-yl) -benzonitrile

Step 1: MsCl (290mg,2.4mmol) was slowly added dropwise to a solution of compound 188-1(540mg,2mmol) and DIPEA (774mg,6mmol) in DCM (10mL), the reaction was stirred at room temperature for 30min and LCMS was monitored to the end of the reaction. The mixture was poured into water, extracted with EtOAc, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel column (MeOH: EtOAc ═ 5:1) to give compound 188-2(500mg, yield 72%) as a white solid. MS ESI calculated value C₁₂H₁₈BrN₃O₂S[M+H]⁺350, found 350.

Step 2: pd (dppf) Cl₂(102mg,0.14mmol) was added to a solution of compound 188-2(500mg,1.4mmol),3(432mg,1.7mmol) and AcOK (300mg,2.8mmol) in dioxane (10mL), the reaction was stirred at 70 ℃ for 2h and LCMS was monitored to the end of the reaction. The mixture was then poured into water, extracted with EtOAc, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel column (PE: EtOAc ═ 1:1) to give compound 188-4(460mg, yield 100%) as a yellow solid. MS ESI calculated value C₁₂H₂₀BN₃O₄S[M+H]⁺314, measured value 314.

And step 3: the title compound (120mg, 23%) was prepared as a yellow solid by the foregoing method.¹H NMR(400MHz,CDCl₃)8.90(s,1H),8.50(d, J ═ 2.0Hz,1H),8.33(d, J ═ 6.8Hz,1H),7.90-7.73(m,7H),6.82(d, J ═ 8.8Hz,1H),4.28-4.22(m,4H),3.80(s,3H),3.29(dd, J ═ 4.4,12.8Hz2H),2.96(s,3H),1.51(d, J ═ 7.2Hz,6H), MS ESI C calculated value₂₉H₂₉N₅O₃S[M+H]⁺528, found 528.

Example 189

4- (3- (6- (4- (2-hydroxy-acetyl) -3, 5-dimethylpiperazin-1-yl) -pyridin-3-yl) -4-methoxy-quinolin-8-yl) -benzonitrile

Step 1: compound 189-2(227mg,1.7mmol) was added to a solution of compound 189-1(300mg,1.1mmol) and DIPEA (430mg,3.3mmol) in DCM (30mL), the reaction was stirred at 0deg.C for 30min and LCMS was monitored to the end of the reaction. The mixture was then poured into water, extracted with EtOAc, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel column (PE: EtOAc ═ 5:1) to give 189-3(260mg, yield 63%) as a red oil. MS ESI calculated value C₁₅H₂₀BrN₃O₃[M+H]⁺370, found 370.

Step 2: pd (dppf) Cl₂(102mg,0.14mmol) was added to a solution of compound 189-3(260mg,0.7mmol),189-4(213mg,0.84mmol) and AcOK (205mg,2.1mmol) in dioxane (6mL), the reaction was stirred at 100 ℃ for 2h and LCMS was monitored to the end of the reaction. The mixture was then poured into water, extracted with EtOAc, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel column (PE: EtOAc ═ 1:1) to give 189-5(170mg, yield 70%) as a yellow solid. MS ESI calculated value C₁₅H₂₂BN₃O₅[M+H]⁺336, measured value 336.

And step 3: compound 189-7(60mg, 22%) was prepared as a white solid by the method described previously. MS ESI calculated value C₃₂H₃₁N₅O₄[M+H]⁺550, found 550.

And 4, step 4: NaOH (132mg,3.3mmol) was added to compound 189-7(60mg,0.11mmol) in MeOH (2mL)/THF (2mL)/H₂To a solution of O (2mL), the reaction was stirred at room temperature for 2h. LC-MS monitors until the reaction is completed. The mixture was poured into water, washed with EtOAc, the aqueous phase acidified to pH 4 with 1N HCl, followed by extraction with e.a, and the organic phase extracted with anhydrous Na₂SO₄Dry and concentrate to give the crude product, which is further purified by TLC (DCM: MeOH ═ 20:1) to give the title compound (10mg) as a white solid.¹H NMR(400MHz,CDCl₃)8.91(s,1H),8.51(s,1H),8.35-8.33(m,1H),7.86-7.70(m,7H),6.87(d, J ═ 8.8Hz,1H),3.80(s,3H),1.67(s,3H),1.44(m,6H). MS ESI calculated value C₃₀H₂₉N₅O₃[M+H]⁺508, found 508.

Example 190

4- (4-methoxy-3- (4- (5-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) phenyl) quinolin-8-yl) benzonitrile

To a solution of 190-1(0.185g,0.5mmol) and 190-2(0.12g,0.6mmol) in toluene (30mL) was added Pd₂(dba)₃(45m g,0.05mmol), Xantphos (50m g,0.1mmol) and KO^tBu (0.23g,2mmol), the reaction mixture was stirred at 120 ℃ for 5h under nitrogen, then poured into water, the mixture was extracted with diethyl ether (3X 30mL), the organic phase was dried over sodium sulfate, and the residue was purified by preparative HPLC to give the title compound (70mg, 30% yield) as a white solid。¹H NMR (400MHz, CDCl3)8.88(s,1H),8.40(t, J ═ 4.8Hz,1H),7.75-7.74(m,4H),7.62-7.52(m,4H),7.04(d, J ═ 8.4Hz,2H),4.93(d, J ═ 16Hz,1H),4.69(s,1H),4.45(d, J ═ 12.0Hz,1H),3.88-3.81(m,5H),1.64(d, J ═ 9.8Hz,3H), MS ESI calculated C₃₀H₂₃F₃N₆O[M+H]⁺541, found value 541.

Example 191

4- (3- (4- (4-acetyl-3- (2-hydroxypropan-2-yl) -5-methylpiperazin-1-yl) phenyl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: to a solution of compound 191-1(10g,135mmol) in methanol (100mL) at 0deg.C was added benzaldehyde (29g,270mmol), the reaction was stirred at room temperature for 2 hours and cooled to 0deg.C, and sodium borohydride (10g,270mmol) was added in portions. The mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was diluted with water and dichloromethane and then filtered. The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography to give compound 191-2(14g, 40% yield) as a clear oil. MS ESI calculated value C₁₇H₂₂N₂[M+H]⁺255, found 255.

Step 2: to a solution of methyl 2, 3-dibromopropionate (16.5mL, 55mmol) and 191-2(14g,55mmol) in toluene (50mL) was added diisopropylethylamine (33mL, 239mmol), and the mixture was stirred at room temperature overnight, then diluted with ethyl acetate and washed with brine. The organic layer was collected and concentrated. The crude product was purified by column chromatography to give compound 191-3(12.5g, 66% yield) as a yellow liquid.MS ESI calculated value C₂₁H₂₆N₂O₂[M+H]⁺339, found 339.

And step 3: to a solution of compound 191-3(5.6g,15.9mmol) in tetrahydrofuran (50mL) was added dropwise magnesium bromide grade (48mL, 143 mmol). The reaction was stirred at room temperature for 1 hour. The mixture was poured into saturated ammonium chloride, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give compound 191-4(3.3g, 61% yield) which was used directly in the next reaction. MS ESI calculated value C₂₂H₃₀N₂O [M+H]⁺339, found 339.

And 4, step 4: a solution of compound 191-4(3.3g,9.8mmol) and Pd/C (330m g) in methanol (50mL) was stirred under hydrogen (50psi) at room temperature for 24 h. The reaction was filtered and concentrated to give compound 191-5(1.4g, 82% yield) as a pale yellow oil. MS ESI calculated value C₈H₁₈N₂O[M+H]⁺159, found 159.

And 5: compound 191-7(120m g, 25% yield) was prepared as a light yellow oil by the method described previously. MSESI calculated value C₃₁H₃₂N₄O₂[M+H]⁺493, found 493.

Step 6: the title compound (13mg, yield 12%) was prepared as a white solid by the foregoing method.¹H NMR (400MHz, CDCl3)8.89(s,1H),8.34-8.31(m,1H),7.84-7.77(m,4H),7.69-7.65(m,2H),7.58(d, J ═ 8.4Hz,2H),6.86(d, J ═ 8.4Hz,2H),4.41-4.31(m,1H),4.11-4.01(m,1H),3.91-3.81(m,2H),3.72(s,3H),3.71-3.62(m,1H),3.32-3.21(m,1H),2.23(s,3H),1.35(d, J ═ 7.6Hz,3H),1.29(s,6H), MS ESI C calculated value₃₃H₃₄N₄O₃[M+H]⁺535, found 535.

Example 192

4- (3- (4- ((2S, 6S) -2- (2-hydroxypropan-2-yl) -6-methylmorpholino) phenyl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: a solution of compound 192-1(2g,26.67mmol), benzaldehyde (2.8mL,29mmol) and magnesium sulfate (8g) in dichloromethane (70mL) was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness. The crude product was dissolved in MeOH (70mL) and sodium borohydride (1g,26.6mmol) was added and stirred at room temperature for 5 h. The mixture was concentrated to dryness and extracted with 1N dilute hydrochloric acid and ethyl acetate. The aqueous layer was basified with NaOH (2M) to pH 11 and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to give crude compound 192-2(3.17g, 72%) which was used in the next step without further purification. MS ESI calculated value C₁₀H₁₅NO[M+H]⁺166, found 166.

Step 2: the compound 192-2(15g,91mmol) and 2-chloroacrylonitrile (9.5g,109mmol) were stirred in tetrahydrofuran (300mL) at room temperature for 36 hours, and KO was added to the reaction system^tBu (15.3g,136.5mmol) was then heated to 70 ℃ and stirring was continued for 2 hours. The reaction solution was extracted with ethyl acetate and water. The organic layer was concentrated, and the residue was purified by column chromatography to give compound 192-4(3.5g, yield 16%) as a clear oil. MS ESI calculated value C₁₃H₁₆N₂O[M+H]⁺217, found value 217.

And step 3: a solution of compound 192-3(1g,4.63mmol) and concentrated sulfuric acid (2.5mL) in MeOH (15mL) was stirred at 100 deg.C overnight. After the reaction was cooled, it was added to saturated sodium bicarbonate (20mL), and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography to give compound 192-4(460m g, 40% yield) as a pale yellow oil. MS ESI calculated value C₁₄H₁₉NO₃[M+H]⁺250, found 250.

And 4, step 4: to a solution of compound 192-4(260m g,1.04mmol) in tetrahydrofuran (4mL) was added methylmagnesium bromide (1.4mL, 4.16mmol) at room temperature and stirred for 1 hour. The reaction was quenched with saturated ammonium chloride (1 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to give compound 192-5(200m g, 77% yield) which was used directly in the next step. MS ESI calculated value C₁₅H₂₃NO₂[M+H]⁺250, found 250.

And 5: a solution of compound 192-5(280m g,1.12mmol) and Pd/C (100m g) in EtOH (10mL) was heated to 75 deg.C and stirred under hydrogen (50psi) for 2h. The reaction was cooled to room temperature and filtered, and the filtrate was concentrated to give compound 192-6(170m g, 95% yield) as a clear oil. MS ESI calculated value C₈H₁₇NO₂[M+H]⁺160, found 160.

Step 6: the title compound (50mg, 28% yield) was prepared as a white solid by the foregoing method.¹H NMR (400MHz, CDCl3) ppm8.90(s,1H)8.36-8.32(m,1H)7.85-7.78(m,4H)7.70-7.65(m,2H)7.60-7.58(d, J ═ 8,2H)7.07-7.05(d, J ═ 8,2H)3.87-3.76(m,1H)3.72(s,3H)3.642-3.52(m,3H)2.73-2.68(m,1H)2.55-2.49(m,2H)1.32-1.28(m,9H). MS calculated value C ESI₃₁H₃₁N₃O₃[M+H]⁺494, found 494.

Example 193

4- (3- (6- ((3S,5R) -4- (2-Fluoropropionyl) -3, 5-dimethylpiperazin-1-yl) pyridin-3-yl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: to a solution of compound 193-1(8.0g,23.6mmol), compound 193-2(4.5g,28.3mmol) and sodium carbonate (6.3g,59mmol) in tetrahydrofuran (160mL) and water (32mL) under nitrogen, was added Pd (dppf) Cl₂(1.7g,2 mmol). The reaction mixture was heated to 80 ℃ and stirred for 16 hours. The reaction solution was cooled and extracted with ethyl acetate, the organic phase was dried over sodium sulfate and concentrated, and the residue was purified by column chromatography to give pure compound 193-3(8.51g, yield 97%) as a yellow solid. MS ESI calculated value C₂₂H₁₄ClN₃O[M+H]⁺372, measured value 372.

Step 2: to compound 193-3(8.51g,23mmol), compound 193-4(2.88g,25mmol), NaO under a nitrogen atmosphere^tBu (5.51g,57mmol) and Xantphos (2.65g,4.6mmol) in toluene (100mL) was added Pd₂(dba)₃(2.1g,2.3 mmol). The reaction was heated to 130 ℃ and stirred for 16 hours. The mixture was cooled and extracted with ethyl acetate, the organic phase was dried over sodium sulfate and concentrated, and the residue was purified by column chromatography to give compound 193-5(4g, yield 39%) as a yellow solid. MS ESI calculated value C₂₈H₂₇N₅O[M+H]⁺450, found 450.

And step 3: to a solution of compound 193-5(1g,2.23mmol) and HATU (1.35g,3.56mmol) in dichloromethane (15mL) was added compound 193-6(294m g,3.34mmol) and pyridine (440m g,5.57mmol), the reaction was refluxed overnight and concentrated. The residue was extracted with ethyl acetate and water, the organic layer was dried over sodium sulfate and concentrated, and the crude product was purified by column chromatography to give compound 193-7(226m g, yield 20%) as a pale yellow solid. MS ESI calculated value C₃₁H₂₉N₅O₃[M+H]⁺520, found 520.

And 4, step 4: to a solution of compound 193-7(226m g,0.44mmol) in tetrahydrofuran (10mL) was added sodium borohydride (33m g, 0.87 mmol). The reaction was stirred at room temperature for 1 hour and quenched with water (2 drops). The mixture was dried over sodium sulfate and concentrated to dryness. The residue was purified by preparative HPLC to give compound 193-8(220m g, 97% yield) as a white solid.¹H NMR(400MHz, CDCl3)8.90(s,1H),8.50(d, J ═ 4.0Hz,1H),8.31(s,1H),7.90-7.79(m,5H),7.72-7.68(m,2H),6.87-6.85(d, J ═ 8.0Hz,1H),4.75-4.74(m,1H),4.46-4.43(m,2H),4.22-4.19(m,1H),4.02-4.00(m,1H),3.83-3.81(m,1H),3.79(s,3H),3.20-3.12(m,2H),1.53-1.47(m,3H),1.43-1.40(m,6H), MS ESI C calculated₃₁H₃₁N₅O₃[M+H]⁺522, measured value 522.

And 5: to a solution of compound 193-8(120m g,0.23mmol) in dichloromethane (10mL) at 0deg.C was added DAST (740m g,4.6 mmol). The reaction was stirred at room temperature for 1 hour, the mixture was diluted with dichloromethane and washed three times with saturated sodium bicarbonate, the organic layer was dried over sodium sulfate and concentrated, and the residue was purified by preparative TLC to give the title compound (41mg, yield 33%) as a white solid.¹H NMR (400MHz, CDCl3)8.94(s,1H),8.55(s,1H),8.37(d, J ═ 8.0Hz,1H),7.94-7.83(m,5H),7.76-7.72(m,2H),6.90(d, J ═ 8.4Hz,1H),5.46-5.35(m,1H),4.84(brs,1H),4.51-4.21(m,3H),3.83(s,3H),3.36-3.19(m,2H),1.72-1.64(m,3H),1.53-1.45(m,6H), MSESI calculated value C₃₁H₃₀FN₅O₂[M+H]⁺524, found 524.

The compounds in Table 18 were synthesized from compound 193-5 and the corresponding acid

Example 205

4- (4-methoxy-3- (6- (8-propionyl-3, 8-diaza-bicyclo [3.2.1] oct-3-yl) -pyridin-3-yl) -quinolin-8-yl) benzonitrile

Step 1: to a solution of compound 205-1(100mg,0.47mmol) propionyl chloride (87mg,0.94mmol) in dichloromethane (3mL) was added potassium carbonate (27.6g,0.2mol), and after stirring at room temperature for 1 hour, filtration was carried out to concentrate the filtrate to give 120mg of compound 205-2 as a yellow oily liquid (95%).

Step 2: trifluoroacetic acid (3mL) was added dropwise to a solution of compound 205-2(120mg,0.47mmol) in dichloromethane (6mL), and reacted dropwise at room temperature for 1 hour, followed by evaporation of the solvent to give 80mg of compound 205-3 as a brown oily liquid with a yield of 95%.

And step 3: to a solution of compound 205-3(70mg,0.4mmol) and compound 205-4(73mg,0.4mmol) in DMF (2mL) was added potassium carbonate (100mg,0.8mmol) followed by reaction at 120 ℃ for 2 hours, the reaction was cooled and poured into water and extracted with ethyl acetate (10mL), the extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 40mg of compound 205-5 as a white solid in 31% yield. MS ESI calculated value C₁₄H₁₈BrN₃O[M+H]⁺325, found value 325.

And 4, step 4: compound 205-5(33mg,0.1mmol), compound 205-6(50mg,0.2mmol), Pd (dppf) Cl₂(8mg,0.01mmol) and potassium acetate (20mg,0.2mmol) were added to 1, 4-dioxane (2mL) with stirring at 110 ℃ under nitrogenStirring for 2 hours. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to give compound 205-7(20mg, yield 95%) as a white solid. MS ESI calculated value C₁₄H₂₀BN₃O₃[M+H]⁺290, found value 290.

And 5: the title compound (10mg, yield 20%) was prepared as a white solid by the foregoing method.¹H NMR (400MHz, CDCl3)8.89(s,1H),8.49-8.50(d, J ═ 2.4Hz,1H), 8.31-8.33(m,1H)7.78-7.86(m,5H)7.68-7.72(m,2H)6.73-6.75(d, J ═ 8.8Hz,1H)4.93-4.95(d, J ═ 5.2Hz,2H),4.36-4.38(d, J ═ 6.0Hz,2H),4.24-4.27(m,2H)3.92-3.94(m,2H)3.78(s,3H)3.12-3.25(d d, J ═ 10.8Hz2H)2.38-2.47(m,2H)1.95 (m,1H) 1.35 (m,1H) 3.35-1.35 (m,1H) 3.35H), calculated values₃₁H₂₉N₅O₂[M+H]⁺504, found 504.

Example 206

4- (3- (6- ((3S,5R) -3, 5-dimethyl-4- (thiazol-2-yl) piperazin-1-yl) pyridin-3-yl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: to a solution of compound 206-1(250m g,0.71mmol) and compound 206-2(216mg,0.85mmol) in dioxane (5mL) under nitrogen atmosphere was added Pd (dppf)₂Cl₂(50m g,0.07mmol) and potassium acetate (150m g,1.42 mmol). The reaction was stirred at 120 ℃ for 4 hours and used directly in the next step.

Step 2: the title compound (30mg yield 12%) was prepared as a white solid by the foregoing method.¹H NMR(400MHz, CDCl3)8.86(s,1H),8.49(s,1H),8.33(d, J ═ 8.0Hz,1H),7.85-7.55(m,7H),7.23(d, J ═ 4.0Hz,1H),6.87(d, J ═ 8.8Hz,1H),6.57(d, J ═ 4.0Hz,1H),4.33-4.28(m,4H),3.78(s,3H),3.35-3.30(m,2H),1.43(d, J ═ 6.8Hz,6H), MS ESI calcd C₃₁H₂₈N₆OS[M+H]⁺533, measured value 533.

Example 207

4- (4-methoxy-3- (4- (2- (pyridin-4-yl) acetyl) piperazin-1-yl) quinolin-8-yl) benzonitrile

Step 1: to a toluene solution (15mL) of compound 207-1(1g,3mmol) and piperazine (270mg,3mmol) under nitrogen atmosphere was added sodium tert-butoxide (900mg,9mmol), Pd₂(dba)₃(270mg,0.3mmol) and Xantphos (350mg,0.6 mmol). The reaction mixture was stirred at 130 ℃ for 3 hours. The mixture was concentrated in vacuo and the crude product was purified by column (ethyl acetate/methanol ═ 1:1) to give compound 207-2(420mg, 42% yield) as a yellow solid. MS ESI calculated value C₂₁H₂0N₄O[M+H]⁺345, found 345.

Step 2: to a solution of compound 207-2(69mg,0.2mmol), compound 207-3(144mg,1mmol) in DMF was added diisopropylethylamine (260mg,2mmol) and HATU (380mg,1 mmol. the mixture was stirred at room temperature for 30min and purified by preparative HPLC to give the title compound (20mg, 21%) as a white solid.¹H NMR (400MHz, CDCl3)8.68(s,1H),8.59(d, J ═ 8.0Hz,2H),7.75-7.73(m,4H),7.61-7.59(m,2H),7.24-7.22(m,2H),4.09(s,3H),3.88-3.85(m,2H),3.80(s,2H),3.68-3.65(m,2H),3.28-3.25(m,2H),3.18-3.15(m,2H), MS ESIC₂₈H₂₅N₅O₂[M+H]⁺464, found 464.

The compounds shown in Table 19 were synthesized from Compound 207-2 and the corresponding acid

Example 217

4- (3- (4- (2, 6-dimethylpyridin-4-yl) piperazin-1-yl) -4-methoxyquinolin-8-yl) benzonitrile

Compound 217-1(490mg,1.1mmol), compound 217-2(253mg,1.7mmol), Pd (dppf) Cl₂(81mg,0.11mmol) and sodium carbonate (233mg,2.2mmol) were added to THF/H₂O (10:1,11mL) was stirred overnight at 80 ℃ under nitrogen. The mixture was filtered through celite, the filtrate was washed with water (50mL) and extracted with ethyl acetate (100mL), and the extracts were washed with brine and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (200mg, 45% yield) as a white solid.¹H NMR (400MHz, CDCl3)8.93(s,1H),8.31(d, J ═ 8.0Hz,1H),7.76-7.74(m,6H),7.48-7.38(m,1H),6.60(s,2H),4.27(s,3H),3.83(s,4H),3.41(s,4H),2.51(s,6H). MS ESI calculated C₂₈H₂₇N₅O[M+H]⁺450, found 450.

Example 218

4- (3- (4- (5- (2-hydroxypropan-2-yl) pyridin-2-yl) piperazin-1-yl) -4- (trifluoromethyl) quinolin-8-yl) benzonitrile

Step 1: to a solution of compound 218-1(300mg,0.55mmol) and compound 218-2(210mg,1.1mmol) in DMF (10mL) were added cuprous iodide (155mg,0.82mmol) and potassium fluoride (32mg,0.55 mmol). The suspension was stirred at 110 ℃ for 3 hours, then poured into water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography to give compound 218-3 as a yellow solid (200mg, 70% yield). MS ESI calculated value C₂₈H₂₂F₃N₅O₂[M+H]⁺518, measured value 518.

Step 2: to a solution of compound 218-3(200mg,0.38mmol) in THF (20mL) was added a MeMgBr solution (3M, 0.13mL, 0.38mmol) at 0 deg.C. The mixture was stirred at 0 ℃ for 2 hours, then poured into saturated ammonium chloride, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC to give the title compound (30mg, 15% yield) as a yellow solid.¹H NMR(400MHz,CDCl3)8.96(s,1H),8.36(s,1H),8.22(d,J＝8.0Hz,1H),7.75-7.53(m,7H),6.75-6.70(m,1H),3.77(t,J＝4.4Hz,4H),3.40(t,J＝4.4Hz,4H),1.56(s,6H) MS ESI calculated value C₂₉H₂₆F₃N₅O[M+H]⁺518, measured value 518.

Example 219

4- (4-bromo-3- (4- (5- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-methylpiperazin-1-yl) quinolin-8-yl) benzonitrile

Step 1: to a solution of compound 219-1(30g, 0.3mol) and diisopropylethylamine (40g, 0.3mol) in dichloromethane (200mL) at 0deg.C was added benzyloxycarbonyl chloride (17g,0.1mol), stirred at room temperature for 3 hours, the solvent was removed, and the crude product was purified by column to give 2(11g, 47% yield) as a yellow oil. MS ESI calculated value C₁₃H₁₈N₂O₂[M+H]⁺235, found 235.

Step 2: to a solution of compound 219-2(2.25g,14.5mmol) and compound 219-3(3.41g,14.5mmol) in DMF (10mL) was added potassium carbonate (4g,0.029 mol). The mixture was stirred at 160 ℃ for 4 hours and poured into water. The mixture was extracted with ethyl acetate, dried over sodium sulfate and concentrated, and the crude product was purified by column chromatography to give compound 219-4(2.8g, 52% yield). MS ESI calculated value C₂₀H₂₃N₃O₄[M+H]⁺370, found 370.

And step 3: to a solution of compound 219-4(370mg,1mmol) in THF (10mL) at 0deg.C was slowly added a solution of methylmagnesium bromide (3.3mL, 11 mmol). Stirring the mixture at 0deg.C for 1 hr, heating to 80 deg.C, stirring for 2 hr, pouring into saturated ammonium chloride solution, extracting the mixture with ethyl acetate, and filteringDrying over sodium sulfate and concentration gave compound 219-5(100mg, 42% yield) as a white solid. MS ESI calculated value C₁₃H₂₁N₃O[M+H]⁺236, found value 236.

And 4, step 4: the title compound (120mg, yield 23%) was prepared as a white solid by the foregoing method.¹H NMR (400MHz, CDCl3)8.74(s,1H),8.39-8.34(m,2H),7.76-7.63(m,5H),6.67-6.61(m,1H),4.65(brs,1H),4.22-4.19(m,1H),3.62-3.32(m,4H),3.20-3.01(m,4H),1.60(s,6H),1.47(d, J ═ 6.4Hz,3H). MS ESI calculated value C₂₉H₂₈BrN₅O[M+H]⁺542, measured value 542.

Example 220

4- (3- (4- (5- (2-hydroxypropan-2-yl) pyridin-2-yl) piperazin-1-yl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: a solution of compound 220-1(5g,36.9mmol), compound 220-2(5.34g,28.8mmol) and diisopropylethylamine (7mL, 40mmol) in DME (30mL) was heated to 130 deg.C in an autoclave overnight. The mixture was diluted with ethyl acetate (200mL), washed twice with 10% aqueous sodium hydroxide solution and once with citric acid and brine. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography to give compound 220-3(7.7g, 85% yield) as a yellow solid.¹H NMR (400MHz, CDCl3)8.81(s,1H)8.04(d, J ═ 12.0Hz,1H)6.59(d, J ═ 8.0Hz,1H)4.37-4.31(m,2H)3.70-3.67(m,4H)3.56-3.54(m,4H)1.49(s,9H)1.39-1.36(m,3H) MS ESI calcd C₁₇H₂₅N₃O₄[M+H]⁺336, measured value 336.

Step 2: a solution of methylmagnesium bromide (24mL, 71.6mmol) was added dropwise to a solution of compound 220-3(6g,17.9mmol) in THF (80mL) and stirred at room temperature for 3 hours. The reaction was quenched with saturated ammonium chloride (10mL) and extracted with EtOAc (200 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography to give pure compound 220-4(4.3g, 74% yield) as a yellow solid.¹H NMR (400MHz, CDCl3)8.30(s,1H)7.68-7.60(m,1H)6.64(d, J ═ 8.0Hz,1H)3.54-3.52(m,8H)1.57(s,6H)1.49(s,9H). MS ESI calcd C₁₇H₂₇N₃O₃[M+H]⁺322, measured value 322.

And step 3: to a solution of compound 220-4(3g,9.33mmol) in dichloromethane (30mL) was added trifluoroacetic acid (15 mL). The mixture was then stirred at room temperature for 30 minutes. Basified to pH 9 by addition of sodium hydroxide (6M) and then extracted three times with chloroform. The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by column chromatography to give compound 220-5(1.6g, 75% yield) as a pale yellow solid.¹H NMR (400MHz, CDCl3)8.22(s,1H)7.71-7.68(m,1H)6.80-6.75(m,1H)3.47-3.40(m,4H)2.94-2.88(m,4H),1.51(s,6H). MS ESI calcd C₁₂H₁₉N₃O[M+H]⁺222, measured value 222.

And 4, step 4: the title compound (21mg, yield 11%) was prepared as a white solid by the foregoing method.¹H NMR (400MHz, CDCl3)8.79(s,1H)8.36-8.35(m,1H)8.24-8.22(m,1H)7.81-7.78(m,4H)7.76-7.70(m,1H)7.60-7.59(m,2H)6.75-6.73(m,1H)4.16(s,3H)3.78-3.76(m,4H)3.42-3.39(m,4H)1.67(s,1H)1.60(s,6H) MS ESI₂₉H₂₉N₅O₂[M+H]⁺480, found 480.

The compounds in Table 20 were synthesized from compounds 220-6 and the corresponding amines

Example 227

4- (3- (4- (2, 6-dimethyl-morpholin-4-yl) -piperidin-1-yl) -4-methoxy-quinolin-8-yl) -benzonitrile

Step 1: a solution of compound 227-1(2.0g,10mmol) and cis-2, 6-dimethylmorpholine (1.25g,11mmol) in dichloromethane (40mL) was stirred at 0deg.C for 1 hour, followed by addition of sodium borohydride acetate (5.3g,25mmol) at 20deg.C and stirring at 20deg.C for 5 hours. The reaction was then quenched with saturated aqueous sodium carbonate solution and extracted with dichloromethane (30X 2 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography on silica gel (5: 1-1:1 petroleum ether/ethyl acetate) gave compound 227-2(1.5g, 50%) as a white solid. MS ESI calculated value C₁₆H₃₀N₂O₃[M+H]⁺299, and measuring the value 299.

Step 2: to a solution of compound 227-2(3.0g,10mmol) in methanol (20mL) was added HCl (4M in methanol, 10 mL). The resulting solution was stirred at 20 ℃ for 4 hours and then concentrated under reduced pressure. The resulting yellow solid was used directly in the next step without further purification (1.9g, 99%). MS ESI calculated value C₁₁H₂₂N₂O[M+H]⁺199, measurement 199.

And step 3: to a mixture of compound 227-3(1.0g,5.0mmol) and 8-bromo-3-iodo-4-methoxyquinoline (1.4g,4mmol) in toluene (3)0mL) solution under nitrogen atmosphere was added Pd₂(dba)₃(180mg,0.2mmol), Xantphos (290mg,0.5mmol) and sodium tert-butoxide (1.0g,10mmol), the reaction mixture is stirred at 120 ℃ for 5 hours, then poured into water and extracted with ether (3 × 3mL), the organic layers are combined, dried over sodium sulfate, concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel (petroleum ether/ethyl acetate ═ 1:2) to give compound 227-4(0.36g, 50%) as a yellow solid. MS ESI calculated value C₂₁H₂₈BrN₃O₂[M+H]⁺435, measurement 435.

And 4, step 4: the title compound (0.1g, 40%) was prepared as a white solid by the method described previously.¹H NMR(400MHz,CDCl₃)8.75(s,1H),8.23-8.15(m,1H),7.79-7.74(m,4H),7.58-7.46(m,2H),4.11(s,3H),3.72-3.65(m,4H),2.90-2.84(m,4H),2.35-2.28(m,1H),2.20-2.10(m,2H),1.90-1.80(m,2H),1.77-1.67(m,2H),1.21(d, J ═ 5.6Hz,6H). MS ESI C calculated value₂₈H₃₂N₄O₂[M+H]⁺457, measurement 457.

Example 228

4- (3- (3- (2, 6-dimethyl-morpholin-4-yl) -azetidin-1-yl) -4-methoxy-quinolin-8-yl) -benzonitrile

Step 1: a solution of compound 228-1(1.7g,10mmol) and cis-2, 6-dimethylmorpholine (1.4g,12mmol) in dichloromethane (30mL) was stirred at 0deg.C for 1 hour, followed by addition of sodium borohydride acetate (6.0g,30mmol) at 20deg.C and stirring at 20deg.C for 5 hours. The reaction was quenched with saturated aqueous sodium carbonate and then with dichloromethaneAlkane (30X 2 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate 5:1-1:1) gave compound 228-2(1.8g, 67%) as a white solid. MS ESI calculated value C₁₄H₂₆N₂O₃[M+H]⁺271, and measuring the value 271.

Step 2: to a solution of compound 228-2(2.6g,10mmol) in methanol (20mL) was added HCl (4M in methanol, 10 mL). The resulting solution was stirred at 20 ℃ for 4 hours and then concentrated under reduced pressure. The resulting yellow solid was used directly in the next step without further purification (1.6g, 99%). MS ESI calculated value C₉H₁₈N₂O[M+H]⁺171, and a measured value 171.

And step 3: to a solution of compound 228-3(1.1g,3mmol) and 8-bromo-3-iodo-4-methoxyquinoline (0.55g,3.3mmol) in toluene (10mL) under a nitrogen atmosphere was added Pd₂(dba)₃(90mg,0.1mmol), Xantphos (120mg,0.2mmol) and sodium tert-butoxide (0.6g,6mmol), the reaction mixture is stirred at 120 ℃ for 5 hours, then poured into water and extracted with ether (3 × 3mL), the organic layers are combined, dried over sodium sulfate, concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel (petroleum ether/ethyl acetate ═ 1:2) to give compound 228-4(0.57g, 47%) as a yellow solid. MS ESI calculated value C₁₉H₂₄BrN₃O₂[M+H]⁺407, measured value 407.

And 4, step 4: the title compound (0.045g, 10%) was prepared as a white solid by the method described previously.¹H NMR(400MHz,CDCl₃)8.50(s,1H),8.09(d, J ═ 8.0Hz,1H),7.80-7.65(m,6H),4.56(brs,2H),4.41(brs,2H),4.06(brs,2H),3.94(s,3H),3.91(brs,1H),3.49(d, J ═ 7.6Hz,2H),2.34(t, J ═ 11.6Hz,2H),1.26(d, J ═ 6.0Hz,6H), MS ESI calcd C₂₆H₂₈N₄O₂[M+H]⁺429, found 429.

Example 229

4- (3- (3- (26-dimethyl-morpholin-4-yl) -pyrrolidin-1-yl) -4-methoxy-quinolin-8-yl) -benzonitrile

Step 1: after stirring a solution of 229-1(2.0g,10mmol) and cis-2, 6-dimethylmorpholine (1.25g,11mmol) in dichloromethane (40mL) at 0deg.C for 1 hour, sodium borohydride acetate (6.0g,30mmol) was added at 20deg.C and stirred at 20deg.C for 5 hours. The reaction was then quenched with saturated aqueous sodium carbonate solution and extracted with dichloromethane (30X 2 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography on silica gel (5: 1-1:1 petroleum ether/ethyl acetate) gave compound 229-2(1.5g, 60%) as a white solid. MS ESI calculated value C₁₈H₂₆N₂O₃[M+H]⁺319, measured value 319.

Step 2: to a solution of compound 229-2(0.65g,2mmol) in methanol (10mL) was added Pd/C (100mg), and the mixture was hydrogenated at 20 ℃ at 30psi for 4 hours. The mixture was then filtered and concentrated under reduced pressure. The resulting yellow solid was used directly in the next step without further purification (0.37g, 99%). MS ESI calculated value C₁₀H₂₀N₂O[M+H]⁺185, measured value 185.

And step 3: to a solution of compound 229-3(0.4g,1.1mmol) and 8-bromo-3-iodo-4-methoxyquinoline (0.2g,1.1mmol) in toluene (10mL) under nitrogen atmosphere was added Pd2(dba)3(90mg,0.1mmol), Xantphos (120mg,0.2mmol) and sodium tert-butoxide (0.4g,3mmol), the reaction mixture was stirred at 120 ℃ for 5 hours, then poured into water, ether and (3 × 3mL) extracted, the organic layers were combined, dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography on silica gel (petroleum ether/ethyl acetate ═ 1:1-1:2) to give compound 229-4(0.36g, 42%) was a yellow solid. MS ESI calculated value C₂₀H₂₆BrN₃O₂[M+H]⁺421, measured value 421.

And 4, step 4: the title compound (0.13g, 60%) was prepared as a white solid by the method described previously.¹H NMR(400MHz, CDCl₃)8.68(s,1H),8.14-8.12(m,1H),7.72-7.65(m,4H),7.49-7.47(m,2H),4.04(s3H),3.64-3.60(m,4H),2.82-2.78(m,4H),2.24-2.20(m,1H),2.00-1.92(m,2H)1.86-1.72(m,2H),1.68-1.56(m,2H),1.16(d, J ═ 6.0Hz,6H). MS ESI C calculated value₂₇H₃₀N₄O₂[M+H]⁺443, measured value 443.

Example 230

4- (3- (3- (2, 6-dimethyl-morpholin-4-yl) -8-aza-bicyclo [3.2.1] oct-8-yl) -4-methoxy-quinolin-8-yl) benzonitrile

Step 1: to a solution of compound 230-1(4.5g,20mmol) and cis-2, 6-dimethylmorpholine (2.5g,22mmol) in dichloromethane (60mL) was added sodium borohydride acetate (6.3g,30mmol) at 0deg.C and the mixture was stirred at 25 deg.C for 12 h. The reaction was then poured into water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) gave compound 230-2(1.1g, 17%) as a white solid. MS ESI calculated value C₁₈H₃₂N₂O₃[M+H]⁺325, and a measurement value 325.

Step 2: to a solution of compound 230-2(324mg,1mmol) in methanol (5mL) was added HCl (4M in methanol, 10 mL). The resulting solution was stirred at 25 ℃ for 2 hours and then concentrated under reduced pressure. The resulting yellow solid was used directly in the next step without further purification (224mg, 100%). MS ESI calculated value C₁₃H₂₄N₂O[M+H]⁺225, measured value 225.

And step 3: the title compound (40mg, 8.3%) was prepared as a white solid by the preceding method.¹H NMR(400MHz,CDCl₃)8.71(s,1H),8.24-8.21(m,1H),7.82-7.75(m,4H),7.59-7.57(m,2H),4.75-4.60(m,2H),3.97(s,3H),3.74-3.68(m,3H),3.52(d, J ═ 12.0Hz,2H),2.62-2.50(m,2H),2.20-2.18(m,4H),2.00-1.89(m,2H),1.21(d, J ═ 6.4Hz,6H), MS ESI calculated value C₃₀H₃₄N₄O₂[M+H]⁺483, found 483.

Example 231

4- (3- (4 '-hydroxy-4, 6-dimethyl-3', 4',5',6 '-tetrahydro-2' H- [2,4'] bipyridinyl-1' -yl) -4-methoxy-quinolin-8-yl) -benzonitrile

Step 1: to a solution of compound 231-1(10g,82mmol) in HBr (41mL) was added Br2(36.8g,0.23mmol) and stirred at-10 ℃ for 10 min. Sodium nitrite (14.1g,210mmol) was then added while maintaining the reaction temperature below 0 ℃. The reaction mixture was stirred for 30 minutes. Then sodium hydroxide solution (35g dissolved in 35mL water) was added and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) gave compound 231-2(3.36g, 22%) as a pale yellow oil. MS ESI calculated value C₇H₈BrN[M+H]⁺187, measuring the value 187.

Step 2: to a solution of compound 231-2(3.36g,18.1mmol) in THF (70mL) was added n-butyllithium (8mL,19.91mmol) at-70 deg.C and stirred for 1h. Then compound 231-3(4.32g,21.71mmol) was added at-70 ℃. Slowly warmed to room temperature and stirred at room temperature for 2 hours. The reaction was then quenched with saturated aqueous ammonium chloride (2mL) and extracted with ethyl acetate (200 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (petroleum ether/ethyl acetate ═ 5:1) gave compound 231-4(3.11g, 56%) as a pale yellow oil. MS ESI calculated value C₁₇H₂₆N₂O₃[M+H]⁺307, measurement value 307.

And step 3: to a solution of compound 231-4(2g,6.5mL) in dichloromethane (30mL) was added trifluoroacetic acid (6mL) dropwise. The reaction mixture was stirred at room temperature for 30 minutes. Then basified with 6N NaOH to pH 9 and extracted with chloroform (70 × 3 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give crude compound 231-5(1.197g, 89%) as a yellow solid which was used in the next step without further purification. MS ESI calculated value C₁₂H₁₈N₂O[M+H]⁺207, measurement 207.

And 4, step 4: the title compound (18mg, 9.5%) was prepared as a white solid by the preceding method.¹H NMR(400MHz,CDCl₃)8.89(s,1H),8.24-8.21(m,1H),7.83-7.76(m,4H),7.60-7.56(m,2H),7.01(s,1H),6.94(s,1H),5.74(s,1H),4.19(s,3H),3.63-3.49(m,4H),2.54(s,3H),2.37(s,3H),2.28-2.21(m,2H),1.79-1.76(m,2H) MS ESI₂₉H₂₈N₄O₂[M+H]⁺465 and measured values 465.

Example 232

4- (3- (4- (2, 6-dimethyl-morpholin-4-yl) -cyclohexyl) -4-methoxy-quinolin-8-yl) -benzonitrile

Step 1: to a solution of compound 232-1(20g,0.13mol), cis-2, 6-dimethylmorpholine (14.74g,0.13mol) and acetic acid (7.69mg,0.13mol) in 1, 2-dichloroethane (400mL) was added sodium borohydride acetate (54.3g,0.26mol) at 0deg.C and the mixture was stirred at 25 deg.C for 16 hours. Then quenched slowly dropwise (20 min) with 10% aqueous sodium hydroxide (200mL) and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give compound 232-3(30g, 92%) as a white solid. MS ESI calculated value C₁₄H₂₅NO₃ [M+H]⁺256, measured value 256.

Step 2: to a solution of compound 232-3(10g,39.2mmol) in THF (200mL) was added 7N aqueous HCl (40mL), and the mixture was stirred at 25 ℃ for 16 h. The reaction was then quenched with 2N aqueous NaOH (500mL) and extracted with ethyl acetate (1 ×) and dichloromethane (3 ×). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give crude compound 232-4(8g, 96%) as a white solid. MS ESI calculated value C₂₁H₁₂NO₂[M+H]⁺212, and a measured value 212.

And step 3: to a solution of compound 232-4(3g,14.2mmol) in THF (50mL) was added LiHMDS (17mL,17mmol) at 0deg.C and the mixture was stirred for 30 min. N, N-bis (trifluoromethylsulfonyl) aniline (5.58g,15.6mmol) was then added, and the mixture was stirred at 25 ℃ for 6 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography on silica gel (5:1 petroleum ether/ethyl acetate) gave compound 232-5(2.3g, 47%) as a white solid. MS ESI calculated value C₁₃H₂₀F₃NO₄S[M+H]⁺344, measureA constant value 344.

And 4, step 4: to a solution of compound 232-5(0.76g,2.2mmol) and compound 232-6(0.67g,2.6mmol) in 1, 4-dioxane (15mL) was added Pd (dppf) Cl under a nitrogen atmosphere₂(0.4mg,0.11mmol) and potassium acetate (0.65g,6.6 mmol). The reaction mixture was stirred at 100 ℃ for 15 hours, then poured into water and extracted with ethyl acetate (50X 2 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate ═ 5:1) gave compound 232-7(0.35g, 49%) as a yellow solid. MS ESI calculated value C₁₈H₃₂BNO₃[M+H]⁺322, and a measured value 322.

And 5: to a solution of compound 232-7(600mg,1.87mmol) and compound 232-8(601mg,1.56mmol) in THF (10mL) and water (2mL) under a nitrogen atmosphere was added Pd (dppf) Cl₂(113.8mg,0.16mmol) and sodium carbonate (412mg,3.89 mmol). The reaction mixture was stirred at 80 ℃ for 4 hours, then extracted with ethyl acetate (50X 2 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate ═ 5:1) gave compound 232-7(400mg, 48%) as a white solid. MS ESI calculated value C₂₉H₃₁N₃O₂[M+H]⁺454, and a measurement value 454.

Step 6: to a solution of compound 232-9(100mg,0.22mmol) in ethyl acetate (20mL) was added Pd/C (100mg), and the mixture was hydrogenated under a hydrogen balloon at 20 ℃ for 50 hours. The mixture was then filtered and concentrated under reduced pressure. The resulting yellow solid was purified by preparative HPLC to give the title compound (27mg, 54%) as a white solid.¹HNMR (400MHz, DMSO)8.99(s,1H),8.17-8.15(J ═ 8Hz, d,1H),7.94-7.92(d, J ═ 12Hz,2H),7.85-7.83(d, J ═ 8Hz,2H),7.80-7.78(J ═ 8Hz, d,1H),7.74-7.72(J ═ 8Hz, d,1H),3.98(s,3H)3.54(s,2H),3.18-3.17(J ═ 4Hz, d,1H),3.54(s,1H),2.76-2.74(J ═ 8Hz, d,2H),1.95-1.71(m,8H),1.49-1.44(m,2H),1.07-1.05(J ═ 8H), 6H, 6(m,6H), C, calculated values₂₉H₃₃N₃O₂[M+H]⁺465 and measured values 465.

Example 233

4- (3- (4- (2, 6-dimethyl-morpholin-4-yl) -3-fluoro-piperidin-1-yl) -4-methoxy-quinolin-8-yl) -benzonitrile

Step 1: a solution of compound 1(3.0g,13.8mmol) and cis-2, 6-dimethylmorpholine (1.7g,15.2mmol) in dichloromethane (15mL) was stirred at 20 ℃ for 0.5h, then sodium borohydride acetate (4.4g,20.7mmol) was added at 20 ℃ and stirred at 20 ℃ for 15 h. The reaction was then quenched with saturated aqueous sodium carbonate (50mL) and extracted with dichloromethane (50 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate 8:1-1:1) gave compound 233-3(1.2g, 27%) as a white solid. MS ESI calculated value C₁₆H₂₉FN₂O₃[M+H]⁺317, measurement value 317.

Step 2: to a solution of compound 233-3(1.2g,3.8mmol) in methanol (10mL) was added HCl (4M in methanol, 60 mL). The resulting solution was stirred at 20 ℃ for 0.5 hour and then concentrated under reduced pressure. The resulting yellow solid was used directly in the next step without further purification (0.6g, 75%). MS ESI calculated value C₁₁H₂₁FN₂O[M+H]⁺217, measured value 217.

And step 3: the title compound (27mg, 15%) was prepared as a white solid by the preceding method.¹H NMR(400MHz,CDCl₃)8.73(s,1H),8.24-8.21(m,1H),7.80-7.75(m,4H),7.59-7.58(d,J＝4Hz,2H),4.15(s,3H),4.03-4.00(m,1H),3.74-3.71(m,3H),3.07-2.92(m,4H),2.25-1.94(m,6H),1.21-1.19(d,J＝8Hz,6H) MS ESI calculated value C₂₈H₃₁FN₄O₂[M+H]⁺475, and measurement 475.

The compounds shown in Table 21 were synthesized from compounds 233-5 and the corresponding amines

Example 235

4- (3- (4- (2, 6-dimethyl-3-oxo-morpholin-4-yl) -piperidin-1-yl) -4-methoxy-quinolin-8-yl) -benzonitrile

Step 1: a solution of compound 235-1(15g,64mmol), compound 235-A (12mL,192mmol) and acetic acid (11.04mL,192mmol) in methanol (200mL) was stirred at 20deg.C for 1 hour, then sodium cyanoborohydride (12.11g,192mmol) was added in one portion, and the mixture was stirred at 25 deg.C overnight. LCMS showed the reaction was complete, then the reaction mixture was extracted with dichloromethane and saturated aqueous sodium bicarbonate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give compound 235-2(15.6g, 83%) as a yellow oil. MS ESI calculated value C₁₆H₂₄N₂O₃[M+H]⁺293, measurement value 293.

Step 2: to a solution of compound 235-2(1.36g,4.65mmol) in dichloromethane (20mL) were added triethylamine (0.7g,7mmol) and compound 235-B (0.59g,4.65mmol), and the mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete, then extracted with dichloromethane.The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography on silica gel (5:1 petroleum ether/ethyl acetate) gave compound 235-3(1.2g, 67.4%) as a yellow oil. MS ESI calculated value C₁₉H₂₇ClN₂O₄[M+H]⁺383, found 383.

And step 3: to a solution of compound 235-3(760mg,2mmol) in THF (10mL) was added potassium tert-butoxide (225mg,2mmol), and the mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete, then the reaction mixture was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give compound 235-4(500mg, 70%) as a yellow oil. MS ESI calculated value C₁₉H₂₆N₂O₄[M+H]⁺347, measurement 347.

And 4, step 4: to a solution of compound 235-4(3.0g,8.6mmol) in methanol (10mL) was added Pd/C (300mg), and the mixture was hydrogenated at 40psi at room temperature overnight. The mixture was then filtered and concentrated under reduced pressure. The resulting colorless oil was used directly in the next step without further purification (1.3g, 71%). The calculated MS ESI C₁₁H₂₀N₂O₂[M+H]⁺213, measured value 213.

And 5: the title compound (20mg, 1.8%) was prepared as a yellow solid by the preceding method.¹H NMR(400MHz,CDCl₃)8.93(s,1H),8.35-8.32(m,1H),7.83-7.72(m,4H),7.59-7.57(m,2H),4.55-4.50(m,1H),4.49-4.45(m,1H),4.32(s,3H),4.15-4.02(m,2H),3.75-3.52(m,2H),3.22-3.02(m,4H),2.15-2.07(m,2H),2.05-1.92(m,2H),1.48(d, J ═ 7.2Hz,3H). MS ESI calcd C₂₈H₃₀N₄O₃[M+H]⁺471, measured value 471.

Example 236

4- (4-cyclopropyl-3- (4- (5- (1-hydroxy-1-methyl-ethyl) -pyridin-2-yl) -3-oxo-piperazin-1-yl) -quinolin-8-yl) -benzonitrile

Step 1: compound 236-1(4.35g,10mmol), compound 236-2(1.0g,10mmol), Pd2(dba)3(920mg,1.0mmol), Xantphos (1.15g,2.0mmol) and sodium tert-butoxide (2.0g,20mmol) were added to toluene (30mL) and stirred at 120 ℃ for 2 hours under nitrogen. The mixture was poured into water and extracted with ethyl acetate (100mL), and the extract was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give 1.5g of compound 236-3 in 37.5% yield as a yellow solid. MS ESI calculated value C₂₀H₁₅BrN₄O[M+H]⁺407, measured value 407.

Step 2: mixing compound 236-3(407mg,1.0mmol), compound 236-4(870mg,10mmol), n-BuPAd₂(71mg,0.2mmol), palladium acetate (23mg,0.1mmol) and cesium carbonate (650mg,2.0mmol) were added to toluene/water (5:1, 12mL) and stirred under nitrogen at 110 ℃ for 2h. The mixture was poured into water and extracted with ethyl acetate (50mL), and the extract was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give 230mg of compound 236-5 in 64% yield as a yellow solid. MS ESI calculated value C₂₃H₂₀N₄O[M+H]⁺369, found 369.

And step 3: mixing 236-5(185mg,0.5mmol), 236-6(86mg,0.5mmol), Pd₂(dba)₃(46mg,0.05mmol), Xantphos (57.7mg,0.1mmol) and cesium carbonate (325mg,1.0mmol) were added to toluene (10mL) and stirred under nitrogen at 120 ℃ for 2h. The mixture was poured into water and extracted with ethyl acetate (100mL), and the extract was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (80mg,yield 32%) as a white solid.¹H NMR (400MHz, CDCl3)8.78(s,1H),8.61-8.62(d, J ═ 2.0Hz,1H), 8.53-8.55(d, J ═ 7.6Hz,1H), 8.01-8.04(d, J ═ 8.4Hz,1H), 7.78-7.80(m,4H)7.61-7.67(m,2H)4.26-4.28(t, J ═ 10.4Hz2H),4.23(s,2H)3.74-3.76(t, J ═ 10.8Hz2H),2.11-2.15(m,1H)1.65(s,6H),1.34-1.37(m,2H)0.98-1.00(d, J ═ 6.25 Hz, 25Hz calculated values (C, 2H Hz), 1.98-1H) and C (d, J ═ 2H)₃₁H₂₉N₅O₂[M+H]⁺504, found 504.

Example 237

4- (4-cyclopropyl-3- (3-hydroxy-4- (5- (1-hydroxy-1-methyl-ethyl) -pyridin-2-yl) -3-methyl-piperazin-1-yl) -quinolin-8-yl) -benzonitrile

Step 1: mixing compound 237-1(150mg,0.4mmol), compound 237-2(70mg,0.4mmol), Pd₂(dba)₃(37mg,0.04mmol), Xantphos (45mg,0.08mmol) and cesium carbonate (260mg,0.8mmol) were added to toluene (2mL) and stirred under nitrogen at 120 ℃ for 2h. The mixture was poured into water and extracted with ethyl acetate (10mL), and the extract was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give 80mg of the compound 237-3 in 39% yield as a yellow solid. MSESI calculated value C₃₀H₂₅N₅O₃[M+H]⁺504, found 504.

Step 2: dissolve compound 237-3(50mg,0.1mmol) in THF (5mL) and dissolve methylmagnesium bromide (0.1mL, 3M in Et at-76 deg.C₂O) is slowly added into the solution, the temperature is kept, the mixture is stirred and reacts for 1 hour, and then ammonium chloride is poured into the mixture to dissolve in waterThe solution was extracted with ethyl acetate (10mL), and the extract was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (10mg, yield 20%) as a white solid.¹H NMR (400MHz, CDCl3)8.76(s,1H),8.66(s,1H),8.38-8.39(d, J ═ 6.4Hz,1H), 7.83-7.85(d d, J ═ 2.0Hz,1H), 7.80-7.83(m,4H)7.54-7.57(m,2H)6.25-6.33(m,2H)4.29(s,2H),3.84(s,3H)3.72-3.75(t, J ═ 11.2Hz2H),3.47-3.49(d, J ═ 6.8Hz, 2H),2.16(s,6H)1.92-1.95(m,1H),1.22-1.26(m,2H) 0.75-0.esi (m,2H), 2.79 (MS, 2H) calculated values₃₂H₃₃N₅O₂[M+H]⁺520, found 520.

Example 238

4- (3- (4-hydroxy-4- (5- (2-hydroxypropan-2-yl) pyridin-2-yl) piperidin-1-yl) -4-methoxyquinolin-8-yl) benzonitrile

Step 1: to a solution of compound 238-1(2.64g,7.8mmol) in toluene (70mL) were added compound 238-2(930mg,6.5mmol) and sodium tert-butoxide (1.9g,19.5mmol), followed by Pd under nitrogen protection₂(dba)₃(595mg,0.65mmol) and Xantphos (750mg,1.3mmol), the reaction was heated to 100 ℃ and stirred for 3h. The solvent was spun dry, water (100mL) was added, and extracted with ethyl acetate (50mL × 3). The organic phase was washed with brine, dried over sodium sulfate and concentrated to give the crude product. The crude product was purified by column chromatography (PE/EtOAc ═ 5/1) to afford compound 238-3 as a yellow solid (1g of crop)₂₄H₂₃N₃O₃[M+H]⁺402, measured value 402.

Step 2: to a solution of compound 238-3(1g of crede, 2.5mmol) in THF (15mL) was added 2N HCl (15mL) and the reaction was stirred at room temperature for 3 hours. The mixture was quenched with 2N aqueous NaOH and adjusted to pH 7to 8. Water (20mL) was added and extracted with ethyl acetate (20 mL. times. 2). The organic phase was washed with brine, dried over sodium sulfate and concentrated to give compound 238-4 as a yellow oil (380mg of crode). calculated by MS ESI C₂₂H₁₉N₃O₂[M+H]⁺358, found 358.

And step 3: compound 238-5 was dissolved in THF (150mL), cooled to-70 deg.C, n-BuLi (5mL,12.5mmol) was added dropwise, after reaction for 30 minutes, acetone (2mL,20mmol) was added dropwise, and the reaction was stirred at-70 deg.C for 1 hour. The reaction was quenched with saturated ammonium chloride solution, water (30mL) was added, and extracted with ethyl acetate (30mL × 3). The organic phase was washed with brine, dried over sodium sulfate and concentrated to give the crude product. Crude column chromatography purification (PE/EtOAc ═ 3/1) afforded compound 238-6 as a white solid (462mg, 17.1%). MSESI calcd₈H₁₀BrNO[M+H]⁺216, found value 216.

And 4, step 4: compound 238-6(30mg,0.14mmol) was dissolved in THF (5mL), cooled to-70 deg.C and n-BuLi (0.12mL,0.31mmol) was added dropwise, after 30 minutes of reaction, a solution of compound 238-4(50mg of crede, 0.14mmol) in THF (2mL) was added dropwise, and the reaction was stirred at-70 deg.C for 1 hour. The reaction solution was quenched with a saturated ammonium chloride solution, water (10mL) was added, and extraction was performed with ethyl acetate (20 mL). The organic phase was washed with brine, dried over sodium sulfate and concentrated to give the crude product. Preparative isolation of the crude product by prep-HPLC afforded the title compound as a yellow oil (3mg, 4.3%). In calculated MS ESI C₃₀H₃₀N₄O₃[M+H]⁺495, found value 495.

Example 239

3- (8- (4-cyanophenyl) -4-cyclopropylquinolin-3-yl) -6- (2, 6-dimethyl-morpholin-4-yl) -pyridine-2-carboxylic acid

Step 1: the compound 239-1(5g,35mmol) and K₂CO₃(10g,70mmol) was added to a solution of MeI (5g,35mmol) in DMF (40mL) and the reaction stirred at 60 ℃ for 2h and LCMS monitored to the end of the reaction. 2, 6-Dimethylmorpholine (6.1g,53mmol) was then added to the reaction and stirred at 110 ℃ for 2h, after TLC monitoring of the reaction, the mixture was poured into water, extracted with EtOAc and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel column (MeOH: EtOAc ═ 5:1) to give compound 239-3(3.5g, yield 40%) as an oil. MS ESI calculated value C₁₃H₁₈N₂O₃[M+H]⁺251, found value 251.

Step 2: NBS (1.6g,9mmol) was slowly added to a solution of compound 239-3(5g,35mmol) in DMF (15mL), the reaction stirred at room temperature for 6h, LCMS monitored to completion. The mixture was then poured into water, extracted with EtOAc (100 × 3mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel column (PE: EtOAc ═ 5:1) to give compound 239-4(3g, yield 91%) as a white solid. MSESI calculated value C₁₃H₁₇BrN₂O₃[M+H]⁺329 found, value 329.

And step 3: compound 239-4(2g,6mmol), compound 239-5(1.82g,7.2mmol) and KOAc (1.2g,12mmol) were dissolved in dioxane (50mL) and Pd (dppf) Cl was added thereto under nitrogen protection₂(440mg,0.6 mmol.) the reaction was stirred at 120 ℃ for 3h after the reaction was complete, the mixture was poured into water and extracted with EtOAc. Anhydrous Na for organic phase₂SO₄Drying and concentrating to obtain a crude product. The crude product was purified over a silica gel column (PE: EtOAc ═ 5:1) to give a yellow solidCompound 239-6(1.3g, 60%). MS ESI calculated value C₁₉H₂₉BN₂O₅[M+H]⁺377, found 377.

And 4, step 4: mixing compound 239-7(1.74g,4mmol), compound 239-6(1.5g,4mmol), and Na₂CO₃(848mg,8mmol) dissolved in DMF (2mL)/H₂O (2mL)/THF (10mL), then Pd (dppf) Cl₂(293mg,0.4mmol) was added to the solution. The reaction was allowed to react at 70 ℃ overnight. LC-MS monitors until the reaction is completed. The mixture was poured into water and extracted with EtOAc. Anhydrous Na for organic phase₂SO₄Drying and concentrating to obtain a crude product. The crude product was purified by silica gel column (PE: EtOAc ═ 2:1) to give compound 239-8(474mg, 21%) as a red solid. MS ESI calculated value C₂₉H₂₅BrN₄O₃[M+H]⁺557, found 557.

And 5: compound 239-8(474mg,0.85mmol), cyclopropylboronic acid (731mg,8.5mmol) and Na₂CO₃(180mg,1.7mmol) in DMF (2mL)/H₂O (2mL)/THF (10mL), then Pd (dppf) Cl₂(73mg,0.1mmol) was added to the solution. The reaction was allowed to react at 70 ℃ overnight. LC-MS monitors until the reaction is completed. The mixture was poured into water and extracted with EtOAc. Anhydrous Na for organic phase₂SO₄Drying and concentrating to obtain a crude product. The crude product was purified by silica gel column (PE: EtOAc ═ 2:1) to give red solid compound 239-9(200mg, 21%). MS ESI calculated value C₃₂H₃₀N₄O₃[M+H]⁺519, found 519.

Step 6: NaOH (80mg,2mmol) was added to compound 239-9(200mg,0.4mmol) in MeOH (5mL)/H₂O (1mL) solution, and the reaction was allowed to react overnight at room temperature. LC-MS monitors until the reaction is completed. The crude product was purified by HPLC to give the title compound (30mg, 15%) as a yellow solid.¹H NMR(400MHz,CDCl₃)8.77(d,J＝8.4Hz,1H),7.86-7.82(m,5H),7.76-7.06(m,3H),7.07(d,J＝8.4Hz,1H),4.10(d,J＝12.0Hz,2H),3.81(m,2H),2.76(m,2H),2.32(m,2H),1.37(d,J＝6.0Hz,6H),1.08(m,2H),0.49(d, J ═ 5.2Hz,2H), MS ESI calcd C₃₁H₂₈N₄O₃[M+H]⁺505, measured value 505.

Example 240

4- (3- (4-hydroxy-5 '- (1-hydroxy-1-methyl-ethyl) -3,4,5, 6-tetrahydro-2H- [1,2' ] bipyridinyl-4-yl ] 4-methoxy-quinolin-8-yl) -benzonitrile

Step 1: n-BuLi (2.5M,1.25mmol) was slowly added to a solution of compound 240-1(170mg,0.5mmol) in THF (10mL) at-78 deg.C, the reaction was stirred at-78 deg.C for 0.5h, then 2(100mg,0.5mmol) was added to the reaction and stirred at-78 deg.C for 2h, after TLC monitoring of the reaction was complete, the mixture was poured into NH₄Cl (aq), extracted with EtOAc, and the organic phase dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel column (MeOH: EtOAc ═ 2:1) to give compound 240-3(100mg, yield 33%) as an oil. MS ESI calculated value C₂₇H₂₉N₃O₄[M+H]⁺460, measured value 460.

Step 2: CF is prepared by₃COOH (2mL) was added to a solution of compound 240-3(400mg,0.9mmol) in DCM (4mL), the reaction was stirred at RT for 1h, and TLC monitored to completion. The solvent was then spin dried and the crude product was used directly in the next step.

And step 3: the compound 240-4(250mg,0.7mmol), K₂CO₃(292mg,2.1mmol) was dissolved in ACN (10mL), 240-5(120mg,0.7mmol) was added thereto, the reaction was stirred at 100 ℃ for 8h, LCMS was used to monitor the reaction and after completion of the reaction, filtration was carried out, the filtrate was concentrated to give a crude productA compound (I) is provided. The crude product was purified by silica gel column (PE: EtOAc ═ 1:1) to give compound 240-6(200mg, 58%) as a white solid. MS ESI calculated value C₂₉H₂₆N₄O₄[M+H]⁺495, found value 495

And 4, step 4: MeMgBr (1mL,3.0mmol) was slowly added dropwise at room temperature to a solution of compound 240-6(200mg,0.4mmol) in THF (10mL), and the reaction was stirred at room temperature for 30 min. LC-MS monitors until the reaction is completed. Pouring the mixture into NH₄Cl (aq), extracted with EtOAc (100X 3 mL). Anhydrous Na for organic phase₂SO₄Drying and concentrating to obtain a crude product. The crude product was purified by HPLC to give the title compound (25mg, 13%) as a yellow solid compound.¹H NMR(400MHz,CDCl₃)8.95(s,1H),8.35(d, J ═ 3.2Hz,1H),8.15(dd, J ═ 1.2,8.0Hz,1H),7.79(s,4H),7.74-7.68(m,3H),6.76(d, J ═ 7.2Hz,1H),4.29-4.26(m,2H),4.20(s,3H),3.86(s,1H),3.51(t, J ═ 12Hz,2H),2.40-2.33(m,2H),2.09-2.03(m,2H),1.61(s,6H). MS ESI calculated value C ESI₃₀H₃₀N₄O₃[M+H]⁺495, found value 495.

Example 241

N- (8- (4-cyanophenyl) -4-methoxy-quinolin-3-yl) -6- (2, 6-dimethyl-morpholin-4-yl) -nicotinamide

Compound 241-1(100mg,0.36mmol), compound 241-2(100mg,0.4mmol) and a trimethylaluminum solution (0.9mL,0.9mmol) were dissolved in toluene (2mL), and the reaction solution was stirred at 800 ℃ for 12 hours. The reaction mixture was cooled to room temperature, water was then added to the reaction mixture, the solution was extracted with ethyl acetate (50 mL. times.2), and the organic layers were separated with waterAnd washing with brine. Dried over sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by silica gel column to give the title compound (80mg, yield 44%) as a white solid.¹H NMR (400MHz, CD3OD) ppm8.89(s,1H),8.84(s,1H),8.33-8.36(d, J ═ 8.4Hz,1H),8.17(d, J ═ 8.8Hz,1H),7.71-7.85(m,5H),6.94(d, J ═ 9.2Hz,1H),5.51(s,1H),4.35(d, J ═ 13.2Hz,2H),4.16(s,3H),2.66(t, J ═ 12.8Hz,2H),1.28(d, J ═ 6.4Hz,6H), MS esic calculated value₂₉H₂₇N₅O₃[M+H]⁺494, found 494.

Example 242

8- (4-cyanophenyl) -N- (4- ((2S,6R) -2, 6-dimethylmorpholinyl) phenyl) -4-methoxyquinoline-3-carboxamide

Step 1: diethyl (ethoxymethylene) malonate (13g,60mmol) and 2-bromoaniline (10.3g,60mmol) were mixed and stirred at 100 ℃ for 2 hours. After cooling to room temperature, the reaction solution was poured into methanol and recrystallized from methanol to give compound 242-2(14.5g, yield 70.7%) as a yellow solid. MS ESI calculated value C₁₄H₁₆BrNO₄[M+H]⁺342, found 342.

Step 2: compound 242-2(10g,29.2mmol) was refluxed in diphenyl ether (100mL) for 30 minutes, then cooled to room temperature, hexane was added, and filtered to give compound 242-3(2.8g, yield 32.6%) as a brown solid. MS ESI calculated value C₁₂H₁₀BrNO₃[M+H]⁺295, found 295.

And step 3: compound 242-3(500mg,1.7mmol) was dissolved in phosphorus oxychloride (C: (C))4mL) and stirred at 110 ℃ for 1 hour. The reaction was then poured into methanol and then an aqueous solution of sodium carbonate was added. The mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo to give compound 242-4(400mg, yield 76%) as a brown solid. MS ESI calculated value C₁₃H₁₂BrNO₃[M+H]⁺310, found 310.

And 4, step 4: compound 242-4(527mg, 1.7mmol) was dissolved in methanol (5mL), water (1mL), and sodium hydroxide (340mg,8.5mmol) was added and stirred at room temperature for 5 hours. Poured into water, then HCl solution was added until PH7, extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo to give compound 242-5(478mg, 99% yield) as a yellow solid. MS ESI calculated value C₁₁H₈BrNO₃[M+H]⁺282, measured value 282.

And 5: compound 242-5(478mg,1.7mmol),4- ((2S,6R) -2, 6-dimethylmorpholinyl) aniline 6(525mg,2.55mmol), triethylamine (515mg,5.1mmol) were dissolved in DMF (5mL), HATU (980mg,2.55mmol) was added, and the mixture was stirred at room temperature for 2 hours. Then poured into water, extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo, and purified by a silica gel column to give compound 242-7(400mg, yield 50%) as a yellow solid. MS ESI calculated value C₂₃H₂₄BrN₃O₃[M+H]⁺470, found 470.

Step 6: the title compound (100mg, yield 32%) was prepared as a white solid by the foregoing method.¹H NMR (400MHz, CDCl3)9.49(s,1H),9.23(s,1H),8.28(d, J ═ 8.0Hz,1H),7.74-7.84(m,7H),7.65-7.67(m,2H),7.02(s,1H),4.21(s,3H),3.90(s,1H),3.44-3.49(m,3H),2.48(s,2H),1.28(d, J ═ 6.0Hz,6H) MS ESI calcd for C ESI₃₀H₂₈N₄O₃[M+H]⁺493, found 493.

Example 243

8- (4-cyanophenyl) -N- (6- ((2S,6R) -2, 6-dimethylmorpholinyl) pyridin-3-yl) -4-methoxyquinoline-3-carboxamide

Step 1: the compounds 2-chloro-5-nitropyridine (5g,32mmol) and K₂CO₃(8.8g,64mmol) was dissolved in MeCN (40mL) and (2S,6R) -2, 6-dimethylmorpholine (4.4g,38.4mmol) was added. The reaction solution was stirred at 110 ℃ for 2 hours. The reaction solution was then filtered, and the filtrate was concentrated to give compound 243-3(7.3g) as a yellow solid. MS ESI calculated value C₁₁H₁₅N₃O₃[M+H]⁺238, found value 238.

Step 2: compound 243-3(7.3g,31mmol) and ammonium chloride (16.7g,310mmol) are dissolved in a solution of MeOH (80mL) and water (80mL), and iron powder (20.8g,372mmol) is added. The reaction mixture was kept at 80 ℃ for 3 hours with stirring. The mixture was then filtered, the filtrate was concentrated, the residue was taken up in acetone, filtered and concentrated in vacuo and the crude product was purified on a silica gel column to give compound 243-4(800mg) as a brown solid. MS ESI calculated value C₁₁H₁₇N₃O[M+H]⁺208, found 208.

And step 3: 4-cyanophenylboronic acid (1.8g,12mmol), compound 243-4(3.1g,10mmol) and sodium carbonate (2.1g,20mmol) were dissolved in DMF (5mL), H₂To O (5mL) and tetrahydrofuran (25mL) was added Pd (dppf) Cl₂(732mg,1 mmol). The reaction solution was stirred at 70 ℃ for 2 hours. Then poured into water, extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated, and purified on silica gel column to give compound 243-6(2.8g) as a white solid. MS ESI calculated value C₂₀H₁₆N₂O₃[M+H]⁺333, found 333. step 4: compound 243-6(1.8g,5.4mmol) is dissolved in MeOH (10 m)L) and H₂To a solution of O (4mL) was added sodium hydroxide (1g,27mmol) and stirred at room temperature for 2h, then the reaction was poured into water and extracted with ethyl acetate, the aqueous layer acidified to pH 4 with 1N hydrochloric acid, extracted with ethyl acetate, the organic layer washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give compound 243-7(580mg) as a white solid MS calculated for ESI C₁₈H₁₂N₂O₃[M+H]⁺305, measured value 305.

And 5: compound 243-7(200mg,0.65mmol), HATU (494mg,1.3mmol) and compound 243-4(136mg,0.65mmol) were dissolved in DMF (5mL) and DIPEA (387mg,3mmol) was added. The reaction was stirred at room temperature overnight and the reaction was purified by HPLC to give the title compound (100mg) as a white solid.¹H NMR (400MHz, CDCl3)9.49(s,1H),9.23(s,1H),8.27-8.30(m,3H),7.73-7.85(m,7H),6.73-6.75(m,1H),4.21(s,3H),4.05-4.08(m,2H),3.74-3.79(m,2H),2.56-2.61(m,2H),1.29(d, J ═ 6.0Hz,6H). MS ESI calculated value C₂₉H₂₇N₅O₃[M+H]⁺494, found 494.

Example 244

8- (4-cyanophenyl) -4-cyclopropyl-N- (6- ((2S,6R) -2, 6-dimethylmorpholinyl) pyridin-3-yl) quinoline-3-carboxamide

Step 1: 4-cyanophenylboronic acid (2g,14.4mmol), ethyl 8-bromo-4-hydroxyquinoline-3-carboxylate (3.5g,12mmol) and sodium carbonate (2.5g,24mmol) were dissolved in DMF (5mL), H₂To O (5mL) and tetrahydrofuran (25mL) was added Pd (dppf) Cl₂(878mg,1.2 mmol). The reactionStirring was carried out at 70 ℃ for 2 hours. The mixture was then poured into water and filtered to give compound 244-2(3.2g) as a brown solid. MS ESI calculated value C₁₉H₁₄N₂O₃[M+H]⁺319, found 319.

Step 2: compound 244-2(3.2g,10mmol) was dissolved in DMF (40mL) and PBr was added₃(4mL,10M), the reaction mixture was stirred at room temperature for 1 hour. The mixture was then poured into water, the solid filtered off and washed with water and dried in air to give compound 244-3(3.0g) as a brown solid. MS ESI calculated value C₁₉H₁₃BrN₂O₂[M+H]⁺381, found value 381.

And step 3: cyclopropylboronic acid (6.7g,78mmol), compound 244-3(3.0g,7.8mmol) and sodium carbonate (1.7g,15.6mmol) were dissolved in DMF (5mL), H2O (5mL) and tetrahydrofuran (25mL), Pd (dppf) Cl was added₂(571mg,0.78 mmol). The reaction was stirred at 70 ℃ for 2 hours. The mixture was then poured into water, extracted with ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified on a silica gel column to give compound 244-4(1.8g) as a yellow solid. MS ESI calculated value C₂₂H₁₈N₂O₂[M+H]⁺343, found value 343.

And 4, step 4: compound 244-4(1.8g,5.4mmol) was dissolved in MeOH (10mL) and H2O (4mL), and sodium hydroxide (1g,27mmol) was added. The reaction was stirred at room temperature for 2 hours. Then poured into water, extracted with ethyl acetate, the aqueous layer acidified with 1N HCl, extracted with ethyl acetate, the organic layer washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give compound 244-5(570mg) as a yellow solid. MS ESI calculated value C₂₀H₁₄N₂O₂[M+H]⁺315, measured value 315.

And 5: compound 244-5(200mg,0.65mmol), HATU (494mg,1.3mmol) and 6- ((2S,6R) -2, 6-dimethylmorpholinyl) pyridin-3-amine (136mg,0.65mmol) were dissolved in DMF (5mL) and DIPEA (387mg,3mmol) was added. The reaction solution is stirred at room temperature, is prepared and purified by HPLC,the title compound (100mg) was obtained as a white solid.¹H NMR (400MHz, CDCl3)10.2(s,1H),8.95(s,1H),8.61-8.74(m,3H),7.75-7.78(m,4H),7.63-7.65(m,2H),7.08(d, J ═ 9.2Hz,1H),4.04(d, J ═ 13.2Hz,2H),3.74(s,2H),2.83-2.89(m,2H),2.64(s,1H),1.27(d, J ═ 6.0Hz,8H),0.72-0.73(m,1H), MS ESI calcd C₃₁H₂₉N₅O₂[M+H]⁺504, found 504.

Example 245

8- (4-cyanophenyl) -N- (6- ((3S,5R) -3, 5-dimethyl-4-propionylpiperazin-1-yl) pyridin-3-yl) -4-methoxyquinoline-3-carboxamide

Step 1: 2-chloro-5-nitropyridine (5g,32mmol) and potassium carbonate (8.8g,64mmol) were dissolved in acetonitrile (40mL) and compound 245-1(4.3g,38.4mmol) was added. The reaction solution was stirred at 80 ℃ for 1 hour, and then the reaction solution was filtered and concentrated to give compound 245-3(4.5g) as a yellow solid. MS ESI calculated value C₁₁H₁₆N₄O₂[M+H]⁺237, found 237.

Step 2: to DCM (40mL) was added propionyl chloride (2.2g,23mmol) and DIPEA (7.4g,57 mmol). The reaction solution was stirred at 0 ℃ for 30 minutes. Then poured into water, extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give compound 245-4(3.2g) as a yellow solid. MS ESI calculated value C₁₄H₂₀N₄O₃[M+H]⁺293, found 293.

And step 3: compound 245-4(3.2g,11mmol) and palladium on charcoal (0.32g) were dissolved in methanol (500mL) and the reaction was stirred under 40psi of hydrogen at room temperature overnight. Then filtered and the solvent concentrated under reduced pressure to give crude compound 245-5(800mg) as a red oil. MS ESI calculated value C₁₄H₂₂N₄O[M+H]⁺263, found 263.

And 4, step 4: a solution of 8- (4-cyanophenyl) -4-methoxyquinoline-3-carboxylic acid (100mg,0.33mmol), HATU (251mg,0.66mmol) and compound 245-5(86mg,0.33mmol) were dissolved in DMF (5mL) and DIPEA (86mg,0.33mmol) was added. The reaction was stirred at room temperature overnight and purified by HPLC to give the title compound (80mg) as a white solid.¹H NMR (400MHz, CDCl3)9.47(s,1H),9.24(s,1H),8.26-8.28(m,3H),7.72-7.84(m,6H),6.77(d, J ═ 9.2Hz,1H),4.21(s,3H),3.05-3.10(m,2H),1.34(s,6H),1.19(t, J ═ 7.4Hz,1H), MS ESI calcd for C₃₂H₃₂N₆O₃[M+H]⁺548, found 548.

The compounds shown in Table 22 were synthesized from compound 245-5 and the corresponding acid

Example 247

4- (4-methoxy-3- (3-trifluoromethyl-5, 6-dihydro-8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) -quinolin-8-yl) -benzonitrile

Will be transformed intoCompound 247-1(339mg,1mmol), Xantphos (115mg,0.2mmol),247-2(192mg,1mmol) and t-BuONa (200mg,2mmol) were dissolved in toluene (10mL) and Pd was added thereto under nitrogen protection₂(dba)₃(92mg,0.1mmol) the reaction was stirred at 110 ℃ for 2h after the reaction was complete, the mixture was poured into water and extracted with EtOAc. Anhydrous Na for organic phase₂SO₄Drying and concentrating to obtain a crude product. The crude product was purified by HPLC to give the title compound (30mg, 7%) as a yellow solid.¹H NMR(400MHz,CDCl₃)9.48(s,1H),8.45(d, J ═ 8.0Hz,1H),7.87(m,4H),7.66(m,2H),4.98(s,1H),4.45-4.39(m,5H),4.02(s,2H). MS ESI calcd for C₂₃H₁₇F₃N₆O[M+H]⁺451, found value 451.

Example 248

4- (3- (4-cyclopropanecarbonyl-piperazin-1-yl) -4-methoxy-quinolin-8-yl) -benzonitrile

Compound 248-1(172mg,0.5mmol), HATU (380mg,1mmol) and 248-2(86mg,1mmol) were dissolved in DMF (4mL), then DIPEA (194mg,1.5mmol) was added thereto and the reaction was stirred at room temperature overnight. LCMS monitor to end reaction. The reaction was purified by HPLC to give the title compound (40mg, 20%) as a yellow solid compound.¹H NMR(400MHz,CDCl₃)8.76(s,1H),8.4(t, J ═ 4.8Hz,1H),7.82-7.79(m,4H),7.63-7.59(m,2H),4.16(s,3H),3.92(m,4H),3.33-3.30(m,4H),1.85-1.80(m,1H),1.08-1.05(m,2H),0.86-0.83(m,2H), MS ESI calcd for C, ESI₂₅H₂₄N₄O₂[M+H]⁺413, found value 413.

Example 249

4- (4-methoxy-3- (4- (propane-2-sulfonyl) -piperazin-1-yl) -quinolin-8-yl) -benzonitrile

Compound 249-1(172mg,0.5mmol) and DIPEA (194mg,1.5mmol) were dissolved in DCM (5mL), and then 2(142mg,1mmol) was added thereto, and the reaction was stirred at room temperature for 30 min. LCMS monitor to end reaction. The mixture was poured into water and extracted with EtOAc. Anhydrous Na for organic phase₂SO₄Drying and concentrating to obtain a crude product. The crude product was purified by HPLC to give the title compound (20mg, 10%) as a yellow solid.¹H NMR(400MHz,CDCl₃)8.75(s,1H),8.22(dd, J ═ 4.4,5.6Hz,1H),7.82-7.77(m,4H),7.63-7.61(m,2H),4.13(s,3H),3.62-3.60(m,4H),3.33-3.30(m,4H),3.31-3.26(m,1H),1.43(d, J ═ 7.2Hz,6H), MS ESI calcd C₂₄H₂₆N₄O₃S[M+H]⁺451, found value 451.

Example 250

4- (2- (6- (3, 5-dimethyl-4-propionylpiperazin-1-yl) -pyridin-3-yl) -1H-benzimidazol-4-yl) -benzonitrile

Step 1: compound 250-2(1.14g,10mmol) was added to compound 250-1(1.71g,10mmol) and K₂CO₃(2.78g,20mmol) in DMF (20mL) and the reaction stirred at 110 ℃ for 2h and LCMS monitored to completion. The mixture was then poured into water, extracted with EtOAc, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel column (PE: EtOAc ═ 1:1) to give 250-3(2.3g, 92% yield) as an oil. MS ESI calculated value C₁₃H₁₉N₃O₂[M+H]⁺250, found 250.

Step 2: 250-4(1.0g,10.8mmol) was slowly added to a solution of compound 250-3(2.3g,9mmol) and DIPEA (2.3g,18mmol) in DCM (30mL), the reaction was stirred at 0 ℃ for 30min and LCMS monitored to the end of the reaction. The mixture was then poured into water, extracted with EtOAc (100X 3mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated to give crude product 250-5(2.5g, 91% yield). MS ESI calculated value C₁₆H₂₃N₃O₃[M+H]⁺306, found value 306.

And step 3: NaOH (1.28g,32mmol) was added to compound 250-5(2.5g,8mmol) in MeOH (10mL)/H₂O (2mL), reaction stirred at 40 ℃ for 1h after reaction, the mixture was poured into water, washed with EtOAc, the aqueous phase acidified to pH 4 with 1N HCl, then extracted with EtOAc, and the organic phase extracted with anhydrous Na₂SO₄Drying and concentration gave 250-6(1g, 43%) as crude product. The crude product was used directly in the next step.

And 4, step 4: mixing compound 250-10(374mg,2mmol), compound 250-11(294mg,2mmol) and Na₂CO₃(424mg,4mmol) dissolved in DMF (2mL)/H₂O (2mL)/THF (10mL), then Pd (dppf) Cl₂(146mg,0.2mmol) was added to the solution. The reaction was allowed to react at 70 ℃ overnight. LC-MS monitors until the reaction is completed. The mixture was poured into water and extracted with EtOAc. Anhydrous Na for organic phase₂SO₄Drying and concentratingObtaining a crude product. The crude product was purified by silica gel column (PE: EtOAc ═ 1:1) to give compound 250-7(200mg, 50%) as a red solid. MS ESI calculated value C₁₃H₁₁N₃[M+H]⁺210, measured value 210.

And 5: compounds 250-7(200mg,1mmol), HATU (760mg,2mmol) and 250-6(291mg,1mmol) were dissolved in DMF (10mL) and DIPEA (387mg,3mmol) was added to the solution. The reaction system was reacted at room temperature for 1h. LC-MS monitors until the reaction is completed. The mixture was poured into water and extracted with EtOAc. Anhydrous Na for organic phase₂SO₄Drying and concentrating to obtain a crude product. The crude product was purified by silica gel column (PE: EtOAc ═ 1:1) to give 250-5(200mg, 42%) as a brown solid. MS ESI calculated value C₂₈H₃₀N₆O₂[M+H]⁺483, found 483.

Step 6: compound 250-5(80mg,0.16mmol) was dissolved in AcOH (2mL) and the reaction was reacted at 180 ℃ for 40min under microwave. LC-MS monitors until the reaction is completed. The crude product was purified by HPLC to afford the title compound (10mg, 14%) as a yellow solid.¹H NMR(400MHz,CDCl₃)8.83-8.82(m,1H),8.30-8.26(m,3H),7.78-7.62(m,3H),7.52-7.32(m,2H),6.79-6.75(m,1H),3.23-3.18(m,2H),1.67(s,3H),1.34(s,6H),1.22(t, J ═ 7.6Hz,3H). MS ESI calcd for C₂₈H₂₈N₆O[M+H]⁺465, found 465.

Example 251

Step 1: to a solution of compound 251-1(4g,20mmol) in THF (50mL) under ice bath was added NaH (6.4g,160 mmol). The reaction mixture was then stirred at room temperature for 0.5h, the reaction mixture was cooled again to 0 ℃ and iodomethane (10mL,160mmol) was added dropwise, followed by warming to room temperature and stirring for an additional 2h. The reaction was detected by TLC. The mixture was quenched with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were taken up in saturated aqueous solution. Sodium chloride, sodium sulfate was dried and concentrated under reduced pressure to give the desired product 251-2(4.5g, 88%). In calculated MS ESI C₁₄H₂₅NO₃[M+H]⁺256, found 256.

Step 2: compound 251-2(410mg,1.6mmol) was dissolved in hydrochloric acid/methanol (4M,10mL) and stirred at room temperature for 2h after completion of the reaction, concentrated under reduced pressure to give the desired product 251-3(330mg, 86%). MSESI calculated C₉H₁₇NO[M+H]⁺156, measured value 156.

And step 3: synthesis of compound 251-5(300mg, yield 75%) was as previously described. MS ESI calculated value C₃₂H₃₁N₃O₂[M+H]⁺490, found 490.

And 4, step 4: to a solution of compound 251-5(490mg,1mmol) in THF (10mL) was added NaBH₄(57mg,1.5mmol), followed by stirring at room temperature for 0.5 h. After completion of the reaction, as detected by LC-MS, the residue was poured into water. The aqueous layer was extracted with DCM. The combined organic layers were taken up in saturated aqueous solution. The crude product was purified by preparative HPLC to give the title compound as a white solid (64mg, yield 13%).¹H NMR(400MHz,CDCl3)8.93(s,1H),8.47-8.44(m,1H),7.83-7.78(m,4H),7.66(d,J＝7.6Hz,2H),7.43(d,J＝8.4Hz,2H),7.00(d,J＝8.8Hz,2H),3.88(s,3H),3.47(d,J＝12.4Hz,2H),3.12(s,1H),2.64(s,2H),1.08(s,6H),1.05(s,6H).

Experimental example 1: in vitro Activity assay

Purpose of the experiment:

stably transfecting a luciferase (Gli-Luc) reporter gene with Gli response elements into a C3H10T1/2 cell, and detecting the expression condition of the intracellular reporter gene under the Shh-N stimulation condition so as to judge the activity of the Hedgehog signal pathway inhibitor. The inhibitory effect of the compound on the Hedgehog signaling pathway was evaluated by using the IC50 value of the compound as an index in this experiment.

Experimental materials:

cell line: C3H10T1/2/Gli-Luc stable transfer cell strain

C3H10T1/2/Gli-Luc cell culture medium (DMEM/high-sugar Hyclone, # SH30022.01B; 10% serum Hyclone, # SV 30087; 0.4% Hygromycin B Roche, #13398200)

0.25％Trypsin-EDTA(Gibco,#25200)

PBS(KH₂PO₄0.24g，Na₂HPO₄1.44g, NaCl8.0g, KCl0.2g, adding water to 1L to adjust the PH to be 7.4)

Shh-N, HEK293/SHH-N Steady cell culture supernatant

Lysis solution (Promega, # E1531)

Reaction solution (Promega, # E1501)

384 well plates, Greiner #781074

96 well culture plates, Greiner #655180

96-well micro-porous plate, Biyuntian # FPT019

CO2 incubator, Thermo #3423

Clean bench, AIRTECH # A10051560

Inverted microscope, Nikon # TS100

Centrifuge, Xiang apparatus # L530

Therom Varioskan Flash multifunctional reading instrument

Experimental procedures and methods

Taking C3H10T1/2/Gli-Luc cells in logarithmic growth phase, plating the cells in a 96-well plate according to 20000 cells per well, placing the cells at 37 ℃ and 5% CO₂Was cultured overnight in an incubator. The following day, compounds were diluted as follows: the positive compound GDC0449(1mM) and test compound (1mM) were serially diluted 1:3 and 1:10 in DMSO, respectively, to 7 compound concentrations, 8 being a DMSO control, and 100-fold diluted in fresh medium. The overnight cultured cells were removed from the medium, 80. mu.L of fresh medium was added to each well, 20. mu.L of the serially diluted positive and test compounds and 100. mu.L of conditioned medium containing 30nM Shh-N were added in duplicate, 2 wells were set for each concentration, and positive and negative reference wells were set (i.e., Shh Ctrl: 80. mu.L of fresh medium + 20. mu.L of 1% DMSO medium + 100. mu.L of conditioned medium containing 30nM Shh-N; nonstimed Ctrl: 180. mu.L of fresh medium + 20. mu.L of 1% DMSO medium) were placed in the cells with CO₂The incubator continues to incubate for 24 hours.

Detection of intracellular luciferase activity: the cells were removed from the 96-well plate, the medium was discarded, the cells were washed twice with PBS, and then 20. mu.L of lysis buffer (Promega E1531) was added to each well and lysed for 30min at room temperature with shaking. mu.L of the cell lysate was transferred to 384 well plates (Greiner781074) and 25. mu.L of luciferase reaction medium (Promega E1501) was added to each well, mixed quickly and immediately put in a Varioskan Flash multifunctional reader to read the Relative Light Unit (RLU) values.

And (3) data analysis: data analysis was performed using Prism5 from GraphPad. The concentration of the compound logarithmized was plotted against the RLU reading representing luciferase activity, and the IC was obtained by fitting the following equation to a curve₅₀Value, Y (RLU reading) ═ min reading + (max reading-min reading)/(1 +10^ (LogIC concentration of logarithmic compound-LogIC)₅₀))。

TABLE 1 IC50 value for the inhibitory Activity of a Compound on the hedgehog pathway or the rate of inhibition of a Compound at a certain concentration

EXAMPLES Compounds	Biological activity
		Example 1	C
Example 2	C
		Example 3	C
Example 4	C
		Example 5	C
Example 6	D
		Example 7	D
Example 8	C
		Example 9	E
Example 10	C
		Example 11	C
Example 12	D
		Example 13	C
Example 14	B
		Example 15	C
Example 16	C

Example 17	B
		Example 18	C
Example 19	C
		Example 20	C
Example 21	C
		Example 22	B
Example 23	A
		Example 24	B
Example 25	B
		Example 26	B
Example 27	A
		Example 28	A
Example 29	C
		Example 30	C
Example 31	C
		Example 32	C
Example 33	C
		Example 34	C
Example 35	C
		Example 36	C
Example 37	C
		Example 38	A
Example 39	A
		Example 40	A
EXAMPLE 41	A
		Example 42	C
Example 43	E
		Example 44	D
Example 45	E

Example 46	C
		Example 47	E
Example 48	E
		Example 49	D
Example 50	D
		Example 51	C
Example 52	C
		Example 53	D
Example 54	E
		Example 55	E
Example 56	D
		Example 57	D
Example 58	E
		Example 59	D
Example 60	C
		Example 61	C
Example 62	C
		Example 63	E
Example 64	D
		Example 65	D
Example 66	D
		Example 67	D
Example 68	E
		Example 69	D
Example 70	D
		Example 71	E
Example 72	E
		Example 73	D
Example 74	E

Example 75	E
		Example 76	C
Example 77	D
		Example 78	C
Example 79	D
		Example 80	E
Example 81	E
		Example 82	E
Example 83	E
		Example 84	E
Example 85	D
		Example 86	D
Example 87	C
		Example 88	A
Example 89	A
		Example 90	B
Example 91	A
		Example 92	A
Example 93	A
		Example 94	A
Example 95	A
		Example 96	C
Example 97	C
		Example 98	A
Example 99	A
		Example 100	C
Example 101	C
		Example 102	B
Example 103	B

Example 104	A
		Example 105	A
Example 106	B
		Example 107	A
Example 108	C
		Example 109	B
Example 110	C
		Example 111	C
Example 112	A
		Example 113	A
Example 114	E
		Example 115	E
Example 116	C
		Example 117	E
Example 118	B
		Example 119	B
Example 120	D
		Example 121	A
Example 122	B
		Example 123	A
Example 124	B
		Example 125	A
Example 126	C
		Example 127	C
Example 128	D
		Example 129	B
Example 130	D
		Example 131	E
Example 132	A

Example 133	A
		Example 134	A
Example 135	C
		Example 136	B
Example 137	C
		Example 138	A
Example 139	B
		Example 140	D
Example 141	C
		Example 142	D
Example 143	A
		Example 144	C
Example 145	A
		Example 146	D
Example 147	C
		Example 148	B
Example 149	A
		Example 150	D
Example 151	A
		Example 152	A
Example 153	C
		Example 154	A
Example 155	C
		Example 156	D
Example 157	E
		Example 158	A
Example 159	A
		Example 160	A
Example 161	A

Example 162	A
		Example 163	C
Example 164	C
		Example 165	C
Example 166	A
		Example 167	A
Example 168	A
		Example 169	A
Example 170	A
		Example 171	A
Example 172	A
		Example 173	C
Example 174	C
		Example 175	C
Example 176	A
		Example 177	A
Example 178	C
		Example 179	D
Example 180	A
		Example 181	A
Example 182	A
		Example 183	B
Example 184	B
		Example 185	C
Example 186	A
		Example 187	A
Example 188	A
		Example 189	A
Example 190	A

Example 191	A
		Example 192	A
Example 193	C
		Example 194	A
Example 195	B
		Example 196	C
Example 197	D
		Example 198	B
Example 199	C
		Example 200	A
Example 201	A
		Example 202	A
Example 203	A
		Example 204	A
Example 205	B
		Example 206	A
Example 207	C
		Example 208	C
Example 209	A
		Example 210	A
Example 211	A
		Example 212	A
Example 213	A
		Example 214	A
Example 215	C
		Example 216	C
Example 217	C
		Example 218	A
Example 219	A

Example 220	A
		Example 221	A
Example 222	A
		Example 223	C
Example 224	A
		Example 225	A
Example 226	A
		Example 227	A
Example 228	C
		Example 229	C
Example 230	C
		Example 231	A
Example 232	C
		Example 233	A
Example 234	A
		Example 235	A
Example 236	A
		Example 237	C
Example 238	A
		Example 239	C
Example 240	C
		Example 241	C
Example 242	A
		Examples243	A
Example 244	A
		Example 245	C
Example 246	A
		Example 247	C
Example 248	A

Example 249	A
		Example 250	C
Example 251	A

Note: a is less than or equal to 50 nM; b is more than 50nM and less than or equal to 100 nM; c is more than 100nM and less than or equal to 500 nM; d is more than 500nM and less than or equal to 1000 nM; e is more than 1000nM and less than or equal to 5000 nM.

And (4) conclusion: the compound has obvious inhibition effect on hedgehog pathway.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein A is selected from

(R₂₀)₃C-E₁₃-；

T_11-17Each independently selected from N, C (R)₁₃)；

E_11-13、L₁、L₂Are each independently selected from N (R)₁₄)、C(=O)N(R₁₅)、S(=O)₂N(R₁₆)、C=N(R₁₇)、C(R₁₈)(R₁₉) S, C (= O) O, C (= O), C = S, S (= O) or S (= O)₂；

L₁、L₂Each may also be independently selected from single bonds;

Q_11-12each independently selected from phenyl, pyridyl, thienyl, furyl;

structural unitCan be replaced by

m_21-24each independently selected from 0, 1 or 2;

b is selected from

E_31-38、L_3a、L_3bare each independently selected from N (R)₄₀)、C(=O)N(R₄₁)、S(=O)₂N(R₄₂)、C=N(R₄₃)、C(R₄₄)(R₄₅) S, C (= O) O, C (= O), C = S, S (= O) or S (= O)₂；

L_3a、L_3bEach may also be independently selected from single bonds;

E₃₁、E₃₅may also each independently be selected from-T₃₉=T₄₀-；

T_31-40Each independently selected from N, C (R)₄₆)；

R_31-39、R_44-46each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH₂C (= O) OH, optionally substituted by R₀₁Substituted C_1-6Alkyl or heteroalkyl, optionally substituted with R₀₂Substituted C_3-8A cyclic or heterocyclic group or a heterocyclic or heterocyclic group;

each heteroatom or heteroatom group is independently selected from C (= O) NR₀₄、N(R₀₅)、C=N(R₀₆)、O、S、C(=O)O、C(=O)、C=S、S(=O)、S(=O)₂And/or S (= O)₂N(R₀₇)；

R_04-07Each independently selected from H, R₀₈；

R₀₈Is selected from C_1-6Alkyl or C_3-8A cycloalkyl group;

optionally, R₃₁And R₃₂、R₃₁And R₃₃、R₃₁And R₃₅、E₃₃And E₃₄Together form a connecting bond (CH)₂)_1-6；

preferably, the first and second electrodes are formed of a metal,

c above_3-8The cyclic or heterocyclic group or the heterocyclic or heterocyclic group is selected from the group consisting of phenyl, pyridyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein a is selected from (CH₃)₃CC(=O)NH。

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the structural unitIs selected fromIs selected fromStructural unitIs selected fromWherein,

preferably, the first and second electrodes are formed of a metal,

R₂₀₁selected from methyl, F, Cl, Br, I; r₂₀₂、R₂₀₃Selected from each independently C_1-6Alkoxy, more preferably methoxy.

4. The compound of claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein the structural unitSelected from:

structural unitSelected from:

5. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected fromWherein,

R_301-305each independently selected from H, OH, NH₂F, Cl, Br, I, CN, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or alkoxy or alkylamino or cyclopropyl;

R₃₀₀₁the number of (a) is selected from 1,2 or 3;

preferably, the first and second electrodes are formed of a metal,

It is further preferred that the first and second liquid crystal compositions,

b is selected from

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected fromWherein,

R₃₀₀₁the number of (a) is selected from 1,2 or 3;

L₃₁selected from single bond, R₃₀₀₂N(R₃₀₀₃)R₃₀₀₄、O、S、CO₂C (= O), C = S, S (= O) and/or S (= O)₂，

R₃₀₀₂Selected from a single bond or C (= O);

R₃₀₀₃is selected from H or C_1-3Alkyl or cyclopropyl;

R₃₀₀₄is selected from (CH)₂)_0-3；

Preferably, the first and second electrodes are formed of a metal,

R₃₀₈and R₃₁₀Together form a connecting bond CH₂、R₃₀₈And R_309aTogether form a connecting bond CH₂CH₂；

Preferably, the first and second electrodes are formed of a metal,

R_306-312each independently selected from methyl, cyclopropyl, C (CH)₃)₂(OH)、CH₂CH₂OH、CH₂N(CH₃)₂、H、OH、NH₂、F、Cl、Br、I、CN；

L₂₁Selected from single bond, NHCH₂CH₂；

It is further preferred that the first and second liquid crystal compositions,

b is selected from

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected fromWherein,

R₃₀₀₁the number of (a) is selected from 1,2 or 3;

Preferably, the first and second electrodes are formed of a metal,

R₃₁₃、R₃₁₅、R₃₁₆each independently selected from H, methyl;

R₃₁₄selected from H, methyl, ethyl, phenylmethylene, cyclopropylmethylene, methoxyphenyl,

Further preferably, B is selected from

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected fromWherein,

R₃₁₇selected from the group consisting of CR₃₀₀₆Or N;

R_320-321each independently selected from C (R)₃₀₀₇)(R₃₀₀₈)、O、CON(R₃₀₀₉)、N(R₃₀₁₀)、C=N(R₃₀₁₁)、S、CO₂C (= O), C = S, S (= O) and/or S (= O)₂；

R₃₀₀₁the number of (a) is selected from 1,2 or 3;

Preferably, the first and second electrodes are formed of a metal,

R₃₁₇selected from the group consisting of CR₃₀₀₆Or N; r₃₀₀₆、R₃₁₈、R₃₁₉Selected from methyl, trifluoromethyl;

R_320-321each independently selected from CH₂、O、C(=O)；

It is further preferred that the first and second liquid crystal compositions,

b is selected from

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected fromWherein,

L₃₂is selected from C (R)₃₀₀₇)(R₃₀₀₈)、O、CON(R₃₀₀₉)、N(R₃₀₁₀)、C=N(R₃₀₁₁)、S、CO₂C (= O), C = S, S (= O) and/or S (= O)₂；

R₃₂₂、R₃₂₄、R₃₀₀₇、R₃₀₀₈、R₃₀₁₂each independently selected from H, OH, NH₂F, Cl, Br, I, CN, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or alkoxy or alkylamino or cyclopropyl;

R₃₀₀₁、R₃₀₁₂the number of (a) is selected from 1,2 or 3.

Preferably, the first and second electrodes are formed of a metal,

R₃₂₂、R₃₂₄each independently selected from H, methyl, phenyl, C (CH)₃)₂OH；

L₃₂Selected from C (= O), S (= O)₂；

R₃₂₃Selected from tert-butoxy, methyl, ethyl, ethoxy, propoxy, isopropyl, cyclopropyl, and methylaminePhenyl, pyridyl, 3-methylpyridyl, imidazolyl, C (CH)₃)₂OH；

Preferably, the first and second electrodes are formed of a metal,

b is selected from

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected fromWherein,

R₃₂₉Is selected from N (R)₃₀₁₄)、O、C(R₃₀₁₅)(R₃₀₁₆)、CON(R₃₀₁₇)、N(R₃₀₁₈)、C=N(R₃₀₁₉)、S、CO₂C (= O), C = S, S (= O) and/or S (= O)₂；

R₃₀₁₄Selected from C (= O) R₃₀₂₀、S(=O)₂R₃₀₂₀Thiazolyl, isothiazolyl, phenyl, pyridyl, imidazolyl, thienyl, furyl, oxazolyl;

R₃₀₁₃、R₃₀₁₅、R₃₀₁₆、R_330-331each independently selected from H, OH, NH₂F, Cl, Br, I, CN, C (= O) OH, optionally substituted by R₃₀₀₁Substituted C_1-3Alkyl or alkoxy or alkylamino or cyclopropyl;

R_3017-3019each independently selected from H, optionally substituted by R₃₀₀₁Substituted byC_1-3Alkyl or cyclopropyl;

R₃₀₀₁the number of (a) is selected from 1,2 or 3;

optionally, R₃₃₀And R₃₃₁Together form a connecting bond (CH)₂)_1-3；

preferably, the first and second electrodes are formed of a metal,

R_325-3281 or 2 of them are selected from N, and the others are selected from CH, CC (= O) OH or CCH₃；

R₃₂₉Is selected from N (R)₃₀₁₄)、O；

R₃₀₁₄Selected from C (= O) R₃₀₂₀、

R₃₀₂₀Is selected from C (CH)₃)(F)₂、CH₂CH₃、CH₂CF₃、CH(F)(CH₃)、CH(OH)(CH₃)、CH₂(OH)、CH(NH₂)(CH₃) Methoxy, ethoxy, aminomethyl;

R_330-331is selected from methyl;

preferably, the first and second electrodes are formed of a metal,

b is selected from

11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected fromWherein,

R₃₃₂selected from S, N (R)₃₀₂₁)、O、C(R₃₀₂₂)(R₃₀₂₃)、CON(R₃₀₂₄)、N(R₃₀₂₅)、C=N(R₃₀₂₆)、S、CO₂C (= O), C = S, S (= O) and/or S (= O)₂；

L₃₃Selected from single bond, C (= O), S, O, C (R)₃₀₂₂)(R₃₀₂₃)、CON(R₃₀₂₄)、N(R₃₀₂₅)、C=N(R₃₀₂₆)、S、CO₂C = S, S (= O) and/or S (= O)₂；

R₃₃₃Selected from N, C (R)₃₀₂₇)；

R₃₀₀₁the number of (a) is selected from 1,2 or 3;

preferably, the first and second electrodes are formed of a metal,

R₃₃₂selected from S, R₃₃₃Is selected from N, L₃₃Selected from single bond, C (= O), R₃₃₄、R₃₃₅Is selected from methyl;

preferably, the first and second electrodes are formed of a metal,

b is selected from

12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected fromWherein,

m₃₁、m₃₂each independently selected from 0 or 1;

R_342a、R_342b、R₃₄₃、L₃₄each independently selected from a single bond, C (= O) N (R)₃₀₃₁)、C(=O)C(R₃₀₃₂)(R₃₀₃₃)、C(R₃₀₃₄)(R₃₀₃₅)、CON(R₃₀₃₆)、N(R₃₀₃₇)、C=N(R₃₀₃₈)、O、S、CO₂C (= O), C = S, S (= O) and/or S (= O)₂；

L₃₄May also be selected from single bonds;

R₃₀₀₁the number of (a) is selected from 1,2 or 3;

preferably, the first and second electrodes are formed of a metal,

R₃₃₆、R₃₃₇、R₃₄₂each independently selected from N or CH;

R₃₃₈、R₃₃₉is selected from CH₂Optionally R₃₃₈And R₃₃₉Connected to the same CH at the same time₂CH₂Looping the upper part;

m₃₁、m₃₂each independently selected from 0 or 1;

L₃₄each independently selected from a single bond, C (= O) NH, C (= O) N (CH)₃)、C(=O)CH₂；

R₃₄₀、R₃₄₁、R₃₄₄、R₃₄₅Each independently selected from H or methyl;

R_342a、R_342bselected from C (= O) or CH₂；

Preferably, the first and second electrodes are formed of a metal,

b is selected from

13. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected fromWherein,

L₃₅each independently selected from a single bond, C (= O) N (R)₃₀₃₁)、C(=O)C(R₃₀₃₂)(R₃₀₃₃)、C(R₃₀₃₄)(R₃₀₃₅)、CON(R₃₀₃₆)、N(R₃₀₃₇)、C=N(R₃₀₃₈)、O、S、CO₂C (= O), C = S, S (= O) and/or S (= O)₂；

R₃₀₀₁the number of (a) is selected from 1,2 or 3;

preferably, the first and second electrodes are formed of a metal,

L₃₅selected from single bond, C (= O), CH₂；

R₃₄₆Selected from H, methyl, phenyl, C (CH)₃)₂（OH）、CH₂C(CH₃)₂(OH), cyclopropanoyl, isopropylsulfone;

further preferably, B is selected from

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected fromWherein,

R_347a、R_347beach independently selected from N or C (R)₃₀₂₈)；

R₃₅₂、L₃₆Are respectively and independently selected from single bond, -C (= O) N (R)₃₀₃₁)-、-C(=O)C(R₃₀₃₂)(R₃₀₃₃)-、C(R₃₀₃₄)(R₃₀₃₅)、CON(R₃₀₃₆)、N(R₃₀₃₇)、C=N(R₃₀₃₈)、O、S、CO₂C (= O), C = S, S (= O) and/or S (= O)₂；

L₃₆May also be selected from single bonds;

R₃₀₀₁the number of (a) is selected from 1,2 or 3;

preferably, the first and second electrodes are formed of a metal,

L₃₆selected from single bond, C (= O) NH, C (= O) CH₂；

R_347a、R_347bEach independently selected from N, CH or C (OH);

R₃₀₃₉Selected from H, methyl, trifluoromethyl, C (CH)₃)₂（OH）；

R_351a、R_351bEach independently selected from H, methyl, trifluoromethyl;

R₃₅₂selected from C (= O) and C (CH)₃)(OH)；

It is further preferred that the first and second liquid crystal compositions,

b is selected from

15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected from:

16. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from: