CN117355517A - Macrocyclic glucagon-like peptide 1 receptor agonists - Google Patents

Macrocyclic glucagon-like peptide 1 receptor agonists Download PDF

Info

Publication number
CN117355517A
CN117355517A CN202280036421.2A CN202280036421A CN117355517A CN 117355517 A CN117355517 A CN 117355517A CN 202280036421 A CN202280036421 A CN 202280036421A CN 117355517 A CN117355517 A CN 117355517A
Authority
CN
China
Prior art keywords
preparation
mmol
pharmaceutically acceptable
acceptable salt
title compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202280036421.2A
Other languages
Chinese (zh)
Inventor
F·J·阿吉贾斯奇查罗
R·A·鲍尔
M·G·贝尔
陈琦
G·R·卡明
T·菲尔兹
D·L·格纳特
J·D·何
T·A·考迪
T·J·马斯奎林
J·M·蒙格斯奥尔特加
J·普列戈索勒
A·罗德里格斯埃尔格塔
E·M·韦尔利
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Priority claimed from PCT/US2022/029958 external-priority patent/WO2022246019A1/en
Publication of CN117355517A publication Critical patent/CN117355517A/en
Pending legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

In one embodiment, the invention provides a compound of the formula or a pharmaceutically acceptable salt thereof, and methods of using such compounds to treat type II diabetes.

Description

Macrocyclic glucagon-like peptide 1 receptor agonists
The present invention relates to glucagon-like peptide-1 receptor agonists and therapeutic uses of such compounds for the treatment of type II diabetes.
Glucagon-like peptide-1 (GLP-1) is a member of the incretin family of peptide hormones secreted by enteroendocrine L-cells. GLP-1 induces beta cells to release insulin in a glucose dependent manner. However, GLP-1 is metabolized so rapidly that only a small percentage of GLP-1 can be utilized to elicit insulin secretion. To compensate for this, GLP-1 receptor (GLP-1R) agonists have been developed to enhance insulin secretion as a treatment for type II diabetes.
Most GLP-1R agonists approved for the treatment of type II diabetes are injectable. Patients often prefer oral medications due to injection-related drawbacks such as inconvenience, pain, and the possibility of injection site irritation.
WO2018/109607 discloses certain benzimidazole derivatives described as GLP-1R agonists. Other GLP-1 agonist compounds are disclosed in WO 2019/2393171, WO2019/239319, WO2020/103815, WO2020/207474, WO2020/263695, WO2021/018023, WO2021/081207, WO2021/096284, WO2021/096304, WO2021/112538, WO2021/154796, WO2021/160127, WO2021/187886, WO2021/197464, CN113480534, WO2021/219019, WO2021/244645, WO2021/249492, CN113801136, WO2021/254470, WO2021/259309, WO 2022/00799, WO2022/031994, WO2022/028572, WO2022/040600, WO2022/042691, WO2022/068772, WO2022/078407, WO2022/078380 and WO 2022/810752.
However, alternative GLP-1R agonists are needed. There is a particular need for orally administrable GLP-1R agonists. There is a particular need for potent GLP-1R agonists with an advantageous toxicological profile and/or pharmacokinetic profile to support once-daily dosing.
Accordingly, the present invention provides a compound of the formula:
wherein-A-is-CR a R b CR a R b CR b R b O-、-OCR b R b CR a R b CR a R b -、-OCR b R b CR b R b O-、-CR a R b CR b R b OCR b R b -、-CR b R b OCR b R b CR a R b -、-CR b R b OCR b R b -、-CR a R b CR b R b O-or-OCR b R b CR a R b -；
R a At each occurrence independently H, halogen, C 1 -C 2 Alkyl, OH or C 1 -C 3 An alkoxy group;
R b at each occurrence independently is H, halogen or C 1 -C 2 An alkyl group;
is->Wherein a is the point of attachment to linker A; b is the point of attachment to linker B;
X 1 、X 2 、X 3 and X 4 N, CH or CR independently 1 Wherein X is 1 、X 2 、X 3 And X 4 Not more than two of which are N, and X 1 、X 2 、X 3 And X 4 Not more than two of them are CR 1 ；
X 5 Is N, CH or CR 1a ，X 6 、X 7 And X 8 N, CH or CR independently 1 Wherein X is 5 、X 6 、X 7 And X 8 Not more than two of which are N, and X 5 、X 6 、X 7 And X 8 Not more than two of them are CR 1a Or CR (CR) 1 ；
R 1 Independently at each occurrence is CN; halogen; c optionally substituted by OH 1 -C 3 An alkyl group; c (C) 1 -C 3 A haloalkyl group; c (C) 1 -C 3 An alkoxy group; c (C) 3 -C 5 Cycloalkyl; -SO 2 C 1 -C 3 An alkyl group;
wherein each X 9 Is independently CH or N, and no more than one X in the ring 9 Is N, each R e Independently selected from: H. c (C) 1 -C 3 Haloalkyl, halogen, C 3 -C 5 Cycloalkyl and optionally OH-substituted C 1 -C 3 Alkyl, R h Is H, C 1 -C 3 Haloalkyl, halogen, C 3 -C 5 Cycloalkyl, OH, -NR c R d Or C optionally substituted by OH 1 -C 3 An alkyl group;
a 5-or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is optionally substituted with one or two substituents independently selected from: c (C) 1 -C 3 Alkoxy, C 3 -C 5 Cycloalkyl, -CH 2 -C 3 -C 5 Cycloalkyl, -SO 2 C 1 -C 3 Alkyl, C 4 -C 5 Heterocyclyl, -CH 2 -C 4 -C 5 Heterocyclyl, halogen, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, CN, -CONR c R d 、-NR c R d Or C optionally substituted by OH 1 -C 3 An alkyl group;
R 1a is CN; halogen; c optionally substituted by OH 1 -C 3 An alkyl group; c (C) 1 -C 3 A haloalkyl group; or C 1 -C 3 An alkoxy group;
-B-is-CH 2 O-、-OCH 2 -or-CH 2 NH-；
Y 1 、Y 2 And Y 7 N, CH or CR independently 2 Wherein Y is 1 、Y 2 And Y 7 Not more than one of them is N, and Y 1 、Y 2 And Y 7 Not more than two of them are CR 2 ；
Y 3 、Y 4 、Y 5 And Y 6 N, CH or CR independently 2 Wherein Y is 3 、Y 4 、Y 5 And Y 6 Not more than two of them areN, and Y 3 、Y 4 、Y 5 And Y 6 Not more than two of them are CR 2 ；
R 2 Independently at each occurrence is halogen or methyl;
Z 1 、Z 2 and Z 3 N, CH or CR independently 3 Wherein Z is 1 、Z 2 And Z 3 Not more than two of which are N, and Z 1 、Z 2 And Z 3 Not more than two of them are CR 3 ；
R 3 Independently at each occurrence, is halogen; c (C) 1 -C 4 An alkyl group; optionally by C 1 -C 2 Alkoxy, OH, C 1 -C 3 Alkyl or C 1 -C 3 haloalkyl-substituted-OC 4 -C 6 Cycloalkyl; optionally by C 1 -C 2 Alkoxy, OH, C 1 -C 3 Alkyl or C 1 -C 3 haloalkyl-substituted-OC 4 -C 6 A heterocyclic group; or C optionally substituted by one or two substituents 1 -C 4 Alkoxy, said substituents being selected from: c (C) 1 -C 2 Alkoxy, OH, -NR f R g 、-CONR c R d CN, halogen or optionally C 1 -C 3 Alkyl-substituted 5-or 6-membered heteroaryl;
R 4 is that
R 5 is-CO 2 H、
R c And R is d Each independently is H or C 1 -C 3 An alkyl group;
R f is H or C 1 -C 3 An alkyl group; and is also provided with
R g Is H, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 3 -C 5 Cycloalkyl, C (O) C 1 -C 3 Alkyl or C 1 -C 3 Alkyl C 3 -C 5 Cycloalkyl;
or a pharmaceutically acceptable salt thereof.
Formula IX includes all individual enantiomers and mixtures thereof, as well as racemates.
In an embodiment, there is provided a compound of the formula:
or a pharmaceutically acceptable salt thereof.
In an embodiment, there is provided a compound of the formula:
or a pharmaceutically acceptable salt thereof.
In an embodiment, there is provided a compound of the formula:
or a pharmaceutically acceptable salt thereof.
In embodiments of formulas V, va and VI, Y 4 、Y 5 、Y 6 And Y 7 Are CH.
In the context of an embodiment of the present invention,is->In one embodiment, the ∈ ->Is->X 1 、X 3 And X 4 Is CH; and X is 2 Is CR (CR) 1 . In an alternative embodiment, +.>Is->X 1 Is N; x is X 2 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And X is 3 And X 4 Is CH. In a further alternative embodiment, +.>Is->X 1 、X 3 And X 4 Is CH; and X is 2 Is N. In a further alternative embodiment, +.>Is->X 1 And X 4 Is CH; x is X 2 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And X is 3 Is N. In a further alternative embodiment, +.>Is->X 1 And X 3 Is CH; x is X 2 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And X is 4 Is N. In a further alternative embodiment, +.>Is->X 1 And X 3 Is CH; and X is 2 And X 4 Is CR (CR) 1 。
In embodiments, X 1 、X 2 、X 3 And X 4 Is N.
In an alternative embodiment of the present invention,is->In one embodiment, the ∈ ->Is thatX 5 、X 7 And X 8 Is CH; and X is 6 Is CR (CR) 1 . In an alternative embodiment, +.>Is->X 5 Is N; x is X 6 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And X is 7 And X 8 Is CH.
In embodiments, X 5 、X 6 、X 7 And X 8 Is N.
In embodiments, R 1 Is CN; halogen; c optionally substituted by OH 1 -C 3 An alkyl group; c (C) 1 -C 3 A haloalkyl group;wherein each R is e Independently selected from: H. c (C) 1 -C 3 Alkyl or halogen, andR h is H or halogen; a 5-or 6-membered heteroaryl or phenyl, wherein said heteroaryl or phenyl is optionally substituted with a substituent selected from the group consisting of: c (C) 1 -C 3 Alkoxy, C 3 -C 5 Cycloalkyl, -SO 2 C 1 -C 3 Alkyl, C 4 -C 5 Heterocyclyl, -CH 2 -C 4 -C 5 Heterocyclyl, halogen, -CONR c R d 、-NR c R d Or C optionally substituted by OH 1 -C 3 Alkyl, wherein R is c And R is d Each independently is H or C 1 -C 3 An alkyl group.
In embodiments, R 1 Is CN, halogen, CF 3 、-CH 2 OH、 Preferably, R 1 Is CN, cl, F, CF 3 、 In embodiments, R 1 Is CN; halogen; c optionally substituted by OH 1 -C 3 An alkyl group; c (C) 1 -C 3 A haloalkyl group; />Wherein each R is e Independently selected from: h or C 1 -C 3 An alkyl group; a 5-or 6-membered heteroaryl or phenyl, wherein said heteroaryl or phenyl is optionally substituted with one substituent,the substituents are selected from: c (C) 1 -C 3 Alkoxy, C 3 -C 5 Cycloalkyl, -SO 2 C 1 -C 3 Alkyl, -CH 2 -C 4 -C 5 Heterocyclyl, -CONR c R d Or C optionally substituted by OH 1 -C 3 Alkyl, wherein R is c And R is d Each independently is H or C 1 -C 3 An alkyl group. In embodiments, R 1 Is CN, halogen, CF 3 、-CH 2 OH、/> Preferably, R 1 Is CN, cl, F, CF 3 、/> In a further embodiment, R 1 Is CN, halogen or C 1 -C 3 Alkyl or C 1 -C 3 A haloalkyl group. In embodiments, R 1 Is CN, halogen or CF 3 . In embodiments, R 1 Is CN or halogen.
In one embodiment of the present invention, in one embodiment,is->X 1 、X 3 And X 4 Is CH; x is X 2 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And R is 1 Is CN; halogen; c optionally substituted by OH 1 -C 3 An alkyl group; c (C) 1 -C 3 A haloalkyl group;
wherein each R is e Independently selected from: H. c (C) 1 -C 3 Alkyl or halogen, and R h Is H or halogen; a 5-or 6-membered heteroaryl or phenyl, wherein said heteroaryl or phenyl is optionally substituted with a substituent selected from the group consisting of: c (C) 1 -C 3 Alkoxy, C 3 -C 5 Cycloalkyl, -SO 2 C 1 -C 3 Alkyl, C 4 -C 5 Heterocyclyl, -CH 2 -C 4 -C 5 Heterocyclyl, halogen, -CONR c R d 、-NR c R d Or C optionally substituted by OH 1 -C 3 Alkyl, wherein R is c And R is d Each independently is H or C 1 -C 3 An alkyl group. Preferably, R 1 Is CN, halogen, CF 3 、-CH 2 OH、 More preferably, R 1 Is CN, cl, F, CF 3 、/>
In one embodiment of the present invention, in one embodiment,is->X 1 、X 3 And X 4 Is CH; x is X 2 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And R is 1 Is CN; halogen; c optionally substituted by OH 1 -C 3 An alkyl group; c (C) 1 -C 3 A haloalkyl group; />Wherein each R is e Independently selected from: h or C 1 -C 3 An alkyl group; a 5-or 6-membered heteroaryl or phenyl, wherein said heteroaryl or phenyl is optionally substituted with a substituent selected from the group consisting of: c (C) 1 -C 3 Alkoxy, C 3 -C 5 Cycloalkyl, -SO 2 C 1 -C 3 Alkyl, -CH 2 -C 4 -C 5 Heterocyclyl, -CONR c R d Or C optionally substituted by OH 1 -C 3 Alkyl, wherein R is c And R is d Each independently is H or C 1 -C 3 An alkyl group. Preferably, R 1 Is CN, halogen, CF 3 、-CH 2 OH、/> More preferably, R 1 Is CN, cl, F, CF 3 、/> In a further embodiment, X 1 、X 3 And X 4 Is CH; x is X 2 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And R is 1 Is CN. In a further embodiment, X 1 、X 3 And X 4 Is CH; x is X 2 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And R is 1 Is Cl. In a further embodiment, X 1 、X 3 And X 4 Is CH; x is X 2 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And R is 1 Is CF (CF) 3 。
In an alternative embodiment of the present invention,is->X 1 Is N; x is X 2 Is CR (CR) 1 ；X 3 And X 4 Is CH; and R is 1 Is CF (CF) 3 。
In an alternative embodiment of the present invention,is->X 1 And X 4 Is CH; x is X 2 Is CR (CR) 1 ；X 3 Is N; and R is 1 Is CF (CF) 3 。
In an alternative embodiment of the present invention,is->X 1 And X 3 Is CH; x is X 2 Is CR (CR) 1 ；X 4 Is N; and R is 1 Is CN.
In an alternative embodiment of the present invention,is->X 1 And X 3 Is CH; x is X 2 And X 4 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And each R 1 Independently selected from halogen and CN. Preferably, each R 1 Independently selected from F, cl and CN.
In an alternative embodiment of the present invention,is->X 5 、X 7 And X 8 Is CH; x is X 6 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And R is 1 Is CN or Cl. In particular, R 1 Is CN.
In an alternative embodiment of the present invention,is->X 5 Is N; x is X 6 Is CR (CR) 1 ；X 7 And X 8 Is CH; and R is 1 Is CN.
In embodiments, -A-is-CH 2 CH 2 CH 2 O-、-OCH 2 CH 2 O-、-CH 2 CH 2 OCH 2 -、-CH 2 OCH 2 CH 2 -、-CH 2 OCH 2 -、-CH 2 CH 2 O-、-OCH 2 CH 2 -or-CF 2 CH 2 OCH 2 -. In particular embodiments, -A-is-CH 2 CH 2 CH 2 O-、-CH 2 OCH 2 -、-CH 2 CH 2 OCH 2 -、CH 2 OCH 2 CH 2 -or-CF 2 CH 2 OCH 2 -。
In embodiments, -A-is-CHR a CHR a CHR b O-、-CHR b OCHR b -or-OCHR b CHR b O-. In a further embodiment, -A-is-CHR a CHR a CHR b O-. In particular practiceIn embodiments, -A-is-CHR a CHR a CHR b O-, and R a And R is b Each is H. In an alternative embodiment, -A-is-CHR b OCHR b -. In particular embodiments, -A-is-CHR b OCHR b -and each R b Is H. In an alternative embodiment, -A-is-OCHR b CHR b O-. In particular embodiments, -A-is-OCHR b CHR b O-and each R b Is H. In particular embodiments, -A-is-CH 2 CH 2 CH 2 O-、-OCH 2 CH 2 O-、-CH 2 CH 2 OCH 2 -、-CH 2 OCH 2 -or-CH 2 CH 2 O-; preferably, A-is-CH 2 CH 2 CH 2 O-or-CH 2 OCH 2 -。
In embodiments, -B-is-CH 2 O-or-CH 2 NH-. In an alternative embodiment, B is-CH 2 O-or-OCH 2 -. In a further embodiment, -B-is-CH 2 O-。
In embodiments, Y 3 Is N or CH. In embodiments, Y 3 Is N. In an alternative embodiment, Y 3 Is CH.
In embodiments, Y 4 Is CH.
In embodiments, Y 5 Is CH.
In embodiments, Y 6 Is CH or CR 2 。
In embodiments, Y 3 Is N; and Y is 4 、Y 5 Is CH; and Y is 6 Is CH or CR 2 . In a further embodiment, Y 3 Is N; and Y is 4 、Y 5 Is CH; and Y is 6 Is CH. In yet a further embodiment, Y 3 Is N; and Y is 4 、Y 5 Is CH; and Y is 6 Is CR (CR) 2 Preferably R 2 Is F. In an alternative embodiment, Y 3 、Y 4 、Y 5 And Y 6 Are CH. In a further aspectIn an alternative embodiment, Y 3 And Y 6 Is N; and Y is 4 And Y 5 Is CH.
In embodiments, Y 1 Is CH or CR 2 。
In embodiments, Y 2 Is CH.
In embodiments, Y 7 Is CH.
In embodiments, R 2 Is F or methyl.
In embodiments, Y 1 、Y 2 And Y 7 Are CH. In an alternative embodiment, Y 1 Is CR (CR) 2 ；Y 2 Is CH; y is Y 7 Is CH; and R is 2 Is F. In a further alternative embodiment, Y 1 Is CR (CR) 2 ；Y 2 Is CH; y is Y 7 Is CH; and R is 2 Is methyl.
In embodiments, Y 1 And Y 2 Are CH. In an alternative embodiment, Y 1 Is CR (CR) 2 ，Y 2 Is CH and R 2 Is F. In a further alternative embodiment, Y 1 Is CR (CR) 2 ，Y 2 Is CH and R 2 Is methyl.
In embodiments, Y 4 、Y 5 、Y 6 And Y 7 Are CH.
In embodiments, Z 1 Is CH or CR 3 。
In embodiments, Z 2 Is CH.
In embodiments, Z 3 Is CH. In an alternative embodiment, Z 3 Is N.
In particular embodiments, Z 2 And Z 3 Are CH.
In embodiments, R 3 Is halogen; optionally by C 1 -C 3 alkyl-substituted-OC 4 -C 6 A heterocyclic group; or C optionally substituted by one or two substituents 1 -C 4 Alkoxy, said substituents being selected from: c (C) 1 -C 2 Alkoxy, OH, -NR f R g 、-CONR c R d Or optionally by C 1 -C 3 Alkyl-substituted 5-or 6-membered heteroaryl; wherein R is c And R is d Each independently is H or C 1 -C 3 An alkyl group, a hydroxyl group,
R f is H or C 1 -C 3 Alkyl, and R g Is H, C 1 -C 3 Alkyl or C 1 -C 3 A haloalkyl group. In particular embodiments, R 3 Is halogen or C optionally substituted by one or two substituents 1 -C 4 Alkoxy, said substituents being selected from: c (C) 1 -C 2 Alkoxy, OH or-NR f R g Wherein R is f And R is g Are all CH 3 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, R 3 Is F, -OCH 3 、-OCH 2 CH 2 OCH 3 、OCH 2 CH 2 OH or OCH 2 CH 2 N(CH 3 ) 2 。
In embodiments, R 3 Is halogen, C 1 -C 4 Alkoxy or-C 1 -C 3 Alkoxy C 1 -C 2 An alkoxy group; preferably, R 3 Is F, -OCH 3 or-OCH 2 CH 2 OCH 3 . In an alternative embodiment, R 3 Is halogen, C 1 -C 2 Alkyl or methoxy.
In embodiments, Z 1 Is CR (CR) 3 And R is 3 Is halogen; optionally by C 1 -C 3 alkyl-substituted-OC 4 -C 6 A heterocyclic group; or C optionally substituted by one or two substituents 1 -C 4 Alkoxy, said substituents being selected from: c (C) 1 -C 2 Alkoxy, OH, -NR f R g 、-CONR c R d Or optionally by C 1 -C 3 Alkyl-substituted 5-or 6-membered heteroaryl; wherein R is c And R is d Each independently is H or C 1 -C 3 Alkyl, R f Is H or C 1 -C 3 Alkyl, and R g Is H, C 1 -C 3 Alkyl or C 1 -C 3 A haloalkyl group. In a further embodiment, Z 1 Is CR (CR) 3 And R is 3 Is halogen or C optionally substituted by one or two substituents 1 -C 4 Alkoxy, said substituents being selected from: c (C) 1 -C 2 Alkoxy, OH or-NR f R g Wherein R is f And R is g Are all CH 3 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, R 3 Is F, -OCH 3 、-OCH 2 CH 2 OCH 3 、OCH 2 CH 2 OH or OCH 2 CH 2 N(CH 3 ) 2 . In one embodiment, Z 1 Is CR (CR) 3 And R is 3 Is F. In an alternative embodiment, Z 1 Is CH. In a further alternative embodiment, Z 1 Is CR (CR) 3 And R is 3 Is methoxy.
In embodiments, R 5 is-CO 2 H. In an alternative embodiment, R 5 Is that
In an embodiment, there is provided a compound of the formula:
wherein-A-is-CH 2 CH 2 CH 2 O-、-OCH 2 CH 2 O-、-CH 2 CH 2 OCH 2 -、-CH 2 OCH 2 CH 2 -、-CH 2 OCH 2 -、-CH 2 CH 2 O-、-OCH 2 CH 2 -or-CF 2 CH 2 OCH 2 -；
Is->Wherein a is the point of attachment to linker A; b is the point of attachment to linker B;
X 1 、X 2 、X 3 and X 4 N, CH or CR independently 1 Wherein X is 1 、X 2 、X 3 And X 4 Not more than one of them is N, and X 1 、X 2 、X 3 And X 4 Not more than two of them are CR 1 ；
X 5 Is N or CH, X 6 、X 7 And X 8 N, CH or CR independently 1 Wherein X is 5 、X 6 、X 7 And X 8 Not more than one of them is N, and X 6 、X 7 And X 8 Not more than one of them is CR 1 ；
R 1 Independently at each occurrence is CN; halogen; c optionally substituted by OH 1 -C 3 An alkyl group; c (C) 1 -C 3 A haloalkyl group;wherein each R is e Independently selected from: H. c (C) 1 -C 3 Alkyl or halogen, and R h Is H or halogen; a 5-or 6-membered heteroaryl or phenyl, wherein said heteroaryl or phenyl is optionally substituted with a substituent selected from the group consisting of: c (C) 1 -C 3 Alkoxy, C 3 -C 5 Cycloalkyl, -SO 2 C 1 -C 3 Alkyl, C 4 -C 5 Heterocyclyl, -CH 2 -C 4 -C 5 Heterocyclyl, halogen, -CONR c R d 、-NR c R d Or C optionally substituted by OH 1 -C 3 An alkyl group;
-B-is-CH 2 O-or-CH 2 NH-；
Y 1 Is CH or CR 2 ；
Y 3 Is N or CH;
Y 6 is N, CH or CR 2 ；
R 2 At each occurrenceIndependently halogen or methyl;
Z 1 is CH or CR 3 ；
Z 3 Is N or CH;
R 3 is halogen; optionally by C 1 -C 3 alkyl-substituted-OC 4 -C 6 A heterocyclic group; or C optionally substituted by one or two substituents 1 -C 4 Alkoxy, said substituents being selected from: c (C) 1 -C 2 Alkoxy, OH, -NR f R g 、-CONR c R d Or optionally by C 1 -C 3 Alkyl-substituted 5-or 6-membered heteroaryl;
R 4 is that
R 5 is-CO 2 H、
R c And R is d Each independently is H or C 1 -C 3 An alkyl group;
R f is H or C 1 -C 3 An alkyl group; and is also provided with
R g Is H, C 1 -C 3 Alkyl or C 1 -C 3 A haloalkyl group;
or a pharmaceutically acceptable salt thereof.
In one embodiment of formula VIII, -A-is-CH 2 CH 2 CH 2 O-、-CH 2 OCH 2 -、-CH 2 CH 2 OCH 2 -、CH 2 OCH 2 CH 2 -or-CF 2 CH 2 OCH 2 -。
In one embodiment of the process of formula VIII,is->X 1 、X 3 And X 4 Is CH; and X is 2 Is CR (CR) 1 . In an alternative embodiment of formula VIII,/v>Is->X 1 Is N; x is X 2 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And X is 3 And X 4 Is CH. In a further alternative embodiment of formula VIII,/i>Is->X 1 、X 3 And X 4 Is CH; and X is 2 Is N. In a further alternative embodiment of formula VIII,/i>Is->X 1 And X 4 Is CH; x is X 2 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And X is 3 Is N. In a further alternative embodiment of formula VIII,/i>Is->X 1 And X 3 Is CH; x is X 2 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And X is 4 Is N. In a further alternative embodiment of formula VIII,/i>Is->X 1 And X 3 Is CH; and X is 2 And X 4 Is CR (CR) 1 。/>
In one embodiment of the process of formula VIII,is->X 5 、X 7 And X 8 Is CH; and X is 6 Is CR (CR) 1 . In an alternative embodiment of formula VIII,/v >Is->X 5 Is N; x is X 6 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And X is 7 And X 8 Is CH.
In one embodiment of formula VIII, R 1 Is CN, halogen, CF 3 、-CH 2 OH、
Preferably, R 1 Is CN, cl, F, CF 3 、/>
In one embodiment of the process of formula VIII,is->X 1 、X 3 And X 4 Is CH; x is X 2 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And R is 1 Is CN, halogen, CF 3 、-CH 2 OH、/>/>
Preferably, R 1 Is CN, cl, F, CF 3 、/>
In an alternative embodiment of formula VIII,is->X 1 Is N; x is X 2 Is CR (CR) 1 ；X 3 And X 4 Is CH; and R is 1 Is CF (CF) 3 。
In an alternative embodiment of formula VIII,is->X 1 、X 3 And X 4 Is CH and X 2 Is N.
In an alternative embodiment of formula VIII,is->X 1 And X 4 Is CH; x is X 2 Is CR (CR) 1 ；X 3 Is N; and R is 1 Is CF (CF) 3 。
In an alternative embodiment of formula VIII,is->X 1 And X 3 Is CH; x is X 2 Is CR (CR) 1 ；X 4 Is N; and R is 1 Is CN.
In an alternative embodiment of formula VIII,is->X 1 And X 3 Is CH; x is X 2 And X 4 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And each R 1 Independently selected from halogen and CN. Preferably, each R 1 Independently selected from F, cl and CN.
In an alternative embodiment of formula VIII,is->X 5 、X 7 And X 8 Is CH; x is X 6 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And R is 1 Is CN or Cl. In particular, R 1 Is CN.
In an alternative embodiment of formula VIII，Is->X 5 Is N; x is X 6 Is CR (CR) 1 ；X 7 And X 8 Is CH; and R is 1 Is CN.
In one embodiment of formula VIII, -B-is-CH 2 O-。
In one embodiment of formula VIII, Y 6 Is CH or CR 2 。
In one embodiment of formula VIII, R 2 Is F or methyl.
In one embodiment of formula VIII, Y 3 Is N, and Y 6 Is CH or CR 2 . In a further embodiment of formula VIII, Y 3 Is N, and Y 6 Is CH. In yet a further embodiment, Y 3 Is N, and Y 6 Is CR (CR) 2 Preferably, R 2 Is F. In an alternative embodiment, Y 3 And Y 6 Are CH. In a further alternative embodiment, Y 3 And Y 6 Are all N.
In one embodiment of formula VIII, Z 3 Is CH.
In one embodiment of formula VIII, R 3 Is halogen or C optionally substituted by one or two substituents 1 -C 4 Alkoxy, said substituents being selected from: c (C) 1 -C 2 Alkoxy, OH or-NR f R g Wherein R is f And R is g Are all CH 3 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, R 3 Is F, -OCH 3 、-OCH 2 CH 2 OCH 3 、OCH 2 CH 2 OH or OCH 2 CH 2 N(CH 3 ) 2 。
In one embodiment of formula VIII, R 4 Is that
Certain compounds of formula VIII have the following characteristics:
i. -A-is-CH 2 CH 2 CH 2 O-、-CH 2 OCH 2 -、-CH 2 CH 2 OCH 2 -、CH 2 OCH 2 CH 2 -or-CF 2 CH 2 OCH 2 -；
ii.Is->Wherein X is 1 、X 3 And X 4 Is CH, X 2 Is CR (CR) 1 And R is 1 Is CN, cl, F, CF 3 、/>Or, wherein X 1 Is N, X 2 Is CR (CR) 1- ，X 3 And X 4 Is CH and R 1 Is CF (CF) 3 The method comprises the steps of carrying out a first treatment on the surface of the Or, wherein X 1 、X 3 And X 4 Is CH and X 2 Is N; or, wherein X 1 And X 4 Is CH, X 2 Is CR (CR) 1 ，X 3 Is N, and R 1 Is CF (CF) 3 The method comprises the steps of carrying out a first treatment on the surface of the Or, wherein X 1 And X 3 Is CH, X 2 Is CR (CR) 1 ，X 4 Is N, and R 1 Is CN; or, wherein X 1 And X 3 Is CH, X 2 And X 4 Is CR (CR) 1 And each R 1 Independently selected from F, cl and CN;
or,is->Wherein X is 5 、X 7 And X 8 Is CH, X 6 Is CR (CR) 1 And R is 1 Is CN or Cl; or, wherein X 5 Is N, X 6 Is CR (CR) 1 ，X 7 And X 8 Is CH and R 1 Is CN;
-B-is-CH 2 O-；
iv.Y 1 Is CH or CR 2 And R is 2 Is F or methyl;
v.Y 6 is CH or CR 2 And R is 2 Is F;
vi.Z 3 is CH;
vii.Z 1 is CH or CR 3 And R is 3 Is F, -OCH 3 、-OCH 2 CH 2 OCH 3 、OCH 2 CH 2 OH or OCH 2 CH 2 N(CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
viii.R 4 Is that
In an embodiment, there is provided a compound of the formula:
or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, compounds of the formula:
or a pharmaceutically acceptable salt thereof.
In one embodiment of formulas VII and VIIa, X 2 Is CR (CR) 1 And R is 1 Is CN. In an alternative embodiment of formulas VII and VIIa, X 2 Is CR (CR) 1 And R is 1 Is CF (CF) 3 。
In one embodiment of formulas VII and VIIa, Y 3 Is N. In an alternative embodiment, Y 3 Is CH.
In one embodiment of formulas VII and VIIa, Y 1 Is CH. In an alternative embodiment, Y 1 Is CR (CR) 2 And R is 2 Is methyl.
In one embodiment of formulas VII and VIIa, R 5 is-CO 2 H. In an alternative embodiment, R 5 Is that
In an embodiment, there is provided a compound of the formula:
wherein-A-is-CHR a CHR a CHR b O-、-OCHR b CHR a CHR a -、-OCHR b CHR b O-、-CHR a CHR b OCHR b -、-CHR b OCHR b CHR a -、-CHR b OCHR b -、-CHR a CHR b O-or-OCHR b CHR a -；
R a At each occurrence independently H, halogen, C 1 -C 2 Alkyl or OH;
R b at each occurrence independently is H, halogen or C 1 -C 2 An alkyl group;
is->Wherein a is the point of attachment to linker A; b is the point of attachment to linker B;
X 1 、X 2 、X 3 and X 4 N, CH or CR independently 1 Wherein X is 1 、X 2 、X 3 And X 4 Not more than two of which are N, and X 1 、X 2 、X 3 And X 4 Not more than two of them are CR 1 ；
R 1 Is CN; halogen; c optionally substituted by OH 1 -C 3 An alkyl group; c (C) 1 -C 3 A haloalkyl group; c (C) 1 -C 3 An alkoxy group; c (C) 3 -C 5 Cycloalkyl; -SO 2 C 1 -C 3 An alkyl group; wherein each R is e Independently selected from: H. c optionally substituted by OH 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, halogen and C 3 -C 5 Cycloalkyl; a 5-or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is optionally substituted with one or two substituents independently selected from: c optionally substituted by OH 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 3 -C 5 Cycloalkyl, -CH 2 -C 3 -C 5 Cycloalkyl, -SO 2 C 1 -C 3 Alkyl, -CH 2 -C 4 -C 5 Heterocyclyl, halogen, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, CN or-CONR c R d Wherein R is c And R is d Each independently is H or C 1 -C 3 An alkyl group;
-B-is-CH 2 O-、-OCH 2 -or-CH 2 NH-；
Y 1 And Y 2 N, CH or CR independently 2 Wherein Y is 1 And Y 2 May be N;
Y 3 is N or CH;
R 2 is halogen or methyl;
Z 1 is N, CH or CR 3 ；
Z 2 Is CH or CR 3 ；
Z 3 Is N, CH or CR 3 ；
R 3 Is halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy or-C 1 -C 3 Alkoxy C 1 -C 2 An alkoxy group;
R 4 is thatAnd is also provided with
R 5 is-CO 2 H or
Or a pharmaceutically acceptable salt thereof.
In an embodiment, compounds of formula IV are provided wherein-A-is-CHR a CHR a CHR b O-、-OCHR b CHR a CHR a -、-OCHR b CHR b O-、-CHR a CHR b OCHR b -、-CHR b OCHR b CHR a -、-CHR b OCHR b -、-CHR a CHR b O-or-OCHR b CHR a -；
R a At each occurrence independently H, halogen, C 1 -C 2 Alkyl or OH;
R b at each occurrence independently is H, halogen or C 1 -C 2 An alkyl group;
is->Wherein a is the point of attachment to linker A; b is the point of attachment to linker B;
X 1 、X 2 、X 3 and X 4 N, CH or CR independently 1 Wherein X is 1 、X 2 、X 3 And X 4 Not more than two of which may be N, and X 1 、X 2 、X 3 And X 4 Not more than two of them may be CR 1 ；
R 1 Is CN, halogen or C 1 -C 3 Alkyl or C 1 -C 3 A haloalkyl group;
-B-is-CH 2 O-、-OCH 2 -or-CH 2 NH-；
Y 1 And Y 2 N, CH or CR independently 2 Wherein Y is 1 And Y 2 May be N;
Y 3 is N or CH;
R 2 is halogen or methyl;
Z 1 is N, CH or CR 3 ；
Z 2 Is CH or CR 3 ；
Z 3 Is N, CH or CR 3 ；
R 3 Is halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy or-C 1 -C 3 Alkoxy C 1 -C 2 An alkoxy group;
R 4 is thatAnd is also provided with
R 5 is-CO 2 H or
Or a pharmaceutically acceptable salt thereof.
In an alternative embodiment, there is provided a compound of the formula:
Wherein the method comprises the steps of
-A-is-CHR a CHR a CHR b O-、-OCHR b CHR a CHR a -、-OCHR b CHR b O-、-CHR a CHR b OCHR b -、-CHR b OCHR b CHR a -、-CHR b OCHR b -、-CHR a CHR b O-or-OCHR b CHR a -；
R a At each occurrence independently H, halogen, C 1 -C 2 Alkyl or OH;
R b at each occurrence independently is H, halogen or C 1 -C 2 An alkyl group;
X 1 、X 2 、X 3 and X 4 N, CH or CR independently 1 Wherein X is 1 、X 2 、X 3 And X 4 Only one of which may be N, and X 1 、X 2 、X 3 And X 4 Not more than two of them may be CR 1 ；
R 1 Is CN or halogen;
-B-is-CH 2 O-or-OCH 2 -；
Y 1 And Y 2 N, CH or CR independently 2 Wherein Y is 1 And Y 2 May be N;
R 2 is halogen or methyl;
Z 1 is N, CH or CR 3 ；
Z 2 Is CH or CR 3 ；
Z 3 Is N, CH or CR 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 3 Is halogen, C 1 -C 2 Alkyl or methoxy;
or a pharmaceutically acceptable salt thereof.
In an embodiment, there is provided a compound of the formula:
or a pharmaceutically acceptable salt thereof.
In an embodiment, there is provided a compound of the formula:
or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, compounds of the formula:
or a pharmaceutically acceptable salt thereof.
In an embodiment, there is provided a compound of the formula:
or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, compounds of the formula:
or a pharmaceutically acceptable salt thereof.
In embodiments, -A-is-CHR a CHR a CHR b O-. In a further embodiment, R a And R is b Each is H.
In embodiments, X 1 、X 3 And X 4 Is CH and X 2 Is CR (CR) 1 . In one embodiment, R 1 Is CN. In an alternative embodiment, R 1 Is Cl.
In embodiments, -B-is-CH 2 O-。
In one embodiment, Y 1 And Y 2 Are CH. In an alternative embodiment, Y 1 Is CR (CR) 2 ，Y 2 Is CH and R 2 Is F.
In embodiments, Z 2 And Z 3 Are CH.
In embodiments, Z 1 Is CH or CR 3 . In one embodiment, Z 1 Is CH. In an alternative embodiment, Z 1 Is CR (CR) 3 And R is 3 Is F.
In an embodiment, a compound selected from the group consisting of:
/>
/>
/>
/>
/>
/>
/>
or a pharmaceutically acceptable salt thereof.
In the linker A, the left-hand end group written out is linked to the X ring and the right-hand end group is linked to the Y-containing ring 1 、Y 2 And Y 7 Is connected by a ring. For example, at the radical-CR a R b CR a R b CR b R b O-, oxygen and Y-containing 1 、Y 2 And Y 7 Is connected by a ring. In the linker B, the left terminal group is linked to the X ring and the right terminal group is linked to the Y-containing ring 3 Is connected by a ring.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "C 1 -C n Alkyl "refers to a straight or branched chain saturated hydrocarbon containing 1 to n carbon atoms. C (C) 1 -C 4 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, and t-butyl. C (C) 1 -C 3 Examples of alkyl groups include, but are not limited to, methyl, ethyl, and propyl. C (C) 1 -C 2 Alkyl is methyl or ethyl.
The term "C 1 -C n Haloalkyl "means C as defined herein substituted with one or more halo 1 -C n An alkyl group. C (C) 1 -C 3 Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, and pentafluoroethyl.
The term "C 1 -C n Alkoxy "refers to a straight or branched chain saturated hydrocarbon containing 1 to n carbon atoms, which contains a terminal" O "in the chain, i.e., -O (alkyl). C (C) 1 -C 4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy.
The term "C 1 -C n Haloalkoxy "means C as defined herein substituted with one or more halogens 1 -C n An alkoxy group. C (C) 1 -C 3 Examples of haloalkoxy groups include, but are not limited toLimited to trifluoromethoxy, difluoromethoxy and pentafluoroethoxy.
The term "C 3 -C 5 Cycloalkyl "refers to a monocyclic saturated carbocycle containing 3 to 5 carbon atoms. In particular, it refers to cyclopropyl, cyclobutyl or cyclopentyl.
The term "C 4 -C 6 Cycloalkyl "refers to a monocyclic saturated carbocycle containing 4 to 6 carbon atoms. In particular, it refers to cyclobutyl, cyclopentyl or cyclohexyl.
The term "heteroaryl" refers to a monocyclic aromatic ring containing one or more heteroatoms preferably selected from N, S and O. Examples of 5-membered heteroaryl groups include, but are not limited to, pyrazole, triazole, and thiazole. Examples of 6-membered heteroaryl groups include, but are not limited to, pyridine and pyridazine.
The term "C 4 -C 6 Heterocyclyl "refers to a 4, 5 or 6 membered monocyclic saturated ring containing one or more heteroatoms, such as pyrrolidine.
The term "C 4 -C 5 Heterocyclyl "refers to a 4 or 5 membered monocyclic saturated ring containing one or more heteroatoms, such as oxetane.
Formula IX encompasses formulas I, ia, ib, II, IIa, IIb, III, IIIa, IIIb, IV, V, va, vb, VI, VII, VIIa and VIIb, and references to formula IX hereinafter, e.g., in therapeutic methods and therapeutic uses, are also considered to refer to each and all of these subformulae.
In another embodiment, a pharmaceutically acceptable composition is provided comprising a compound of formula IX or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent or excipient. In a preferred embodiment, the pharmaceutically acceptable composition is formulated for oral administration.
In another embodiment, a method of treating type II diabetes in a patient is provided, the method comprising administering to a patient in need of treatment a pharmaceutically acceptable composition comprising an effective amount of a compound of formula IX or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the pharmaceutically acceptable composition is formulated for oral administration. Preferably, the patient is a human.
In another embodiment, a method of treating type II diabetes in a patient is provided, the method comprising administering to a patient in need of treatment an effective amount of a compound of formula IX or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is a human.
In another embodiment, a method of reducing blood glucose levels in a patient is provided, the method comprising administering to a patient in need of treatment an effective amount of a compound of formula IX or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is a human.
In another embodiment, a method of treating hyperglycemia in a patient is provided, comprising administering to a patient in need of treatment an effective amount of a compound of formula IX or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is a human.
In another embodiment, a method of treating obesity in a mammal is provided, comprising administering to a patient in need of treatment an effective amount of a compound of formula IX or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is a human.
In another embodiment, a method of treating non-alcoholic steatohepatitis (NASH) in a patient is provided, the method comprising administering to a patient in need of treatment an effective amount of a compound of formula IX or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is a human.
In embodiments, compounds of formula IX or pharmaceutically acceptable salts thereof are provided for use in therapy.
In another embodiment, a compound of formula IX, or a pharmaceutically acceptable salt thereof, is provided for use in treating type II diabetes.
In another embodiment, a compound of formula IX, or a pharmaceutically acceptable salt thereof, is provided for use in lowering blood glucose levels.
In another embodiment, there is provided a compound of formula IX, or a pharmaceutically acceptable salt thereof, for use in the treatment of hyperglycemia.
In another embodiment, there is provided a compound of formula IX, or a pharmaceutically acceptable salt thereof, for use in treating obesity.
In another embodiment, there is provided a compound of formula IX, or a pharmaceutically acceptable salt thereof, for use in the treatment of NASH.
In an embodiment, there is provided the use of a compound of formula IX or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of type II diabetes.
In an embodiment, there is provided the use of a compound of formula IX or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for lowering blood glucose levels.
In an embodiment, there is provided the use of a compound of formula IX or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of hyperglycemia.
In an embodiment, there is provided the use of a compound of formula IX or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of obesity.
In an embodiment, there is provided the use of a compound of formula IX or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of NASH.
The compounds of formula IX may be used in combination with one or more therapeutic agents, either simultaneously, separately or sequentially. Examples of other therapeutic agents include, but are not limited to, metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporters, and ketohexokinase inhibitors.
In a preferred embodiment, the compound of formula IX is administered orally. In a preferred embodiment, the compound of formula IX is administered once daily. In another preferred embodiment, the therapeutic use is in a human.
The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds of the invention which are considered acceptable for clinical use and/or veterinary use. Examples of pharmaceutically acceptable salts and common methods for preparing them can be found in "Handbook of Pharmaceutical Salts:properties, selection and Use" P.Stahl et al, second revised edition, wiley-VCH,2011 and S.M.Berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Sciences,1977,66 (1), 1-19.
The term "effective amount" refers to the amount or dose of a compound of formula IX or a pharmaceutically acceptable salt thereof that provides the desired effect in the patient being diagnosed or treated when administered to the patient in a single dose or multiple doses. The effective amount can be readily determined by the attending physician as one skilled in the art by using routine techniques and by observing results obtained under analogous circumstances. Factors considered in the determination of an effective amount or dose of a compound include: whether to administer a compound or salt thereof; co-administration of other agents, if used; the size, age and general health of the patient; the degree or severity of the condition involved; response of the individual patient; mode of administration; bioavailability characteristics of the administered formulation; a selected dosage regimen; and other related situations. The compounds of the present invention are effective at daily doses falling within the range of about 0.01 to about 15mg/kg body weight.
The term "treating" or "treating" as used herein refers to reducing, alleviating or reversing the progression or severity of an existing symptom, disorder or condition, such as hyperglycemia, which may include increasing insulin secretion.
The term "patient" as used herein includes mammals. The patient is preferably a human.
The compound of formula IX may be formulated into a pharmaceutical composition for administration by any route that makes the compound bioavailable. Such compositions are preferably for oral administration. Preferably, the pharmaceutical composition is formulated as a tablet, capsule or solution. The tablet, capsule or solution may comprise a compound of formula IX in an amount effective to treat a patient in need of treatment. Such pharmaceutical compositions and methods for their preparation are well known in the art (see, e.g., "Remington: the Science and Practice of Pharmacy", edited by a. Adejare, 23 rd Ed.,2020,Elsevier Science)。
The compounds of formula IX and pharmaceutically acceptable salts thereof are useful in the therapeutic uses of the invention, with certain configurations being preferred.
The compounds of the present invention include:
/>
/>
or a pharmaceutically acceptable salt thereof.
Although the present invention contemplates all individual enantiomers, mixtures and racemates thereof, the compounds of formulas Ia, IIa, IIIa, va and VIIa and pharmaceutically acceptable salts thereof are particularly preferred.
The individual Enantiomers may be separated or resolved by methods such as selective crystallization techniques, chiral chromatography (see, e.g., J.Jacques et al, "Enntiomers, minerals, and resolution", john Wiley and Sons, inc.,1981, and E.L. Eliel and S.H. Wilen, "Stereochemistry of Organic Compounds", wiley-Interscience, 1994) or Supercritical Fluid Chromatography (SFC) (see, e.g., T.A. Berger; "Supercritical Fluid Chromatography Primer," Agilent Technologies, month 2015) at any convenient point in the synthesis of the compounds of the present invention.
Pharmaceutically acceptable salts of the compounds of the invention may be formed, for example, by reaction of a compound of formula IX with a suitable pharmaceutically acceptable base in a suitable solvent under standard conditions well known in the art (see, e.g., bastin, r.j. Et al; org. process.res. Dev.,4,427-435,2000, and Berge, s.m. et al; j. Pharm. Sci.,66,1-19,1977).
Certain abbreviations used herein are defined according to Daub g.h. et al, "The Use of Acronyms in Organic Chemistry" Aldrichimica Acta,1984,17 (1), 6-23. Some abbreviations are defined as follows: "ACN" refers to acetonitrile; "Boc" means t-butoxycarbonyl; "cAMP" refers to cyclic adenosine-3 ',5' -monophosphate; "DCM" refers to dichloromethane or methylene chloride; "DEAD" refers to diethyl azodicarboxylate;"DIAD" refers to diisopropyl azodicarboxylate; "DIPEA" means N, N-diisopropylethylamine; "DMF" refers to N, N-dimethylformamide; "DMSO" refers to dimethylsulfoxide; "EC (E) 50 "refers to the concentration of the agent that produces a 50% response to the target activity as compared to the predetermined positive control compound (absolute EC 50 ) The method comprises the steps of carrying out a first treatment on the surface of the "EDC" means N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride; "ES/MS" refers to electrospray mass spectrometry; "EtOAc" refers to ethyl acetate; "HATU" refers to 1- [ bis (dimethylamino) methylene hexafluorophosphate ]-1H-1,2, 3-triazolo [4,5-b]Pyridinium 3-oxide; "HEK" refers to human embryonic kidney; "HEPES" means 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid; "h" means one hour or several hours, respectively; ir [ dF (CF 3) ppy]2 (dtbpy)) PF6 refers to hexafluorophosphoric acid [4,4' -bis (1, 1-dimethylethyl) -2,2' -bipyridine-N1, N1 ] ']Bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinyl-N]phenyl-C]Iridium (III); "KOAc" refers to potassium acetate; "MeOH" refers to methanol or methyl alcohol; "min" means one or several minutes; "MTBE" refers to tert-butyl ether; "Pd (dppf) Cl 2 "means [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride; pdCl 2 (dtbpf) means [1,1' -bis (di-t-butylphosphino) ferrocene]Palladium (II) dichloride; "RT" refers to room temperature; s (S) N Ar "refers to nucleophilic aromatic substitution; "TBAF" refers to tetrabutylammonium fluoride; "TBS" means t-butyldimethylsilane; "TEA" refers to triethylamine; "TFA" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; "TMAD" refers to tetramethyl azodicarbonamide; and "TMSCN" refers to trimethylcyanosilane.
The compounds of the present invention may be prepared by a variety of procedures, some of which are set forth in the preparations and examples below. The specific synthetic steps of the routes described may be combined in different ways to prepare the compounds of the invention or salts thereof. The products of the following steps may be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration and crystallization. Reagents and starting materials are readily available to those of ordinary skill in the art. Individual isomers, enantiomers and diastereomers may be separated or resolved at any convenient point in the synthesis by methods such as selective crystallization techniques or chiral chromatography (see, e.g., j. Jacques et al, "antibodies, minerals, and solutions", john Wiley and Sons, inc.,1981 and e.l. eliel and s.h. wilen, "Stereochemistry of Organic Compounds", wiley-Interscience, 1994). The following preparations and examples are provided to further illustrate the present invention without limiting the scope of the invention.
Scheme 1
Scheme 1 shows the synthesis of intermediates 7, 8 and 9 for the preparation of the compounds of the present invention. In step 1, the hydroxy group of intermediate 1 is methylated with methyl iodide and carbonate base at high temperature to give methoxy intermediate 2. In step 2, naBH is then used 4 The ester group of intermediate 2 is reduced to alcohol intermediate 3. In step 3, PBr is used 3 The alcohol of intermediate 3 is converted to bromide intermediate 4, which is then reacted with TMSCN and TBAF in step 4 to afford intermediate 5. Treatment of the cyano group of intermediate 5 with an alcoholic solution of sulfuric acid at elevated temperature in step 5 to give ester intermediate 6, followed by BBr in step 6 3 The methoxy group was demethylated to give intermediate 7. Optionally, KOAc and Pd (dppf) Cl may be used in step 7 2 And bis (pinacolato) diboron or bis (neopentyl glycol) diboron converts intermediate 7 to a borate at elevated temperature to give borate 8 or 9 respectively.
Scheme 2
Scheme 2 shows the synthesis of intermediates 15, 18, 22 and 23, which are also useful in the preparation of the compounds of the present invention. In step 1, bromide 10 is converted to nitrile 11 at elevated temperature using zinc cyanide and a palladium catalyst. In step 2a, nitrile intermediate 11 is converted to ester intermediate 12 using an alcoholic solution of thionyl chloride at elevated temperature, then at S in step 3a at elevated temperature with amine 13 and carbonate base N Fluorine is displaced in the Ar reaction to afford intermediate 14. Then in step 4a, the nitro group is reduced in methanol under hydrogen atmosphere using Lindlar catalyst (5% pd) to give intermediate 15. Intermediate 15 may be reacted with 2-chloroacetyl chloride using a tertiary amine base to afford 2-chloromethylimidazole intermediate 23.
In order to obtain the tetrazole intermediate, intermediate 11 and amine 13 are subjected to S in step 2b using an amine base N Ar is reacted to give intermediate 16 which is then converted to tetrazole intermediate 17 using tributyltin azide at elevated temperature in step 3 b. The nitro group is then reduced in step 4b under hydrogen pressure (4 bar) using a palladium on carbon catalyst to give intermediate 18. Alternatively, intermediate 11 is reacted with tributyltin azide at elevated temperature in step 2c to afford tetrazole intermediate 19, which is then protected on tetrazole nitrogen with a group such as SEM (trimethylsilylethoxymethyl) in step 3c to afford intermediate 20. In step 4c, in S with amine 13 and a tertiary amine base N The fluorine is displaced in the Ar reaction to give intermediate 21, which is then reduced in step 5c at elevated temperature using iron in acetic acid to give protected tetrazole intermediate 22.
Scheme 3
Scheme 3 shows three synthetic routes for preparing intermediate 32 of the compounds of the invention. In step 1a of the first route, halide intermediate 24 is Heck coupled with ethyl acrylate using palladium acetate and carbonate base at elevated temperature to afford intermediate 25, followed by olefin reduction under hydrogen (40 psi) in step 2a to afford intermediate 26. In step 3a, PBr is used 3 The alcohol group of intermediate 26 is converted to bromide and then reacted with intermediate 27 and Ag at elevated temperature 2 CO 3 Reaction to afford intermediate 29. In step 4a LiBH is used 4 Reducing the ester groups affords intermediate 32.
In the second stripIn route, intermediate 33 (PBr may be used) is first reacted in step 1c 3 Prepared from intermediate 24) and intermediate 27 using Ag at high temperature 2 CO 3 Reaction to give intermediate 34, then in step 2c with bromo- [3- [ tert-butyl (dimethyl) silyl ]]Oxypropyl radical]The zinc and palladium catalysts are root-bank coupled at elevated temperature to afford intermediate 35. Deprotection using TBAF then takes place in step 3c, yielding intermediate 32.
In a third route, intermediate 24 is Sonogashira coupled with tert-butyldimethyl (2-propynyloxy) silane using a palladium catalyst and a tertiary amine base in step 1b to afford intermediate 28, which is then subject to a casting reaction with intermediate 27 to afford intermediate 30. Deprotection using TBAF in step 3b and then hydrogenation of alkyne in hydrogen atmosphere using platinum oxide in step 4b gives intermediate 32.
Scheme 4
Scheme 4 shows the synthesis of intermediate 42 for preparing the compounds of the present invention. In step 1, bromide intermediate 36 is reacted with potassium phthalimide at elevated temperature to afford intermediate 37. In step 2, sonogashira coupling with propynyl alcohol gives alkyne intermediate 38. In step 3, the alkyne of intermediate 38 is reduced with a rhodium catalyst at elevated temperature under hydrogen pressure (90 psi) to afford intermediate 39. In step 4, the phthalimide group is reacted with hydrazine at an elevated temperature to give amine 40, which is then reacted with intermediate 41 at an elevated temperature for S with DIPEA in step 5 N Ar reacts to afford intermediate 42.
Scheme 5
Scheme 5 shows the synthesis of intermediate 47 for preparing the compounds of the present invention. In step 1, intermediate 43 is reacted with (2-bromoethoxy) -t-butyldimethylsilane with a carbonate base at elevated temperature. The aldehyde of intermediate 44 is reduced in step 2 using sodium borohydride to give alcohol 45, which is then subjected to a casting reaction with intermediate 27 in step 3 to give intermediate 46. The tert-butyldimethylsilyl group was removed with TBAF in step 4 to afford intermediate 47.
Scheme 6
Intermediate 32 can be prepared by the alternative route shown in scheme 6, as depicted in scheme 3. Intermediate 48 is root-coupled with bromo- [3- [ tert-butyl (dimethyl) silyl ] oxypropyl ] zinc and palladium catalyst at elevated temperature in step 1a to afford intermediate 49, which is then reduced to alcohol intermediate 50 in step 2a using lithium aluminum hydride. In step 3a, intermediate 50 is reacted with intermediate 27 under casting conditions to afford intermediate 32.
Alternatively, in step 1b, intermediate 24 is reacted with intermediate 27 under casting conditions, or with potassium tert-butoxide and aryl fluoride intermediate 41, to afford intermediate 34. Steps 2b and 3b were root-coupled as described in scheme 3 (with bromo- [3- [ tert-butyl (dimethyl) silyl ] oxypropyl ] zinc, followed by deprotection to afford intermediate 32).
Scheme 7
Scheme 7 shows two synthetic routes for the preparation of intermediate 55 of the compounds of the invention. In the first route, intermediate 51 is subjected to a casting reaction with intermediate 8 or 9 to obtain intermediate 52 in step 1 a. In step 2a, intermediate 52 is then intramolecular cross-coupled with a palladium catalyst to form macrocyclic intermediate 54. In the second route, intermediate 51 is subjected to a casting reaction with intermediate 7 in step 1b to give intermediate 53, followed by palladium-catalyzed intramolecular Stille coupling at elevated temperature in step 2b to give intermediate 54. The ester groups of intermediate 54 are hydrolyzed using aqueous LiOH or guanidine in ACN/water in step 3 to afford intermediate 55.
Scheme 8
Scheme 8 shows the synthesis of intermediate 64 for the preparation of the compounds of the present invention. Intermediate 56 is reductively coupled with 3-bromo-1-propanol at elevated temperature in step 1 to afford intermediate 57, which is then protected with a TBS group in step 2 to afford intermediate 58. The ester is then reduced with lithium borohydride in step 3 to give alcohol intermediate 59, which is then subjected to a casting reaction with intermediate 27 in step 4 to give intermediate 60. In step 5, the TBS protecting group is removed with TBAF to afford intermediate 61, which is then reacted with intermediate 8 in step 6 to afford intermediate 62. Intermediate 62 is cyclized using a palladium catalyst and potassium phosphate in step 7 to afford intermediate 63, which is then hydrolyzed using an aqueous LiOH solution or guanidine base in ACN/water in step 8 to afford acid intermediate 64.
Scheme 9
Scheme 9 shows the synthesis of intermediate 77 for the preparation of the compounds of the present invention, and shows two synthetic routes to common intermediate 74.
In a first route to intermediate 74, the acid intermediate 65 is reduced in step 1a using a borane-dimethyl sulfide complex to give the alcohol intermediate 66, which is then reacted in step 2a with sodium hydride and bromide intermediate 67 to give intermediate 68. In step 3a, the ester reduction with lithium borohydride gives intermediate 73, which is then subjected to a casting reaction with intermediate 27 in step 4a to give intermediate 74.
In a second route to intermediate 74, in step 1b, alkyl bromide intermediate 69 is reacted with intermediate 27 using silver carbonate at an elevated temperature to afford intermediate 70. In step 2b, the ester of intermediate 70 is reduced with lithium borohydride to give alcohol 71, which is then reacted with alkyl bromide 72 in step 3b with potassium tert-butoxide to give intermediate 74.
In step 5, intermediate 74 is coupled with ethyl diazoacetate at elevated temperature with a palladium catalyst to afford intermediate 75. In step 6, intramolecular Stille coupling is performed at elevated temperature using a palladium catalyst to afford intermediate 76. Alternatively, step 6 is accomplished by one-pot coupling with bis (neopentyl glycol) diboron using a palladium catalyst and potassium pivalate and intramolecular cross-coupling to afford the cyclic intermediate 76. Aqueous LiOH or guanidine in ACN/water is then used in step 7 to base intermediate 76 to yield acid intermediate 77.
Scheme 10
Scheme 10 shows the preparation of intermediate 83 for the preparation of the compounds of the present invention. Two routes to a common intermediate 81 are shown. In the first route, intermediate 78 is coupled with 2- [ (E) -2-ethoxyvinyl ] -4, 5-tetramethyl-1, 3, 2-dioxaborolan at elevated temperature using a palladium catalyst and a carbonate base in step 1a to afford intermediate 79. In step 2a, the ester is treated with a reducing agent such as diisobutylaluminum hydride to give alcohol 80, which is then reacted with aryl fluoride 41 using a strong organic base such as potassium t-butoxide to give intermediate 81. In the second route, in step 1b, intermediate 34 (see scheme 3) is first coupled with (E) -1-ethoxyethylene-2-boronic acid pinacol ester using a palladium catalyst and an inorganic base at elevated temperature to afford intermediate 81.
In step 4, intermediate 81 is treated with HCl in an organic solvent to giveAldehyde 82, then in step 3 with NaBH 4 Reduction to give alcohol intermediate 83. Alternatively, mercury acetate and NaBH can be used 4 Intermediate 81 is converted in one step to intermediate 83.
Scheme 11
/>
Scheme 11 shows the preparation of intermediate 86 for the preparation of the compounds of the present invention. In step 1, aryl iodide 84 is subjected to a root-shore coupling reaction with (2-ethoxy-2-oxoethyl) zinc (II) bromide and a palladium catalyst at elevated temperature. In step 2, intermediate 85 is subjected to a photochemical bromination reaction with N-bromosuccinimide in a flow reactor to afford bromide intermediate 86.
Scheme 12
Scheme 12 shows a number of routes to intermediate 92 for the preparation of the compounds of the present invention. In step 1a, intermediate 83 is reacted with intermediate 86 using 2, 6-di-tert-butylpyridine and silver triflate to afford intermediate 89. Alternatively, in step 1b, intermediate 83 may first be reacted with alkyl bromide 87 under similar conditions to step 1a to afford intermediate 88, which is then subjected to root-to-root coupling with (2-ethoxy-2-oxoethyl) zinc bromide and palladium catalyst in step 1c at elevated temperature to afford intermediate 89. In step 2a, intermediate 89 is subjected to palladium-catalyzed intramolecular Stille coupling at elevated temperature to afford intermediate 91. Alternatively, in step 2b, bromide 89 is reacted with bis (pinacolato) diboron, pd (dppf) Cl 2 And potassium acetate at elevated temperature, and then cyclized in step 2c by intramolecular cross-coupling with a palladium catalyst to form macrocyclic intermediate 91 (steps 2b and 2c may be performed as a single reaction step). Finally, in step 3, the process is carried out,aqueous LiOH or guanidine in ACN/water is used to hydrolyze the ester to give acid intermediate 92.
Scheme 13
Scheme 13 shows the preparation of intermediate 100 for the preparation of the compounds of the present invention. In step 1, intermediate 93 is first coupled with intermediate 27 using casting conditions to afford intermediate 94. In step 2, intermediate 94 was coupled with bromoethanol using nickel and iridium catalysts and reacted by irradiation with blue light (456 nm) to give intermediate 95. Alternatively, intermediate 95 is prepared in a manner analogous to the synthetic route to intermediate 83 in scheme 10, starting with intermediate 93 in place of intermediate 78. In step 3, intermediate 95 is reacted with intermediate 96 using 2, 6-di-tert-butylpyridine and silver triflate to afford intermediate 97. In step 4, bromide intermediate 97 is purified by reacting with bis (pinacolato) diboron, pd (dppf) Cl at elevated temperature 2 And potassium acetate to borate intermediate 98. In step 5, intermediate 98 is then intramolecular cross-coupled with a palladium catalyst to form macrocyclic intermediate 99. Alternatively, intermediate 97 is converted in one step to intermediate 99 by intramolecular Stille coupling at elevated temperature using hexamethyl-ditin and palladium catalyst. The aqueous LiOH or guanidine base in ACN/water is then used in step 6 to base intermediate 99 to afford acid intermediate 100.
Scheme 14
Scheme 14 shows the preparation of intermediate 109 for the preparation of the compounds of the present invention. In step 1, intermediate 101 is free-radically brominated with N-bromosuccinimide at high temperature, then reacted with trimethylcyanosilane and TBAF, and then treated with sulfuric acid in EtOH aqueous solution at high temperature to afford ester intermediate 102. Intermediate 102 is coupled with (E) -1-ethoxyethylene-2-boronic acid pinacol ester using a palladium catalyst and a carbonate base in step 2 to afford intermediate 103, which is then converted to alcohol 104 in step 3 using mercury acetate and sodium borohydride. Separately, in step 4, aldehyde intermediate 43 is first protected, for example with an SEM group, and then reduced with sodium borohydride to afford intermediate 105. In step 5, intermediate 105 is subjected to a casting reaction with intermediate 27 to obtain intermediate 106. Intermediate 104 and 106 are coupled by a casting reaction to afford intermediate 107, which is then subjected to intramolecular cyclization in step 7 in a manner analogous to step 2a (one-pot Stille coupling) or steps 2b and 2c (boration followed by Pd-catalyzed cross coupling) in scheme 12 to afford intermediate 108. Ester hydrolysis using aqueous LiOH or guanidine base in ACN/water in step 8 gives intermediate 109.
Scheme 15
Scheme 15 shows the preparation of intermediate 115 for the preparation of the compounds of the present invention. In step 1a, alkyl bromide intermediate 144 is reacted with intermediate 27 at elevated temperature using silver carbonate, then used in step 2aEster reduction was performed to afford intermediate 112. Alternatively, intermediate 34 is carbonylated in step 1b using a potassium formate and palladium catalyst to provide intermediate 111, then NaBH is used in step 2b 4 The aldehyde is reduced to afford intermediate 112. In step 3, CBr is used 4 And triphenylphosphine converts the alcohol of intermediate 112 to alkyl bromide to give intermediate 113. In step 4, intermediates 113 and 104 are reacted with silver triflate to afford intermediate 114. Intermediate 114 is then either intramolecular cyclized in step 5 in a manner similar to step 2a in scheme 12 (one pot Stille coupling) or in steps 5 and 6 in a manner similar to steps 2b and 2c in scheme 12 (borated then Pd catalyzed crossover)Coupling) to effect intramolecular cyclization. In step 7, the resulting ester is hydrolyzed using aqueous LiOH or guanidine in ACN/water to afford intermediate 115.
Scheme 16
Scheme 16 shows the preparation of intermediate 123 for the preparation of the compounds of the present invention. Intermediate 116 is reacted with methyl bromodifluoroacetate and copper in step 1 to afford intermediate 117, which is then photochemically brominated in a flow reactor using N-bromosuccinimide in step 2 to afford alkyl bromide intermediate 118. Intermediate 118 is reacted with intermediate 27 at an elevated temperature using a phosphate salt to afford intermediate 119 in step 3, followed by LiBH in step 4 4 Reduction to give alcohol intermediate 120. In step 5, intermediate 120 is treated with NaH and reacted with intermediate 124 to afford intermediate 121. In step 6, intermediate 121 is root-coupled with (2-ethoxy-2-oxo-ethyl) zinc bromide and a palladium catalyst at elevated temperature to afford intermediate 122. Intermediate 122 is then subjected to intramolecular cyclization in step 7 in a manner similar to step 2a (one-pot Stille coupling) or steps 2b and 2c (boration followed by Pd-catalyzed cross coupling) in scheme 12. Ester hydrolysis is performed in step 8 using aqueous LiOH or guanidine base in ACN/water, then intermediate 123 is obtained.
Scheme 17
Scheme 17 shows the preparation of borate intermediate 128 for use in preparing compounds of the present invention. Intermediate 83 is reacted with alkyl bromide intermediate 125 using silver triflate in step 1 to afford intermediate 126, which is then subjected to intramolecular cyclization in step 2 in a manner similar to that of step 2a (one-pot Stille coupling) or steps 2b and 2c (borated and then Pd catalyzed cross-coupling) in scheme 12. Finally, in step 3, intermediate 127 is coupled with bis (pinacolato) diboron using a palladium catalyst and potassium acetate at elevated temperature to afford borate intermediate 128.
Scheme 18
Scheme 18 shows the preparation of the compounds of the invention from either intermediate 129 (covering the general formula of intermediate 128) or intermediate 130 (covering the general formulae of intermediates 55, 64, 77, 92, 100, 109, 115 and 123) via a number of different routes.
To prepare the acid compound of formula IX ', intermediate 129 is coupled with chloromethylimidazole intermediate 23 at elevated temperature using a palladium catalyst and a phosphoric acid base in step 1a to afford intermediate 143, which is then hydrolyzed at elevated temperature using an aqueous LiOH solution or guanidine base in ACN/water in step 3a to afford the acid of formula IX'. Alternatively, in step 1c, acid intermediate 130 is coupled with intermediate 15 using an amide coupling reagent such as EDC or HATU to afford intermediate 132. Intermediate 132 is then cyclized with acetic acid at elevated temperature in step 2a to afford intermediate 143, which is then used to hydrolyze the ester as described in step 3 a.
In step 4a, the acid of formula IX' is coupled with cyclopropylmethylsulfonamide using EDC and 4-dimethylaminopyridine to prepare the compound of formula IX ".
The compound of formula IX' "was prepared by: in step 1b, intermediate 130 is coupled with intermediate 18 (without tetrazole nitrogen protecting groups, such as SEM) or 22 (with tetrazole nitrogen protecting groups) using HATU to afford intermediate 131, which is then cyclized with acetic acid at elevated temperature in step 2b (if necessary, tetrazole deprotection is performed in step 3b, e.g., SEM groups are removed with TBAF) to afford tetrazole compounds of formula IX "".
Scheme 19
Scheme 19 shows the preparation of compounds of formula IX "" of the invention. Intermediate 133 is subjected to a casting reaction with alcohol intermediate 136 in step 1a to give 135, which is then subjected to S with amine 13 and a tertiary amine base at elevated temperature in step 2 N Ar reacts to afford intermediate 138. Alternatively, difluoroaryl intermediate 134 is first subjected to S with alcohol 136 in step 1b N Ar, first treating the alcohol with NaH, then reacting with intermediate 134 at an elevated temperature to afford intermediate 135. A second alternative is to proceed S in step 1c with intermediates 137 and 136 in a similar manner to step 1b N Ar, to afford intermediate 138. In step 3, the nitro group of intermediate 138 is reduced, for example with hydrogen and palladium on carbon, to give aniline intermediate 139. Then, in a manner similar to steps 1c, 2a and 3a in scheme 18, the compound of formula IX "" was prepared in three steps from intermediates 139 and 130. If the "-O-R" group depicted in scheme 19 bears a protecting group, such as a Boc group on nitrogen or a tert-butyldimethylsilyl group on oxygen, then the protecting group may be removed in the final step (e.g., removal of the Boc group using TFA or removal of the tert-butyldimethylsilyl group using TBAF).
Scheme 20
Scheme 20 shows the preparation of the compounds of the present invention from halide intermediate 140. Intermediate 140 is cross-coupled reacted (e.g., suzuki) with an optionally substituted 5-or 6-membered aryl or heteroaryl boronic acid or ester at elevated temperature using a palladium catalyst and an inorganic base to afford 141. Alternatively, 140 can be converted to a borate 142, for example using a tetrahydroxydiboron and palladium catalyst at an elevated temperature, to yield 142 as boric acid, which is then cross-coupled reacted (e.g., suzuki) with an optionally substituted 5-or 6-membered aryl or heteroaryl halide to yield 141. These steps may be performed at protected or unprotected R 5 Proceeding above, for example, esters can act as protected functional groups, which can be hydrolyzed to give R 5 ＝-CO 2 H。
Preparation and examples
At the position ofLC-ES/MS was performed on the HP1200 liquid chromatography system. Electrospray mass spectrometry measurements (acquired in positive and/or negative modes) were performed on a mass selective detector quadrupole mass spectrometer connected to HPLC, with or without ELSD. LC-ES/MS conditions (low pH): column: />NX C 182.0×50mm 3.0μm，/>Gradient: 5-95% b in 1.5min, then 95% b for 0.5min, column temperature: 50 ℃ +/-10 ℃; flow rate: 1.2mL/min;1 mu L of sample injection quantity; solvent a: deionized water containing 0.1% hcooh; solvent B: ACN containing 0.1% formic acid; wavelengths 200-400nm and 212-216nm. If the HPLC is equipped with ELSD, set to 45℃evaporator temperature, 40℃atomizer temperature and 1.6SLM gas flow rate. Alternative LC-MS conditions (high pH): column: waters->C18 column 2.1X105 mm,3.5 μm; gradient: 5-95% b in 1.5min, then 95% b for 0.50min; column temperature: 50 ℃ +/-10 ℃; flow rate: 1.2mL/min;1 mu L of sample injection quantity; solvent a:10mM NH 4 HCO 3 pH 9; solvent B: ACN; wavelength: 200-400nm and 212-216nm; if there is an ELSD:45℃evaporator temperature, 40℃atomizer temperature and 1.60SLM gas flow rate.
Preparation 1
4-bromo-5-fluoro-2-methoxy-benzoic acid methyl ester
To 4-bromo-5-fluoro-2-hydroxy-benzoic acidMethyl iodide (5.0 mL,80.2 mmol) was added to a mixture of methyl ester (10.0 g,40.1 mmol) and potassium carbonate (13.8 g,100 mmol) in ACN (200 mL). The reaction was stirred at 60℃for 15 hours. The reaction mixture was diluted with water (150 mL) and extracted with DCM (3×60 mL). The combined organic layers were washed with water (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 10.3g of the title compound (98%) which was used as crude material for preparation 2. 1 H-NMR(400MHz,CDCl 3 )δ7.60(d,J＝9Hz,1H),7.15(d,J＝5Hz,1H),3.90(s,6H).
Preparation 2
(4-bromo-5-fluoro-2-methoxy-phenyl) methanol
To a solution of methyl 4-bromo-5-fluoro-2-methoxy-benzoate (14 g,53.2 mmol) and MeOH (30 mL) in THF (300 mL) was added sodium borohydride (10.7 g,272 mmol). The reaction was stirred at 50℃for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL) and washed with brine (2×100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 20% etoac/hexanes to give 11.5g of the title compound (92%). 1 H-NMR(400MHz,CDCl 3 )δ7.14(d,J＝8Hz,1H),7.0(d,J＝6Hz,1H),4.63(s,2H),3.85(s,3H).
Preparation 3
1-bromo-4- (bromomethyl) -2-fluoro-5-methoxy-benzene
To a solution of (4-bromo-5-fluoro-2-methoxy-phenyl) methanol (11.5 g,48.9 mmol) in DCM (200 mL) was added phosphorus tribromide (5.6 mL,59 mmol). The reaction was stirred at RT for 1 hour. The reaction was quenched by addition of ice water (50 mL) and basified to pH 7 with saturated aqueous sodium bicarbonate. The organic layer was washed with water (100 mL). The organic phase is dried over sodium sulfate Drying, filtration and concentration under reduced pressure gave 12.5g of the title compound (86%) which was used as crude material for preparation 4. 1 H-NMR(400MHz,CDCl 3 )δ7.13(d,J＝8Hz,1H),7.03(d,J＝6Hz,1H),4.46(s,2H),3.89(s,3H).
Preparation 4
2- (4-bromo-5-fluoro-2-methoxy-phenyl) acetonitrile
To a solution of 1-bromo-4- (bromomethyl) -2-fluoro-5-methoxy-benzene (12.5 g,42.0 mmol) and TMSCN (6.8 mL,50.5 mmol) in ACN (250 mL) was added TBAF solution (1.0M in THF, 50mL,50 mmol). The reaction was stirred at RT for 4 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with saturated aqueous sodium chloride (2×50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 10% etoac/petroleum ether to give 8.0g of the title compound (78%). 1 H-NMR(400MHz,CDCl 3 )δ7.19(d,J＝8Hz,1H),7.04(d,J＝5Hz,1H),3.86(s,3H),3.64(s,2H).
Preparation 5
2- (4-bromo-5-fluoro-2-methoxy-phenyl) acetic acid ethyl ester
To a solution of 2- (4-bromo-5-fluoro-2-methoxy-phenyl) acetonitrile (8.0 g,32.8 mmol) in ethanol (100 mL) was added concentrated sulfuric acid (25 mL). The reaction was stirred at 80℃for 18 hours. The reaction was neutralized to pH 7 with saturated aqueous sodium bicarbonate. The reaction mixture was extracted with DCM (2X 100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 9.3g of the title compound (97%) which was used as crude material for preparation 6.1H-NMR (400 MHz, CDCl 3) delta 7.02-6.99 (m, 2H), 4.16 (q, J=7Hz, 2H), 3.80 (s, 3H), 3.56 (s, 2H), 1.26 (t, J=7Hz, 3H).
Preparation 6
2- (4-bromo-5-fluoro-2-hydroxy-phenyl) acetic acid ethyl ester
A solution of ethyl 2- (4-bromo-5-fluoro-2-methoxy-phenyl) acetate (5.0 g,17.2 mmol) in DCM (100 mL) was cooled to-78deg.C. Boron tribromide (8.0 mL,84.8 mmol) was added and the reaction stirred at RT for 2 hours. The reaction mixture was cooled to 0 ℃ and quenched with ice water (40 mL). The solution was basified to pH 7 with saturated aqueous sodium bicarbonate. The organic layer was washed with water (20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4.0g of the title compound (84%) which was used in the crude form for the preparation 10, 54 and 60. 1 H-NMR(400MHz,CDCl 3 )δ7.69(s,1H),7.14(d,J＝6Hz,1H),6.90(d,J＝4Hz,1H),4.22(q,J＝7Hz,2H),3.61(s,2H),1.31(t,J＝8Hz,3H).
Preparation 7
2- (4-bromo-2-hydroxy-5-methyl-phenyl) acetic acid methyl ester
The title compound was prepared as described essentially in preparation 6 using methyl 2- (4-bromo-2-methoxy-5-methyl-phenyl) acetate. ES-MS M/z 259 and 261 (M+H).
Preparation 8
2- [ 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid methyl ester
To methyl 2- (4-bromo-2-hydroxy-phenyl) acetate (1.30 g,5.30 mmol), bis (pinacolato) diboron (1.98 g,7.72 mmol), KOAc (2.23 g,22.5 mmol) and Pd (dppf) Cl 2 To a mixture of (420 mg,0.57 mmol)1, 4-Dioxane (24 mL). The reaction mixture was stirred under nitrogen at 80 ℃ for 60 hours. By passing through The mixture was pad filtered and rinsed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM, adsorbed onto silica and purified by flash chromatography on silica gel using a gradient of 0 to 55% etoac/hexanes to give 748mg of the title compound (48%). ES-MS M/z 293 (M+H).
Preparation 9
2- [ 2-hydroxy-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid methyl ester
The title compound was prepared as described essentially in preparation 8 using methyl 2- (4-bromo-2-hydroxy-5-methyl-phenyl) acetate. Purification by flash chromatography on silica gel using a gradient of 5 to 80% etoac/hexanes. ES-MS M/z 304 (M-H).
Preparation 10
2- [4- (5, 5-dimethyl-1, 3, 2-dioxaborolan-2-yl) -5-fluoro-2-hydroxyphenyl ] acetic acid ethyl ester
A flask containing ethyl 2- (4-bromo-5-fluoro-2-hydroxy-phenyl) acetate (2.43 g,8.16 mmol), bis (neopentyl glycol) diboron (2.82 g,12.2 mmol) and KOAc (2.04 g,20.4 mmol) was purged with nitrogen. Anhydrous 1, 4-dioxane (33 mL) was added and sparged with nitrogen for 5 minutes while stirring. Bis (tricyclohexylphosphine) palladium (II) dichloride (0.31 g,0.41 mmol) was added and sparged with nitrogen for 5 minutes while stirring. Stirred at 90 ℃ for 6 hours, then the solid was rinsed with 1, 4-dioxane (15 mL) and stirred at RT overnight. Diatomaceous earth was added and diluted with MTBE (0.1L). Stirred for 30 minutes by The pad was filtered and rinsed with MTBE (0.1L). The filtrate was concentrated under reduced pressure at 50 ℃. The residue was dissolved in toluene (0.1L) and concentrated again at 50 ℃. The residue was purified by eluting with a 1:1 mixture of EtOAc and heptane over a pad of silica gel. The fractions containing the title compound were concentrated to a final volume of 30mL and the resulting slurry was stirred at ambient temperature for 1 hour. The solid was collected by filtration, washed with heptane (0.1L) and dried under reduced pressure at 50 ℃ for 19 hours to yield 1.77g of the title compound (64%) as a pale orange solid. ES-MS M/z 243 (M+H for boric acid). 1 H-NMR(400MHz,CDCl 3 )δ7.28(s,1H),7.27(d,J＝5.2Hz,1H),6.81(d,J＝9.2Hz,1H),4.22(q,J＝7.2Hz,2H),3.80(s,4H),3.65(s,2H),1.30(t,J＝7.2Hz,3H),1.05(s,6H).
Preparation 11
2- [ 5-fluoro-2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid ethyl ester
The title compound was prepared using bis (pinacolato) diboron as described essentially for preparation 10, stirring the mixture at 90 ℃ for 2 hours, then at 100 for 18 hours. The title compound was purified by flash chromatography on silica gel using a gradient of 0 to 50% etoac/cyclohexane, followed again by flash chromatography on silica gel using a gradient of 0 to 40% etoac/cyclohexane. ES-MS M/z 325 (M+H).
Preparation 12
(5-bromo-4-fluoro-2-iodophenyl) methanol
To a solution of 5-bromo-4-fluoro-2-iodo-benzoic acid (6.3 g,18.2 mmol) in THF (55 mL) was added borane dimethyl sulfide complex (2M in THF, 27mL,54 mmol). Stirring at RT The reaction mixture was 21 hours. The reaction mixture was concentrated and the residue was dissolved in EtOAc. The solution was washed with saturated aqueous ammonium chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 10 to 30% etoac/heptane to give 5.1g of the title compound (85%). ES-MS M/z 313 and 315 (M-H) 2 O).
Preparation 13
3, 5-difluoro-4-nitro-benzoic acid methyl ester
A solution of thionyl chloride (37 mL,74 mmol) in MeOH (110 mL) was cooled to-10deg.C and 3, 5-difluoro-4-nitro-benzonitrile (2.8 g,15 mmol) was added. Stirred at RT for 3 hours, then the temperature was gradually increased to 65 ℃ over 2 hours. The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in EtOAc (150 mL). Washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 10% etoac/petroleum ether to give 2.24g of the title compound (66%). 1 H-NMR(400MHz,CDCl 3 )δ7.78(d,2H),4.0(s,3H).
Preparation 14
3-fluoro-4-nitro-5- [ [ (2S) -oxetan-2-ylmethyl ] amino ] benzoic acid methyl ester
A mixture of [ (2S) -oxetan-2-yl ] methylamine (545mg,6.13mmol,CAS 2091328-57-1), methyl 3, 5-difluoro-4-nitro-benzoate (1.4 g,6.1 mmol) and potassium carbonate (1.7 g,12 mmol) in ACN (14 mL) was stirred at 70℃for 16 hours. The reaction mixture was diluted with water (14 mL) and extracted with EtOAc (3X 14 mL). The combined organic layers were washed with brine (14 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 30% etoac/petroleum ether to give 1.68g of the title compound (79%). ES-MS M/z 285 (M+H).
Preparation 15
(S) -3-methoxy-4-nitro-5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The title compound was prepared as described essentially in preparation 14 using 3-fluoro-5-methoxy-4-nitro-benzoic acid methyl ester. The residue was purified by silica gel chromatography using a gradient of 5 to 30% etoac/DCM to give the title compound. ES-MS M/z 296 (M+H).
Preparation 16
4-amino-3-fluoro-5- [ [ (2S) -oxetan-2-ylmethyl ] amino ] benzoic acid methyl ester
/>
To a solution of methyl 3-fluoro-4-nitro-5- [ [ (2S) -oxetan-2-ylmethyl ] amino ] benzoate (1.68 g,4.84 mmol) in MeOH (17 mL) was added Lindlar catalyst (600 mg,0.28 mmol) containing 5% palladium. Stirred at RT under hydrogen atmosphere for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 1.4g of the title compound (100%) which was used in the crude form for preparation 86 and 91.ES-MS M/z 255 (M+H).
Preparation 17
4-amino-3-methoxy-5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoic acid methyl ester
The title compound was prepared as described essentially in preparation 16 using methyl (S) -3-methoxy-4-nitro-5- ((oxetan-2-ylmethyl) amino) benzoate. The title compound was used in crude form for preparation 89, 93, 99 and 100.ES-MS M/z 267 (M+H).
Preparation 18
3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) -4-nitrobenzoic acid methyl ester
To a solution of methyl 3-fluoro-4-nitrobenzoate (300 mg,1.5 mmol) and TEA (1.1 mL,8.1 mmol) in THF (6 mL) and DMF (3 mL) was added (1-ethyl-1H-imidazol-5-yl) methylamine dihydrochloride (399 mg,1.6 mmol). Stirred at 35℃for 2 hours and then at 50℃for 16 hours. The crude reaction mixture was diluted with water and extracted with EtOAc (3×15 mL). The combined organic layers were washed with water and saturated aqueous sodium chloride, and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 100% etoac/heptane followed by 5% meoh/DCM to give 395mg of the title compound (88%). ES-MS M/z 305 (M+H).
Preparation 19
4-amino-3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) benzoic acid methyl ester
A solution of iron (193 mg,3.5 mmol), ammonium chloride (10 mg,0.19 mmol) and acetic acid (46 mg,0.77 mmol) in water (3 mL) was stirred at 50℃for 15 min. A solution of methyl 3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) -4-nitrobenzoate (117 mg,0.38 mmol) in DMF (1 mL) was added. Stirred at 50℃for 15 minutes. Quench the reaction with aqueous sodium carbonate to pH 8 and pass And (5) filtering. The residue was washed with water (2X 20 mL) and the aqueous layer was back extracted with EtOAc (2X 20 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. To obtain106mg of the title compound (100%) was used in the crude form for the preparation of 95.ES-MS M/z 275 (M+H).
Preparation 20
3-fluoro-5-methoxy-4-nitrobenzonitrile
To a mixture of 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (700 mg,2.7 mmol), zinc cyanide (226 mg,1.9 mmol) and tetrakis (triphenylphosphine) palladium (0) (317 mg,0.27 mmol) was added DMF (17.8 mL). Stirred at 100℃for 1.5 hours. The crude reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 15% etoac/heptane to give 479mg of the title compound (89%). ES-MS M/z 197 (M+H).
Preparation 21
(S) -3-methoxy-4-nitro-5- ((oxetan-2-ylmethyl) amino) benzonitrile
TEA (1.07 mL,7.7 mmol) and (S) -oxetan-2-ylmethylamine (235 mg,2.56 mmoL) were added to a solution of 3-fluoro-5-methoxy-4-nitrobenzonitrile (457 mg,2.3 mmol) in DMF (7 mL). Stir at 35 ℃ overnight. The crude reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 30% etoac/heptane to give 471mg of the title compound (77%). ES-MS M/z 264 (M+H).
Preparation 22
(S) -3-methoxy-2-nitro-N- (oxetan-2-ylmethyl) -5- (1H-tetrazol-5-yl) aniline
Tributyltin azide (1.96 mL,7.0 mmol) was added to a solution of (S) -3-methoxy-4-nitro-5- ((oxetan-2-ylmethyl) amino) benzonitrile (217 mg,0.82 mmol) in toluene (9.3 mL). Heated to 150 ℃ in a microwave oven with stirring for 2.5 hours. The crude reaction mixture was filtered through a 10% w/w KF/silica plug. Concentrate and triturate the residue with DCM to give 194mg of the title compound (62%). ES-MS M/z 307 (M+H).
Preparation 23
(S) -3-methoxy-N1- (oxetan-2-ylmethyl) -5- (1H-tetrazol-5-yl) benzene-1, 2-diamine
Palladium on carbon (20 mg, 0.09 mmol) was added to a mixture of (S) -3-methoxy-2-nitro-N- (oxetan-2-ylmethyl) -5- (1H-tetrazol-5-yl) aniline (160 mg,0.42 mmol) and MeOH (3 mL). Stirred at RT for 8 hours under a hydrogen pressure of 4 bar. By passing throughThe crude reaction mixture was filtered and concentrated to give 120mg of the title compound (52%) which was used as crude material for preparation 96.ES-MS M/z 277 (M+H).
Preparation 24
4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3-iodo-benzonitrile
To a mixture of 4- (bromomethyl) -3-iodo-benzonitrile (2.88 g,8.93 mmol), 6-bromopyridin-2-ol (1.10 g,6.30 mmol) and silver carbonate (5.1 g,18.0 mmol) was added 1, 4-dioxane (50 mL). The reaction mixture was stirred at 60℃for 15 hours. The reaction was diluted with EtOAc (50 mL) and filtered through celite. The filtrate was washed with water (2X 50 mL) and saturated aqueous sodium chloride (50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 5 to 30% etoac/hexanes to give 2.8g of the title compound (76%). ES-MS M/z 415 and 417 (M+H).
Preparation 25
4-cyano-3- (3-hydroxypropyl) benzoic acid ethyl ester
A mixture of nickel (II) bromide (67 mg,0.76 mmol) and 4,4 '-di-tert-butyl-2, 2' -bipyridine (210 mg, 0.77) in anhydrous 1, 4-dioxane (40 mL) was stirred at RT for 15 min while sparging with nitrogen. Ethyl 3-bromo-4-cyanobenzoate (2 g,7.71 mmol), 3-bromo-1-propanol (1.7 mL,18 mmol) and cobalt (II) phthalocyanine (447mg, 0.77 mmol) were added. The mixture was stirred at RT for 5 min while sparging with nitrogen. Tetra (dimethylamino) ethylene (2.5 ml,11 mmol) was added and the mixture stirred for 5 minutes at RT while bubbling with nitrogen. The vessel was sealed and the mixture was stirred overnight at 85 ℃. The mixture was cooled to RT byFiltered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 20 to 50% etoac/cyclohexane to give the title compound (863 mg, 46%) as a green solid. ES-MS M/z 251 (M+NH) 4 + ).
Preparation 26
3- [3- [ tert-butyl (dimethyl) silyl ] oxypropyl ] -4-cyano-benzoic acid ethyl ester
Tert-butyldimethylchlorosilane (616 mg,3.96 mmol) and imidazole (298 mg,4.33 mmol) were added to a solution of ethyl 4-cyano-3- (3-hydroxypropyl) benzoate (863 mg,3.59 mmol) in DCM (15 mL). The mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0% to 50% etoac/cyclohexane to afford the title compound (1.24 g, 94%) as a colorless oil. ES-MS M/z 348 (M+H).
Preparation 27
2- [3- [ tert-butyl (dimethyl) silyl ] oxypropyl ] -4- (hydroxymethyl) benzonitrile
Lithium borohydride/THF (2.0M, 3.9mL,7.8 mmol) was added to a solution of ethyl 3- [3- [ tert-butyl (dimethyl) silyl ] oxypropyl ] -4-cyano-benzoate (1.24 g,3.39 mmol) in anhydrous THF (9 mL) at 0deg.C under nitrogen. After 5 minutes the cooling bath was removed and stirred at RT overnight. Most of the reaction solvent was removed by concentration, and citric acid (5%) was carefully added at 0 ℃. The aqueous layer was extracted with DCM and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 10% to 50% etoac/cyclohexane to afford the title compound (935 mg, 90%) as a colorless waxy solid. ES-MS M/z 306 (M+H).
Preparation 28
4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3- [3- [ tert-butyl (dimethyl) silyl ] oxypropyl ] benzonitrile
To a mixture of 4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3-iodo-benzonitrile (2.6 g,6.3 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.27 g,0.23 mmol) in 1, 4-dioxane (50 mL) was added bromo- [3- [ tert-butyl (dimethyl) silyl ] oxypropyl ] zinc (0.50M in THF, 25mL,12.5 mmol). Stirred at 60℃for 1 hour. The reaction mixture was diluted with EtOAc (100 mL) and then washed with saturated aqueous ammonium chloride (100 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 5 to 50% etoac/hexanes to give 1.07g of the title compound (37%). ES-MS M/z 461 and 463 (M+H).
Preparation 29
4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3- (3-hydroxypropyl) benzonitrile
To a mixture of 4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3- [3- [ tert-butyl (dimethyl) silyl ] oxypropyl ] benzonitrile (1.32 g,2.86 mmol) in THF (50 mL) was added TBAF solution (1.0M in THF, 2.9mL,2.9 mmol). The reaction mixture was stirred at RT for 1 hour. Dilute with EtOAc (50 mL) and wash with saturated aqueous ammonium chloride (50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 5 to 75% etoac/hexanes to give 0.90g of the title compound (92%). ES-MS M/z 347 and 349 (M+H).
Preparation 30
4- [ (6-bromo-2-pyridinyl) oxymethyl ] -2- [3- [ tert-butyl (dimethyl) silyl ] oxypropyl ] benzonitrile
DIAD (915. Mu.L, 4.5 mmol) was added slowly to a solution of triphenylphosphine (1.21 g,4.61 mmol) in anhydrous THF (15 mL) under nitrogen at 0deg.C. The mixture was stirred for 30 minutes, then a solution of 2- [3- [ tert-butyl (dimethyl) silyl ] oxypropyl ] -4- (hydroxymethyl) benzonitrile (925 mg,3.03 mmol) in anhydrous THF (6 mL) and 2-bromo-6-hydroxypyridine (610 mg,3.33 mmol) was added. The cooling bath was removed, stirred at RT for 2 hours, and the mixture concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 30% etoac/cyclohexane to afford 1.12g of the title compound (78%). ES-MS M/z 461 and 463 (M+H).
Preparation 31
4- [ (6-bromo-2-pyridinyl) oxymethyl ] -2- (3-hydroxypropyl) benzonitrile
TBAF solution (1.0M in THF, 2.7mL,2.7 mmol) was slowly added to 4- [ (6-bromo-2-pyridinyl) oxymethyl at RT]-2- [3- [ tert-butyl (dimethyl) silyl ]]Oxypropyl radical]A solution of benzonitrile (1.12 g,2.43 mmol) in THF (24 mL). The mixture was stirred for 1 hour. The reaction mixture was concentrated and the residue was diluted with MTBE and water. The organic layer was separated and washed with water and saturated aqueous NaCl solution, dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 25 to 50% etoac/cyclohexane to afford the title compound (79mg, 89%) as a white solid. ES-MS M/z 347 and 349 (M+H).
Preparation 32
3- (2- ((tert-Butyldimethylsilyl) oxy) ethoxy) -4-formylbenzonitrile
To a solution of 4-formyl-3-hydroxybenzonitrile (3.0 g,18.8 mmol) in DMF (56 mL) was added sodium iodide (1.4 g,9.3 mmol), potassium carbonate (3.8 g,38 mmol) and (2-bromoethoxy) -tert-butyldimethylsilane (6.1 mL,28 mmol). The mixture was stirred at 70℃for 24 hours. The crude reaction mixture was diluted with water and EtOAc, and the aqueous layer was extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 30% etoac/heptane to give 5.68g of the title compound (99%). ES-MS M/z 306 (M+H).
Preparation 33
3- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -4- (hydroxymethyl) benzonitrile
A solution of 3- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -4-formylbenzonitrile (450 mg,1.47 mmol) in MeOH (4.6 mL) was cooled to 0deg.C. Sodium borohydride (112 mg,2.96 mmol) was added and the mixture stirred at 0deg.C for 15 min. The mixture was warmed to RT and stirred for 1 hour. The mixture was diluted with water and adjusted to pH 7 with 1M aqueous HCl, then extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was passed through a pad of silica gel to give 350mg of the title compound (77%). 1 H-NMR(400MHz,CDCl 3 )δ7.32(d,J＝7.7Hz,1H),7.15(d,J＝7.7Hz,1H),7.02(d,J＝1.0Hz,1H),4.60(s,2H),4.0(m,2H),3.8(m,2H),3.03(s,1H),0.81(s,9H),0.0(s,6H).
Preparation 34
4- (((6-bromopyridin-2-yl) oxy) methyl) -3- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) benzonitrile
To a solution of 3- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -4- (hydroxymethyl) benzonitrile (350 mg,1.14 mmol), 6-bromopyridin-2-ol (1.4 g,8.0 mmol) and triphenylphosphine (2.35 g,8.96 mmol) in THF (50 mL) was added DIAD (1.76 mL,8.94 mmol). The mixture was stirred at 50 ℃ for 4 hours, then the crude reaction mixture was concentrated. The residue was diluted with EtOAc, then washed with water (3×) and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 20% etoac/heptane to give 247mg of the title compound (47%). ES-MS M/z 463 and 465 (M+H).
Preparation 35
4- (((6-bromopyridin-2-yl) oxy) methyl) -3- (2-hydroxyethoxy) benzonitrile
The title compound was prepared using 4- (((6-bromopyridin-2-yl) oxy) methyl) -3- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) benzonitrile as essentially described in preparation 31 and stirring at RT for 2 hours. The title compound was purified by flash chromatography on silica gel using a gradient of 0 to 20% etoac/DCM. ES-MS M/z 349 and 351 (M+H).
Preparation 36
(E) -3- [ 5-chloro-2- (hydroxymethyl) phenyl ] prop-2-enoic acid ethyl ester
To a mixture of (2-bromo-4-chloro-phenyl) methanol (17.5 g,79.0 mmol), tetrabutylammonium chloride (26.1 g,93.9 mmol), potassium carbonate (16.7 g,121 mmol) and palladium acetate (1.47 g,6.55 mmol) in DMF (400 mL) was added ethyl acrylate (10.3 mL,94.8 mmol). The reaction mixture was stirred under nitrogen at 90 ℃ for 6 hours. By passing throughThe reaction mixture was pad filtered and then rinsed with EtOAc (200 mL). The filtrate was diluted with EtOAc (200 mL) and washed with water (800 mL). The aqueous layer was back extracted with EtOAc (250 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DCM, adsorbed on silica and purified by silica gel chromatography using a gradient of 15 to 40% etoac/hexanes to give 6.14g of the title compound (32%). ES-MS M/z 258 (M+NH) 4 + ).
Preparation 37
3- [ 5-chloro-2- (hydroxymethyl) phenyl ] propionic acid ethyl ester
To a mixture of platinum sulfide/carbon (5%, 220mg,0.056 mmol) in EtOAc (20 mL) was added (E) -3- [ 5-chloro-2- (hydroxymethyl) phenyl ] in EtOAc (30 mL)]Ethyl prop-2-enoate (2.21 g,9.18 mmol). In a Parr shaker, at RT for 1 hour under a hydrogen pressure of 40 psi. By passing throughThe pad was filtered and the filtrate concentrated under reduced pressure to afford 1.91g of the title compound (86%) which was used as crude material for preparation 38.ES-MS M/z 225 (M-H) 2 O).
Preparation 38
3- [2- (bromomethyl) -5-chloro-phenyl ] propionic acid ethyl ester
To 3- [ 5-chloro-2- (hydroxymethyl) phenyl ]]To a mixture of ethyl propionate (1.90 g,7.80 mmol) in diethyl ether (40 mL) was added dropwise phosphorus tribromide (0.80 mL,8.5 mmol). Stirred at RT under nitrogen for 1 hour. Quenched by slow dropwise addition of saturated aqueous sodium bicarbonate (5 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (5 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 2.40g of the title compound (100%) which was used in the crude form for preparation 45.ES-MS M/z 322 and 324 (M+NH) 4 + ).
Preparation 39
4- [ (1, 3-dioxoisoindolin-2-yl) methyl ] -3-iodo-benzonitrile
To a solution of 4- (bromomethyl) -3-iodobenzonitrile (10 g,30,13 mmol) in DMF (100 mL) was added potassium phthalimide (6, 14g,33,14 mmol). The reaction mixture was heated at 80℃for 2 hours, then at R T is stirred for 16 hours. The solvent was removed and the solid residue was triturated in 500mL of water for 30 minutes. The white solid was filtered, washed with water, and the solid was dried in vacuo at 45 ℃ for 20 hours to afford the title compound (11.5 g, 88%) as a white solid. ES-MS M/z 405 (M+OH) - ).
Preparation 40
4- [ (1, 3-dioxoisoindolin-2-yl) methyl ] -3- (3-hydroxypro-1-ynyl) benzonitrile
To 4- [ (1, 3-dioxoisoindolin-2-yl) methyl]To a suspension of 3-iodo-benzonitrile (5.0 g,11.7 mmol) in THF (50 mL) and TEA (50 mL) was added bis (triphenylphosphine) palladium dichloride (0.33 g,0.47 mmol), cuprous iodide (0.18 g,0.94 mmol) and propynyl alcohol (2.05 mL,35.2 mmol). The reaction mixture was heated at 40℃for 3 hours. Cooled to RT, diluted with EtOAc (50 mL) and water (50 mL), and passed throughThe mixture was filtered. The phases were separated and the aqueous phase was extracted with more EtOAc (2×50 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 30% etoac/cyclohexane to 100% etoac to give 3.2g (79%) of the title compound as a cream solid. ES-MS M/z 315 (M-H).
Preparation 41
4- [ (1, 3-dioxoisoindolin-2-yl) methyl ] -3- (3-hydroxypropyl) benzonitrile
At 250mLIn a Miniclave reactor, 4- [ (1, 3-dioxoisoindolin-2-yl) methyl was introduced]-3-(3To a suspension of hydroxy prop-1-ynyl) benzonitrile (3 g,9.48 mmol) in MeOH (60 mL) was added rhodium (I) 1,1' -bis (di-isopropylphosphino) ferrocene (1, 5-cyclooctadiene) tetrafluoroborate (0.34 g,0.47 mmol). The reactor was charged with 90psi of hydrogen and heated at 50 ℃ for 2 hours. The reaction mixture was cooled to RT, the solvent evaporated, and the residue purified by silica plug using EtOAc as solvent to afford 2.4g (75%) of the title compound as a pale cream solid. ES-MS M/z 321 (M+H).
Preparation 42
4- (aminomethyl) -3- (3-hydroxypropyl) benzonitrile
To a suspension of 4- [ (1, 3-dioxoisoindolin-2-yl) methyl ] -3- (3-hydroxypropyl) benzonitrile (2.4 g,7.49 mmol) in MeOH (45 mL) was added hydrazine monohydrate (1.90 mL,37.6 mmol) and stirred at 60℃for 20 h. The reaction mixture was cooled to RT and the solid was filtered. The filtrate was evaporated, the residue was diluted with water (30 mL) and extracted with DCM/MeOH 9:1 (3X 20 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a reddish oil (660 mg, 49%). ES-MS M/z 191 (M+H).
Preparation 43
2- (((5-bromo-4-fluoro-2-iodobenzyl) oxy) methyl) -4-cyanobenzoic acid methyl ester
To a solution of (5-bromo-4-fluoro-2-iodophenyl) methanol (1.5 g,4.5 mmol) in THF (24 mL) was added sodium hydride (60%, in mineral oil, 362mg,9.1 mmol) at 0 ℃. Stirred at 0℃for 30 minutes. Methyl 2- (bromomethyl) -4-cyano-benzoate (2.3 g,9.1 mmol) was added and stirred at RT for 1 hour. The reaction was diluted with EtOAc and the organic layer was washed with water and saturated aqueous NaCl. The aqueous layer was back extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM to give 2.5g of the title compound (67%) which was 61% pure and used for preparation 44 without further purification. ES-MS M/z 504 and 506 (M+H).
Preparation 44
3- (((5-bromo-4-fluoro-2-iodobenzyl) oxy) methyl) -4- (hydroxymethyl) benzonitrile
The title compound was prepared essentially as described in preparation 27 using methyl 2- (((5-bromo-4-fluoro-2-iodobenzyl) oxy) methyl) -4-cyanobenzoate (preparation 43) and a 10:1 THF/MeOH mixture as the reaction solvent. After stirring the reaction at RT for 20 hours, an additional portion of lithium borohydride (0.5 eq.) was added and stirred at RT for 2 hours. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and saturated aqueous NaCl. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 50% etoac/heptane to give the title compound. ES-MS M/z 476 and 478 (M+H).
Preparation 45
3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-chloro-phenyl ] propionic acid ethyl ester
To 3- [2- (bromomethyl) -5-chloro-phenyl]To a mixture of ethyl propionate (2.40 g,7.85 mmol), 6-bromopyridin-2-ol (1.98 g,11.4 mmol) and silver carbonate (4.34 g,15.7 mmol) was added 1, 4-dioxane (40 mL). The reaction mixture was stirred at 40℃for 15 hours. By passing throughThe pad was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in DCM, adsorbed onto silica and purified by silica gel chromatography using a gradient of 0 to 40% etoac/hexanes to give 1.16g of the title compound (37%). ES-MS M/z 398,400 and 402 (M+H).
Preparation 46
3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-chloro-phenyl ] propan-1-ol
To a mixture of ethyl 3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-chloro-phenyl ] propanoate (1.16 g,2.90 mmol) in THF (12 mL) was added dropwise lithium borohydride (2.0M in THF, 3.2mL,6.4 mmol). The reaction mixture was stirred at RT for 6 hours. A further portion of lithium borohydride (2.0M in THF, 2.0mL,4.0 mmol) was added. The reaction mixture was stirred at RT for an additional 17 hours. The reaction was quenched by dropwise addition of water. The mixture was diluted with EtOAc (50 mL) and washed with water (40 mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DCM, adsorbed onto silica and purified by flash chromatography on silica gel eluting with a gradient of 0 to 55% etoac/hexanes to give 461mg of the title compound (35%). ES-MS M/z 356,358 and 360 (M+H).
Preparation 47
4- [ [ (6-bromo-2-pyridinyl) amino ] methyl ] -3- (3-hydroxypropyl) benzonitrile
To a solution of 4- (aminomethyl) -3- (3-hydroxypropyl) benzonitrile (800 mg,3.36 mmol) in DMSO (16 mL) was added 2-bromo-6-fluoropyridine (610 mg,3.36 mmol) and DIPEA (1.17 mL,6.72 mmol) and stirred at 100deg.C for 18 hours. The reaction mixture was cooled to room temperature, diluted with water (40 mL) and extracted with EtOAc (3×20 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 30% etoac/cyclohexane to 100% etoac to afford the title compound (400 mg, 33%) as a thick brown oil. ES-MS M/z 346 and 348 (M+H).
Preparation 48
4- [ (3-bromophenoxy) methyl ] -3-iodo-benzonitrile
To a mixture of 4- (bromomethyl) -3-iodo-benzonitrile (2.0 g,6.2 mmol), 3-bromophenol (1.10 g,6.4 mmol) and potassium carbonate (2.6 g,19.0 mmol) was added 1, 4-dioxane (20 mL). The reaction mixture was stirred at RT for 15 hours. The reaction was diluted with EtOAc (100 mL) and passed throughAnd (5) filtering. The filtrate was washed with water (2X 50 mL) and saturated aqueous sodium chloride (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 30% etoac/hexanes to give 2.4g of the title compound (93%). 1 H NMR(400.13MHz,CDCl 3 )δ8.16(d,J＝1.5Hz,1H),7.71(dd,J＝1.5,8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.23-7.17(m,3H),6.92(dt,J＝7.5,2.1Hz,1H),5.05(s,2H).
Preparation 49
4- [ (3-bromophenoxy) methyl ] -3- [3- [ tert-butyl (dimethyl) silyl ] oxypropyl ] benzonitrile
The title compound was prepared as described essentially for preparation 28 using 4- [ (3-bromophenoxy) methyl ] -3-iodo-benzonitrile. ES-MS M/z 460 and 462 (M+H).
Preparation 50
4- [ (3-bromophenoxy) methyl ] -3- (3-hydroxypropyl) benzonitrile
The title compound was prepared as described essentially for preparation 29 using 4- [ (3-bromophenoxy) methyl ] -3- [3- [ tert-butyl (dimethyl) silyl ] oxypropyl ] benzonitrile. ES-MS M/z 344 and 346 (M-H).
Preparation 51
2-bromo-6- [ [ 2-iodo-4- (trifluoromethyl) phenyl ] methoxy ] pyridine
To [ 2-iodo-4- (trifluoromethyl) phenyl ]]To a mixture of methanol (2.0 g,6.6 mmol), 2-bromo-6-fluoro-pyridine (1.2 g,6.6 mmol) and 1, 4-dioxane (25 mL) was added potassium tert-butoxide (0.98 g,8.6 mmol). The reaction mixture was stirred at 50℃for 2 hours. The reaction was diluted with EtOAc (100 mL) and passed throughAnd (5) filtering. The filtrate was washed with water (2X 50 mL) and saturated aqueous sodium chloride (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 10 to 50% etoac/hexanes to give 2.0g of the title compound (66%). ES-MS M/z 458 and 460 (M+H).
Preparation 52
3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5- (trifluoromethyl) phenyl ] propoxy-tert-butyl-dimethyl-monosilane
The title compound was prepared as described essentially in preparation 28 using 2-bromo-6- [ [ 2-iodo-4- (trifluoromethyl) phenyl ] methoxy ] pyridine. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 0 to 10% etoac/hexanes. Directly used for preparation 53 without further characterization.
Preparation 53
3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5- (trifluoromethyl) phenyl ] propan-1-ol
The title compound was prepared as described essentially for preparation 29 using 3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5- (trifluoromethyl) phenyl ] propoxy-tert-butyl-dimethyl-silane. ES-MS M/z390 and 392 (M+H).
Preparation 54
2- [ 4-bromo-2- [3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-cyano-phenyl ] propoxy ] -5-fluoro-phenyl ] acetic acid ethyl ester
To a mixture of 4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3- (3-hydroxypropyl) benzonitrile (550 mg,1.58 mmol) and ethyl 2- (4-bromo-5-fluoro-2-hydroxy-phenyl) acetate (0.40 g,1.4 mmol) in THF (10 mL) was added tri-n-butylphosphine (0.90 mL,4.0 mmol). A solution of DEAD (40% toluene solution, 1.1mL,2.8 mmol) in DCM (1.1 mL) was added dropwise. The reaction mixture was stirred at RT for 15 hours. The reaction was quenched with MeOH (5 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 5 to 40% etoac/hexanes to give 1.1g of the title compound (92%). ES-MS M/z 605,607 and 609 (M+H).
Preparation 55
2- [2- [3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-chloro-phenyl ] propoxy ] -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid methyl ester
To a mixture of 3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-chloro-phenyl ] propan-1-ol (420 mg,1.18 mmol), methyl 2- [ 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate (428 mg,1.45 mmol) and triphenylphosphine (460 mg,1.75 mmol) in THF (8 mL) was added dropwise DIAD (0.35 mL,1.80 mmol). The reaction mixture was stirred at RT for 1.5 hours. The mixture was adsorbed onto silica and purified by flash chromatography on silica gel eluting with a gradient of 0 to 30% etoac/hexanes to give 306mg of the title compound (41%). ES-MS M/z 630 and 632 (M+H).
Preparation 56
2- [2- [3- [2- [ [ (6-bromopyridin-2-yl) oxy ] methyl ] -5-cyanophenyl ] propoxy ] -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid methyl ester
To a mixture of 4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3- (3-hydroxypropyl) benzonitrile (14.5 g,41.9 mmol) and methyl 2- [ 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate (18.7 g,63.9 mmol) in THF (250 mL) was added tri-n-butylphosphine (21 mL,84 mmol). The solution was cooled in an ice bath and DIAD (17 mL,86 mmol) was added dropwise. The reaction mixture was stirred at 45 ℃ for 14 hours and then concentrated under reduced pressure. The residue was suspended in EtOAc (100 mL) and the solid was collected by filtration. The solid was washed with EtOAc (3X 25 mL) to afford 19.7g of the title compound (76%). ES-MS M/z 621,623 (M+H).
Preparation 57
2- [2- [3- [2- [ [ (6-bromo-2-pyridinyl) amino ] methyl ] -5-cyano-phenyl ] propoxy ] -4- (5, 5-dimethyl-1, 3, 2-dioxaborolan-2-yl) -5-fluoro-phenyl ] acetic acid ethyl ester
To a solution of 4- [ [ (6-bromo-2-pyridinyl) amino ] methyl ] -3- (3-hydroxypropyl) benzonitrile (380 mg,1.04 mmol) and ethyl 2- [4- (5, 5-dimethyl-1, 3, 2-dioxaborolan-2-yl) -5-fluoro-2-hydroxyphenyl ] acetate (0.38 g,1.15 mmol) in THF (5.2 mL) was added triphenylphosphine (0.30 g,1.15 mmol) and di-tert-butyl azodicarboxylate (0.27 g,1.15 mmol) at 4 ℃. The reaction mixture was concentrated and the residue was purified by silica gel chromatography using a gradient of 10 to 70% etoac/cyclohexane stirred at RT for 22 h to give the title compound as a pale brown solid (500 mg, 60%). ES-MS M/z 570 and 572 (M+H for boric acid).
Preparation 58
2- [2- [3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-cyano-phenyl ] propoxy ] -5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid methyl ester
The title compound was prepared as described essentially in preparation 55 using 4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3- (3-hydroxypropyl) benzonitrile and methyl 2- [ 2-hydroxy-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate. Trin-butylphosphine was used instead of triphenylphosphine, DEAD was used instead of DIAD and dioxane was used as solvent instead of THF. Purification by flash chromatography on silica gel using a gradient of 80-100% dcm/hexane. ES-MS M/z635 and 637 (M+H).
Preparation 59
2- [2- [3- [5- [ (6-bromo-2-pyridinyl) oxymethyl ] -2-cyano-phenyl ] propoxy ] -5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid ethyl ester
A solution of di-tert-butyl azodicarboxylate (390 mg,1.7 mmol) in dry THF (2 mL) was slowly added to a solution of triphenylphosphine (435 mg,1.66 mmol), 4- [ (6-bromo-2-pyridinyl) oxymethyl ] -2- (3-hydroxypropyl) benzonitrile (400 mg,1.09 mmol) and ethyl 2- [ 5-fluoro-2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate (480 mg, 83% purity, 1.23 mmol) in dry THF (8 mL) at RT. The mixture was stirred at RT for 1 hour. Triphenylphosphine (170 mg,0.65 mmol) was added and after 5 minutes a solution of di-tert-butyl azodicarbonate (157 mg,0.65 mmol) in anhydrous THF (2 ml) was slowly added. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel using a gradient of 10 to 50% etoac/cyclohexane to give the title compound as a brown waxy solid (689 mg, purity 90%, 86%). ES-MS M/z 653 and 655 (M+H).
Preparation 60
Ethyl 2- (4-bromo-2- (2- (2- (((6-bromopyridin-2-yl) oxy) methyl) -5-cyanophenoxy) ethoxy) -5-fluorophenyl) acetate
To a solution of 4- (((6-bromopyridin-2-yl) oxy) methyl) -3- (2-hydroxyethoxy) benzonitrile (640 mg,1.83 mmol), ethyl 2- (4-bromo-5-fluoro-2-hydroxy-phenyl) acetate (506 mg,1.83 mmoL) and TMAD (671 mg,3.70 mmol) in THF (9 mL) was added tri-n-butylphosphine (0.91 mL,3.65 mmol). Stirred at 35℃for 2 hours. The reaction was quenched with MeOH and the crude mixture was concentrated. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 30% etoac/heptane to give 876mg of the title compound (79%). ES-MS M/z 607,609 and 611 (M+H).
Preparation 61
3- (((5-bromo-4-fluoro-2-iodobenzyl) oxy) methyl) -4- (((6-bromopyridin-2-yl) oxy) methyl) benzonitrile
The title compound was prepared using 3- (((5-bromo-4-fluoro-2-iodobenzyl) oxy) methyl) -4- (hydroxymethyl) benzonitrile essentially as described in preparation 34. The title compound was purified by flash chromatography on silica gel using a gradient of 0 to 10% etoac/heptane. ES-MS M/z 631,633 and 635 (M+H).
Preparation 62
Ethyl 2- (4-bromo-2- (((2- (((6-bromopyridin-2-yl) oxy) methyl) -5-cyanobenzyl) oxy) methyl) -5-fluorophenyl) acetate
To a solution of 3- (((5-bromo-4-fluoro-2-iodobenzyl) oxy) methyl) -4- (((6-bromopyridin-2-yl) oxy) methyl) benzonitrile (2.69 mg,4.3 mmol) in ACN (75 mL) was added bis (triphenylphosphine) palladium (II) dichloride (305 mg,0.43 mmol), TEA (1.48 mL,10.6 mmol) and formic acid (0.24 mL,6.4 mmol). The reaction was stirred at 70℃and a solution of ethyl diazoacetate (2M in DCM, 8.5mL,17 mmol) in ACN (25 mL) was added over 10 min. Stirred at 70℃for 2 hours. A second portion of all reagents (half of the initial addition) was added and heated for an additional 1.5 hours. The reaction mixture was diluted with EtOAc and the organic layer was washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 10% etoac/heptane to give 898mg of the title compound (36%). ES-MS M/z 591,593 and 595 (M+H).
Preparation 63
2- [2- [3- [2- [ (3-bromophenoxy) methyl ] -5-cyano-phenyl ] propoxy ] -5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid methyl ester
The use of 4- [ (3-bromophenoxy) methyl ] as described in preparation 54]-3- (3-hydroxypropyl) benzonitrile and 2- [ 2-hydroxy-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ]]Methyl acetate, using 1, 4-dioxane as the reaction solvent and adding DEAD in the form of a 40% toluene solution, prepared the title compound. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 80 to 100% dcm/hexane. ES-MS M/z651 and 653 (M+NH) 4 + ).
Preparation 64
2- [2- [3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5- (trifluoromethyl) phenyl ] propoxy ] -5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid methyl ester
The title compound was prepared as described essentially in preparation 54 using 3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5- (trifluoromethyl) phenyl ] propan-1-ol and methyl 2- [ 2-hydroxy-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate, and adding to the reaction DEAD in the form of a 40% toluene solution. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 85 to 100% dcm/hexane. ES-MS M/z 678 and 680 (M+H).
Preparation 65
2-(5 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid ethyl ester
To a solution of ethyl 2- [ 4-bromo-2- [3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-cyano-phenyl ] propoxy ] -5-fluoro-phenyl ] acetate (1.1 g,0.92 mmol) in 1, 4-dioxane (40 mL) was added hexamethylditin (0.71 g,2.2 mmol). Tetrakis (triphenylphosphine) palladium (0) (0.20 g,0.20 mmol) was added. The reaction mixture was stirred at 90℃for 60 hours. Concentrate under reduced pressure and purify the residue by flash chromatography on silica gel eluting with a gradient of 5 to 45% etoac/hexanes to give 303mg of the title compound (47%). ES-MS M/z 447 (M+H).
Preparation 66
2-(5 4 -chloro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid methyl ester
To 2- [2- [3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ]]-5-chloro-phenyl]Propoxy group]-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]To a mixture of methyl acetate (306 mg,0.49 mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (XPhos Gen 2,28.9mg,0.036 mmol) and potassium phosphate (420 mg,1.94 mmol) was added THF (48 mL) and water (5.4 mL). The reaction mixture was stirred under nitrogen at 40 ℃ for 15 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM and adsorbed to Purified by flash chromatography on silica gel eluting with a gradient of 0 to 40% etoac/hexanes to give 152mg of the title compound (74%). ES-MS M/z 424 and 426 (M+H).
Preparation 67
2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid methyl ester
To 2- [2- [3- [2- [ [ (6-bromopyridin-2-yl) oxy ] oxy]Methyl group]-5-cyanophenyl]Propoxy group]-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]To a mixture of methyl acetate (19.7 g,31.7 mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (XPhos Gen 2,1.3g,1.6 mmol) and potassium phosphate (28.5 g,132 mmol) was added THF (500 mL) and water (52 mL). The reaction mixture was stirred at 45 h 15 min under nitrogen atmosphere. The reaction was diluted with EtOAc (200 mL) and washed with half-saturated brine (400 mL). The organic phase was dried over MgSO 4 Dried, filtered and concentrated under reduced pressure. The residue was suspended in EtOAc (100 mL) and filteredThe solid was collected. The solid was washed with EtOAc (3X 30 mL) to give 10.7g of the title compound (82%). ES-MS M/z 415 (M+H).
Preparation 68
2-(5 4 -cyano-1 6 -fluoro-9-oxa-3-aza-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid ethyl ester
To 2- [2- [3- [2- [ [ (6-bromo-2-pyridinyl) amino ] amino group]Methyl group]-5-cyano-phenyl]Propoxy group]-4- (5, 5-dimethyl-1, 3, 2-dioxaborolan-2-yl) -5-fluoro-phenyl]To a solution of ethyl acetate (460 mg,0.57 mmol) in 1, 4-dioxane (11.5 mL) was added PdCl 2 (dtbpf) (77 mg,0.11 mmol) and 1M aqueous potassium phosphate (1.73 mL,1.73 mmol). Stirred at 70 ℃ for 2 hours, cooled to RT and the reaction mixture diluted with saturated ammonium chloride solution (15 mL) and EtOAc (10 mL). The phases were separated and the aqueous phase extracted with EtOAc (2X 5 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 30% etoac/cyclohexane as an elution system to afford the title compound (125 mg, 49%) as a pale yellow solid. ES-MS M/z 446 (M+H).
Preparation 69
2-(5 4 -cyano-1 6 -methyl-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid methyl ester
The title compound was prepared as described essentially for preparation 66 using methyl 2- [2- [3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-cyano-phenyl ] propoxy ] -5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate. Purification by flash chromatography on silica gel using a gradient of 0 to 20% etoac/DCM. ES-MS M/z 429 (M+H).
Preparation 70
2-(5 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid ethyl ester
To 2- [2- [3- [5- [ (6-bromo-2-pyridinyl) oxymethyl ]]-2-cyano-phenyl]Propoxy group]-5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]To a solution of ethyl acetate (650 mg,90% purity, 0.89 mmol) in 1, 4-dioxane (30 mL) was added PdCl 2 (dtbpf) (119 mg,0.18 mmol) and 1M aqueous potassium phosphate (2.7 mL,2.7 mmol). The mixture was stirred under nitrogen at 50 ℃ for 15 min, then cooled to RT and diluted with DCM. Anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 10 to 30% etoac/cyclohexane to afford the title compound (150 mg, 38%) as an extremely pale brown solid. ES-MS M/z 447 (M+H).
Preparation 71
2-(5 4 -cyano-1 6 -fluoro-3, 6, 9-trioxa-2 (2, 6) -pyridinio-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid ethyl ester
To a solution of ethyl 2- (4-bromo-2- (2- (2- (((6-bromopyridin-2-yl) oxy) methyl) -5-cyanophenoxy) ethoxy) -5-fluorophenyl) acetate (400 mg,0.66 mmol), KOAc (0.2 g,2.0 mmol), bis (pinacolato) diboron (187 mg,0.72 mmol) in 1, 4-dioxane (2.2 mL) was added Pd (dppf) Cl 2 DCM complex (27 mg,0.032 mmol). The mixture was stirred at 85 ℃ for 1 hour, then diluted with water and extracted three times with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. THF (66 mL), tripotassium phosphate (0.6 g, 3.0) was added to the residuemmol), water (7.3 mL), palladium (II) chloride (6.0 mg,0.033 mmol) and 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (32 mg,0.066 mmol) in THF (1 mL). Stirred at 45℃for 16 hours. The crude mixture was diluted with water and extracted three times with EtOAc (3×). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 30% etoac/heptane to give 94mg of the title compound (32%). ES-MS M/z 449 (M+H).
Preparation 72
2-(5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetic acid ethyl ester
Ethyl 2- (4-bromo-2- (((2- (((6-bromopyridin-2-yl) oxy) methyl) -5-cyanobenzyl) oxy) methyl) -5-fluorophenyl) acetate was used essentially as described in preparation 65, using 1.1eq of hexamethylditin with Pd (dppf) Cl 2 The title compound was prepared by stirring the reaction at 100℃for 3.5 hours with DCM as catalyst. The crude reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 80% etoac/heptane to give the title compound. ES-MS M/z 433 (M+H).
Preparation 73
2-(5 4 -cyano-1 6 -methyl-3, 9-dioxa-1, 2 (1, 3), 5 (1, 2) -triphenylheterocyclicallyl-1 4 -yl) acetic acid methyl ester
The title compound was prepared essentially as described for preparation 66 using methyl 2- [2- [3- [2- [ (3-bromophenoxy) methyl ] -5-cyano-phenyl ] propoxy ] -5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate and stirring the reaction mixture at 40 ℃ for 1 hour. The mixture was purified by flash chromatography on silica gel eluting with a gradient of 0 to 20% etoac/DCM to give the title compound. ES-MS M/z 428 (M+H).
Preparation 74
2-(1 6 -methyl-5 4 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylheterocyclo-nonatomato-1 4 -yl) acetic acid methyl ester
The title compound was prepared as described essentially for preparation 66 using methyl 2- [2- [3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5- (trifluoromethyl) phenyl ] propoxy ] -5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate and stirring at 40 ℃ for 1 hour. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 0 to 20% etoac/DCM. ES-MS M/z 472 (M+H).
Preparation 75
2-(5 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
To 2- (5) 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 Ethyl acetate (290 mg,0.649 mmol) in a mixture of ACN: water (5 mL:0.5 mL) was added 1,3,4,6,7,8-hexahydro-2H-pyrimido [1, 2-a)]Pyrimidine (0.30 g,2.0 mmol). The reaction mixture was stirred at RT for 15 hours. The pH of the reaction mixture was adjusted to pH 7 with 1.0M aqueous citric acid and concentrated under reduced pressure to remove volatiles. The residue was diluted with EtOAc (100 mL) and washed with water (50 mL) and saturated aqueous NaCl solution (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 238mg of titledCompound (88%) was used in crude form for preparation 85 and 86.ES-MS M/z 419 (M+H).
Preparation 76
2-(5 4 -chloro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
To 2- (5) 4 -chloro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 To a mixture of ACN (3.6 mL) and THF (3 mL) was added aqueous lithium hydroxide (1.0M, 1.1mL,1.1 mmol) methyl acetate (152 mg,0.36 mmol). The mixture was stirred at 40℃for 2 hours. The reaction was quenched with aqueous citric acid (1.0M, 2.2 mL) and then diluted with EtOAc. The aqueous layer was removed and extracted with EtOAc (2X 3 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 150mg of the title compound (100%) which was used in preparation 87 as crude material. ES-MS M/z 410 (M+H).
Preparation 77
2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
From 2- (5) substantially as described in preparation 75 4 Cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl acetate starts to prepare the title compound. After completion of the reaction, it was cooled to RT and neutralized with aqueous citric acid. The resulting precipitate was filtered and the resulting filter cake was dried under vacuum to give the title compound (100%). ES-MS M/z 401 (M+H)
Preparation 78
2-(5 4 -cyano-1 6 -fluoro-9-oxa-3-aza-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diBenzene heterocycle Jiuqian-1 4 -yl) acetic acid
To 2- (5) 4 -cyano-1 6 -fluoro-9-oxa-3-aza-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 To a suspension of ethyl acetate (122 mg,027 mmol) in ACN (3 mL), THF (1 mL) and water (1 mL) was added 1,5, 7-triazabicyclo [ 4.4.0)]Dec-5-ene (116 mg,0.81 mmol). Stirred at 45 ℃ for 2 hours, cooled to RT and quenched with 1M citric acid solution (2 mL). Extracted with EtOAc (3X 3 mL). The organics were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a waxy pale yellow solid (115 mg, 100%). ES-MS M/z 418 (M+H).
Preparation 79
2-(5 4 -cyano-1 6 -methyl-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
The use of 2- (5) was essentially as described in preparation 75 4 -cyano-1 6 -methyl-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl acetate to prepare the title compound. ES-MS M/z 415 (M+H).
Preparation 80
2-(5 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
The use of 2- (5) is substantially as described in preparation 78 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocycleJiuqian-1 4 -yl) ethyl acetate to prepare the title compound. ES-MS M/z419 (M+H).
Preparation 81
2-(5 4 -cyano-1 6 -fluoro-3, 6, 9-trioxa-2 (2, 6) -pyridinio-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
The use of 2- (5) was essentially as described in preparation 75 4 -cyano-1 6 -fluoro-3, 6, 9-trioxa-2 (2, 6) -pyridinio-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) ethyl acetate to prepare the title compound, stirring at 45 ℃ for 3 hours. The reaction was quenched with formic acid to pH 7 and diluted with water. Three times with EtOAc, then with 3:1 chloroform: the isopropanol was extracted three times. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 10 to 80% etoac/DCM to give the title compound. ES-MS M/z 421 (M+H).
Preparation 82
2-(5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetic acid
Use of ethyl 2- (5) as described in preparation 75 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -base) the title compound was prepared and reacted at 45 ℃ with stirring for 1 hour. The reaction was quenched with formic acid to pH 6-7 and extracted with EtOAc then with 3:1 chloroform: 2-propanol extraction. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (95%) which was used in the preparation 98 as a crude material. ES-MS M/z 405 (M+H).
Preparation 83
2-(5 4 -cyano-1 6 -methyl-3, 9-dioxa-1, 2 (1, 3), 5 (1, 2) -triphenylheterocyclicallyl-1 4 -yl) acetic acid
The use of 2- (5) was essentially as described in preparation 75 4 -cyano-1 6 -methyl-3, 9-dioxa-1, 2 (1, 3), 5 (1, 2) -triphenylheterocyclicallyl-1 4 -methyl acetate), the reaction mixture was stirred at 45 ℃ for 1 hour to prepare the title compound. The title compound was used in crude form for preparation 99.ES-MS M/z 412 (M-H).
Preparation 84
2-(1 6 -methyl-5 4 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylheterocyclo-nonatomato-1 4 -yl) acetic acid
The use of 2- (1) is substantially as described in preparation 75 6 -methyl-5 4 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylheterocyclo-nonatomato-1 4 -methyl acetate) and stirred at 50 ℃ for 1 hour to prepare the title compound. The title compound was used in crude form for preparation 100.ES-MS M/z 458 (M+H).
Preparation 85
(S)-4-(2-(5 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
To 2- (5) 4 -cyano-1 6 -fluoro-3, 9-dioxa-22, 6) -Pyridinza-1 (1, 3), 5 (1, 2) -Diphenyl-heterocycle nona-1 4 -yl) acetic acid (crude material, 0.170g,0.361 mmol) and 4-amino-3- [ [ (2S) -oxetan-2-yl]Methylamino group]To a mixture of methyl benzoate (prepared essentially as described in WO 2020/263695; 100mg,0.423 mmol) in pyridine (3 mL) was added EDC (125 mg,0.639 mmol). The reaction mixture was stirred at RT for 15 hours. The reaction was quenched with saturated aqueous ammonium chloride to pH 6. The mixture was diluted with water (5 mL) and extracted with EtOAc (3X 10 mL). The combined organics were washed with saturated aqueous sodium chloride (10 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 50% etoac/petroleum ether to give 225mg of the title compound (71%). ES-MS M/z 637 (M+H).
Preparation 86
(S)-4-(2-(5 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3-fluoro-5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
To 2- (5) 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid (238 mg, 0.618 mmol) and 4-amino-3-fluoro-5- [ [ (2S) -oxetan-2-ylmethyl]Amino group]To a mixture of methyl benzoate (0.20 g,0.79 mmol) in DMF (5 mL) was added DIPEA (0.15 mL,0.86 mmol). HATU (0.20 g,0.53 mmol) was added. Stirred at RT for 4 hours. The reaction was diluted with EtOAc (100 mL) and washed with water (50 mL) and saturated aqueous NaCl solution (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.46g of the title compound (99%) which was used in the crude form for preparation 102.ES-MS M/z 655 (M+H).
Preparation 87
(S)-4-(2-(5 4 -chloro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -group) acetamido group) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -chloro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid and 4-amino-3- [ [ (2S) -oxetan-2-yl ]Methylamino group]Methyl benzoate (prepared essentially as described in WO 2020/263695) was stirred for 16 hours and then worked up to prepare the title compound. The title compound was used in crude form for preparation 104.ES-MS M/z 628 (M+H).
Preparation 88
(S)-4-(2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid and 4-amino-3- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (prepared essentially as described in WO 2020/263695) was used to prepare the title compound. The crude title compound was obtained and used for preparation 105 without purification. ES-MS M/z 619 (M+H)
Preparation 89
(S)-4-(2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3-methoxy-5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid and 4-amino-3-methoxy-5- [ [ (2S) -oxetan-2-yl ]Methylamino group]Methyl benzoate (preparation 17) the title compound was prepared. The residue was purified by silica gel chromatography using a gradient of 5 to 80% etoac/DCM to give the title compound. ES-MS M/z 649 (M+H).
Preparation 90
(S)-5-(2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylheterocyclo nona-14-yl) acetamido) -6- ((oxetan-2-ylmethyl) amino) picolinic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid (0.3 g,0.75 mmol) and methyl (S) -5-amino-6- ((oxetan-2-ylmethyl) amino) picolinate. The title compound was used in the next step (preparation 107) without purification. ES-MS M/z 620 (M+H)
Preparation 91
(S)-4-(2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3-fluoro-5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid and 4-amino-3-fluoro-5- [ [ (2S) -oxetan-2-ylmethyl]Amino group]Methyl benzoate the title compound was prepared. The title compound was used in the next step (preparation 108) without purification. ES-MS m/z 637(M+H)
Preparation 92
(S)-4-(2-(5 4 -cyano-1 6 -fluoro-9-oxa-3-aza-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
To 2- (5) 4 -cyano-1 6 -fluoro-9-oxa-3-aza-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 To a solution of acetic acid (115 mg,0.27 mmol) in DMF (3.0 mL) was added 4-amino-3- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (prepared essentially as described in WO 2020/263695) (75 mg,0.32 mmol), HATU (160 mg,0.42 mmol) and DIPEA (0.15 mL,0.86 mmol). Stirred at RT for 2 hours, diluted with water (10 mL) and extracted with EtOAc (4X 5 mL). The organics were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a brown solid (160 mg, 79%). ES-MS M/z 636 (M+H).
Preparation 93
(S)-4-(2-(5 4 -cyano-1 6 -methyl-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3-methoxy-5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-1 6 -methyl-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid and 4-amino-3-methoxy-5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (preparation 17) the title compound was prepared. The title compound was used in the next step (preparation 103) as crude product without purification. E (E)S-MS m/z 663(M+H).
Preparation 94
(S)-4-(2-(5 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid and 4-amino-3- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (prepared essentially as described in WO 2020/263695) was used to prepare the title compound. The title compound was used in its crude form for preparation 110 without purification. ES-MS M/z 637 (M+H).
Preparation 95
4-(2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) benzoic acid methyl ester
/>
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid (100 mg,0.25 mmol) and methyl 4-amino-3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) benzoate (preparation 19) the title compound was prepared. The reaction was stirred at RT for 18 hours, then diluted with water and EtOAc, followed by four extractions of the aqueous layer with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used in the form of crude material for preparation 111.ES-MS M/z 657 (M+H).
Preparation 96
(S)-2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) -N- (2-methoxy-6- ((oxetan-2-ylmethyl) amino) -4- (1H-tetrazol-5-yl) phenyl) acetamide
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid and (S) -3-methoxy-N1- (oxetan-2-ylmethyl) -5- (1H-tetrazol-5-yl) benzene-1, 2-diamine. Stirred at RT for 67 hours. The mixture was diluted with water and EtOAc, and the aqueous layer was extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 100% etoac/heptane followed by 0 to 10% meoh/DCM. ES-MS M/z 659 (M+H).
Preparation 97
(S)-4-(2-(5 4 -cyano-1 6 -fluoro-3, 6, 9-trioxa-2 (2, 6) -pyridinio-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-1 6 -fluoro-3, 6, 9-trioxa-2 (2, 6) -pyridinio-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid and 4-amino-3- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (prepared essentially as described in WO 2020/263695) was reacted at RT with stirring for 24 hours to prepare the title compound. The crude reaction was diluted with water and extracted three times with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound, which was used in preparation 112 as a crude material. ES-MS M/z 639 (M+H).
Preparation 98
(S)-4-(2-(5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetic acid and 4-amino-3- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (prepared essentially as described in WO 2020/263695) was used to prepare the title compound and the reaction was stirred at RT for 2 hours. The reaction was diluted with water and EtOAc, and the aqueous layer was extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used as crude material for preparation 113.ES-MS M/z 623 (M+H).
Preparation 99
(S)-4-(2-(5 4 -cyano-1 6 -methyl-3, 9-dioxa-1, 2 (1, 3), 5 (1, 2) -triphenylheterocyclicallyl-1 4 -yl) acetamido) -3-methoxy-5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 85 4 -cyano-1 6 -methyl-3, 9-dioxa-1, 2 (1, 3), 5 (1, 2) -triphenylheterocyclicallyl-1 4 -yl) acetic acid (preparation 83) and 4-amino-3-methoxy-5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (preparation 17) the title compound was prepared. The title compound was used for preparation 114 without purification. ES-MS M/z 662 (M+H).
Preparation 100
(S) -3-methoxy-4- (2- (1) 6 -methyl-5 4 - (trifluoromethyl) -3, 9-dioxoHetero-2 (2, 6) -pyridinio-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (1) as described substantially in preparation 85 6 -methyl-5 4 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylheterocyclo-nonatomato-1 4 -yl) acetic acid (preparation 84) and 4-amino-3-methoxy-5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (preparation 17) the title compound was prepared. The title compound was used in crude form for preparation 115 without purification. ES-MS M/z 706 (M+H).
Preparation 101
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
(S) -4- (2- (5) 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 A solution of methyl-3- ((oxetan-2-ylmethyl) amino) benzoate (220 mg,0.295 mmol) in acetic acid (3.0 mL) was stirred at 80℃for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give 200mg of the title compound (87%) which was used as crude material in example 1.ES-MS M/z 619 (M+H).
Preparation 102
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
(S) -4- (2- (5) in acetic acid (5.0 mL) 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -methyl 3-fluoro-5- ((oxetan-2-ylmethyl) amino) benzoate (0.46 g,0.56 mmol) was stirred at 55 ℃ for 15 hours. The reaction mixture was concentrated and the residue was dissolved in EtOAc (100 mL). The organic phase was washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 5 to 60% etoac/hexanes to give 0.24g of the title compound (67%). ES-MS M/z 637 (M+H).
Preparation 103
(S)-2-((5 4 -cyano-1 6 -methyl-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 102 4 -cyano-1 6 -methyl-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -methyl 3-methoxy-5- ((oxetan-2-ylmethyl) amino) benzoate (preparation 93) and 1:1 DCM: acetic acid. Purification by flash chromatography on silica gel using a gradient of 5 to 60% etoac/DCM. ES-MS M/z 645 (M+H).
Preparation 104
(S)-2-((5 4 -chloro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 102 4 -chloro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester the title compound was prepared, the reaction mixture was stirred at 55 ℃ for 3.5 hours, then at 65 ℃ for 2 hours. The mixture was concentrated under reduced pressure and azeotroped with ACN. The residue was dissolved in DCM and adsorbed toAnd purified by silica gel chromatography eluting with a gradient of 0 to 100% etoac/hexanes. ES-MS M/z 610 (M+H).
Preparation 105
(S)-2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
(S) -4- (2- (5) in 1:1 dichloroethane: acetic acid was used substantially as described in preparation 102 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester (preparation 88) the title compound was prepared. The residue was purified by silica gel chromatography using a gradient of 5 to 60% etoac/DCM to give the title compound. ES-MS M/z 601 (M+H).
Preparation 106
(S)-2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
(S) -4- (2- (5) in 1:1 dichloroethane: acetic acid was used substantially as described in preparation 102 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3-methoxy-5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester. The residue was purified by silica gel chromatography using a gradient of 5 to 60% etoac/DCM to give the title compound. ES-MS M/z 631 (M+H).
Preparation 107
(S)-2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -3- (oxetan-2-ylmethyl) -3H-imidazo [4,5-b]Pyridine-5-carboxylic acid methyl ester
(S) -5- (2- (5) in 1:1 dichloroethane: acetic acid was used substantially as described in preparation 102 4 -methyl cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-14-yl) acetamido) -6- ((oxetan-2-ylmethyl) amino) picolinate the title compound was prepared, increasing the reaction time to 48 hours. The residue was purified by silica gel chromatography using a gradient of 5 to 60% etoac/DCM to give the title compound. ES-MS M/z 602 (M+H).
Preparation 108
(S)-2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
Substantially as in preparation 102 (S) -4- (2- (5) in 1:1 dichloroethane and acetic acid 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -methyl 3-fluoro-5- ((oxetan-2-ylmethyl) amino) benzoate (0.38 g,0.48 mmol) the title compound was prepared. The residue was purified by silica gel chromatography using a gradient of 5 to 60% etoac/DCM to give 0.24g of the title compound (67%). ES-MS M/z 619 (M+H).
Preparation 109
(S)-2-((5 4 -cyano-1 6 -fluoro-9-oxa-3-aza-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] ]Imidazole-6-carboxylic acid methyl ester
(S) -4- (2- (5) 4 -cyano-1 6 -fluoro-9-oxa-3-aza-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 A solution of methyl-3- ((oxetan-2-ylmethyl) amino) benzoate (160 mg,0.20 mmol) in 1, 2-dichloroethane (1.5 mL) and acetic acid (1.25 mL) was heated at 50℃for 6 h. The reaction mixture was cooled to RT, the solvent concentrated under reduced pressure and the residue purified by silica gel chromatography using a gradient of 10 to 50% etoac/DCM to afford 70mg (53%) of the title compound as a white solid. ES-MS M/z 618 (M+H).
Preparation 110
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 109 4 -cyano-1 6 -fluorine-3, 9-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester the title compound was prepared and the reaction mixture was stirred at 60 ℃ for 5.5 hours. The mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 10 to 30% etoac/DCM. ES-MS M/z 619 (M+H).
Preparation 111
2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of 4- (2- (5) as described in preparation 101 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) benzoic acid methyl ester (preparation 95) the title compound was prepared, reacted at 65 ℃ with stirring for 5 hours, then at 80 ℃ with stirring for 17 hours. The solution was concentrated and azeotroped with ACN. The residue was purified by silica gel chromatography using a gradient of 0 to 100% etoac/heptane followed by a gradient of 0 to 10% meoh/DCM. ES-MS M/z 639 (M+H).
Preparation 112
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 6, 9-trioxa-2 (2, 6) -pyridinio-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 101 4 -cyano-1 6 -fluoro-3, 6, 9-trioxa-2 (2, 6) -pyridinio-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -base) acetamidesMethyl) -3- ((oxetan-2-ylmethyl) amino) benzoate was reacted at 65 c with stirring for 3 hours to prepare the title compound. The reaction was concentrated and azeotroped with ACN. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 100% etoac/heptane followed by a gradient of 0 to 2% meoh/DCM to give the title compound. ES-MS M/z 621 (M+H).
Preparation 113
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 101 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester, the title compound was prepared by stirring reaction at 65 ℃ for 1.5 hours. The solution was concentrated and azeotroped with ACN, then the residue was purified by flash chromatography on silica gel using a gradient of 0 to 60% etoac/heptane to give the title compound. ES-MS M/z 605 (M+H).
Preparation 114
(S)-2-((5 4 -cyano-1 6 -methyl-3, 9-dioxa-1, 2 (1, 3), 5 (1, 2) -triphenylheterocyclicallyl-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
(S) -4- (2- (5) in 1:1 dichloroethane: acetic acid was used substantially as described in preparation 102 4 -cyano-1 6 -methyl-3, 9-dioxa-1, 2 (1, 3), 5 (1, 2) -triphenylheterocyclicallyl-1 4 -yl) acetamido) -3-methoxy-5- ((oxa)Cyclobutan-2-ylmethyl) amino) methyl benzoate (preparation 99) to prepare the title compound. ES-MS M/z 645 (M+H).
Preparation 115
(S) -4-methoxy-2- ((1) 6 -methyl-5 4 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylheterocyclo-nonatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
(S) -3-methoxy-4- (2- (1) in 1:1 dichloroethane: acetic acid was used substantially as described in preparation 102 6 -methyl-5 4 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylheterocyclo-nonatomato-1 4 -yl) acetamido) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester (preparation 100) the title compound was prepared. The title compound was purified by silica gel chromatography using a gradient of 80 to 100% dcm/hexane. ES-MS M/z 688 (M+H).
Preparation 116
2- (4-bromo-2-methylphenyl) acetic acid methyl ester
Thionyl chloride (2.5 mL,34.3 mmol) was added dropwise over 15 minutes to a solution of 2- (4-bromo-2-methylphenyl) acetic acid (5 g,20.74 mmol) in MeOH (42 mL) at 4deg.C. The reaction was stirred for 3 hours, then the solvent was evaporated under reduced pressure. To the residue was added water (50 mL) and saturated NaHCO 3 The solution was brought to ph=7-8 and then extracted with EtOAc (3×30 mL). The organics were combined, washed with water and saturated aqueous NaCl solution, dried over MgSO 4 Dried, then filtered and concentrated under reduced pressure to give the title compound (5.06 g, 100%) as an orange oil. The title compound was not ionized by LCMS and was not further characterized for preparation 117.
Preparation 117
4-bromo-2- (bromomethyl) phenylacetic acid methyl ester
A solution of methyl 2- (4-bromo-2-methylphenyl) acetate (4.03 g,15.7 mmol) and N-bromosuccinimide (2.66 g,14.9 mmol) in ACN (85 mL) was transferred through a photochemical flow reactor (reactor size=52 mL, residence time=1.3 mL/min,40 ℃) equipped with a 4X 370nm lamp and a 4X 440nm lamp. The solution was collected over 2 hours, the solvent was evaporated, and then water (20 mL) and MTBE (20 mL) were added to the residue. The layers were separated and the aqueous phase was extracted with MTBE (2X 20 mL). The organics were combined and treated with 20% NaHSO 3 Aqueous solution, water and saturated aqueous NaCl solution, washed over MgSO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 10 to 40% dcm/cyclohexane to give the title compound as a white waxy solid (5.1 g,85% purity, 75% yield). ES-MS M/z338/340/342 (M+NH) 4 + ).
Preparation 118
3-fluoro-5-methoxy-4-nitro-benzoic acid methyl ester
To a solution of methyl 3, 5-difluoro-4-nitro-benzoate (0.3 g,1.38 mmol) in MeOH (4 mL) was added sodium formate solution (25 mass% in MeOH, 0.33mL,1.44 mmol) and reacted by heating at 65 ℃ for 2.5 hours. The reaction mixture was cooled to RT, then water was added and extracted with EtOAc (3×5 mL). The organics were combined, washed with saturated aqueous NaCl solution, and dried over MgSO 4 Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of EtOAc/heptane (0 to 10%) to give 245mg (76%) of the title compound as a yellow oil. ES-MS M/z 230 (M+H).
Preparation 119
3-fluoro-5-methoxy-4-nitro-benzoic acid ethyl ester
Sulfuric acid (2 mL,3.1g,31 mmol) was added to a solution of 3-fluoro-5-methoxy-4-nitro-benzoic acid (0.67 g,3.1 mmol) in EtOH (10 mL) and the mixture was heated to 80℃for 1 hour. With saturated NaHCO 3 The reaction mixture was quenched with aqueous solution and extracted with DCM. Over MgSO 4 The organic layer was dried, filtered and concentrated to give the title compound (0.73 g, 96%), which was used for preparation 121 without further purification. ES-MS M/z 244 (M+H).
Preparation 120
3-fluoro-5- (2-methoxyethoxy) -4-nitro-benzoic acid methyl ester
Sodium hydride (92 mg,2.30 mmol) was suspended in THF (10 ml), then 2-methoxyethanol (0.18 ml,2.31 mmol) was added and stirred at RT for 30 min. Next, methyl 3, 5-difluoro-4-nitro-benzoate (0.5 g,2.30 mmol) was added and the mixture was stirred at 60℃for 16 hours. The reaction was diluted with water (100 mL) and extracted with EtOAc (3X 50 mL). Through Na 2 SO 4 The organics were dried, filtered and concentrated. Purification by silica gel chromatography using a gradient of 0 to 20% etoac/heptane gave the title compound as a yellow oil (225 mg, 40%). ES-MS M/z 274 (M+H).
Preparation 121
3-methoxy-4-nitro-5- (oxazol-2-ylmethylamino) benzoic acid ethyl ester
The title compound was prepared essentially as described for preparation 14 using ethyl 3-fluoro-5-methoxy-4-nitro-benzoate (0.30 g,1.0 mmol) and 1- (1, 3-oxazol-2-yl) methylamine hydrochloride (0.20 g,1.0 mmol). The title compound was purified by silica gel chromatography using a gradient of 0 to 50% etoac/heptane. ES-MS M/z 322 (M+H).
Preparation 122
4-amino-3-methoxy-5- (oxazol-2-ylmethylamino) benzoic acid ethyl ester
Iron powder (0.33 g,5.8 mmol) and NH 4 Cl (0.015 g,0.28 mmol) was suspended in water (4.4 mL) and acetic acid (0.07 mL,1.18 mmol) was added. Stirred at 50 ℃ for 15 min, then a solution of ethyl 3-methoxy-4-nitro-5- (oxazol-2-ylmethylamino) benzoate (0.165 g,0.514 mmol) in DMF (1.45 mL) was added. The mixture was stirred at 50 ℃ for 20 min, cooled to RT, and passed throughThe mixture was filtered and rinsed with EtOAc (100 mL). With saturated NaHCO 3 The organics were washed with solution (100 mL) and dried over MgSO 4 And (5) drying. Filtration and concentration gave the title compound (0.11 g, 74%) as a yellow oil which was used without purification in preparation 169.ES-MS M/z 292 (M+H).
Preparation 123
3- (2-methoxyethoxy) -4-nitro-5- [ [ (2S) -oxetan-2-yl ] -methylamino ] benzoic acid methyl ester
The title compound was prepared as described essentially in preparation 14 using 3-fluoro-5- (2-methoxyethoxy) -4-nitro-benzoic acid methyl ester and [ (2S) -oxetan-2-yl ] methylamine. The title compound was purified by silica gel chromatography using a gradient of 0 to 30% etoac/heptane. ES-MS M/z 341 (M+H).
Preparation 124
4-amino-3- (2-methoxyethoxy) -5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoic acid methyl ester
The title compound was prepared as described essentially for preparation 122 using methyl 3- (2-methoxyethoxy) -4-nitro-5- (oxetan-2-yl-methylamino) benzoate. The product was used for preparation 170 without further purification. ES-MS M/z 311 (M+H).
Preparation 125
4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3- [ (E) -2-ethoxyvinyl ] benzonitrile
4- [ (6-bromo-2-pyridinyl) oxymethyl ] under nitrogen bubbling]To a solution of 3-iodo-benzonitrile (6 g,14.45 mmol) in 1, 4-dioxane (100 mL) was added Cs 2 CO 3 (9.5 g,29 mmol), tetrakis (triphenylphosphine) palladium (0) (835 mg,0.72 mmol) and (E) -1-ethoxyethylene-2-boronic acid pinacol ester (4.2 mL,18.8 mmol). The reaction mixture was heated at 90℃for 1 day under nitrogen, then more tetrakis (triphenylphosphine) palladium (0) (835 mg,0.72 mmol) and (E) -1-ethoxyethylene-2-boronic acid pinacol ester (1 mL,4.48 mmol) were added. The mixture was heated at 90℃for an additional 2 days. The mixture was cooled, water (100 mL) was added and extracted with EtOAc (3X 60 mL). The organics were combined, passed over MgSO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 10% etoac/cyclohexane to give 3.6g (60% yield) of the title compound as a pale yellow solid. ES-MS M/z 359/361 (M+H).
Preparation 126
4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3- (2-oxoethyl) benzonitrile
To 4- [ (6-bromo-2-pyridinyl) oxymethyl]-3- [ (E) -2-ethoxyvinyl]To a solution of benzonitrile (3.6 g,8.5 mmol) in THF (54 mL) was added 4M HCl/1, 4-dioxane (21 mL,85 mmol). The mixture was stirred at RT for 20 hours. The mixture was concentrated, water (50 mL) and 2M aqueous sodium carbonate solution were added to ph=8, then extracted with EtOAc (3×40 mL). The organics were combined, passed over MgSO 4 Dried, filtered and concentrated under reduced pressure to give the title compound (3.9 g, 97%) as a pale orange solid. ES-MS M/z 331/333 (M+H).
Preparation 127
4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3- (2-hydroxyethyl) benzonitrile
To 4- [ (6-bromo-2-pyridinyl) oxymethyl]To a solution of 3- (2-oxoethyl) benzonitrile (3.9 g,8.24 mmol) in MeOH (60 mL) was added sodium borohydride (550 mg,14.53 mmoL) in portions. The mixture was stirred at RT for 1 hour, the solvent was evaporated, DCM (30 mL) and 1M NaOH solution (10 mL) were added and stirred for 10 min. The phases were separated and the aqueous phase was extracted with more DCM (2X 5 mL). The organics were combined, washed with water and saturated aqueous NaCl solution, dried over MgSO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 10 to 40% etoac/cyclohexane to give the title compound (1.71 g, 60%) as a white waxy solid. ES-MS M/z 333/335 (M+H).
Preparation 128
2-bromo-4- (hydroxymethyl) benzonitrile
Lithium borohydride/THF (7.7 mL,15.4mmol,2.0 mol/L) was added to ethyl 3-bromo-4-cyanobenzoate (2 g,7.71 mmol) at 0deg.C under nitrogenIn solution in aqueous THF (20 mL). The mixture was brought to RT and stirred overnight. Most of the THF was removed and citric acid (5% aqueous solution) was carefully added at 0 ℃. The aqueous layer was extracted with EtOAc, the organic layers were combined, washed with water and saturated aqueous NaCl, and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 30 to 100% etoac/cyclohexane to afford the title compound as a white solid (1.56 g,92% purity, 88%). 1 H NMR(400MHz,DMSO)δ7.91(d,J＝7.9Hz,1H),7.80(s,1H),7.51(d,J＝7.5Hz,1H),5.57(t,J＝5.8Hz,1H),4.59(d,J＝5.9Hz,2H).
Preparation 129
2-bromo-4- [ (6-chloro-2-pyridinyl) oxymethyl ] benzonitrile
The title compound was prepared as described essentially in preparation 30 using 2-bromo-4- (hydroxymethyl) benzonitrile and 6-chloropyridin-2-ol. The title compound was purified by silica gel chromatography using a gradient of 10 to 30% etoac/cyclohexane. ES-MS M/z 323,325,327 (M+H).
Preparation 130
4- [ (6-chloro-2-pyridinyl) oxymethyl ] -2- (2-hydroxyethyl) benzonitrile
The vial was charged with nickel (II) chloride ethylene glycol dimethyl ether complex (34 mg,0.15 mmol) and 4,4 '-di-tert-butyl-2, 2' -bipyridine (48 mg,0.17 mmol). The vial was purged with nitrogen and anhydrous 1, 2-dimethoxyethane (3 mL) was added. The mixture was stirred for 15 minutes.
Fill another vial with Na 2 CO 3 (335 mg,3.13 mmol), 2-bromo-4- [ (6-chloro-2-pyridinyl) oxymethyl)]Benzonitrile (502 mg,1.55 mmol) and (Ir [ dF (CF) 3 )ppy] 2 (dtbpy))PF 6 (18 mg,0.016 mmol). Blowing with nitrogenThe vial was purged and charged with anhydrous 1, 2-dimethoxyethane (12 mL), 2-bromoethanol (1.1 mL,15 mmol), tris (trimethylsilyl) monosilane (740. Mu.L, 2.33 mmol) and Ni catalyst prepared beforehand. The mixture was bubbled with nitrogen for 5 minutes and then heated in EvoluChem TM The photooxidation reduction box was irradiated overnight with fan Kessil LED light 456 nm. The solid was filtered off, washed with DCM and the filtrate concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 10% etoac/DCM as an elution system to afford the title compound (190 mg, 42%) as a yellow waxy solid. ES-MS M/z 289,291 (M+H).
Preparation 131
2-bromo-6- [ (4-fluoro-2-iodo-phenyl) methoxy ] pyridine
To a mixture of (4-fluoro-2-iodo-phenyl) methanol (2.0 g,7.9 mmol), 2-bromo-6-fluoro-pyridine (1.4 g,7.9 mmol) and 1, 4-dioxane (25 mL) was added potassium tert-butoxide (1.20 g,10.0 mmol). The reaction mixture was stirred at 60℃for 16 hours. The reaction was diluted with EtOAc (100 mL) and passed through And (5) filtering. The filtrate was washed with water (2X 50 mL) and saturated aqueous sodium chloride (50 mL). The organic phase was taken up in Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 5 to 50% dcm/hexane to give 2.16g of the title compound (67%). ES-MS M/z 408 and 410 (M+H).
Preparation 132
3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-fluoro-phenyl ] propoxy-tert-butyl-dimethyl-silane
The title compound was prepared as described essentially in preparation 28 using 2-bromo-6- [ (4-fluoro-2-iodo-phenyl) methoxy ] pyridine. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 0 to 10% etoac/hexanes to give an oil that was not ionized by ES-MS, which was used directly without further identification for preparation 133.
Preparation 133
3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-fluoro-phenyl ] propan-1-ol
The title compound was prepared as described essentially for preparation 29 using 3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-fluoro-phenyl ] propoxy-tert-butyl-dimethyl-monosilane (preparation 132). ES-MS M/z 340 and 342 (M+H).
Preparation 134
2- [3- [ tert-butyl (dimethyl) silyl ] oxypropyl ] -6- (trifluoromethyl) pyridine-3-carboxylic acid methyl ester
The title compound was prepared as described essentially in preparation 28 using methyl 2-bromo-6- (trifluoromethyl) pyridine-3-carboxylate. The title compound was purified by silica gel chromatography using a gradient of 0 to 10% etoac/DCM. ES-MS M/z 378 (M+H).
Preparation 135
[2- [3- [ tert-butyl (dimethyl) silyl ] oxypropyl ] -6- (trifluoromethyl) -3-pyridinyl ] methanol
2- [3- [ tert-butyl (dimethyl) silyl ] in an ice/salt bath]Oxypropyl radical]A mixture of methyl-6- (trifluoromethyl) pyridine-3-carboxylate (2.0 g,5.3 mmol) and THF (40 mL) was cooled to-10deg.C. Adding lithium aluminum hydride to the mixture(0.20 g,5.3 mmol) and stirred under cooling for 1 hour. The reaction was quenched by the dropwise addition of water (1 mL) and then diluted with EtOAc (50 mL). By passing throughThe resulting mixture was filtered and rinsed with EtOAc (100 mL). The filtrate was washed with water (100 mL) and saturated aqueous NaCl solution (100 mL), then with Na 2 SO 4 And (5) drying. Filtered and concentrated to give the title compound as a tan oil (1.66 g, 84%) which was used without further purification for preparation 136.ES-MS M/z 350 (M+H).
Preparation 136
3- [3- [ (6-bromo-2-pyridinyl) oxymethyl ] -6- (trifluoromethyl) -2-pyridinyl ] propoxy-tert-butyl-dimethyl-monosilane
The title compound was prepared as described essentially for preparation 51 using [2- [3- [ tert-butyl (dimethyl) silyl ] oxypropyl ] -6- (trifluoromethyl) -3-pyridinyl ] methanol and 2-bromo-6-fluoro-pyridine and stirring at 60 ℃ for 16 hours. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 5 to 50% dcm/hexane. ES-MS M/z 506 and 508 (M+H).
Preparation 137
3- [3- [ (6-bromo-2-pyridinyl) oxymethyl ] -6- (trifluoromethyl) -2-pyridinyl ] propan-1-ol
The title compound was prepared as described essentially in preparation 29 using 3- [3- [ (6-bromo-2-pyridinyl) oxymethyl ] -6- (trifluoromethyl) -2-pyridinyl ] propoxy-tert-butyl-dimethyl-monosilane. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 5 to 50% etoac/hexanes. ES-MS M/z 390 and 392 (M+H).
Preparation138
(3-iodo-4-pyridinyl) methanol
A mixture of methyl 3-iodopyridine-4-carboxylate (5.0 g,19 mmol) in THF (40 mL) and MeOH (10 mL) was cooled to-10deg.C using an ice/salt bath, then sodium borohydride (1.52 g,40.2 mmol) was added and stirred under cooling for 1 hour. The reaction was quenched by the dropwise addition of water (1 mL) and then diluted with EtOAc (50 mL). By passing throughThe resulting mixture was filtered and rinsed with EtOAc (100 mL). The filtrate was washed with water (100 mL) and saturated aqueous NaCl solution (100 mL), then with Na 2 SO 4 And (5) drying. The residue was purified by silica gel chromatography using a gradient of 5 to 50% (1:4 meoh: etoac)/DCM to give the title compound (1.63 g, 36%) as a tan solid. ES-MS M/z 236 (M+H).
Preparation 139
2-bromo-6- [ (3-iodo-4-pyridinyl) methoxy ] pyridine
The title compound was prepared as described essentially for preparation 51 using (3-iodo-4-pyridinyl) methanol and 2-bromo-6-fluoro-pyridine with stirring at 60 ℃ for 16 hours. The title compound was purified by silica gel chromatography using a gradient of 5 to 50% etoac/DCM. ES-MS M/z 390 and 392 (M+H).
Preparation 140
3- [4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3-pyridinyl ] propoxy-tert-butyl-dimethyl-monosilane
/>
The title compound was prepared as described essentially in preparation 28 using 2-bromo-6- [ (3-iodo-4-pyridinyl) methoxy ] pyridine. Purification of the title compound by silica gel chromatography using a gradient of 0 to 80% etoac/hexanes was not further characterized for preparation 141.
Preparation 141
3- [4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3-pyridinyl ] propan-1-ol
The title compound was prepared as described essentially for preparation 29 using 3- [4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3-pyridinyl ] propoxy-tert-butyl-dimethyl-monosilane (preparation 140). The title compound was purified by chromatography on silica gel eluting with a gradient of 5 to 75% (1:4 meoh: etoac)/DCM. ES-MS M/z 322 and 324 (M+H).
Preparation 142
2- [ 4-bromo-2- [2- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-cyano-phenyl ] ethoxymethyl ] phenyl ] acetic acid methyl ester
To 4- [ (6-bromo-2-pyridinyl) oxymethyl at 4 ℃]To a solution of 3- (2-hydroxyethyl) benzonitrile (1 g,2.85 mmol) and methyl 4-bromo-2- (bromomethyl) phenylacetate (1.65 g,4.10 mmol) in DCM (15 mL) was added 2, 6-di-tert-butylpyridine (0.93 mL,4.24 mmol) and silver triflate (1.10 g,4.24 mmol). The mixture was stirred at low temperature for 1 hour and then at RT. After 5 hours, more silver triflate (220 mg,0.85 mmol) was added. After 20 hours, by The reaction mixture was filtered and washed with DCM. The filtrate was evaporated and purified by silica gel chromatography using a gradient of 10 to 100% dcm/cyclohexane to give the title compound as a white solid (570 mg,75% purity, 26% yield)。ES-MS m/z573/575/577(M+H).
Preparation 143
2- [2- [2- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-cyano-phenyl ] ethoxymethyl ] -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid methyl ester
To 2- [ 4-bromo-2- [2- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] under nitrogen]-5-cyano-phenyl]Ethoxymethyl group]Phenyl group]To a solution of methyl acetate (630 mg,0.83mmol,75% purity) in anhydrous 1, 4-dioxane (8.2 mL) was added bis (pinacolato) diboron (260 mg,1 mmol) and KOAc (202 mg,2.01 mmol). After 5 minutes, pd (dppf) Cl was added 2 DCM complex (40 mg,0.048 mmol) and heating the reaction mixture at 80 ℃. After 3 hours, the reaction mixture was cooled to RT, then water (10 mL) and EtOAc (10 mL) were added. The layers were separated and the aqueous phase extracted with EtOAc (2X 5 mL). The organics were combined, washed with water and saturated aqueous NaCl solution, dried over MgSO 4 Dried, filtered and concentrated under reduced pressure to give the title compound as a brown oil (850 mg,60% purity) which was used for preparation 150 without further purification. ES-MS M/z 621/623 (M+H).
Preparation 144
2- [ 4-bromo-2- [2- [5- [ (6-chloro-2-pyridinyl) oxymethyl ] -2-cyano-phenyl ] ethoxymethyl ] phenyl ] acetic acid methyl ester
The use of 4- [ (6-chloro-2-pyridinyl) oxymethyl ] as described in preparation 142]-2- (2-hydroxyethyl) benzonitrile and adding an activated to the reaction mixtureMolecular sieves to prepare the title compound. By using a gradient of 50% to 100% DCM/cyclohexaneThe title compound was purified by silica gel chromatography. ES-MS M/z 529,531,533 (M+H).
Preparation 145
2- [2- [2- [5- [ (6-chloro-2-pyridinyl) oxymethyl ] -2-cyano-phenyl ] ethoxymethyl ] -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid methyl ester
2- [ 4-bromo-2- [2- [5- [ (6-chloro-2-pyridinyl) oxymethyl ] using essentially as in preparation 143]-2-cyano-phenyl]Ethoxymethyl group]Phenyl group]Methyl acetate prepared the title compound. After the reaction was completed, cooled to RT and saturated NaHCO was added 3 And EtOAc, and passing throughThe mixture was filtered. The aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl solution, dried over anhydrous Na 2 SO 4 Drying, filtering and removing the solvent. The residue was purified by silica gel chromatography using a gradient of 0 to 2% etoac/DCM to afford the title compound as a colorless waxy solid. ES-MS M/z 577 and 579 (M+H).
Preparation 146
2- [2- [3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-fluoro-phenyl ] propoxy ] -5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid methyl ester
The title compound was prepared essentially as described for preparation 54 using 3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-fluoro-phenyl ] propan-1-ol and methyl 2- [ 2-hydroxy-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate and using 40% dead in toluene. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 85 to 100% dcm/hexane. ES-MS M/z 628 and 630 (M+H).
Preparation 147
2- [2- [3- [3- [ (6-bromo-2-pyridinyl) oxymethyl ] -6- (trifluoromethyl) -2-pyridinyl ] propoxy ] -5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid methyl ester
The title compound was prepared as described essentially in preparation 55 using 3- [3- [ (6-bromo-2-pyridinyl) oxymethyl ] -6- (trifluoromethyl) -2-pyridinyl ] propan-1-ol and methyl 2- [ 2-hydroxy-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate in 1, 4-dioxane as solvent. The reaction mixture was stirred at RT for 15 hours, then quenched with MeOH and concentrated under reduced pressure. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 85 to 100% dcm/hexane. ES-MS M/z 678 and 680 (M+H).
Preparation 148
2- [2- [3- [4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3-pyridinyl ] propoxy ] -5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid methyl ester
The title compound was prepared essentially as described in preparation 55 using 3- [4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3-pyridinyl ] propan-1-ol and methyl 2- [ 2-hydroxy-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate in 1, 4-dioxane as solvent and stirring at RT for 15 hours. The reaction was quenched with MeOH and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 85 to 100% dcm/hexane to give the title compound. ES-MS M/z 611 and 613 (M+H).
Preparation 149
2-(5 4 - (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-1 4 -yl) acetic acid methyl ester
/>
Bis (pinacolato) diboron (3.93 g,15.2 mmol) and KOAc (3.04 g,30.4 mmol) are added to 2- (5) 4 -chloro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 Methyl-acetate (4.33 g,10.1 mmol) in 1, 4-dioxane (0.2L). The mixture was sparged with nitrogen for 5 minutes, then [ chloro (2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) was added ](0.25 g,0.31 mmol). The mixture was stirred at 85 ℃ under nitrogen positive pressure for 2.5 hours, then cooled and concentrated under reduced pressure to remove most volatiles. The residue was partitioned between DCM (0.15L) and water (0.15L), the phases separated and the aqueous phase was extracted with DCM (50 mL). By 2M K 2 CO 3 The combined organic phases were washed with aqueous solution (50 mL), then brine (50 mL), then over MgSO 4 Drying and filtering. The filtrate was concentrated to a volume of 30mL, meOH (0.2L) was added, and then concentrated to a volume of 60 mL. The mixture was stirred at ambient temperature for 3 hours, the solid was collected by filtration and washed with MeOH (30 mL). The filter cake was dried under reduced pressure at 50 ℃ for 13 hours to give 4.95g of the title compound (94%) as a grey solid. ES-MS M/z 515 and 516 (M+H).
Preparation 150
2-(5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid methyl ester
The title compound was prepared as described essentially for preparation 68 using methyl 2- [2- [2- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-cyano-phenyl ] ethoxymethyl ] -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate (preparation 143). ES-MS M/z 415 (M+H).
Preparation 151
2-(5 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetic acid ethyl ester
4- [ (6-bromo-2-pyridinyl) oxymethyl was added to a round bottom flask under nitrogen atmosphere]-3- (2-hydroxyethyl) benzonitrile (400 mg,1.20 mmol), triphenylphosphine (473 mg 1.80 mmol) and 2- [ 5-fluoro-2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ]]A solution of ethyl acetate (563 mg,1.44 mmol) in dry THF (10 mL). The mixture was stirred until the solid dissolved and cooled in an ice bath. To the mixture was added a solution of di-tert-butyl azodicarbonate (423 mg,1.80 mmol) in THF (1.6 mL). The ice bath was removed and the reaction was left at RT for 2 hours. THF (26 mL) and aqueous potassium phosphate (1M, 7.2 mL) were added to the reaction and the mixture was stirred for 5 min. Pd (dtbpf) Cl was added to the reaction 2 (80 mg,0.12 mmol) was flushed with nitrogen and the reaction was heated to 80℃for 3 hours. Cool reaction to RT, dilute with EtOAc and add
The mixture was stirred for 10 minutes byThe mixture was pad filtered and washed with EtOAc>And (3) a pad. The filtrate was subjected to MgSO 4 Dried, filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 100% etoac/cyclohexane to give the title product as a white solid (150 mg, 28.9%). ES-MS m/z 433(M+H).
Preparation 152
2-(5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid methyl ester
To 2- [2- [2- [5- [ (6-chloro-2-pyridinyl) oxymethyl ]]-2-cyano-phenyl]Ethoxymethyl group]-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]A mixture of methyl acetate (132 mg,0.20mmol,88 mass%), THF (5 mL) and aqueous tripotassium phosphate (1.0M, 1mL,1.0 mmol) was purged with nitrogen for 5 minutes. XPhos Pd (crotyl) Cl (Pd-170 catalyst, CAS number 1798782-02-1,6mg,0.009 mmol) was added and the mixture stirred at 50℃for 50 minutes. The reaction mixture was cooled to RT and water and EtOAc were added. The aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl solution, dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by silica gel chromatography using DCM to give the title compound (51 mg, 61%) as a white solid. ES-MS M/z 415 (M+H).
Preparation 153
2-(5 4 -fluoro-1 6 -methyl-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid methyl ester
The title compound was prepared using methyl 2- [2- [3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-fluoro-phenyl ] propoxy ] -5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate substantially as described in preparation 66 and stirring the reaction mixture under nitrogen atmosphere at 40 ℃ for 1 hour. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 0 to 20% etoac/DCM. ES-MS M/z 422 (M+H).
Preparation154
2-(1 6 -methyl-5 6 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6), 5 (3, 2) -dipyridyl-1 (1, 3) -phenylheterocyclo-nonatomato-1 4 -yl) acetic acid methyl ester
The title compound was prepared as described essentially for preparation 66 using methyl 2- [2- [3- [3- [ (6-bromo-2-pyridinyl) oxymethyl ] -6- (trifluoromethyl) -2-pyridinyl ] propoxy ] -5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate and stirring at 40 ℃ for 1 hour. The title compound was purified by silica gel chromatography using a gradient of 0 to 20% etoac/DCM. ES-MS M/z 473 (M+H).
Preparation 155
2-(1 6 -methyl-3, 9-dioxa-2 (2, 6), 5 (4, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) acetic acid methyl ester
The title compound was prepared using methyl 2- [2- [3- [4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3-pyridinyl ] propoxy ] -5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate substantially as described in preparation 66 and stirring at 40 ℃ for 1 hour. The title compound was purified by silica gel chromatography using a gradient of 5 to 35% etoac/DCM. ES-MS M/z 405 (M+H).
Preparation 156
2-(5 4 -bromo-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
MeOH (20 mL) and water (5 mL) were added To 2- (5) 4 - (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-1 4 Methyl acetate (4.45 g,8.55 mmol) and copper bromide (5.73 g,25.7 mmol). The mixture was stirred at 80℃for 30 hours. The mixture was cooled to ambient temperature and 30% NH was added 4 The aqueous OH solution was diluted with water to a final volume of about 0.5L. The mixture was stirred for 0.5 hours, the solid was collected by filtration and taken up with 10% NH 4 Aqueous OH (0.1L) and then water (0.1L). THF (0.14L), meOH (70 mL) and 1M aqueous LiOH (35 mL) were added to the wet solid and stirred at 60℃for 3.5 hours. To the mixture was added 1M KH 2 PO 4 Aqueous solution (0.1L) was then diluted with water to a final volume of about 1L. The mixture was allowed to cool naturally for 1 hour with stirring, the solids were collected by filtration and washed with 1:4 water: meOH (0.2L) and water (0.1L). The filter cake was dried under reduced pressure at 50 ℃ for 16 hours to give 3.66g of the title compound (92%) as an off-white solid. ES-MS M/z 454 and 456 (M+H).
Preparation 157
2-(5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
The use of 2- (5) is substantially as described in preparation 78 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl acetate to prepare the title compound. ES-MS M/z401 (M+H).
Preparation 158
2-(5 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetic acid
The use of 2- (5) is substantially as described in preparation 78 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) ethyl acetate to prepare the title compound. ES-MS M/z 418 (M+H).
Preparation 159
2-(5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
The use of 2- (5) is substantially as described in preparation 78 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl acetate to prepare the title compound. ES-MS M/z401 (M+H).
Preparation 160
2-(1 6 -methyl-5 4 - (fluoro) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
The use of 2- (1) is substantially as described in preparation 75 6 -methyl-5 4 - (fluoro) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl acetate) and stirred at 50 ℃ for 1 hour to prepare the title compound. The title compound was used in preparation 168 without purification. ES-MS M/z408 (M+H).
Preparation 161
Methyl 2- (1) 6 -methyl-5 6 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6), 5 (3, 2) -dipyridyl-1 (1, 3) -phenylheterocyclo-nonatomato-1 4 -yl) acetic acid
The use of 2- (1) is substantially as described in preparation 75 6 -methyl-5 6 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6), 5 (3, 2) -dipyridyl-1 (1, 3) -phenylheterocyclo-nonatomato-1 4 -methyl acetate), the title compound was prepared by stirring at 50 ℃ for 1 hour. The title compound was used for preparation 171 without further purification. ES-MS M/z 459 (M+H).
Preparation 162
2-(1 6 -methyl-3, 9-dioxa-2 (2, 6), 5 (4, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) acetic acid
The use of 2- (1) is substantially as described in preparation 75 6 -methyl-3, 9-dioxa-2 (2, 6), 5 (4, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) methyl acetate and stirred at 50 ℃ for 1 hour. The title compound was used in preparation 172 without further purification. ES-MS M/z 391 (M+H).
Preparation 163
(S)-4-(2-(5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetamido) -3-methoxy-5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetic acid and 4-amino-3-methoxy-5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate was stirred for 16 hours to prepare the title compound. The title compound was used in the next step (preparation 173) without purification. ES-MS M/z 653 (M+H).
Preparation 164
(S)-4-(2-(5 4 -bromo-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
DMF (33 mL) and pyridine (6 mL) were added to 2- (5) 4 -bromo-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid (3.10 g,6.69 mmol) and 4-amino-3- [ [ (2S) -oxetan-2-yl]Methylamino group]A mixture of methyl benzoate (prepared essentially as described in WO 2020/263695; 1.75g,7.41 mmol) was stirred for 30 minutes. 2,4, 6-tripropyl-1,3,5,2,4,6-trioxatriphosphohexane-2, 4, 6-trioxide (1.68 mol/L in EtOAc, 10mL,16.8 mmol) was added and the mixture stirred for 50 min. The reaction mixture was diluted with water to a final volume of 0.2L and stirred for 20 minutes. The solid was collected by filtration and washed with water (0.1L). The filter cake was dried under reduced pressure at 50 ℃ for 24 hours to give 4.64g of the title compound (99%) as a pale pink solid. ES-MS M/z 672 and 674 (M+H).
Preparation 165
(S)-4-(2-(5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid and 4-amino-3- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (prepared essentially as described in WO 2020/263695) was used to prepare the title compound. The title compound was used in the next step without purification (preparation 175). ES-MS M/z 619 (M+H).
Preparation 166
(S)-4-(2-(5 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetic acid and 4-amino-3- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (prepared essentially as described in WO 2020/263695) was used to prepare the title compound. The title compound was used in crude form for preparation 176.ES-MS M/z 623 (M+H).
Preparation 167
(S)-4-(2-(5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid and 4-amino-3- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (prepared essentially as described in WO 2020/263695) was used to prepare the title compound. The title compound was used in crude form for preparation 177.ES-MS M/z 619 (M+H).
Preparation 168
(S) -3-methoxy-4- (2- (1) 6 -methyl-5 4 - (fluoro) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -5- ((oxetan-2-ylmethyl) amino)Benzoic acid methyl ester
The use of 2- (1) is substantially as described in preparation 86 6 -methyl-5 4 - (fluoro) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid (preparation 160) and 4-amino-3-methoxy-5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate the title compound was prepared. The title compound was used for preparation 178 without purification. ES-MS M/z 656 (M+H).
Preparation 169
4-(2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3-methoxy-5- ((oxazol-2-ylmethyl) amino) benzoic acid ethyl ester
The use of 2- (5) is substantially as described in preparation 85 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid and ethyl 4-amino-3-methoxy-5- (oxazol-2-ylmethylamino) benzoate (preparation 122) the title compound was prepared. The title compound was used for preparation 179 without purification. ES-MS M/z 674 (M+H).
Preparation 170
(S)-4-(2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- (2-methoxyethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 85 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2)) -diphenyl heterocycles nonatomato-1 4 -yl) acetic acid and 4-amino-3- (2-methoxyethoxy) -5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (preparation 124) the title compound was prepared. The title compound was used for preparation 180 without further purification. ES-MS M/z 693 (M+H).
Preparation 171
(S) -3-methoxy-4- (2- (1) 6 -methyl-5 6 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6), 5 (3, 2) -dipyridyl-1 (1, 3) -phenylheterocyclo-nonatomato-1 4 -yl) acetamido) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The methyl 2- (1) radical is used essentially as described in preparation 86 6 -methyl-5 6 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6), 5 (3, 2) -dipyridyl-1 (1, 3) -phenylheterocyclo-nonatomato-1 4 -yl) acetic acid (preparation 161) and 4-amino-3-methoxy-5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate the title compound was prepared. The title compound was used in preparation 183 without further purification. ES-MS M/z707 (M+H).
Preparation 172
(S) -3-methoxy-4- (2- (1) 6 -methyl-3, 9-dioxa-2 (2, 6), 5 (4, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) acetamido) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (1) is substantially as described in preparation 86 6 -methyl-3, 9-dioxa-2 (2, 6), 5 (4, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) acetic acid (preparation 162) and 4-amino-3-methoxy-5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate the title compound was prepared. The title compound was used in the next step (preparation 184) without further purification. ES-MS M/z 639 (M+H).
Preparation 173
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 102 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetamido) -methyl 3-methoxy-5- ((oxetan-2-ylmethyl) amino) benzoate (from preparation 163) the title compound was prepared and reacted with heating at 65 ℃ for 9 hours. The mixture was cooled to RT and the solvent was evaporated under reduced pressure and ACN was added to aid in the removal of acetic acid. The residue was purified by silica gel chromatography using a gradient of 0 to 40% etoac/DCM followed by 10% meoh/DCM to give the title compound as a pale orange solid. ES-MS M/z 635 (M+H).
Preparation 174
(S)-2-((5 4 -bromo-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 102 4 -bromo-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester and using 1:1 acetic acid: 2-chlorotoluene as solvent to prepare the title compound. The reaction was stirred at 60℃under nitrogen under positive pressure for 32 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM, concentrated onto celite and purified by using 0-50% EtOAc/DCM Is purified by silica gel chromatography to give the title compound as a white solid. ES-MS M/z 654 and 656 (M+H).
Preparation 175
(S)-2-((5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 102 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester in 1:11, 2-dichloroethane:acetic acid as solvent, heating at 50 ℃ for 5 hours to prepare the title compound. The reaction mixture was cooled to RT, the solvent concentrated under reduced pressure and the residue purified by silica gel chromatography using a gradient of 10 to 50% etoac/DCM to give the title compound as a white solid. ES-MS M/z 601 (M+H).
Preparation 176
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 102 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester in 1:11, 2-dichloroethane:acetic acid as solvent, heating to 52 ℃ for 4 hours to prepare the title compound. The reaction was cooled to RT and the solvent was removed under reduced pressure. By using 0 toThe residue was purified by silica gel chromatography with a gradient of 100% etoac/DCM to give the title compound as a yellow solid. ES-MS M/z 605 (M+H).
Preparation 177
(S)-2-((5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 102 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester in 1:11, 2-dichloroethane: acetic acid as solvent, heating at 60 ℃ for 5 hours to prepare the title compound. The reaction mixture was cooled to RT, the solvent concentrated under reduced pressure and the residue purified by silica gel chromatography using a gradient of 25 to 50% etoac/DCM to give the title compound as a white solid. ES-MS M/z 601 (M+H).
Preparation 178
(S) -4-methoxy-2- ((1) 6 -methyl-5 4 - (fluoro) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -3-methoxy-4- (2- (1) as described in preparation 102 6 -methyl-5 4 - (fluoro) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester the title compound was prepared in 1:1 dichloroethane in acetic acid. Purification of the title by silica gel chromatography using a gradient of 80 to 100% dcm/hexaneAnd (3) a compound. ES-MS M/z 638 (M+H).
Preparation 179
2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl) -4-methoxy-1- (oxazol-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid ethyl ester
The use of 4- (2- (5) as described in preparation 101 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3-methoxy-5- ((oxazol-2-ylmethyl) amino) benzoic acid ethyl ester in acetic acid to prepare the title compound. The reaction mixture was concentrated and the title compound was precipitated from heptane, which was used in example 23 without further purification. ES-MS M/z 656 (M+H).
Preparation 180
(S)-2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 101 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- (2-methoxyethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester the title compound was prepared in acetic acid. The title compound was purified by silica gel chromatography using a gradient of 0 to 80% etoac/heptane. ES-MS M/z 675 (M+H).
Preparation 181
(S)-2-((5 4 -formyl-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylheterocyclo-nonatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
A Schlenk tube was charged with bis (acetonitrile) palladium (II) dichloride (11 mg,0.042 mmol) and butyl bis-1-adamantylphosphine (48 mg,0.13 mmol). The tube was purged with nitrogen (3 Xvacuum/nitrogen recycle) and 4-methylmorpholine (3 mL,27.24 mmol) was added. The tube was again purged with nitrogen while stirring (5 Xvacuum/nitrogen cycle). The tube was closed and stirred at ambient temperature for 1 hour. Filling a glass pressure vessel with (S) -2- ((5) 4 -bromo-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (290 mg,0.42 mmol) and 4-methylmorpholine (9 mL,81.73mmol,100 mass%). The lid was closed with a septum and the mixture was bubbled with nitrogen while stirring. After 30 minutes, the catalyst suspension was transferred to a pressure vessel and purged three times with synthesis gas to 80psi, then refilled with synthesis gas to 80psi. The mixture was stirred and heated at 105 ℃ overnight. The reaction mixture was cooled to RT and the solvent was removed. The residue was taken up in DCM (20 mL) and 2M K 2 CO 3 Aqueous solution (20 mL) was partitioned between. The organic layer was separated and the aqueous layer was extracted with DCM (10 mL). The organic layers were combined, washed with saturated aqueous NaCl (10 mL), filtered and concentrated to give 320mg of an orange residue. The residue was purified by silica gel chromatography using a gradient of 0 to 50% etoac/DCM to give the title compound as a white solid (250 mg, 89%). ES-MS M/z 604 (M+H).
Preparation 182
(S)-2-((5 4 -formyl-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylheterocyclo-nonatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
1M LiOH in water (1.25 mL,1.25 mmol) was added to (S) -2- ((5) 4 -formyl-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylheterocyclo-nonatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (0.25 g,0.37mmol,90 mass%) in a stirred suspension of THF (5 mL) and MeOH (2.5 mL). The reaction vessel was sealed and stirred at 60℃for 2 hours. With 1M K 2 HPO 4 The reaction was quenched with aqueous solution (5 mL), diluted with water to a volume of 60mL, and the mixture was stirred at ambient temperature overnight. The reaction pH was adjusted to 4 by addition of 5% aqueous citric acid, diluted with saturated aqueous NaCl (50 mL) and extracted with DCM (50 mL) then with 1:4 isopropanol: DCM (50 mL,25 mL) was extracted three times. The organic extracts were combined and concentrated under reduced pressure at 50 ℃. The residue was dissolved in 1:1 DCM: in MeOH, concentrate onto celite, then purify by silica gel chromatography using a gradient of 0 to 20% MeOH/DCM. The appropriate fractions were concentrated under reduced pressure at 50 ℃ to give a white residue, which was then stirred in EtOAc (5 mL) for 0.5 h. The solid was collected by filtration and washed with EtOAc (5 mL). The solid was dried under reduced pressure at 45 ℃ for 21 hours to give the title compound (125 mg, 51%) as a white solid. ES-MS M/z 590 (M+H).
Preparation 183
(S) -4-methoxy-2- ((1) 6 -methyl-5 6 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6), 5 (3, 2) -dipyridyl-1 (1, 3) -phenylheterocyclo-nonatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -3-methoxy-4- (2- (1) as described in preparation 102 6 -methyl-5 6 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6), 5 (3, 2) -dipyridyl-1 (1, 3) -phenylheterocyclo-nonatomato-1 4 -yl) acetamido) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester in 1:1dcm: acetic acid as solventThe title compound was prepared. The title compound was purified by silica gel chromatography using a gradient of 80 to 100% dcm/hexane. ES-MS M/z 689 (M+H).
Preparation 184
(S) -4-methoxy-2- ((1) 6 -methyl-3, 9-dioxa-2 (2, 6), 5 (4, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -3-methoxy-4- (2- (1) as described in preparation 102 6 -methyl-3, 9-dioxa-2 (2, 6), 5 (4, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 Methyl-acetamido) -5- ((oxetan-2-ylmethyl) amino) benzoate (preparation 172) the title compound was prepared in 1:1 dichloroethane:acetic acid as solvent. The title compound was purified by silica gel chromatography using a gradient of 80 to 100% etoac/DCM. ES-MS M/z 621 (M+H).
Preparation 185
5- (3-fluoro-4-nitro-phenyl) -1H-tetrazole
To a solution of 3-fluoro-4-nitro-benzonitrile (470 mg,2.8 mmol) and TMSCN (4.5 mL,33 mmol) in toluene (9 mL) was added tributyltin azide (2 mL,7 mmol) and then heated in a microwave reactor at 150℃for 2 hours. With saturated NaHCO 3 The reaction was quenched with aqueous solution and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of DCM/MeOH/formic acid (9:1:0.1) to give 586mg of the title compound (99%). ES-MS M/z 210 (M+H).
Preparation 186
2- [ [5- (3-fluoro-4-nitro-phenyl) tetrazol-1-yl ] methoxy ] ethyl-trimethyl-monosilane
To a solution of 5- (3-fluoro-4-nitro-phenyl) -1H-tetrazole (860 mg,4.1 mmol) in THF (12 mL) at 0deg.C was added sodium hydride (60%, 180mg,4.5mmol in mineral oil). To the mixture was added 2- (chloromethoxy) ethyl-trimethyl-monosilane (0.79 mL,4.5 mmol) and stirred at RT for 16 h. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. By using heptane: the residue was purified by chromatography on silica gel eluting with EtOAc (8:2) to give 240mg of the title compound (17%). ES-MS M/z 377 (M+H).
Preparation 187
Fumaric acid; [ (2S) -oxetan-2-yl ] methylamines
[ (2S) -oxetan-2-yl ] is reacted under nitrogen at 25 ℃]Methylamine (3.6 wt% in EtOH, 1500g,620 mmol) and fumaric acid (72 g,620 mmol) were mixed for 36 hours. The solid was filtered off and dried under reduced pressure to give the title compound (65 g, 52%) as a white solid. 1 H NMR(400.21MHz,MeOH-d 4 )δ6.72(s,2H),5.02(ddd,J＝14.8,7.0,3.7Hz,1H),4.77-4.70(m,1H),4.61(dt,J＝9.0,6.1Hz,1H),3.27(dd,J＝7.1,13.4Hz,1H),3.16(dd,J＝3.7,13.4Hz,1H),2.87-2.81(m,1H),2.60-2.54(m,1H).
Preparation 188
2-nitro-N- [ [ (2R) -oxetan-2-yl ] methyl ] -5- [1- (2-trimethylsilylethoxymethyl) tetrazol-5-yl ] aniline
Fumaric acid; a solution of [ (2S) -oxetan-2-yl ] methylamine (160 mg,0.79 mmol) and TEA (0.39 mL,2.8 mmol) in N, N-dimethylacetamide (2 mL) was stirred at RT for 1 hour. 2- [ [5- (3-fluoro-4-nitro-phenyl) tetrazol-1-yl ] methoxy ] ethyl-trimethyl-monosilane (240 mg,0.7 mmol) was added and the mixture stirred at 35 ℃ for 16 hours. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. By using heptane: the residue was purified by chromatography on silica gel eluting with EtOAc (1:1) to give 200mg of the title compound (70%). ES-MS M/z 429 (M+Na).
Preparation 189
N2- [ [ (2R) -oxetan-2-yl ] methyl ] -4- [1- (2-trimethylsilylethoxymethyl) tetrazol-5-yl ] benzene-1, 2-diamine
A mixture of iron (100 mg,2 mmol), ammonium chloride (7 mg,0.1 mmol) and acetic acid (30. Mu.L, 0.5 mmol) in water (3 mL) was vigorously stirred at 50 for 15 minutes. 2-nitro-N- [ [ (2R) -oxetan-2-yl in DMF (1 mL)]Methyl group]-5- [1- (2-trimethylsilylethoxymethyl) tetrazol-5-yl]Aniline (100 mg,0.2 mmol) and the mixture was stirred at 50 ℃ for 1 hour. By passing throughThe reaction mixture was filtered through a pad, then quenched with water and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 98mg of the title compound (99%). ES-MS M/z 377 (M+H).
Preparation 190
(S)-2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) -N- (2- ((oxetan-2-ylmethyl) amino) -4- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-tetrazol-5-yl) phenyl) acetamide
To 2- (5) 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid (100 mg,0.25 mmol), N2- [ [ (2R) -oxetan-2-yl]Methyl group]-4- [1- (2-trimethylsilylethoxymethyl) tetrazol-5-yl]To a solution of benzene-1, 2-diamine (98 mg,0.26 mmol) and TEA (104. Mu.L, 0.75 mmol) in DMF (2 mL) was added HATU (142 mg,0.37 mmol). The mixture was stirred at RT for 1 hour. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 190mg of the title compound (99%). LC-MS retention time = 2.17min.
Preparation 191
(S)-1 4 - ((1- (oxetan-2-ylmethyl) -6- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-tetrazol-5-yl) -1H-benzo [ d)]Imidazol-2-yl) methyl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-5 4 -carbonitrile
The use of (S) -2- (5) is essentially as described in preparation 102 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) -N- (2- ((oxetan-2-ylmethyl) amino) -4- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-tetrazol-5-yl) phenyl) acetamide was reacted in 1:11, 2-dichloroethane in acetic acid as solvent with heating at 85 ℃ for 16 hours to prepare the title compound. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 100% etoac/heptane to give the title compound. ES-MS M/z 741 (M+H).
Preparation 192
1-bromo-4- (bromomethyl) -2-fluoro-5-iodo-benzene
N-bromobutanediumImide (26.84 g,150.8 mmol) was added to a solution of 4-bromo-5-fluoro-2-iodotoluene (25 g,75.4 mmol) in chloroform (30 mL); 2,2' -azobis (2-methylpropanenitrile) (1.26 g,7.54 mmol) was then added and reacted at 85℃for 5 hours with heating. Cooling to room temperature, adding saturated NaHCO 3 The solution (300 mL) was extracted with DCM (200 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using heptane as eluent to give 16.04g (54% yield) of the title compound. 1 H NMR(400.13MHz,CDCl 3 )δ8.05(d,J＝6.8Hz,1H),7.29(d,J＝9.00,1H),4.51(s,2H).
Preparation 193
2- (4-bromo-5-fluoro-2-iodo-phenyl) acetonitrile
To a solution of 1-bromo-4- (bromomethyl) -2-fluoro-5-iodo-benzene (16.04 g,40.74 mmol) and TMSCN (7.24 mL,53 mmol) in ACN (110 mL) was slowly added TBAF (1M in THF, 53mL,53 mmol). The reaction was heated at 40℃for 3 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in EtOAc (150 mL) and the organics were washed with saturated aqueous NaCl (3×50 mL). The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 15% etoac/heptane to give the title compound as an orange oil (10.34 g, 69%). ES-MS M/z 340/342 (M+H).
Preparation 194
2- (4-bromo-5-fluoro-2-iodo-phenyl) acetic acid ethyl ester
To a solution of 2- (4-bromo-5-fluoro-2-iodo-phenyl) acetonitrile (10.34 g,30.43 mmol) in 8 MEtOH/water (92 mL) at RT was added sulfuric acid (24 mL). The reaction mixture was heated at 80℃for 18 hours. The mixture was cooled to RT by addition of saturated NaHCO 3 Alkalizing the aqueous solution to pH>7, and extracted with DCM (3X 50 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 10% etoac/heptane to give 8.88g (75%) of the title compound as a white solid. ES-MS M/z 387/389 (M+H).
Preparation 195
2- [ 4-bromo-2- [ 2-ethoxyvinyl ] -5-fluoro-phenyl ] acetic acid ethyl ester
Tetrakis (triphenylphosphine) palladium (0) (1.3 g,1.1 mmol), cs were reacted under nitrogen 2 CO 3 (7.4 g,23 mmol) and 2- (2-ethoxyvinyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (3.3 mL,15 mmol) were added to a solution of ethyl 2- (4-bromo-5-fluoro-2-iodo-phenyl) acetate (4.37 g,11.31 mmol) in 1, 4-dioxane (80 mL). The mixture was heated at 90℃for 5 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 10% etoac/heptane to give 2.51g (67%) of the title compound as a yellow oil. ES-MS M/z 331/333 (M+H).
Preparation 196
2- [ 4-bromo-5-fluoro-2- (2-hydroxyethyl) phenyl ] acetic acid ethyl ester
To 2- [ 4-bromo-2- [ 2-ethoxyvinyl ] at 0 DEG C]-5-fluoro-phenyl]To a solution of ethyl acetate (2.51 g,7.59 mmol) in THF (45 mL) was added mercury acetate (6.3 g,19 mmol) and stirred at 0deg.C for 2 hours. At the same time, sodium borohydride (520 mg,13.75 mmol) was added to K 2 CO 3 (60g) In solution in water (56 mL) and this mixture was added to the previous reaction with the starting material. Stirred reaction 4 at RT For 0 min, then diluted with water (50 mL) and extracted with EtOAc (3X 50 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 25% etoac/heptane to give the title compound as a colorless oil (1.31 g,40% yield). ES-MS M/z 305/307 (M+H).
Preparation 197
4-formyl-3-hydroxy-benzonitrile
To a solution of 4-cyano-2-methoxybenzaldehyde (13 g,79.86 mmol) in DCM (480 mL) was added boron tribromide (100 g,399.16 mmol) in portions at-10 ℃. The reaction was stirred at RT for 3 days, cooled to 0 ℃ and water (21 mL) was slowly added. The reaction was diluted with water (100 mL) and extracted with DCM (3X 100 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 20% etoac/heptane to give 7.61g (65%) of the title compound. ES-MS M/z 148 (M+H).
Preparation 198
4-formyl-3- (2-trimethylsilylethoxymethoxy) benzonitrile
DIPEA (9.5 mL,54 mmol) and 2- (trimethylsilyl) ethoxymethyl chloride (5.3 mL,30 mmol) were added to a solution of 4-formyl-3-hydroxy-benzonitrile (4 g,27.18 mmol) in DCM (68 mL) and diethyl ether (30 mL). The reaction mixture was stirred at RT for 3 hours. With saturated NH 4 The reaction was diluted with aqueous Cl and extracted with DCM (3×50 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 20% etoac/heptane to give the title compound (5.67 g, 75%). ES-MS M/z 278 (M+H).
Preparation 199
4- (hydroxymethyl) -3- (2-trimethylsilylethoxymethoxy) benzonitrile
To a solution of 4-formyl-3- (2-trimethylsilylethoxymethoxy) benzonitrile (5.67 g,20.4 mmol) in THF (30 mL) and MeOH (30 mL) at 0deg.C was added sodium borohydride (1.6 g,42 mmol) in portions. The reaction mixture was stirred for 1 hour, then water (50 mL) was added and extracted with EtOAc (3X 50 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 5.55g (97%) of the title compound. ES-MS M/z 280 (M+H).
Preparation 200
4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3- (2-trimethylsilylethoxymethoxy) benzonitrile
Sodium hydride (60%, in mineral oil, 500mg,12.5 mmol) was added to a solution of 4- (hydroxymethyl) -3- (2-trimethylsilylethoxymethoxy) benzonitrile (2.65 g,9.48 mmol) in THF (60 mL) at RT. The mixture was stirred for 30 minutes, then 2-bromo-6-fluoropyridine (1.7 g,9.5 mmol) was added and reacted at 60℃for 3 hours with heating. The reaction was cooled to ambient temperature, diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 10% etoac/heptane to give 3.18g (77%) of the title compound. 1 H NMR(400.13MHz,CDCl 3 )δ7.57(d,J＝7.6Hz,1H),7.46(m,2H),7.32(d,J＝8Hz,1H),7.11(d,J＝7.2Hz,1H),6.77(d,J＝8Hz,1H),5.44(s,2H),5.31(s,2H)；3.78(t,J＝8.4Hz,2H),0.98(t,J＝8.4Hz,2H).0.02(s,9H).
Preparation 201
4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3-hydroxy-benzonitrile
Carbon tetrabromide (264 mg,1.1 mmol) was added to a solution of 4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3- (2-trimethylsilylethoxymethoxy) benzonitrile (3.18 g,7.31 mmol) in 2-propanol (75 mL). The reaction mixture was heated at 80 ℃ for 10 hours, then the solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 20% etoac/heptane to give the title compound (1.72 g, 57%) as a white solid. ES-MS M/z 305/307 (M+H).
Preparation 202
2- [ 4-bromo-2- [2- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-cyano-phenoxy ] ethyl ] -5-fluoro-phenyl ] acetic acid ethyl ester
To a solution of ethyl 2- [ 4-bromo-5-fluoro-2- (2-hydroxyethyl) phenyl ] acetate (719 mg,1.70 mmol), 4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3-hydroxy-benzonitrile (500 mg,1.64 mmol) and triphenylphosphine (640 mg,2.46 mmol) in THF (17 mL) was added DEAD (40% in toluene, 0.97mL,2.46 mmol) diluted in THF (1 mL) at 0 ℃. The reaction mixture was stirred at RT overnight. After 14 hours, more DEAD (40% in toluene, 0.53mL,1.36 mmol) diluted in THF (1 mL) was added at 0deg.C. After 20 hours at RT, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3X 10 mL). The organics were combined, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 10 to 30% etoac/heptane to give 444mg (44%) of the title compound as a white solid. ES-MS M/z 591/593/595 (M+H).
Preparation 203
2-(5 4 -cyano-1 6 -fluoro-3, 6-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetic acid ethyl ester
In two different batches, nitrogen was bubbled through 2- [ 4-bromo-2- [2- [2- [ (6-bromo-2-pyridinyl) oxymethyl } -]-5-cyano-phenoxy]Ethyl group]-5-fluoro-phenyl]A solution of ethyl acetate (299 mg,0.50 mmol) in 1, 4-dioxane (10 mL) was then added hexamethyl-ditin (0.16 mL,0.76 mmol) and Pd (dppf) Cl 2 DCM complex (100 mg,0.12 mmol). The batch was heated at 100℃for 3 hours. The two batches were cooled to RT and combined. Dilute with water and extract three times with EtOAc. The organics were combined, washed with water and saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 10 to 20% etoac/heptane to give the title compound as a white solid (90 mg, 41%). ES-MS M/z 433 (M+H).
Preparation 204
2-(5 4 -cyano-1 6 -fluoro-3, 6-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetic acid
The use of 2- (5) was essentially as described in preparation 75 4 -cyano-1 6 -fluoro-3, 6-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) ethyl acetate, and heating at 45 ℃ for 3 hours. Formic acid was added to the mixture to ph=5-6, diluted with water and taken up in 3:1 DCM: the isopropanol was extracted three times. The organics were combined, washed with water and saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid. ES-MS M/z 405 (M+H).
Preparation 205
(S)-4-(2-(5 4 -cyano-1 6 -fluoro-3, 6-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
To 2- (5) 4 -cyano-1 6 -fluoro-3, 6-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetic acid (82 mg,0.20 mmol) and 4-amino-3- [ [ (2S) -oxetan-2-yl]Methylamino group]To a solution of methyl benzoate (48 mg,0.20 mmol) in DMF (2 mL) was added DIPEA (0.10 mL,0.58 mmol) and HATU (115 mg,0.30 mmol). After stirring at RT for 24 hours, more DIPEA (0.055 mL,0.31 mmol) and HATU (60 mg,0.15 mmol) were added. After 30 hours, water and EtOAc were added and the mixture was extracted three times with EtOAc. The organics were combined, washed with water and saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (200 mg,>100%) which was used for preparation 206 without further purification. ES-MS M/z 623 (M+H).
Preparation 206
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 6-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
Acetic acid (6 mL) was added to (S) -4- (2- (5) 4 -cyano-1 6 -fluoro-3, 6-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester (preparation 205,200mg,0.32 mmol) and stirring at 65 ℃ for 2 hours. The mixture was cooled to RT, the solvent evaporated under reduced pressure and the solvent purified by silica gel using a gradient of 0 to 20% etoac/DCMThe residue was purified by chromatography to give 92mg (47%) of the title compound. ES-MS M/z 605 (M+H).
Preparation 207
3-amino-5-bromo-pyridine-2-carboxylic acid ethyl ester
Sulfuric acid (52 mL,927 mmol) was slowly added to a solution of 3-amino-5-bromopyridine-2-carboxylic acid (15 g,65.66 mmol) in 8M ethanol/water (197 mL). The reaction was heated at 80℃for 18 hours. The mixture was cooled to RT, then NaOH (2M aqueous) was slowly added until ph=8 and extracted with EtOAc (3×100 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a pale yellow solid (13.93 g, 86%). ES-MS M/z 245/247 (M+H).
Preparation 208
(3-amino-5-bromo-2-pyridinyl) methanol
To a solution of 3-amino-5-bromo-pyridine-2-carboxylic acid ethyl ester (13.93 g,56.84 mmol) in THF (230 mL) and MeOH (23 mL) at 0deg.C was added lithium borohydride (3.75 g,172 mmol) in portions. The reaction was stirred at RT for 1 hour. Addition of NaHCO 3 The solution was saturated and extracted with EtOAc (5X 100 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. ACN was added to the residue and the resulting slurry filtered, the solid washed with ACN, and then the solid dried in vacuo to give 9.87g (81%) of the title compound as an off-white solid. ES-MS M/z 203/205 (M+H).
Preparation 209
(5-bromo-3-iodo-2-pyridinyl) methanol
4-Methylbenzenesulfonic acid hydrate (27.81 g,146.2 mmol) was added to a suspension of (3-amino-5-bromo-2-pyridinyl) methanol (9.87 g,48.63 mmol) in ACN (170 mL). The mixture was stirred for 10 minutes and then cooled to 0 ℃. To the mixture was added sodium nitrite (6.72 g,97.4 mmol) in water (20 mL), followed by potassium iodide (20.48 g,123.4 mmol) in water (20 mL). The reaction was stirred at 0deg.C for 10 min and then at RT for 2 h. Saturated NaHCO was added to the mixture 3 Aqueous solution and extracted with EtOAc (3×100 mL). The organics were combined, washed with 5% aqueous sodium bisulphite, water and saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was triturated with ACN, then filtered and the solid dried in vacuo to give the title compound as a slightly brown solid (10.31 g, 61%). ES-MS M/z 314/316 (M+H).
Preparation 210
[ 5-bromo-3- [3- [ tert-butyl (dimethyl) silyl ] oxyprop-1-ynyl ] -2-pyridinyl ] methanol
Bis (triphenylphosphine) palladium (II) dichloride (2.64 g,3.73 mmol), copper iodide (0.71 g,3.76 mmol) and TEA (31 mL,225 mmol) were added to a solution of (5-bromo-3-iodo-2-pyridinyl) in methanol (11.78 g,37.53 mmol) at RT under nitrogen. Tert-butyldimethyl (2-propynyloxy) silane (10 mL,48 mmol) was added and the reaction was heated at 40℃for 20 hours. The reaction was cooled to RT, water and brine were added, and the mixture was extracted three times with EtOAc. The organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 20% etoac/heptane to give 9.03g (67%) of the title compound as a brown oil. ES-MS M/z 356/358 (M+H).
Preparation 211
5- [3- [ tert-butyl (dimethyl) silyl ] oxyprop-1-ynyl ] -6- (hydroxymethyl) pyridine-3-carbonitrile
Zinc cyanide (2.09 g,17.85 mmol) was added to a solution of [ 5-bromo-3- [3- [ tert-butyl (dimethyl) silyl ] oxyprop- -1-ynyl ] -2-pyridinyl ] methanol (9.03 g,25.26 mmol) in DMF (180 mL) under nitrogen followed by tetrakis (triphenylphosphine) palladium (0) (2.93 g,2.54 mmol). The reaction was heated at 100℃for 2 hours. The mixture was cooled to RT, water and saturated aqueous NaCl solution were added, and the mixture was extracted three times with EtOAc. The organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 25% etoac/heptane to give 4.6g (60%) of the title compound as a brown oil. ES-MS M/z 303 (M+H).
Preparation 212
6- [ (6-bromo-2-pyridinyl) oxymethyl ] -5- [3- [ tert-butyl (dimethyl) silyl ] oxyprop-1-ynyl ] pyridine-3-carbonitrile
The title compound was prepared as described essentially for preparation 34 using 5- [3- [ tert-butyl (dimethyl) silyl ] oxyprop-1-ynyl ] -6- (hydroxymethyl) pyridine-3-carbonitrile. After completion, the reaction was cooled to RT, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 15% etoac/heptane to give the title compound as a pale yellow solid. ES-MS M/z 458/460 (M+H).
Preparation 213
6- [ (6-bromo-2-pyridinyl) oxymethyl ] -5- (3-hydroxy-prop-1-ynyl) pyridine-3-carbonitrile
1M TBAF/THF (16.1 mL,16.1 mmol) was added to 6- [ (6-bromo-2-pyridinyl) oxymethyl)]-5- [3- [ tert-butyl (dimethyl) silyl ]]Oxyprop-1-yneBase group]A solution of pyridine-3-carbonitrile (6.15 g,13.42 mmol) in THF (40 mL). The mixture was stirred at RT for 7 hours. Adding saturated NaHCO 3 The mixture was extracted three times with EtOAc. The organics were combined, washed with water and saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 50% etoac/heptane to give 3.04g (66%) of the title compound as a colorless oil. ES-MS M/z 344/346 (M+H).
Preparation 214
6- [ (6-bromo-2-pyridinyl) oxymethyl ] -5- (3-hydroxypropyl) pyridine-3-carbonitrile
Platinum oxide (0.06 g,0.26 mmol) was added to 6- [ (6-bromo-2-pyridinyl) oxymethyl]A solution of 5- (3-hydroxy-prop-1-ynyl) pyridine-3-carbonitrile (0.65 g,1.88 mmol) in MeOH (18 mL) and two drops of acetic acid. The reaction vessel was charged with hydrogen (15 psi) and the mixture was stirred at RT for 5 hours. By passing throughThe reaction was filtered through a pad, washed with MeOH and EtOAc. The filtrate was evaporated in vacuo and the residue was purified by silica gel chromatography using a gradient of 0 to 30% etoac/heptane to give the title compound (0.33 g, 51%). ES-MS M/z 348/350 (M+H)/(S) >
Preparation 215
2- [ 4-bromo-2- [3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-cyano-3-pyridinyl ] propoxy ] -5-fluoro-phenyl ] acetic acid ethyl ester
The title compound was prepared essentially as described in preparation 60 using 6- [ (6-bromo-2-pyridinyl) oxymethyl ] -5- (3-hydroxypropyl) pyridine-3-carbonitrile (1.01 g,2.9 mmol) followed by a MeOH quench step to afford the title compound as a white solid. ES-MS M/z 606/608 (M+H).
Preparation 216
2-(5 5 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6), 5 (2, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) acetic acid ethyl ester
To 2- [ 4-bromo-2- [3- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] under nitrogen]-5-cyano-3-pyridinyl]Propoxy group]-5-fluoro-phenyl]To a mixture of ethyl acetate (0.75 g,1.23 mmol), cesium fluoride (203 mg,1.33 mmol) and hexamethyl-ditin (321 mg,0.98 mmol) in 1, 4-dioxan (55 mL) was added chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) (XPhos Pd G2,75.2mg,0.094 mmol). The reaction mixture was heated at 100℃for 18 hours. Cool the mixture to RT byThe pad was filtered and washed with EtOAc (2X 100 mL) and MeOH (2X 100 mL). The filtrate was evaporated and the residue was purified by silica gel chromatography using a gradient of 0 to 50% etoac/heptane to give 0.27g (49%) of the title compound as a pale yellow solid. ES-MS M/z 448 (M+H).
Preparation 217
2-(5 5 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6), 5 (2, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) acetic acid
To 2- (5) 5 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6), 5 (2, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 Ethyl acetate (0.12 g,0.27 mmol) in a mixture of ACN (3.2 mL), THF (0.8 mL) and water (0.5 mL) was added 1,3,4,6,7,8-hexahydro-2H-pyrimido [1,2-a ]]Pyrimidine0.075g,0.54 mmol). The suspension was heated at 45℃for 2 hours. The mixture was cooled to RT, formic acid was added until ph=4 and extracted with EtOAc (3×5 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.11 g, 98%) as a white solid. ES-MS M/z 420 (M+H).
Preparation 218
(S)-4-(2-(5 5 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6), 5 (2, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) acetamido) -3-methoxy-5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
To 2- (5) 5 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6), 5 (2, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) acetic acid (0.11 g,0.26 mmol) and 4-amino-3-methoxy-5- [ [ (2S) -oxetan-2-yl]Methylamino group]To a solution of methyl benzoate (0.077 g,0.29 mmol) in DMF (1.3 mL) was added DIPEA (0.13 mL,0.74 mmol) and HATU (0.16 g,0.40 mmol). The reaction was stirred at RT for 16 hours. Adding saturated NaHCO 3 The aqueous solution was extracted with EtOAc (2X 40 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.22 g) as a beige solid which was used in preparation 219 without further purification. ES-MS M/z 668 (M+H).
Preparation 219
(S)-2-((5 5 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6), 5 (2, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 102 5 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6), 5 (2, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) acetamido) -methyl 3-methoxy-5- ((oxetan-2-ylmethyl) amino) benzoate (preparation 218) was reacted with heating at 100 ℃ for 2 hours to prepare the title compound. After completion, the reaction was cooled to RT, ACN was added and evaporated. This operation was repeated three times to ensure removal of acetic acid. The residue was purified by silica gel chromatography using a gradient of 0 to 100% etoac/heptane to give the title compound as a light brown solid. ES-MS M/z 650 (M+H).
Preparation 220
4- [ (6-chloro-2-pyridinyl) oxymethyl ] -3-iodo-benzonitrile
A mixture of 4- (bromomethyl) -3-iodo-benzonitrile (20.0 g,62.1 mmol), 6-chloropyridin-2-ol (8.45 g,65.2 mmol) and silver carbonate (17.1 g,62.0 mmol) in 1, 4-dioxane (400 mL) was stirred at 70℃for 20 hours. More 6-chloropyridin-2-ol (1.61 g,12.4 mmol) and silver carbonate (3.5 g,13 mmol) were added and the mixture stirred at 70℃for 5 hours. The mixture was cooled to RT and filtered through a silica gel plug using DCM as eluent to give the title compound as a pale yellow solid (24.6 g, 107%). ES-MS M/z 371.0/373.0 (M+H).
Preparation 221
4- [ (6-chloro-2-pyridinyl) oxymethyl ] -3-formyl-benzonitrile
To a mixture of 4- [ (6-chloro-2-pyridinyl) oxymethyl ] -3-iodo-benzonitrile (15.0 g,40.5 mmol), 1, 4-diazabicyclo [2.2.2] octane (460 mg,4.06 mmol) and potassium formate (6.90 g,81.2 mmol) in DMF (180 mL) was added tert-butyl isocyanate (5.52 mL,48.6 mmol), methanesulfonic acid (tri-tert-butylphosphino) (2 '-methylamino-1, 1' -biphenyl-2-yl) palladium (II) [ P (t-Bu) 3Pd G4,775mg,1.29mmol ] and tri-tert-butylphosphonium tetrafluoroborate (360 mg,1.22 mmol), and the mixture was heated at 75℃for 23 hours. The mixture was cooled to RT and filtered through a silica gel plug using DMF as eluent. The filtrate was cooled to 0deg.C, 1N HCl (120 mL) was added and stirred at 0deg.C for 15 min. The reaction mixture was diluted with water (200 mL) and stirred at RT for 30 min. The resulting solid was filtered to give the title compound as a pale green solid (5.4 g,77% purity, 37% yield). ES-MS M/z 273.0/275.0 (M+H).
Preparation 222
4- [ (6-chloro-2-pyridinyl) oxymethyl ] -3- (hydroxymethyl) benzonitrile
A solution of 4- [ (6-chloro-2-pyridinyl) oxymethyl ] -3-formyl-benzonitrile (1.0 g,3.67 mmol) in MeOH (20 mL) was cooled to 0deg.C and sodium borohydride (290 mg,7.26 mmol) was added in portions. The mixture was stirred at RT for 30 min and then cooled to 0 ℃. To the mixture was added water (25 mL), then 5% aqueous citric acid to ph=5, then more water (50 mL). The reaction mixture was stirred at RT for 30 min. The resulting solid was filtered to give the title compound (901 mg, 89%) as a white solid. ES-MS M/z 275.0/277.0 (M+H).
Preparation 223
3- (bromomethyl) -4- [ (6-chloro-2-pyridinyl) oxymethyl ] benzonitrile
A solution of 4- [ (6-chloro-2-pyridinyl) oxymethyl ] -3- (hydroxymethyl) benzonitrile (870 mg,3.17 mmol) and triphenylphosphine (932 mg,3.52 mmol) in DCM (20 mL) was cooled to 0deg.C. Carbon tetrabromide (920 mg,2.77 mmol) was added and the reaction mixture stirred at RT for 30 min. The reaction mixture was filtered through a silica gel plug using DCM as eluent to give the compound as a pale brown solid (1.25 g;116% yield). ES-MS M/z 337.0/339.0/341.0 (M+H).
Preparation 224
2- [ 4-bromo-2- [2- [ [2- [ (6-chloro-2-pyridinyl) oxymethyl ] -5-cyano-phenyl ] methoxy ] ethyl ] -5-fluoro-phenyl ] acetic acid ethyl ester
A solution of ethyl 2- [ 4-bromo-5-fluoro-2- (2-hydroxyethyl) phenyl ] acetate (750 mg,2.46 mmol), 3- (bromomethyl) -4- [ (6-chloro-2-pyridinyl) oxymethyl ] benzonitrile (1.24 g,3.67 mmol) and 2, 6-di-tert-butylpyridine (2.3 mL,9.9 mmol) in DCM (13.0 mL) was stirred at RT. Silver triflate (2.60 g,10.0 mmol) was added in portions and the reaction mixture stirred at RT for 2 hours. The mixture was filtered and the solid washed with DCM (50 mL). The filtrate solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 100% etoac/DCM to give the title compound as a yellow solid (480 mg, 34%). ES-MS M/z 561/563 (M+H).
Preparation 225
2- [2- [2- [ [2- [ (6-chloro-2-pyridinyl) oxymethyl ] -5-cyano-phenyl ] methoxy ] ethyl ] -5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid ethyl ester
To a mixture of ethyl 2- [ 4-bromo-2- [2- [ [2- [ (6-chloro-2-pyridinyl) oxymethyl ] -5-cyano-phenyl ] methoxy ] ethyl ] -5-fluoro-phenyl ] acetate (150 mg,0.27 mmol), bis (pinacolato) diboron (60 mg,0.23 mmol) and KOAc (54 mg,0.54 mmol) in 1, 4-dioxane (2.5 mL) was added dichlorobis (tricyclohexylphosphine) palladium (II) (30 mg,0.04 mmol) under nitrogen bubbling and the reaction mixture was stirred at 90℃for 30 min. The reaction mixture was cooled to RT, concentrated under reduced pressure and the residue was purified by filtration through a silica plug using a gradient of 0 to 100% etoac/DCM as eluent to give the title compound as an off-white solid (101 mg, 65%). ES-MS M/z 609/611 (M+H).
Preparation 226
2-(5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid ethyl ester
To a mixture of ethyl 2- [2- [2- [ [2- [ (6-chloro-2-pyridinyl) oxymethyl ] -5-cyano-phenyl ] methoxy ] ethyl ] -5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate (160 mg,0.26 mmol) in THF (9.0 mL) was added tripotassium 1N phosphate/water (1.30 mL,1.30 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (XPhos Pd G2,21mg,0.03 mmol) while nitrogen was bubbled through the mixture and the reaction was stirred at 70 ℃ for 30 min. The reaction mixture was cooled to RT, then MTBE (25 mL) and water (25 mL) were added. The phases were separated and the aqueous phase was extracted with MTBE (3X 20 mL). The organic phases were combined, washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 100% etoac/DCM as eluent to give the title compound (45 mg, 34%) as a white solid. ES-MS M/z 447.0 (M+H).
Preparation 227
2-(5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
Bubbling under nitrogen to 2- (5) 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 Ethyl acetate (91 mg,0.24 mmol) in ACN (2.7 mL), THF (0.90 mL) and water (0.90 mL)1,5, 7-Triazabicyclo [4.4.0 ] is added in portions to the mixture]Dec-5-ene (96 mg,0.67 mmol) was reacted at 45℃with stirring for 1 hour. The reaction mixture was cooled to RT, water (5 mL), 5% aqueous citric acid solution was added to ph=5 and the mixture was stirred at RT for 15 min. The resulting solid was filtered to give the title compound (72 mg, 85%) as a white solid. ES-MS M/z 419.0 (M+H).
Preparation 228
(S)-4-(2-(5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -2-methoxy-5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
To 2- (5) 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 To a solution of acetic acid (70 mg,0.167 mmol) in DMF (2.5 mL) was added 4-amino-3-methoxy-5- [ [ (2S) -oxetan-2-yl)]Methylamino group]Methyl benzoate (50 mg,0.19 mmol), HATU (96 mg,0.25 mmol) and DIPEA (0.1 mL,0.60 mmol). The mixture was stirred at RT for 2 hours, then water (10 mL) and EtOAc (10 mL) were added. The phases were separated and the aqueous phase extracted with EtOAc (3X 10 mL). Combining the organics with 2MNA 2 CO 3 Aqueous, water and saturated aqueous NaCl were washed, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a brown solid (193 mg,48% purity, 83% yield) which was used for preparation 229 without further purification. ES-MS M/z 667.2 (M+H).
Preparation 229
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
(S) -4- (2- (5) 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 A solution of methyl-2-methoxy-5- ((oxetan-2-ylmethyl) amino) benzoate (preparation 228,190mg,0.28 mmol) in 1, 2-dichloroethane (3.0 mL) and acetic acid (1.5 mL) was heated at 60℃for 6 h. The reaction mixture was cooled to RT, the solvent concentrated under reduced pressure and the residue purified by silica gel chromatography using a gradient of 0 to 100% etoac/DCM to give the title compound as a white solid (58 mg, 31%). ES-MS M/z649.2/650.2 (M+H).
Preparation 230
2-bromo-4-chloro-6-fluoro-benzaldehyde
To a solution of 1, 2-dibromo-5-chloro-3-fluorobenzene (50 g,170 mmol) in heptane (130 mL) and THF (210 mL) was added dropwise magnesium chloride (2M solution in THF, 94mL,188 mmol) at-45℃with the internal reaction temperature maintained at-40℃to-45 ℃. Stirred at-40℃for 30 min, then DMF (66 mL,853 mmol) was added dropwise and stirred at-20℃for 1 h. The reaction mixture was warmed to 0 ℃, 1N HCl was added to ph=7, and extracted with EtOAc (3×300 mL). (3X 300 mL) the organics were combined, washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 12% etoac/petroleum ether to give the title compound (22.70 g, 52%) as a yellow solid. ES-MS M/z 238 (M+H).
Preparation 231
(2-bromo-4-chloro-6-fluoro-phenyl) methanol
Sodium borohydride (5.16 g,134 mmol) was added to a solution of 2-bromo-4-chloro-6-fluoro-benzaldehyde (22.70 g,89.88 mmol) in MeOH (240 mL) at 0deg.C. Stirred at RT for 2 hours. Cool to 0 ℃ and add 1N HCl to ph=7, concentrate most of the solvent, and extract the mixture with EtOAc (3×150 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (22.3 g, 88%) as an orange solid. ES-MS M/z 263 (M+Na).
Preparation 232
1-bromo-2- (bromomethyl) -5-chloro-3-fluoro-benzene
/>
To a solution of (2-bromo-4-chloro-6-fluoro-phenyl) methanol (22.3 g,79.2 mmol) in DCM (220 mL) was added dropwise phosphorus tribromide (7.51 mL,79.2 mmol) at 0deg.C. The reaction mixture was allowed to go to RT and stirred for 2 hours. The solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 2% etoac/petroleum ether to give the title compound (26.83 g, 95%) as a colorless oil. 1 H-NMR(400MHz,DMSO-d 6 )δ7.75(t,J＝2Hz,1H),7.63(dd,J＝9.5,2Hz,1H),4.70(d,J＝2Hz,2H).
Preparation 233
2- [ (2-bromo-4-chloro-6-fluoro-phenyl) methoxy ] -6-chloro-pyridine
To a solution of 1-bromo-2- (bromomethyl) -5-chloro-3-fluoro-benzene (34.1 g,107 mmol) and 2-chloro-6-hydroxypyridine (57 g,431 mmol) in ACN (1000 mL) was added silver carbonate (180 g,653 mmol). The reaction mixture was stirred at 40 ℃ for 36 hours. The mixture was cooled to RT, then filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 5% etoac/petroleum ether to give the title compound (22.8 g, 52%) as a white solid. ES-MS M/z 350/352 (M+H).
Preparation 234
2-chloro-6- [ [ 4-chloro-2- [ (E) -2-ethoxyvinyl ] -6-fluoro-phenyl ] methoxy ] pyridine
To a mixture of 2- [ (2-bromo-4-chloro-6-fluoro-phenyl) methoxy ] -6-chloro-pyridine (20.8 g,50.4 mmol) and cesium carbonate (33 g,101 mmol) in 1, 4-dioxane (200 mL) was added 2- [ (E) -2-ethoxyvinyl ] -4, 5-tetramethyl-1, 3, 2-dioxaborolane (11.8 mL,55.4 mmol) under nitrogen followed by tetrakis (triphenylphosphine) palladium (0) (6.13 g,5.0 mmol). The reaction was heated at 90℃for 12 hours, then more 2- [ (E) -2-ethoxyvinyl ] -4, 5-tetramethyl-1, 3, 2-dioxaborolan (5.4 mL,25 mmol) and tetrakis (triphenylphosphine) palladium (0) (3.1 g,2.5 mmol) were added. The mixture was stirred at 90℃for a further 4 hours. The mixture was cooled to RT and concentrated under reduced pressure, then water (150 mL) was added and extracted with EtOAc (3×150 mL). The organics were combined, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 20% dcm/petroleum ether to give the title compound (13.71 g, 70%) as a white solid. ES-MS M/z 342 (M+H).
Preparation 235
2- [ 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl ] -3-fluoro-phenyl ] ethanol
/>
To 2-chloro-6- [ [ 4-chloro-2- [ (E) -2-ethoxyvinyl ] at 0deg.C ]-6-fluoro-phenyl]Methoxy group]To a solution of pyridine (12.7 g,35.3 mmol) in THF (280 mL) and water (280 mL) was added mercury acetate (37.53 g,117.8 mmol) and stirred at 0deg.C for 3 hours. 50% K was added to the mixture at 0deg.C 2 CO 3 Aqueous solution (190 mL) and sodium borohydride (6 g,158.59 mmol) were then stirred at 0deg.C for 3 hours. To the mixture was added water (200 mL) and extracted with EtOAc (3X 500 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. By usingThe residue was purified by silica gel chromatography with a gradient of 0 to 25% etoac/petroleum ether to give the title compound (9.46 g, 78%) as a colorless oil. ES-MS M/z 316 (M+H).
Preparation 236
1-bromo-5- (bromomethyl) -2-fluoro-4-iodobenzene
A solution of 5-bromo-4-fluoro-2-iodotoluene (50.2 g,156 mmol) and N-bromosuccinimide (29.2 g,164 mmol) in ACN (0.8L) was prepared. Is pumped through a photochemical reactor consisting of a coiled PFA reactor tube (1/8 "o.d.,52mL volume) maintained at 40℃and surrounded by four Kessil PR160-370 nm (40W) and four Evoluchem 450nm (30W) lamp arrays at a flow rate of 2mL/min to 3mL/min. After completion, ACN (60 mL) was pumped through the reactor at the same rate. The reactor output was stirred and 20% aqueous sodium bisulfite (0.2L) was added followed by water to a final volume of 2L. The resulting slurry was stirred at ambient temperature for 30 minutes. The solid was collected by filtration and washed with water (0.5L). The filter cake was dissolved in a mixture of EtOAc (0.1L) and heptane (0.4L) and taken up in 50mL portions of water, saturated NaHCO 3 The organic layer was washed with aqueous solution and saturated aqueous NaCl solution, then dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure at 50 ℃ to give 35.19g of the title compound (53%, 93% purity) as a cream-colored solid. 1 H-NMR(400MHz,CDCl 3 )δ7.65(d,J＝6.8Hz,1H),7.60(J＝7.6Hz,1H),4.51(s,2H). 19 F{1H}-NMR(386.5MHz,CDCl3)-105.55(s).
Preparation 237
2- [ [2- [2- [ (5-bromo-4-fluoro-2-iodo-phenyl) methoxy ] ethyl ] -4-chloro-6-fluoro-phenyl ] methoxy ] -6-chloro-pyridine
Silver triflate (8.30 g,32 mmol) was added to 2- [ 5-chloro- ] room2- [ (6-chloro-2-pyridinyl) oxymethyl]-3-fluoro-phenyl]A solution of ethanol (5.5 g,16.0 mmol), 1-bromo-5- (bromomethyl) -2-fluoro-4-iodobenzene (10.85 g,24.80 mmol) and 2, 6-di-tert-butyl-4-methylpyridine (5 g,24 mmol) in DCM (30 mL). The reaction was stirred at RT for 5 hours. By passing throughThe reaction mixture was filtered, diluted with water (100 mL) and extracted with EtOAc (3X 100 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 6% etoac/petroleum ether to give the title compound (8.51 g, 76%) as a colorless oil. ES-MS M/z 628/630 (M+H).
Preparation 238
2- [ 4-bromo-2- [2- [ 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl ] -3-fluoro-phenyl ] ethoxymethyl ] -5-fluoro-phenyl ] acetic acid ethyl ester
To 2- [ [2- [2- [ (5-bromo-4-fluoro-2-iodo-phenyl) methoxy ] under nitrogen ]Ethyl group]-4-chloro-6-fluoro-phenyl]Methoxy group]-6-chloro-pyridine (1.49 g,1.94 mmol) and chloro [ (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) -2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) (Xantphos-Pd-G2, 0.2G,0.2 mmol) to a mixture in THF (7 mL) was added (2-ethoxy-2-oxoethyl)) zinc bromide (0.5M in THF, 8mL,4 mmol). The mixture was heated in a microwave reactor at 65 ℃ for 2 hours. The mixture was cooled to RT and saturated NH was added 4 Aqueous Cl (30 mL) was then diluted with water (30 mL) and extracted with EtOAc (3X 50 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 15% etoac/petroleum ether to give 0.57g (45%) of the title compound as a colorless oil. ES-MS M/z 588/590 (M+H).
Preparation 239
2-(5 4 -chloro-1 6 ,5 6 -difluoro-3, 8-dioxa-2 (2, 6)) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid ethyl ester
To a solution of ethyl 2- [ 4-bromo-2- [2- [ 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl ] -3-fluoro-phenyl ] ethoxymethyl ] -5-fluoro-phenyl ] acetate (1.43 g,2.19 mmol), potassium 2, 2-dimethylpropionate (0.78 g,5.49 mmol) and bis (pinacolato) diboron (0.8 g,3 mmol) in THF (85 mL) was added chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (XPhos Pd g2,176mg,0.21 mmol) under nitrogen. The reaction was heated at 55℃for 4 hours. Tripotassium phosphate (1.42 g,6.57 mmol) in water (6.57 mL) was added to the reaction and heated at 55deg.C for 2 hours. The mixture was cooled to RT, water (30 mL) was added and extracted with EtOAc (3X 100 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 15% etoac/petroleum ether to give the title compound as an off-white solid (308 mg, 27%). ES-MS M/z 474 (M+H).
Preparation 240
2-(5 4 -chloro-1 6 ,5 6 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
The use of 2- (5) as described substantially in preparation 227 4 -chloro-1 6 ,5 6 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) ethyl acetate to prepare the title compound. ES-MS M/z 446 (M+H).
Preparation 241
(S)-4-(2-(5 4 -chloro-1 6 ,5 6 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -group) ethylAmido) -3- (2-methoxyethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
To 2- (5) under nitrogen 4 -chloro-1 6 ,5 6 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 To a solution of acetic acid (245 mg,0.54 mmol) and HATU (356 mg,0.91 mmol) in DMF (5.4 mL) was added 4-amino-3- (2-methoxyethoxy) -5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (242 mg,0.70 mmol) and DIPEA (0.28 mL,1.62 mmol). The mixture was stirred at RT for 2 hours, then water (10 mL) was added and extracted with EtOAc (3×25 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid (594 mg,34% purity) which was used in preparation 242 without further purification. ES-MS M/z 738 (M+H).
Preparation 242
(S)-2-((5 4 -chloro-1 6 ,5 6 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 102 4 -chloro-1 6 ,5 6 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -methyl 3- (2-methoxyethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoate was reacted in 1:11, 2-dichloroethane:acetic acid as solvent with heating at 60 ℃ for 6 hours to prepare the title compound. The reaction mixture was cooled to RT, the solvent evaporated under reduced pressure, etOAc/toluene (1:1) was added to the concentrate to help remove ethyl acetateAnd (3) acid. The residue was purified by silica gel chromatography using a gradient of 0 to 5% meoh/DCM to give the title compound as a pale yellow solid (64% purity). ES-MS M/z 720 (M+H).
Preparation 243
2-bromo-6- (bromomethyl) nicotinoyl nitrile
A solution of 2-bromo-6-methylnicotinonitrile (23 g,113.2 mmol) and N-bromosuccinimide (30.8 g,170 mmol) in ACN (560 mL) was transferred through a photochemical flow reactor (reactor size=15 m,15mL, flow rate=1 mL/min,25 ℃ C.) equipped with 440-460nM,200W lamps. The reaction solvent was evaporated and the residue partitioned between water and DCM. The organic layer was separated, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and the solvent was removed. The residue was dissolved in THF (400 mL) at N 2 Diethyl phosphite (8.63 mL,65.8 mmol) and DIPEA (17.8 mL,99.0 mmol) were added at 0deg.C for 0.5 hours. The reaction mixture was warmed to RT and stirred overnight to give a black solution. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 25% etoac/petroleum ether to afford the title compound (28.45 g, 84%) as a white solid. ES-MS M/z 275,277,279 (M+H).
Preparation 244
2-bromo-6- [ (6-chloro-2-pyridinyl) oxymethyl ] pyridine-3-carbonitrile
Silver carbonate (10.5 g,37.3 mmol) was added to a solution of 2-bromo-6- (bromomethyl) nicotinonitrile (1.84 g,6.33 mmol) and 2-chloro-6-hydroxypyridine (3.35 g,25.3 mmol) in ACN (150 mL) at RT. The mixture was stirred at 60℃for 48 hours. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 23% etoac/petroleum ether to afford the title compound as a white solid (957 mg,91wt% purity, 42%). ES-MS M/z 324,326,328 (M+H).
Preparation 245
6- [ (6-chloro-2-pyridinyl) oxymethyl ] -2- [ (E) -2-ethoxyvinyl ] pyridine-3-carbonitrile
2- [ (E) -2-ethoxyvinyl ] -4, 5-tetramethyl-1, 3, 2-dioxaborolan (13.5 mL,63.4 mmol) and 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride (4.7 g,5.65 mmol) in DCM were added to a mixture of 2-bromo-6- [ (6-chloro-2-pyridinyl) oxymethyl ] pyridine-3-carbonitrile (20.4 g,56.6mmol,91wt% purity) and tripotassium phosphate (24.5 g,113 mmol) in 1, 4-dioxane (200 mL) and water (60 mL). The mixture was purged with nitrogen and stirred at 90 ℃ for 4 hours. The mixture was cooled to RT, diluted with water (250 mL) and extracted with EtOAc (250 ml×4). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and the solvent was removed. The residue was purified by silica gel chromatography using a gradient of 0 to 20% etoac/petroleum ether to afford the title compound (15.7 g,83wt% purity, 73%) as a yellow solid. ES-MS M/z 316,318 (M+H).
Preparation 246
6- [ (6-chloro-2-pyridinyl) oxymethyl ] -2- (2-hydroxyethyl) pyridine-3-carbonitrile
The title compound was prepared as described essentially for preparation 235 using 6- [ (6-chloro-2-pyridinyl) oxymethyl ] -2- [ (E) -2-ethoxyvinyl ] pyridine-3-carbonitrile. After completion of the reaction, the solid was filtered off and washed with EtOAc. The organic layer was separated from the filtrate and the aqueous layer was extracted three times with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 45% etoac/petroleum ether to afford the title compound as a pale yellow solid. ES-MS M/z 290,292 (M+H)
Preparation 247
2- [ 4-bromo-2- [2- [6- [ (6-chloro-2-pyridinyl) oxymethyl ] -3-cyano-2-pyridinyl ] ethoxymethyl ] phenyl ] acetic acid methyl ester
The title compound was prepared as described essentially in preparation 224 using 6- [ (6-chloro-2-pyridinyl) oxymethyl ] -2- (2-hydroxyethyl) pyridine-3-carbonitrile and methyl 2- [ 4-bromo-2- (bromomethyl) phenyl ] acetate and stirring overnight at 40 ℃. After completion of the reaction ACN was removed under reduced pressure, the residue was diluted with water and extracted with EtOAc. The organics were dried over anhydrous sodium sulfate, filtered and concentrated. By means of preparative HPLC [ column: phenomenex Luna C18 250X 50mm,10 μm; mobile phase: the residue was purified 40 to 85% acn/formic acid in water (0.225%) ] to provide the title compound as a pale yellow waxy solid. ES-MS M/z 530,532,534 (M+H).
Preparation 248
2-(5 5 -cyano-3, 8-dioxa-2, 5 (2, 6) -dipyridyl-1 (1, 3) -phenylheterocycle nona-tomato-1 4 -yl) acetic acid methyl ester
The title compound was prepared essentially as described in preparation 216 using 2- [ 4-bromo-2- [2- [6- [ (6-chloro-2-pyridinyl) oxymethyl ] -3-cyano-2-pyridinyl ] ethoxymethyl ] phenyl ] acetic acid methyl ester as starting material and (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) methanesulfonate (XPhos Pd G3) as catalyst, heating to 110 ℃ overnight. After completion of the reaction, the reaction mixture was concentrated, water was added, and extracted three times with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated. By HPLC [ column: welch Xtime C18X 40mm,10 μm; mobile phase: the residue was purified 40 to 80% acn/formic acid in water (0.225%) ] to provide the title compound as a white solid. ES-MS M/z 416 (M+H).
Preparation 249
2-(5 5 -cyano-3, 8-dioxa-2, 5 (2, 6) -dipyridyl-1 (1, 3) -phenylheterocycle nona-tomato-1 4 -yl) acetic acid
The use of 2- (5) is substantially as described in preparation 78 5 -cyano-3, 8-dioxa-2, 5 (2, 6) -dipyridyl-1 (1, 3) -phenylheterocycle nona-tomato-1 4 -yl) methyl acetate to prepare the title compound. At the completion of the reaction, the organic solvent and the aqueous solution of water and citric acid (1M) were removed to bring the pH to 5 to 6. The resulting solid was filtered and washed with water to provide the title compound as a white solid. ES-MS M/z 402 (M+H).
Preparation 250
(S)-4-(2-(5 5 -cyano-3, 8-dioxa-2, 5 (2, 6) -dipyridyl-1 (1, 3) -phenylheterocycle nona-tomato-1 4 -yl) acetamido) -3- (2-methoxyethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 5 -cyano-3, 8-dioxa-2, 5 (2, 6) -dipyridyl-1 (1, 3) -phenylheterocycle nona-tomato-1 4 -yl) acetic acid and 4-amino-3- (2-methoxyethoxy) -5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate was reacted overnight at RT with stirring to prepare the title compound. The reaction mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as an orange waxy solid, 54wt% pure. ES (ES) -MS m/z 694(M+H).
Preparation 251
(S)-2-((5 5 -cyano-3, 8-dioxa-2, 5 (2, 6) -dipyridyl-1 (1, 3) -phenylheterocycle nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 109 5 -cyano-3, 8-dioxa-2, 5 (2, 6) -dipyridyl-1 (1, 3) -phenylheterocycle nona-tomato-1 4 -yl) acetamido) -methyl 3- (2-methoxyethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoate (54 wt% purity) was stirred under nitrogen at 60 ℃ for 6 hours to prepare the title compound. Purification by silica gel chromatography using a gradient of 0 to 6% meoh/DCM afforded the title compound as an orange waxy solid, 63wt% purity. ES-MS M/z 676 (M+H).
Preparation 252
2-chloro-5- (((6-chloropyridin-2-yl) oxy) methyl) benzoic acid methyl ester
To a solution of methyl 5- (bromomethyl) -2-chlorobenzoate (25 g,95 mmol) in 1, 4-dioxane (600 mL) was added 6-chloropyridin-2-ol (14.2 g,110 mmol) and silver carbonate (53.2 g,193 mmol). The mixture was stirred at 60℃for 23 hours. By passing throughThe reaction suspension was filtered and rinsed with EtOAc. The filtrate was concentrated under reduced pressure to give 29.4g of the title compound (99%), which was used for preparation 253 without further purification. ES-MS M/z 312,314 (M+H).
Preparation 253
(2-chloro-5- (((6-chloropyrazine)) and methods of preparing samePyridin-2-yl) oxy) methyl)Phenyl group) Methanol
A solution of methyl 2-chloro-5- (((6-chloropyridin-2-yl) oxy) methyl) benzoate (from preparation 252,22g,71 mmol) in THF (200 mL) was cooled to 0deg.C and then added dropwise(60 wt% in toluene, 30mL,92 mL). The mixture was stirred at 0deg.C for 10 min, then quenched with EtOAc (10 mL). The mixture was stirred at RT for 2 h, then the reaction was diluted with water (200 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (2X 100 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 20.7g of the title compound (100%) which was used in preparation 254 without further purification. ES-MS M/z 284,286 (M+H).
Preparation 254
2- ((3- (bromomethyl) -4-chloro)Benzyl group) Oxy) -6-chloropyridine
A solution of (2-chloro-5- (((6-chloropyridin-2-yl) oxy) methyl) phenyl) methanol (from preparation 253,1.5g,5.3 mmoL) and triphenylphosphine (2.0 g,7.5 mmoL) in DCM (35 mL) was cooled to 0deg.C. Carbon tetrabromide (1.9 g,5.7 mmoL) was added and the reaction mixture was stirred at 0deg.C for 10 minutes, then at RT for 30 minutes. The reaction solution was filtered through a pad of silica gel and rinsed with DCM. The filtrate was concentrated under reduced pressure to give 1.8g of the title compound (100%), which was used for preparation 255 without further purification. ES-MS M/z 345/347/349 (M+H).
Preparation 255
Ethyl 2- (4-bromo-2- (2- ((2-chloro-5- (((6-chloropyridin-2-yl) oxy) methyl) benzyl) oxy) ethyl) -5-fluorophenyl) acetate
/>
The title compound was prepared as described essentially in preparation 224 using 2- ((3- (bromomethyl) -4-chlorobenzyl) oxy) -6-chloropyridine (from preparation 254) and ethyl 2- [ 4-bromo-5-fluoro-2- (2-hydroxyethyl) phenyl ] acetate and stirring at RT for 1 hour 15 minutes. The reaction mixture was filtered and concentrated under reduced pressure, then purified by silica gel chromatography using a gradient of 0 to 20% etoac/hexanes to give the title compound. ES-MS M/z 570/572/574 (M+H).
Preparation 256
Ethyl 2- (2- (2- ((2-chloro-5- (((6-chloropyridin-2-yl) oxy) methyl) benzyl) oxy) ethyl) -5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) acetate
To a mixture of ethyl 2- (4-bromo-2- (2- ((2-chloro-5- (((6-chloropyridin-2-yl) oxy) methyl) benzyl) oxy) ethyl) -5-fluorophenyl) acetate (855 mg,1.5 mmol), bis (pinacolato) diboron (480 mg,1.87 mmol), KOAc (450 mg,4.5 mmol) and dichlorobis (tricyclohexylphosphine) palladium (II) (225 mg,0.30 mmol) was added 1, 4-dioxane (15 mL). The mixture was stirred at 90℃for 5 hours, then Pd (dppf) Cl was added 2 (125 mg,0.17 mmoL) and stirring the mixture at 90℃for 15 hours. The crude mixture was filtered through a pad of silica gel and rinsed with EtOAc. The filtrate was concentrated under reduced pressure to give the title compound, which was used for preparation 257 without further purification. ES-MS M/z 536 (M+H for boric acid).
Preparation 257
2-(5 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid ethyl ester
To a solution of ethyl 2- (2- (2- ((2-chloro-5- (((6-chloropyridin-2-yl) oxy) methyl) benzyl) oxy) ethyl) -5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) acetate (from preparation 256,925mg,1.5 mmol) and XPhos Pd G2 (145 mg,0.18 mmoL) in THF (50 mL) was added a solution of potassium phosphate (1.6G, 7.4 mmoL) in water (5 mL). The reaction mixture was stirred at 60℃for 1.5 hours. With EtOAc (50 mL) and 1:1 water: the crude reaction mixture was diluted with saturated aqueous NaCl (50 mL) and the aqueous layer was extracted with EtOAc (50 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 40% etoac/hexanes to give 140mg of the title compound (20%). ES-MS M/z 456 (M+H).
Preparation 258
2-(5 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
The use of 2- (5) was essentially as described in preparation 75 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -base) ethyl acetate, using 3:3:1acn:1, 4-dioxane:water as solvent and heating at 50 ℃ for 1 hour and 20 minutes to prepare the title compound. The reaction was diluted with water and quenched with 1M aqueous citric acid. The precipitated material was collected by filtration and washed with water to give the title compound. ES-MS M/z 428 (M+H).
Preparation 259
(S)-4-(2-(5 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- (2-methoxyethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid and 4-amino-3- (2-methoxyethoxy) -5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate was stirred at RT for 17 hours to prepare the title compound. The reaction was diluted with EtOAc and water, the organic layer was washed with water, and the aqueous layer was back-extracted twice with EtOAc. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound, which was used for preparation 260 without further purification. ES-MS M/z 720 (M+H).
Preparation 260
(S)-2-((5 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 109 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -methyl 3- (2-methoxyethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoate (from preparation 259) the title compound was prepared. Purification by silica gel chromatography using a gradient of 0 to 100% etoac/hexanes gave the title compound. ES-MS M/z 702 (M+H).
Preparation 261
4- [ (6-bromo-5-fluoro-2-pyridinyl) oxymethyl ] -3-iodo-benzonitrile
Two batches were prepared on the same scale as follows: na is mixed with 2 CO 3 Added to 4- (bromomethyl) -3-iodoA solution of benzonitrile (22.4 g,62.6 mmol) in acetone (340 mL) and water (340 mL). The two batches were stirred overnight at 80 ℃ and then the two batches were combined. The mixture was concentrated to remove acetone, and then the solid was filtered off and washed with water. The solid was dried in vacuo and then stirred in DCM (70 mL) for 30 min. The solid was filtered, washed with DCM and dried in vacuo to give 4- (hydroxymethyl) -3-iodo-benzonitrile (23.6 g, 72%) as a white solid. 1 H-NMR(400MHz,DMSO-d 6 )δ8.28(d,J＝1.6Hz,1H),7.88(dd,J＝8.0,1.6Hz,1H),7.62(d,J＝8.0Hz,1H),5.71(t,J＝5.6Hz,1H),4.44(d,J＝5.2Hz,2H).
To a solution of 4- (hydroxymethyl) -3-iodo-benzonitrile (11.5 g,43.5 mmol), 2-bromo-3, 6-difluoro-pyridine (7.08 g,35.8 mmol) in 1, 4-dioxane (80 mL) was added potassium tert-butoxide (1M in THF, 43mL,43 mmol) under nitrogen at 0 ℃. The reaction was stirred at 0deg.C for 1 hour and then at RT for 7 hours. With saturated NH 4 The reaction was diluted with aqueous Cl (50 mL) then water (100 mL) was added and extracted with EtOAc (250 mL. Times.3). The organic layers were combined, washed with saturated aqueous NaCl (60 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 45% dcm/petroleum ether to give the title compound (14.28 g, 88%) as a white solid. ES-MS M/z 432 (M+H).
Preparation 262
4- [ (6-bromo-5-fluoro-2-pyridinyl) oxymethyl ] -3- [ (E) -2-ethoxyvinyl ] benzonitrile
The use of 4- [ (6-bromo-5-fluoro-2-pyridinyl) oxymethyl ] as substantially described in preparation 245]-3-iodo-benzonitrile as starting material and K 2 CO 3 The title compound was prepared as a base by heating the reaction at 90℃for 1.5 hours. After completion, the reaction mixture was concentrated under reduced pressure, then water was added and extracted three times with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. By using a gradient of 0 to 60% EtOAc/petroleum etherPurification by silica gel chromatography gave the title compound as a white solid. ES-MS M/z 377 (M+H).
Preparation 263
4- [ (6-bromo-5-fluoro-2-pyridinyl) oxymethyl ] -3- (2-oxoethyl) benzonitrile
The title compound was prepared as described essentially for preparation 126 using 4- [ (6-bromo-5-fluoro-2-pyridinyl) oxymethyl ] -3- [ (E) -2-ethoxyvinyl ] benzonitrile and stirring at RT for 20 h. After completion, the reaction was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a pale yellow solid which was used in preparation 264 without further purification. ES-MS M/z 349,351 (M+H).
Preparation 264
4- [ (6-bromo-5-fluoro-2-pyridinyl) oxymethyl ] -3- (2-hydroxyethyl) benzonitrile
To 4- [ (6-bromo-5-fluoro-2-pyridinyl) oxymethyl at 0 ℃C]To a solution of 3- (2-oxoethyl) benzonitrile (from preparation 263,8.54g,22.0 mmol) in MeOH (80 mL) was added sodium borohydride (3.59 g,93.9 mmol) and the reaction stirred at RT for 4 hours. With saturated NH 4 The reaction was quenched with aqueous Cl and stirred at RT for 20 min. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (50 mL) and extracted with EtOAc (200 mL. Times.3). The organic layers were combined, washed with saturated aqueous NaCl (60 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 30% etoac/petroleum ether to give the title compound (7.1 g, 87%) as a yellow oil. ES-MS M/z 351/353 (M+H).
Preparation 265
Methyl 2- (4-bromo-2- ((2- (((6-bromo-5-fluoropyridin-2-yl) oxy) methyl) -5-cyanophenethyl) phenyl) acetate
The title compound was prepared essentially as described in preparation 224 using 4- [ (6-bromo-5-fluoro-2-pyridinyl) oxymethyl ] -3- (2-hydroxyethyl) benzonitrile and methyl 2- [ 4-bromo-2- (bromomethyl) phenyl ] acetate as starting materials, using 2, 6-di-tert-butyl-4-methylpyridine instead of 2, 6-di-tert-butylpyridine and stirring overnight at RT. After completion, the reaction mixture was concentrated, then water was added and extracted three times with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography using a gradient of 0 to 100% dcm/petroleum ether afforded the title compound as a pale yellow oil. ES-MS M/z 592 (M+H).
Preparation 266
2-(5 4 -cyano-2 3 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid methyl ester
The title compound was prepared essentially as described in preparation 216 using methyl 2- (4-bromo-2- ((2- (((6-bromo-5-fluoropyridin-2-yl) oxy) methyl) -5-cyanophenethyl) phenyl) acetate as starting material, using (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) methanesulfonate (XPhos Pd G3) as catalyst and protecting the reaction mixture from light during heating. After completion, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0 to 33% etoac/petroleum ether afforded the title compound as a brown solid. ES-MS M/z 433 (M+H).
Preparation 267
2-(5 4 -cyano-2 3 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
The use of 2- (5) is substantially as described in preparation 78 4 -cyano-2 3 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl acetate to prepare the title compound. After completion, the reaction was quenched with 1M aqueous citric acid to ph=4.5. The broken solid was filtered, washed with water, collected and dried under reduced pressure to give the title compound as a white solid, which was used in preparation 268 without further purification. ES-MS M/z 419 (M+H).
Preparation 268
(S)-4-(2-(5 4 -cyano-2 3 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- (2-methoxyethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-2 3 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid (preparation 267) and 4-amino-3- (2-methoxyethoxy) -5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate was reacted overnight at RT with stirring to prepare the title compound. After completion, the reaction was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a pale brown oil, which was not passed throughFurther purification was used to prepare 269.ES-MS M/z 711 (M+H).
Preparation 269
(S)-2-((5 4 -cyano-2 3 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 102 4 -cyano-2 3 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -methyl 3- (2-methoxyethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoate (preparation 268) and 1:11, 2-dichloroethane: acetic acid, were reacted with heating at 55 ℃ for 5 hours to prepare the title compound. After completion of the reaction, the solvent was removed under reduced pressure, and then 1:1etoac was added to the residue: toluene and concentrated in vacuo. Purification by silica gel chromatography using a gradient of 0 to 6% meoh/DCM afforded the title compound as an orange oil. ES-MS M/z 693 (M+H).
Preparation 270
2- (5-cyano-2-methyl-phenyl) -2, 2-difluoro-acetic acid methyl ester
3-iodo-4-methylbenzonitrile (5 g,19.96 mmol) and copper (12 g,179.4 mmol) were stirred in THF (30 mL) and DMSO (80 mL). To the slurry was added methyl bromodifluoroacetate (6 mL,51.9 mmol) and the mixture was stirred under nitrogen at 30℃for 18 hours. Thereafter 100mL of saturated NaHCO was added 3 The aqueous solution was then added 100mL of EtOAc. The mixture was filtered and the solid was washed with EtOAc (3×50 mL). The filtrate is then separated and purified with saturated NH 4 The organic layer was washed with aqueous Cl. Drying the organic material with magnesium sulfate, filtering and concentratingAnd (5) shrinking. The residue was purified by silica gel chromatography (0-25% etoac/hexanes) to give the product as a clear crystalline solid (3.3 g, 73%). 1 H NMR(DMSO-d 6 )δ2.41(s,3H),3.33(s,3H),7.61(d,J＝8.0Hz,1H),7.99(d,J＝7.9Hz,1H),8.04(d,J＝1.2Hz,1H).
Preparation 271
2- [2- (bromomethyl) -5-cyano-phenyl ] -2, 2-difluoro-acetic acid methyl ester
2- (5-cyano-2-methyl-phenyl) -2, 2-difluoro-acetic acid methyl ester (4.4 g,20 mmol) and N-bromosuccinimide (4 g,22.47 mmol) were dissolved in ACN (100 mL). This solution was placed under 4100K white light bulb twice by flowing conditions (1.0 mL/min;72 feet of 1/8' outside diameter reaction tube wrapped around a beaker; maintained at 30 ℃). After this treatment, the reaction was concentrated to dryness and the residue was purified by silica gel chromatography (0-10% etoac/hexanes) to give the product as a clear viscous oil (3.7 g, 62%). 1 H NMR(DMSO-d 6 )δ3.41(s,3H),3.89(s,2H),7.61(d,J＝7.9Hz,1H),7.99(d,J＝8.0Hz,1H),8.03(s,1H).
Preparation 272
2- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-cyano-phenyl ] -2, 2-difluoro-acetic acid
2- [2- (bromomethyl) -5-cyano-phenyl]-methyl 2, 2-difluoro-acetate (6.2 g,20 mmol) and 2-bromo-6-hydroxypyridine (4.5 g,25 mmol) were dissolved in DMSO (50 mL). Tripotassium phosphate (6.6 g,30 mmol) was added to the solution and heated to 60℃for 2 hours. Thereafter, the reaction was quenched with 1N HCl (to pH 6) and extracted with EtOAc. The combined organics were dried over magnesium sulfate, filtered and concentrated to give the product as a viscous brown oil (7.8 g, 100%). ES-MS m/z 79 Br/ 81 Br)382.8/384.8[M+H] + .
Preparation 273
2- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-cyano-phenyl ] -2, 2-difluoro-acetic acid methyl ester
2- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] in MeOH (100 mL)]-5-cyano-phenyl]-2, 2-difluoro-acetic acid (7.8 g,20 mmol). Concentrated sulfuric acid (0.1 mL,2 mmol) was added and heated to reflux for 30 hours. The reaction mixture was concentrated to dryness, and the residue was purified by silica gel chromatography (0-100% etoac/hexanes) to give the product as a white crystalline solid (8 g, 99%). ES-MS m/z 79 Br/ 81 Br)396.8/398.8[M+H] + .
Preparation 274
4- [ (6-bromo-2-pyridinyl) oxymethyl ] -3- (1, 1-difluoro-2-hydroxy-ethyl) benzonitrile
2- [2- [ (6-bromo-2-pyridinyl) oxymethyl]-5-cyano-phenyl]-methyl 2, 2-difluoro-acetate (8 g,20.14 mmol) was dissolved in THF (100 mL). To this solution was added lithium borohydride (0.88 g,40.4 mmol) and stirred under nitrogen at ambient temperature for 2 hours. Thereafter, with saturated NH 4 The reaction was quenched with Cl solution and extracted with EtOAc. The organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% etoac/hexanes) to give the product as a viscous, transparent oil (4.7 g, 63%). ES-MS m/z 79 Br/ 81 Br)368.8/370.8[M+H] + .
Preparation 275
3- [2- [ (5-bromo-2-iodo-phenyl) methoxy ] -1, 1-difluoro-ethyl ] -4- [ (6-bromo-2-pyridinyl) oxymethyl ] benzonitrile
4- [ (6-bromo-2-pyridinyl) oxymethyl]-3- (1, 1-difluoro-2-hydroxy-ethyl) benzonitrile (4.5 g,12 mmol) was dissolved in THF (60 mL) and DMF (10 mL). To this solution was added sodium hydride (0.6 g,15mmol;60% by mass in mineral oil) and stirred under nitrogen at ambient temperature for 5 minutes. 4-bromo-2- (chloromethyl) -1-iodobenzene (4.8 g,14 mmol) was then added and stirring was continued under nitrogen at ambient temperature for 18 hours. Thereafter, with saturated NH 4 The reaction was quenched with aqueous Cl and extracted with EtOAc. The organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% etoac/hexanes) to give the product as a viscous, transparent oil (3.9 g, 48%). ES-MS m/z 79 Br/ 81 Br)663.0/665.0[M+H] + .
Preparation 276
2- [ 4-bromo-2- [ [2- [2- [ (6-bromo-2-pyridinyl) oxymethyl ] -5-cyano-phenyl ] -2, 2-difluoro-ethoxy ] methyl ] phenyl ] acetic acid ethyl ester
3- [2- [ (5-bromo-2-iodo-phenyl) methoxy]-1, 1-difluoro-ethyl group]-4- [ (6-bromo-2-pyridinyl) oxymethyl]Benzonitrile (3.9 g,5.9 mmol) and [ (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) -2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) methanesulfonate (XantPhos Pd G3,0.6G,0.6 mmol) was dissolved in THF (30 mL). To this solution was added (2-ethoxy-2-oxo-ethyl) zinc bromide (0.5M in diethyl ether) (18 ml,9.0 mmol) and the mixture was heated to 60 ℃ under nitrogen for 18 hours. Thereafter, the reaction was cooled to ambient temperature with saturated NaHCO 3 The reaction was quenched with water and extracted with EtOAc. The organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% etoac/hexanes) to give the product as a viscous light brown oil (1.6 g, 44%). ES-MS m/z 79 Br/ 81 Br)623.2/625.2[M+H] + .
Preparation 277
2-(5 4 -cyano-6, 6-difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid ethyl ester
2- [ 4-bromo-2- [ [2- [2- [ (6-bromo-2-pyridinyl) oxymethyl ]]-5-cyano-phenyl]-2, 2-difluoro-ethoxy]Methyl group]Phenyl group]Ethyl acetate (1.6 g,2.9 mmol) was dissolved in 1, 4-dioxane (30 mL). To this solution was added KOAc (0.64 g,6.39 mmol) and bis (pinacolato) diboron (0.8 g,3.09 mmol) and nitrogen was bubbled through for 10 minutes. Thereafter, 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride DCM complex (0.11 g,0.132 mmol) was added and the mixture was heated to 80℃under nitrogen for 18 hours. Thereafter, the reaction was cooled to ambient temperature, diluted with saturated aqueous NaCl and extracted with EtOAc. The organics were dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in 1, 4-dioxane (50 mL) and water (3 mL), tripotassium phosphate (1.4 g,6.5 mmol) was added followed by chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ]Palladium (II) (XPhos Pd G2,0.1G,0.125 mmol). The mixture was heated to 60 ℃ for 2 hours. Thereafter, the reaction was cooled to ambient temperature with saturated NH 4 The reaction was quenched with aqueous Cl and extracted with EtOAc. The organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% etoac/hexanes) to give the product as a white solid (247 mg, 21%). ES-MS (M/z) 465.2 (M+H).
Preparation 278
(S)-2-((5 4 -cyano-6, 6-difluoro-3.8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
Will 2- (5) 4 -cyano-6, 6-difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 Ethyl acetate (249 mg,0.54 mmol) was dissolved in ACN (5 mL), THF (1.8 mL) and water (1.8 mL). 1,5, 7-Triazabicyclo [4.4.0 ] is added to the solution]Dec-5-ene (0.23 g,1.62 mmol) and the mixture was stirred at ambient temperature for 2 hours. Thereafter, with saturated NH 4 The reaction was quenched with aqueous Cl and extracted with EtOAc. The organics were dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in DMF (2 mL) and 4-amino-3- (2-methoxyethoxy) -5- [ [ (2S) -oxetan-2-yl was added ]Methylamino group]Methyl benzoate (0.055 g,0.18 mmol), DMF (0.09 mL,0.5 mmol) and HATU (0.09 g,0.24 mmol) and stirring at ambient temperature for 18 hours. Thereafter, with saturated NH 4 The reaction was quenched with aqueous Cl and extracted with EtOAc. The organics were dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in 1, 2-dichloroethane (1 mL), acetic acid (1 mL) was added and the mixture was heated to 50deg.C for 18 hours. The mixture was concentrated to dryness and the residue was purified by silica gel chromatography (0-100% etoac/hexanes) to give the title compound (61 mg, 52.5%) as an off-white solid. ES-MS (M/z) 711.4 (M+H).
Preparation 279
4- [ (2-Chloropyrimidin-4-yl) oxymethyl ] -3-iodo-benzonitrile
To a solution of 2-chloropyrimidin-4-ol (8.50 g,65.1 mmol) in DMF (150 mL) was added Cs 2 CO 3 (42.5 g,130 mmol) and 4- (bromomethyl) -3-iodo-benzonitrile (21.04 g,65.35 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The crude reaction was poured into water and the precipitate was collected by filtration. The solid material was dissolved in DCM and washed twice with water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (20.3 g, 84%) as a pale orange solid, which was not further purifiedPurification was used to prepare 280.ES/MS M/z 372 (M+H).
Preparation 280
4- [ (2-Chloropyrimidin-4-yl) oxymethyl ] -3- [ (E) -2-ethoxyvinyl ] benzonitrile
To 4- [ (2-chloropyrimidin-4-yl) oxymethyl]To a solution of 3-iodo-benzonitrile (10.1 g,27.2 mmol) in THF (150 mL) was added tripotassium phosphate (40 mL,80mmol,2M aqueous solution), 2- [ (E) -2-ethoxyvinyl]-4, 5-tetramethyl-1, 3, 2-dioxaborolan (7.5 mL,35 mmol) and bis (triphenylphosphine) palladium (II) dichloride (953 mg,1.36 mmol). The solution was sparged with nitrogen for 15 minutes and then stirred at 55 ℃ for 4 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with water to remove pinacol. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 30% etoac/hexanes to give the title compound (5.97 g, 70%). ES/MS m/z 35 Cl/ 37 Cl)315/317[M+H] + .
Preparation 281
4- [ (2-Chloropyrimidin-4-yl) oxymethyl ] -3- (2-hydroxyethyl) benzonitrile
To 4- [ (2-chloropyrimidin-4-yl) oxymethyl]-3- [ (E) -2-ethoxyvinyl]To a solution of benzonitrile (5.75 g,18.2 mmol) in THF (85 mL) was added hydrochloric acid (46 mL,184mmol,4M dioxane solution). Stirred at ambient temperature for 2.5 hours. The reaction was concentrated under reduced pressure and the residue was then diluted with DCM. With saturated NaHCO 3 The mixture was adjusted to ph=8 with aqueous solution and then extracted with DCM. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL), inCooled to 0℃in an ice bath, and then sodium borohydride (1.28 g,33.7 mmol) was gradually added. The mixture was stirred at 0℃for 30 min. The reaction mixture was quenched with 1M aqueous NaOH, then the solution was further diluted with water and DCM and extracted with DCM. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 50% etoac/hexanes to give the title compound (2.86 g, 44%). ES/MS m/z 35 Cl/ 37 Cl)289/291[M+H] + .
Preparation 282
2- [ 4-bromo-2- [2- [2- [ (2-chloropyrimidin-4-yl) oxymethyl ] -5-cyano-phenyl ] ethoxymethyl ] phenyl ] acetic acid methyl ester
4- [ (2-Chloropyrimidin-4-yl) oxymethyl in an ice bath]A solution of 3- (2-hydroxyethyl) benzonitrile (200 mg,0.69 mmol) in anhydrous DCM (4.6 mL) was cooled to 0deg.C and 2- [ 4-bromo-2- (bromomethyl) phenyl was added]Methyl acetate (554 mg,1.73 mmol) followed by 2, 6-di-tert-butylpyridine (0.31 mL,1.38 mmol) and silver triflate (354 mg,1.38 mmol). The mixture was stirred at 0 ℃ for 1 hour and then at ambient temperature for 16 hours. The reaction mixture was filtered through a celite pad and the pad was rinsed with DCM. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 40% etoac/hexanes to give the title compound (128 mg, 35%). ES/MS m/z 79 Br/ 81 Br)529/531[M+H] + .
Preparation 283
2- [2- [2- [2- [ (2-Chloropyrimidin-4-yl) oxymethyl ] -5-cyano-phenyl ] ethoxymethyl ] -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid methyl ester
To 2- [ 4-bromo-2- [2- [2- [ (2-chloropyrimidin-4-yl) oxy)Methyl group]-5-cyano-phenyl]Ethoxymethyl group]Phenyl group]To a solution of methyl acetate (566 mg, 0.015 mmol) in 1, 4-dioxane (7.5 mL) was added bis (pinacolato) diboron (222 mg,0.86 mmol), KOAc (177 mg,1.80 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex (30 mg,0.036 mmol). The solution was sparged with nitrogen for 10 minutes and then heated to 80 ℃. Stirring was carried out for 19 hours. The reaction was cooled to ambient temperature and filtered through a plug of silica gel, which was washed with DCM. The filtrate was concentrated under reduced pressure to give the title compound, which was used for preparation 284 without further purification. ES/MS m/z 35 Cl/ 37 Cl)496/498[M+H] + (as boric acid).
Preparation 284
2-(5 4 -cyano-3, 8-dioxa-2 (2, 4) -pyrimidinyl-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid methyl ester
To a solution of methyl 2- [2- [2- [2- [ (2-chloropyrimidin-4-yl) oxymethyl ] -5-cyano-phenyl ] ethoxymethyl ] -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate (preparation 283,130mg,0.225 mmol) in THF (5.6 mL) was added tripotassium phosphate (0.68 mL,0.68mmol,1m in water). The solution was sparged with nitrogen for 10 minutes, then chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (XPhos Pd G2,8.9mg,0.01 mmol) was added and sparging continued for an additional 5 minutes. The solution was heated at 50℃for 6 hours. The reaction was cooled to ambient temperature, then water was added and extracted with EtOAc. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using a gradient of 0 to 40% EtOAc/hexanes to give the title compound (21 mg, 22%). ES/MS M/z 416 (M+H).
Preparation 285
2-(5 4 -cyano-3, 8-dioxa-2 (2, 4) -pyrimidinyl-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
The use of 2- (5) was essentially as described in preparation 217 4 -cyano-3, 8-dioxa-2 (2, 4) -pyrimidinyl-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl acetate), stirring at ambient temperature for 2 hours. After completion, the reaction was quenched with 5% aqueous citric acid to bring the pH to 4, and then the mixture was diluted with EtOAc. The layers were separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with saturated aqueous NaCl. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was triturated with water to give the title compound. ES/MS M/z402 (M+H).
Preparation 286
(S)-4-(2-(5 4 -cyano-3, 8-dioxa-2 (2, 4) -pyrimidinyl-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3-methoxy-5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 164 4 -cyano-3, 8-dioxa-2 (2, 4) -pyrimidinyl-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid and 4-amino-3-methoxy-5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate was used as starting material, 2,4, 6-tripropyl-1,3,5,2,4,6-trioxatriphosphohexane-2, 4, 6-trioxide in the form of a 50% dmf solution was added and the solution was heated to 42 ℃ for 24 hours to prepare the title compound. The reaction was cooled to ambient temperature and then water was added. The aqueous layer was extracted with EtOAc and then saturated NaHCO 3 The organic was washed with aqueous solution. The organic was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification to prepare 287 (23.6 mg, 83%). ES/MS M/z 650 (M+H).
Preparation 287
(S)-2-((5 4 -cyano-3, 8-dioxa-2 (2, 4) -pyrimidinyl-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 102 4 -cyano-3, 8-dioxa-2 (2, 4) -pyrimidinyl-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3-methoxy-5- ((oxetan-2-ylmethyl) amino) benzoic acid plus ester (preparation 286) and use of 1, 2-dichloroethane: the title compound was prepared by heating a 5:1 mixture of acetic acid as solvent to react to 53 ℃ for 22 hours. After completion, the reaction mixture was cooled to ambient temperature, diluted with DCM and concentrated under reduced pressure. The residue was dissolved in EtOAc and concentrated twice under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 5% meoh/DCM to give the title compound. ES/MS M/z 632 (M+H).
Preparation 288
4- [ (E) -2-ethoxyvinyl ] -6- (trifluoromethyl) pyridine-3-carboxylic acid ethyl ester
To ethyl 4-chloro-6- (trifluoromethyl) nicotinate (15 g,57.4 mmol) and Cs 2 CO 3 (37 g,112.4 mmol) to a solution of 1, 4-dioxane (130 mL) and water (45 mL) was added 2- [ (E) -2-ethoxyvinyl]-4, 5-tetramethyl-1, 3, 2-dioxaborolan (13.4 mL,62.9 mmol) followed by tetrakis (triphenylphosphine) palladium (0) (7 g,5.75 mmol). The solution was sparged with nitrogen and then the mixture was heated to 90 ℃ and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and then diluted with water. The aqueous layer was extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. Elution by gradient with 0 to 23% EtOAc/petroleum etherThe residue was purified by silica gel chromatography to give the title compound (14.5 g, 84%). ES/MS M/z 290 (M+H).
Preparation 289
[4- [ (E) -2-ethoxyvinyl ] -6- (trifluoromethyl) -3-pyridinyl ] methanol
To 4- [ (E) -2-ethoxyvinyl at-78℃under an inert atmosphere]To a solution of ethyl 6- (trifluoromethyl) pyridine-3-carboxylate (14.5 g,48.1 mmol) in THF (100 mL) was added diisobutylaluminum hydride (150 mL,150mmol,1M in toluene). The reaction vessel was removed from the cooling bath and stirred at ambient temperature for 5 hours. The reaction was quenched by the addition of saturated aqueous potassium sodium tartrate (200 mL) at 0deg.C followed by DCM (100 mL). The mixture was extracted with DCM and the combined organic phases were washed with saturated aqueous NaCl. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient elution of 0 to 30% etoac/petroleum ether to give the title compound (11 g, 90%). ES/MS M/z 247 (M) + ).
Preparation 290
5- [ (6-bromo-2-pyridinyl) oxymethyl ] -4- [ (E) -2-ethoxyvinyl ] -2- (trifluoromethyl) pyridine
/>
At 0℃to [4- [ (E) -2-ethoxyvinyl ]]-6- (trifluoromethyl) -3-pyridinyl]To a solution of methanol (10.5 g,40.4 mmol) and 2-bromo-6-fluoropyridine (5.4 mL,51 mmol) in 1, 4-dioxane (100 mL) was added potassium tert-butoxide (52mL,52mmol,1M THF solution). The reaction was stirred at 0deg.C for 30 minutes and then at ambient temperature for 2 hours. With saturated NH 4 The reaction was quenched with aqueous Cl (100 mL) and then extracted with EtOAc. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By silica gel chromatography using a gradient of 0 to 30% etoac/petroleum etherThe residue was purified to give the title compound (17 g, 96%). ES/MS m/z 79 Br/ 81 Br)402/404[M+H] + .
Preparation 291
2- [5- [ (6-bromo-2-pyridinyl) oxymethyl ] -2- (trifluoromethyl) -4-pyridinyl ] ethanol
To 5- [ (6-bromo-2-pyridinyl) oxymethyl at 0 ℃C]-4- [ (E) -2-ethoxyvinyl]To a solution of 2- (trifluoromethyl) pyridine (16.5 g,39.3 mmol) in THF (300 mL) and water (500 mL) was added mercury acetate (14.45 g,44.89 mmol). The mixture was stirred at 0deg.C for 30 min, then 50% K was added 2 CO 3 Aqueous solution (210 mL) and sodium borohydride (6.31 g,165 mmol). The mixture was stirred at 0℃for 2.5 hours. The reaction mixture was filtered and the filter was washed with EtOAc. The filtrate was transferred to a separation funnel and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 25% etoac/petroleum ether to give the title compound (12.1 g, 81%). ES/MS m/z 79 Br/ 81 Br)376/378[M+H] + .
Preparation 292
4- [2- [ (5-bromo-2-chloro-phenyl) methoxy ] ethyl ] -5- [ (6-bromo-2-pyridinyl) oxymethyl ] -2- (trifluoromethyl) pyridine
Silver triflate (12 g,46.24 mmol) was added to a solution of 2- [5- [ (6-bromo-2-pyridinyl) oxymethyl ] -2- (trifluoromethyl) -4-pyridinyl ] ethanol (5.46 g,14.3 mmol), 4-bromo-1-chloro-2- (chloromethyl) benzene (5.19 g,21.4 mmol) and 2, 6-di-tert-butyl-4-methylpyridine (6 g,28.64 mmol) in 1, 2-dichloroethane (100 mL) at ambient temperature under an inert atmosphere. The reaction was heated to 70 ℃ and stirred for 18 hours. The crude reaction was concentrated under reduced pressure and the resulting residue was diluted with water. The combined organic phases were extracted from the aqueous phase with EtOAc and then washed with saturated aqueous NaCl. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient elution of 0 to 20% etoac/petroleum ether to give the title compound (3.3 g, 37%). ES/MS M/z 580 (M+H).
Preparation 293
1 4 -chloro-5 6 - (trifluoromethyl) -3, 8-dioxa-2 (2, 6), 5 (3, 4) -dipyridyl-1 (1, 3) -phenylheterocycle nine-tomato
The title compound was prepared essentially as described in preparation 216 using 4- [2- [ (5-bromo-2-chloro-phenyl) methoxy ] ethyl ] -5- [ (6-bromo-2-pyridinyl) oxymethyl ] -2- (trifluoromethyl) pyridine as starting material and (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) methanesulfonate (XPhos Pd G3) as catalyst and heating at 110 ℃ for 15 hours. The crude reaction was concentrated under reduced pressure and the residue was then diluted with water. The combined organic phases were extracted from the aqueous phase with EtOAc and then washed with saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC chromatography using a gradient of 30-100% acn/formic acid in water to give the title compound (403 mg, 14%) as a white solid. ES/MS M/z 421 (M+H).
Preparation 294
1 4 - (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5 6 - (trifluoromethyl) -3, 8-dioxa-2 (2, 6), 5 (3, 4) -dipyridyl-1 (1, 3) -phenylheterocycle nine-tomato
Direction 1 4 -chloro-5 6 - (trifluoromethyl) -3, 8-dioxa-2 (2, 6), 5 (3, 4) -bipyridineTo a solution of hetero-1 (1, 3) -phenylheterocycloagula (275 mg,0.62 mmol), KOAc (155 mg,1.56 mmol) and bis (pinacolato) diboron (321 mg,1.24 mmol) in 1, 4-dioxan (6.5 mL) was added chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) (XPhos Pd G2,50mg,0.06 mmol). The solution was sparged with nitrogen and then heated to 80 ℃ and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was diluted with water. The combined organic phases were extracted from the aqueous phase with EtOAc and then washed with saturated aqueous NaCl. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient elution of 0 to 30% etoac/petroleum ether to give the title compound (274 mg, 70%). ES/MS M/z 513 (M+H).
Preparation 295
2- (chloromethyl) -7- (2-methoxyethoxy) -3- [ [ (2S) -oxetan-2-yl ] methyl ] benzimidazole-5-carboxylic acid methyl ester
To a solution of methyl 4-amino-3- (2-methoxyethoxy) -5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoate (310 mg,0.93 mmol) in EtOH (6 mL) was added 2-chloro-1, 1-trimethoxyethane (710 mg,4.50 mmol) at ambient temperature. The mixture was heated to 90 ℃ for 2 hours, then the reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient elution of 0 to 5% meoh/DCM to give the title compound (360 mg, 94%). ES/MS M/z 369 (M+H).
Preparation 296
(S) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -2- ((5) 6 - (trifluoromethyl) -3, 8-dioxa-2 (2, 6), 5 (3, 4) -dipyridyl-1 (1, 3) -phenylheterocyclo-nonatomato-1 4 -methyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
Direction 1 4 - (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5 6 - (trifluoromethyl) -3, 8-dioxa-2 (2, 6), 5 (3, 4) -dipyridazin-1 (1, 3) -benzoheterocyclo nine-tomato (160 mg,0.25mmol,81 wt%), 2- (chloromethyl) -7- (2-methoxyethoxy) -3- [ [ (2S) -oxetan-2-yl]Methyl group]To a solution of benzimidazole-5-carboxylic acid methyl ester (256 mg,0.62mmol,89 mass%) and tripotassium phosphate (172 mg,0.79 mmol) in 2-methyltetrahydrofuran (1.6 mL) and water (0.32 mL) was added chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) (XPhos Pd G2,26mg,0.03 mmol). The solution was sparged with nitrogen and then the reaction was heated to 80 ℃ for 18 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was diluted with water. The mixture was extracted with EtOAc, and then the combined organic phases were washed with saturated aqueous NaCl. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient elution of 0 to 60% etoac/petroleum ether to give the title compound (100 mg, 53%). ES/MS M/z 719 (M+H).
Preparation 297
2- (2-Methyloxazol-4-yl) acetic acid ethyl ester
Ethyl 4-chloro-3-oxo-butyrate (40 g, 248 mmol) was added to a solution of acetamide (15 g,254 mmol) in toluene (80 mL) at RT. Heated to 130 ℃ and stirred for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient elution of 10 to 15% etoac/petroleum ether to give the title compound as a yellow oil, 30% purity (19 g, 13%). ES/MS M/z 170 (M+H).
Preparation 298
2- (2-Methyloxazol-4-yl) ethanol
Calcium chloride (26 g,234 mmol) was added to a solution of ethyl 2- (2-methyl oxazol-4-yl) acetate (20 g,35.5 mmol) in EtOH (400 mL). The mixture was stirred for 20 minutes, cooled to 0deg.C, and then sodium borohydride (10 g,265 mmol) was added. The reaction mixture was stirred at RT for 12 hours, then the pH was adjusted to 7 with 1M aqueous HCl. The mixture was extracted with DCM (3×200 mL), and the combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 50 to 100% etoac/petroleum ether followed by a gradient of 0 to 15% meoh/DCM to give the title compound as a yellow oil, 70% purity (5 g, 78%). ES/MS M/z 128 (M+H).
Preparation 299
3-fluoro-5-hydroxy-4-nitro-benzoic acid methyl ester
Boron tribromide (2M in DCM, 65.4mL,131 mmol) was added dropwise to a solution of 3-fluoro-5-methoxy-4-nitro-benzoic acid methyl ester (30 g,131 mmol) in DCM (500 mL) at-40 ℃. The mixture was stirred at-40 ℃ for 30 minutes and then at ambient temperature for 16 hours. The mixture was poured into ice water (2L) and extracted with DCM (3×800 mL). The combined organic layers were washed with saturated aqueous NaCl (2×300 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 30% etoac/petroleum ether to give the title compound (16.5 g, 59%) as a yellow solid. 1 H NMR(CDCl 3 )δ10.31(s,1H),7.63(s,1H),7.41(d,1H,J＝11),3.98(s,3H). 19 F NMR(CDCl 3 )δ-113.37(s).
Preparation 300
3-fluoro-5- [2- (2-methyl-oxazol-4-yl) ethoxy ] -4-nitro-benzoic acid methyl ester
Diisopropyl azodicarboxylate (5.6 g,28 mmol) was added to a solution of methyl 3-fluoro-5-hydroxy-4-nitro-benzoate (3 g,13.9 mmol) and 2- (2-methyl oxazol-4-yl) ethanol (3 g,16.5 mmol) in THF (30 mL) at 0 ℃. The mixture was warmed to ambient temperature and stirred for 12 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (3X 50 mL). The combined organics were washed with saturated aqueous NaCl (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient elution of 0 to 50% etoac/petroleum ether to give the title compound as a pale yellow solid, 17% purity (6 g, 23%). ES/MS M/z 325 (M+H).
Preparation 301
3- [2- (2-Methyloxazol-4-yl) ethoxy ] -4-nitro-5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoic acid methyl ester
(S) -oxetan-2-ylmethylamine (15 g,6.29 mmol) and TEA (1 mL,7.17 mmol) were added to a solution of 3-fluoro-5- [2- (2-methyl-oxazol-4-yl) ethoxy ] -4-nitro-benzoic acid methyl ester (6 g,3.15 mmol) in DMSO (150 mL). The mixture was stirred at 80 ℃ for 12 hours, cooled to ambient temperature, diluted with water (300 mL) and extracted with EtOAc (3×400 mL). The combined organic layers were washed with saturated aqueous NaCl (3×500 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient elution of 0 to 60% etoac/petroleum ether to give the title compound as a yellow oil, 24% purity (2 g, 39%). ES/MS M/z 392 (M+H).
Preparation 302
4-amino-3- [2- (2-methyl oxazol-4-yl) ethoxy ] -5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoic acid methyl ester
Palladium on carbon(1 g,10wt% Pd) was added to 3- [2- (2-methyl-oxazol-4-yl) ethoxy ]]-4-nitro-5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (2 g,1.23 mmol) in EtOAc (150 mL). The reaction vessel was purged with hydrogen and evacuated three times. A balloon of hydrogen was connected to the reaction vessel and stirred for 2 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 100% etoac/petroleum ether and then purified by preparative HPLC [ column: phenomnex C18X 40mm,3 μm; mobile phase: 18 to 48% ACN/NH 4 HCO 3 Aqueous solution (10 mM)]Further purification was performed to give the title compound as a white solid (88 mg, 19%). ES/MS M/z 362 (M+H).
Preparation 303
(S)-4-(2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- (2- (2-methyl oxazol-4-yl) ethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The use of 4-amino-3- [2- (2-methyl oxazol-4-yl) ethoxy substantially as described in preparation 86]-5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (80 mg,0.215 mmol) and 2- (5) 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid, and the product was used for preparation 304 without further purification. ES/MS M/z 744 (M+H).
Preparation 304
(S)-2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2- (2-methyl oxazol-4-yl) ethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 102 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -methyl 3- (2- (2-methyl oxazol-4-yl) ethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoate (preparation 303) and using a 1:1 mixture of 1, 2-dichloroethane: acetic acid to prepare the title compound. After completion, the reaction was cooled to ambient temperature and volatiles were removed in vacuo. 1:1 EtOAc/toluene was added and concentrated three times to remove residual acetic acid. The residue was purified by silica gel chromatography using a gradient elution of 0 to 6% meoh/DCM to give the title compound as an orange solid. ES/MS M/z 726 (M+H).
Preparation 305
N- (2-hydroxyethyl) -N- (2, 2-trifluoroethyl) carbamic acid tert-butyl ester
A mixture of 2-bromoethanol (5 g,38.8 mmol) and 2, 2-trifluoroethylamine (9.66 g,97.0 mmol) in ethanol (50 mL) was heated to 60℃in a sealed tube in a microwave reactor for 3 hours, and the reaction mixture was concentrated. TEA (5.2 mL,3.7g,37 mmol) and di-tert-butyl pyrocarbonate (5.6 mL,5.3g,24 mmol) were added to the residue and taken up in N 2 The mixture was stirred at 55℃overnight. The reaction mixture was partitioned between EtOAc and water, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 38% etoac/petroleum ether to give the title compound (2.5 g, 50%) as a yellow oil. 1 H NMR(400MHz,DMSO)δ4.76(m,1H),4.06(q,J＝9.5Hz,2H),3.67(m,2H),3.30(q,J＝6Hz,2H),1.41(s,9H).
Preparation 306
3- [2- [ tert-Butoxycarbonyl (2, 2-trifluoroethyl) amino ] ethoxy ] -5-fluoro-4-nitro-benzoic acid methyl ester
To a solution of methyl 3-fluoro-5-hydroxy-4-nitro-benzoate (1.5 g,6.6 mmol), tert-butyl N- (2-hydroxyethyl) -N- (2, 2-trifluoroethyl) carbamate (2.1 g,7.8 mmol) and triphenylphosphine (3.5 g,13 mmol) in THF (10 mL) was added DIAD (2.8 mL,13 mmol) at 0deg.C. After the addition, the mixture was stirred at 20 ℃ for 18 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (3X 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient elution of 0 to 20% etoac/petroleum ether afforded the title compound (3.2 g, 93%) as a yellow oil. ES/MS M/z 340.9 (M-Boc+H).
Preparation 307
3- [2- [ tert-Butoxycarbonyl (2, 2-trifluoroethyl) amino ] ethoxy ] -4-nitro-5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoic acid methyl ester
3- [2- [ tert-butoxycarbonyl (2, 2-trifluoroethyl) amino ] ethoxy ] -5-fluoro-4-nitro-benzoic acid methyl ester and fumaric acid are used essentially as described in preparation 301; (S) -oxetan-2-ylmethylamine was reacted in a microwave reactor at 100℃for 3 hours to prepare the title compound. ES/MS M/z 508.1 (M+H).
Preparation 308
4-amino-3- [2- [ tert-Butoxycarbonyl (2, 2-trifluoroethyl) amino ] ethoxy ] -5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoic acid methyl ester
To a solution of methyl 3- [2- [ tert-butoxycarbonyl (2, 2-trifluoroethyl) amino ] ethoxy ] -4-nitro-5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoate (1.1 g,1.8 mmol) in MeOH (10 mL) was added Pd/C (810 mg,10 mass%). The mixture was stirred under hydrogen (15 psi) at ambient temperature for 2 hours. Diatomite was added, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient elution of 0 to 9% meoh/DCM to give the title compound (940 mg, > 99%). ES/MS M/z 478.1 (M+H).
Preparation 309
(S)-4-(2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- [2- [ tert-butoxycarbonyl (2, 2-trifluoroethyl) amino group]Ethoxy group]-5- [ [ (2S) -oxetan-2-yl]Methylamino group]Benzoic acid methyl ester
The use of 2- (5) is substantially as described in preparation 86 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid and 4-amino-3- [2- [ tert-butoxycarbonyl (2, 2-trifluoroethyl) amino group]Ethoxy group]-5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate the title compound was prepared. ES/MS M/z 860.2 (M+H).
Preparation 310
(S) -4- (2- ((tert-Butoxycarbonyl) (2, 2-trifluoroethyl) amino) ethoxy) -2- ((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of (S) -4- (2- (5) as described in preparation 102 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- [2- [ tert-butoxycarbonyl (2, 2-trifluoroethyl) amino group]Ethoxy group]-5- [ [ (2S) -oxetan-2-yl]Methylamino group]A mixture of methyl benzoate and 1:1 DCM: acetic acid as solvent was heated at 55deg.CThe title compound was prepared by reaction for 18 hours. After completion, the reaction was cooled to ambient temperature, diluted with toluene and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a gradient of 0 to 14% meoh/DCM to give the title compound as a brown oil. ES/MS M/z 842.2 (M+H).
Preparation 311
(S) -4- (2- ((tert-Butoxycarbonyl) (2, 2-trifluoroethyl) amino) ethoxy) -2- ((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -4- (2- ((tert-Butoxycarbonyl) (2, 2-trifluoroethyl) amino) ethoxy) -2- ((5) is used essentially as described in example 5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester, 1,5, 7-triazabicyclo [4.4.0]The title compound was prepared by heating the dec-5-ene in a 3:1:1ACN: THF/water mixture at 55deg.C for 2 hours. After completion, the reaction was cooled to ambient temperature and quenched with 1M aqueous formic acid to give a precipitate. The precipitate was filtered and collected to give the title compound which was used in example 54 without further purification. ES/MS M/z 828.2 (M+H).
Preparation 312
2-chloro-6- [ (4-chloro-2-iodo-phenyl) methoxy ] pyridine
A solution of 4-chloro-2-iodo-1-methyl-benzene (40 g,158 mmol) and N-bromosuccinimide (27.3 g,153 mmol) in ACN (500 mL) was prepared. The photochemical reactor consisted of a PFA reaction tube (1/8 "outer diameter) coiled around 4100K white bulb (42W, equivalent to 150W), 53mL volume) at a flow rate of 1.3mL/min, and maintaining the system temperature at 30 to 40 ℃. Once completed, ACN (100 mL) was pumped through the reactor at the same rate. The output was dropped into a solution containing 6-chloropyridin-2-ol (21.8 g,168 mmol) and K 2 CO 3 (44.1 g,319 mmol) in a flask of ACN (400 mL). After complete addition of brominated material, stir at RT for 1 hour. The crude reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using 0 to 10% etoac/hexanes to give 45.8g of the title compound (76%). ES-MS M/z 380 and 382 (M+H).
Preparation 313
2-chloro-6- [ [ 4-chloro-2- [ 2-ethoxyvinyl ] phenyl ] methoxy ] pyridine
At N 2 Downward 2-chloro-6- [ (4-chloro-2-iodo-phenyl) methoxy]To a solution of pyridine (5.0 g,13 mmol) in THF (70 mL) was added aqueous potassium phosphate (2M, 150mL,300 mmol) and 1-ethoxyethylene-2-boronic acid pinacol ester (1/1.3 isomer mixture, 3.81mL,17.1 mmol) and the mixture was stirred for 5 min. Bis (triphenylphosphine) palladium (II) dichloride (470 mg,0.663 mmol) was added and the mixture was heated to 65 ℃ for 21 hours. The mixture was cooled to RT and water (100 mL) and EtOAc (100 mL) were added. The mixture was stirred at RT for 5 min, the organic layer was separated and the aqueous layer was extracted with EtOAc (2×100 mL). The organic layers were combined and washed with water (100 mL), saturated aqueous NaCl solution (100 mL). The organics were concentrated and the residue was purified by filtration through a plug of silica gel using DCM eluent to give the title compound as a brown solid (4.37 g, 100%). ES/MS M/z 324 (M+H).
Preparation 314
2- [ 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl ] phenyl ] ethanal
To 2-chloro-6- [ [4 ]-chloro-2- [ 2-ethoxyvinyl group]Phenyl group]Methoxy group]To a solution of pyridine (54.2 g,161.1 mmol) in acetone (525 mL) and water (175 mL) was added hydrochloric acid (35 mL,407mmol,36.5% in water) and heated to 65℃for one hour. The reaction was cooled to RT and diluted with water (250 mL) and MTBE (250 mL). The organic phase was separated and the aqueous phase was extracted with MTBE (3X 250 mL). With 2M Na 2 CO 3 The combined organic layers were washed with aqueous solution (250 mL), water (250 mL), saturated aqueous NaCl (250 mL), dried over sodium sulfate and the solvent removed in vacuo to give 44.5g of the title compound (93%) which was used in preparation 315 without further purification. ES-MS M/z 296.0,298.0 (M+H).
Preparation 315
2- [ 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl ] phenyl ] ethanol
To a solution of 2- [ 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl ] phenyl ] ethanal (preparation 314,44.5g,150.3 mmol) in EtOH (400 mL) was added sodium borohydride (11.85 g,300.7 mmol) in portions at 5℃and stirred at RT for one hour. The reaction was cooled to 0deg.C and quenched with water (250 mL) and the pH was adjusted to 6 with 5% aqueous citric acid. MTBE (400 mL) was added, the organic phase was separated and the aqueous phase was extracted with MTBE (3X 250 mL). The organic layers were combined and washed with water (250 mL), saturated aqueous NaCl (250 mL), dried over sodium sulfate and the solvent removed in vacuo. The crude material was purified by silica gel chromatography using a gradient of 20 to 40% etoac/cyclohexane to give 31.95g of the title compound (71%) which crystallized upon standing. ES-MS M/z 298.0,300.0 (M+H).
Preparation 316
2- [ [2- [2- [ (5-bromo-2-iodo-phenyl) methoxy ] ethyl ] -4-chloro-phenyl ] methoxy ] -6-chloro-pyridine
To a solution of 2- [ 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl ] phenyl ] ethanol (31.80 g,106.6 mmol) in THF (360 mL) was added sodium hydride (60 wt%, in mineral oil, 8.14g,203 mmol) and stirred for 20 min. 4-bromo-2- (bromomethyl) -1-iodo-benzene (49.4 g,131 mmol) was added in portions and the mixture was warmed to RT and stirred for 18 h. To this was added more sodium hydride (60 wt%, in mineral oil, 1.25g,31.3 mmol) followed by more 4-bromo-2- (bromomethyl) -1-iodo-benzene (4.9 g,13 mmol) and the mixture was stirred at RT for an additional 5 hours. The reaction was cooled to 0deg.C, quenched with 5% aqueous citric acid (250 mL) and MTBE (200 mL) was added. The organic phase was separated and the aqueous phase was extracted with MTBE (3X 250 mL). The organic layers were combined and washed with water (200 mL), saturated aqueous NaCl (200 mL), dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by silica gel chromatography using a gradient of 40 to 100% dcm/cyclohexane to give 45.05g of the title compound (71%) as a yellow oil. ES-MS M/z 593.8 (M+H).
Preparation 317
2- [ 4-bromo-2- [2- [ 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl ] phenyl ] ethoxymethyl ] phenyl ] acetic acid ethyl ester
At N 2 Stirring at RT 2- [ [2- [2- [ (5-bromo-2-iodo-phenyl) methoxy ]]Ethyl group]-4-chloro-phenyl]Methoxy group]-6-chloro-pyridine (13.11 g,22.1 mmol) and chloro [ (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) -2- (2 '-amino-1, 1' -biphenyl)]Palladium (II)](XantPhos Pd G2,1.100G,1.107 mmol) in THF (50 mL). To the mixture was added dropwise bromo- (2-ethoxy-2-oxo-ethyl) zinc (0.4M in THF, 103ml,40 mmol) and the mixture was heated to 65 ℃ for 3 hours. The reaction mixture was cooled to 0deg.C and quenched with 5% aqueous citric acid (200 mL) and MTBE (200 mL) was added. The organic phase was separated and the aqueous phase was extracted with MTBE (3X 100 mL). The combined organic layers were washed with water (200 mL), saturated aqueous NaCl solution (200 mL), dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by silica gel chromatography using a gradient of 20 to 100% dcm/cyclohexane to give a dark brown color9.15g of the title compound (75%) were oily. ES-MS M/z 552.0,554.0 (M+H).
Preparation 318
2- [2- [2- [ 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl ] phenyl ] ethoxymethyl ] -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid ethyl ester
Let N 2 The gas was bubbled through 2- [ 4-bromo-2- [2- [ 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl } - ]Phenyl group]Ethoxymethyl group]Phenyl group]A solution of ethyl acetate (7.50 g,13.6 mmol), bis (pinacolato) diboron (4.39 g,16.9 mmol) and KOAc (4.1 g,41 mmol) in dioxane (270 mL) for 15 min. To the mixture was added bis (tricyclohexylphosphine) palladium (II) dichloride (1.02 g,1.35 mmol) and heated to 90℃for 20 hours. To this mixture was added additional bis (pinacolato) diboron (0.439 g,1.69 mmol), dichlorobis (tricyclohexylphosphine) palladium (II) (0.10 g,0.13 mmol) and KOAc (0.410 g,4.1 mmol). The mixture was heated to 90 ℃ for 4 hours. The mixture was cooled to RT and filtered through a plug of silica eluting with DCM to give 9.11g of the title compound as a crude dark brown oil (112%) which was used in preparation 319 without further purification. ES-MS M/z 600.2,602.2 (M+H).
Preparation 319
2-(5 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid ethyl ester
Let N 2 The gas was bubbled through 2- [2- [2- [ 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl ]]Phenyl group]Ethoxymethyl group]-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]A solution of ethyl acetate (9.10 g,15.2 mmol) and aqueous tripotassium phosphate (1M, 91mL,91 mmol) in THF (610 mL) for 15 min. To the mixture The compound is added with [ chloro (2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II)](XPhos-Pd-G2, 1.22G,1.52 mmol) and heated to 65℃for one hour. The reaction was cooled to RT, diluted with water (300 mL) and extracted with MTBE (3X 250 mL). The combined organics were washed with water (250 mL), saturated aqueous NaCl (250 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 80 to 100% dcm/cyclohexane to give 1.6g of the title compound (24.1%) as a white solid. ES-MS M/z 438.2 (M+H).
Preparation 320
2-(5 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
To a solution of ethyl 2- (54-chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenz-cyclononatomato-14-yl) acetate (900 mg,2.06 mmol) in ACN (5 mL), 1, 4-dioxan (5 mL) and water (5 mL) was added 1,3,4,6,7,8-hexahydro-2H-pyrimido [1,2-a ] pyrimidine (500 mg,3.52 mmol) and heated to 50 ℃ for 3 hours. The reaction was cooled to RT, quenched with 1N HCl (2 mL), diluted with water and extracted with EtOAc (2X 250 mL). The organics were combined, washed with saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated in vacuo to give 835mg of the title compound (99%) as a pale yellow solid. ES-MS M/z 410.9 (M+H).
Preparation 321
3- [2- [ tert-butyl (dimethyl) silyl ] oxyethoxy ] -5-fluoro-4-nitro-benzoic acid methyl ester
To 3-fluoro-5-hydroxy-4-nitro-benzoic acid methyl ester (2 g,9.3 mmol), 2- ((tert-butyldimethylsilyl) oxy) ethanol (2.6 g,14 mmol) and triphenylTo a solution of phenylphosphine (3.5 g,13 mmol) in THF (30 mL) at 0deg.C was added DIAD (3.8 g,19 mmol). Warm to 20 ℃ and stir for 12 hours. Dilute with water (50 mL) and extract with EtOAc (3×80 mL). The combined organic layers were washed with saturated aqueous sodium chloride (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 0-20% etoac/petroleum ether to give the title compound (4 g, 92%) as a colorless oil. 1 H NMR(CDCl 3 )δ7.59(s,1H),7.51(d,J＝24Hz,1H),4.25(t,J＝5Hz,2H),3.98(t,J＝5Hz,2H),3.97(s,3H),0.88(s,9H),0.07(s,6H).
Preparation 322
3- (2-hydroxyethoxy) -4-nitro-5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoic acid methyl ester
To 3- [2- [ tert-butyl (dimethyl) silyl ]]Oxyethoxy radical]To a solution of methyl-5-fluoro-4-nitro-benzoate (2 g,4.32 mmol) in DMSO (200 mL) was added TEA (2.5 mL,18 mmol) and (S) -oxetan-2-ylmethylamine (21 g,8.7 mmol). Stirred at 80℃for 12 hours. Dilute with water (200 mL) and extract with EtOAc (3×300 mL). The combined organic layers were washed with saturated aqueous sodium chloride (400 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 0-50% etoac/petroleum ether to give the title compound (320 mg, 18%). 1 H NMR(CDCl 3 )δ7.16(s,1H),6.93(s,1H),6.39(s,1H),5.11(m,1H),4.72(m,1H),4.59(m,1H),4.24(t,j＝4Hz,2H),3.97–3.93(m,5H),3.50(t,j＝4Hz,2H),2.73(m,1H),2.58(m,1H).
Preparation 323
3- [2- [ tert-butyl (dimethyl) silyl ] oxyethoxy ] -4-nitro-5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoic acid methyl ester
To a solution of methyl 3- (2-hydroxyethoxy) -4-nitro-5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoate (320 mg,0.78 mmol) in DCM (10 mL) was added tert-butyldimethylchlorosilane (200 mg,1.29 mmol) and imidazole (130 mg,1.90 mmol). The mixture was stirred at 20℃for 2 hours. Dilute with water (20 mL) and extract with DCM (3×30 mL). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 0-20% etoac/petroleum ether to give the title compound (400 mg, 93%). ES/MS (M/z): 441.1 (M+H).
Preparation 324
4-amino-3- [2- [ tert-butyl (dimethyl) silyl ] oxyethoxy ] -5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoic acid methyl ester
To a solution of methyl 3- [2- [ tert-butyl (dimethyl) silyl ] oxyethoxy ] -4-nitro-5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoate (640 mg,1.22 mmol) in EtOAc (100 mL) was added Pd/C (300 mg,10 mass%). Three times with hydrogen and stirred for one hour at 20 ℃ under a balloon filled with hydrogen. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 0-10% meoh/DCM to give the title compound (470 mg, 95%). ES/MS (M/z): 411.4 (M+H).
Preparation 325
(S) -3- [2- [ tert-butyl (dimethyl) silyl]Oxyethoxy radical]-4-(2-(5 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
To 2- (5) 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid (80 mg,0.20 mmol) and 4-amino-3- [2- [ tert-butyl (dimethyl) silyl]Oxyethoxy radical]-5- [ [ (2S) -oxetan-2-yl]Methylamino group]To a solution of methyl benzoate (87 mg,0.21 mmol) in DMF (3 mL) was added DIEA (0.07 mL,0.4 mmol) followed by HATU (124 mg,0.32 mmol). The mixture was stirred at 20 ℃ for 2 hours, then diluted with water (20 mL) to form a solid. The solid was filtered off and dried in vacuo to give the title compound (132 mg, 84%). ES/MS m/z 35 Cl/ 37 Cl)802.4/804.4[M+H].
Preparation 326
(S) -4- [2- [ tert-butyl (dimethyl) silyl]Oxyethoxy radical]-2-((5 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
(S) -3- [2- [ tert-butyl (dimethyl) silyl]Oxyethoxy radical]A solution of methyl 4- (2- (54-chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenz-cyclonona-14-yl) acetamido) -5- ((oxetan-2-ylmethyl) amino) benzoate (132 mg,0.165 mmol) in acetic acid (3 mL) was heated to 80℃for 1.5 hours, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a gradient of 50 to 100% EtOAc/toluene followed by 2 to 5% meoh/EtOAc to give the title compound (62 mg, 48%). The product was eluted by LC-ES/MS at 1.8 min but was not ionized. Conditions for LCMS analysis: 2X 50Xbridge C18 3.5 μm,50 ℃,5-95% ACN/10mM NH 4 HCO 3 Aqueous solution (pH 9) for 1.5 minutes followed by 95% acn for 0.5 minutes.
Preparation 327
3- [2- (dimethylamino) ethoxy ] -5-fluoro-4-nitro-benzoic acid methyl ester
To a solution of methyl 3-fluoro-5-hydroxy-4-nitro-benzoate (2 g,9.30 mmol) in THF (20 mL) was added N, N-dimethylethanolamine (994 mg,11.15 mmol), triphenylphosphine (2.92 g,11.15 mmol) and DIAD (2.25 g,11.15 mmol). The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 10% meoh in DCM to give the title compound as a yellow oil (690 mg, 26%). ES/MS M/z 287 (M+H).
Preparation 328
3- [2- (dimethylamino) ethoxy ] -4-nitro-5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoic acid methyl ester
To a solution of 3- [2- (dimethylamino) ethoxy ] -5-fluoro-4-nitro-benzoic acid methyl ester (690 mg,2.41 mmol) in DMSO (8 mL) was added (2S) -oxetan-2-yl-methylamine (420 mg,4.8 mmol) and TEA (1.46 g,14.4 mmol). The reaction mixture was stirred at 80℃for 18 hours. The mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The organics were combined, washed with water and saturated aqueous NaCl (2×50 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 20% meoh in DCM to give the title compound as a colourless oil (1.03 g, 72%). ES/MS M/z 354 (M+H).
Preparation 329
4-amino-3- [2- (dimethylamino) ethoxy ] -5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoic acid methyl ester
To 3- [2- (dimethylamino) ethoxy]-4-nitro-5- [ [ (2S) -oxetan-2-yl]Methylamino group]To a solution of methyl benzoate (1.03 g,1.75 mmol) in EtOAc (100 mL) was added 10% Pd/C (200 mg,0.18 mmol). The mixture was stirred under hydrogen (14.5 psi) at ambient temperature for 2 hours, then filtered through celite and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound as a white solid (102 mg, 17%). [ column: welch Xtime C18X 40mm,3 μm; mobile phase a: h 2 O, NH-containing 3 H 2 O+NH 4 HCO 3 The method comprises the steps of carrying out a first treatment on the surface of the Mobile phase B: ACN; gradient: b,22% to 52%). ES/MS M/z 324 (M+H).
Preparation 330
(S)-4-(2-(5 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- (2- (dimethylamino) ethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
To 2- (5) 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid (75 mg,0.18 mmol) and 4-amino-3- [2- (dimethylamino) ethoxy]-5- [ [ (2S) -oxetan-2-yl]Methylamino group]To a solution of methyl benzoate (60 mg,0.18 mmol) in DMF (2 mL) was added HATU (115 mg,0.3 mmol) and DIPEA (0.10 mL,0.5 mmol). The mixture was stirred at ambient temperature for 17 hours. The reaction was quenched with water and the precipitated white solid was filtered. The filtrate was concentrated and extracted with EtOAc. The organic layers were combined, the organics dried over magnesium sulfate, filtered and concentrated to give a solid residue. The first white solid was combined with the residue to give the title compound (173 mg, 132%) as a white solid. ES/MS M/z 715 (M+H).
Preparation 331
(S)-2-((5 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2- (dimethylamino) ethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
(S) -4- (2- (5) 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -methyl 3- (2- (dimethylamino) ethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoate (130 mg; a mixture of 0.18 mmol) in acetic acid (2 mL) and 1, 2-dichloroethane (1.5 mL) was heated at 55deg.C for 21 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 10% meoh in DCM to give the title compound as a white solid (89 mg, 70%). ES/MS M/z 697 (M+H).
Preparation 332
3- [2- [ tert-Butoxycarbonyl (methyl) amino ] ethoxy ] -5-fluoro-4-nitro-benzoic acid methyl ester
To a solution of methyl 3-fluoro-5-hydroxy-4-nitro-benzoate (2 g,9.30 mmol) and tert-butyl (2-hydroxyethyl) methylcarbamate (3.43 g,18.6 mmol) in THF (20 mL) was added triphenylphosphine (3.7 g,14 mmol) and DIAD (2.82 g,13.9 mmol). The reaction was stirred at ambient temperature for 12 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of 0 to 20% etoac/petroleum ether to give the title compound (2.3 g, 66%) as a yellow oil. ES/MS (M/z): 373 (M+H).
Preparation 333
3- [2- [ tert-Butoxycarbonyl (methyl) amino ] ethoxy ] -4-nitro-5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoic acid methyl ester
To a solution of 3- [2- [ tert-butoxycarbonyl (methyl) amino ] ethoxy ] -5-fluoro-4-nitro-benzoic acid methyl ester (1 g,2.68 mmol) in DMSO (60 mL) was added a solution of 3.6% w/w (2S) -oxetan-2-yl-methylamine in EtOH (13.0 g,5.4 mmol) and TEA (1.6 g,16 mmol). The reaction mixture was stirred at 80℃for 12 hours. The mixture was cooled to ambient temperature, diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The organics were combined, washed with water and saturated aqueous NaCl (3×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient elution of 0 to 20% etoac/petroleum ether to give the title compound as a yellow oil (750 mg, 62%). ES/MS (M/z): 440 (M+H-Boc).
Preparation 334
4-amino-3- [2- [ tert-butoxycarbonyl (methyl) amino ] ethoxy ] -5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoic acid methyl ester
To a solution of methyl 3- [2- [ tert-butoxycarbonyl (methyl) amino ] ethoxy ] -4-nitro-5- [ [ (2S) -oxetan-2-yl ] methylamino ] benzoate (700 mg,1.59 mmol) in EtOAc (50 mL) was added 10% Pd/C (200 mg,0.18 mmol). The mixture was stirred under hydrogen (15 psi) at ambient temperature for 2 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give the title compound (534 mg, 82%). ES/MS (M/z): 410 (M+H).
Preparation 335
(S) -3- (2- ((tert-Butoxycarbonyl) (methyl) amino) ethoxy) -4- (2- (5) 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
To 2- (5) 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid (80 mg,0.19 mmol) and 4-amino-3- [2- [ tert-butoxycarbonyl (methyl) amino group]Ethoxy group]-5- [ [ (2S) -oxetan-2-yl]Methylamino group]To a solution of methyl benzoate (82 mg,0.19 mmol) in DMF (2 mL) was added HATU (130 mg,0.33 mmol) and DIEA (0.11 mL,0.62 mmol). The mixture was stirred at ambient temperature for 15 hours, then quenched with water and extracted with EtOAc. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (155 mg, 80%) as a solid which was used in preparation 336 without further purification. ES/MS (M/z): 801 (M+H).
Preparation 336
(S) -4- (2- ((tert-Butoxycarbonyl) (methyl) amino) ethoxy) -2- ((5 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
(S) -3- (2- ((tert-Butoxycarbonyl) (methyl) amino) ethoxy) -4- (2- (5) 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 A mixture of methyl-5- ((oxetan-2-ylmethyl) amino) benzoate (preparation 335,155mg,0.19 mmol) in acetic acid (1.5 mL) and 1, 2-dichloroethane (1.5 mL) was heated at 55deg.C for 18 h. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 10% meoh/DCM to give the title compound as a white solid (150 mg, 99%). ES/MS (M/z) 783 (M+H).
Preparation 337
(S) -4- (2- ((tert-Butoxycarbonyl) (methyl) amino) ethoxy) -2- ((5 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
To (S) -4- (2- ((tert-butoxycarbonyl) (methyl) amino) ethoxy) -2- ((5 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (150 mg,0.19 mmol) 1,5, 7-triazabicyclo [4.4.0 ] was added to a nitrogen degassing mixture of ACN (2 mL), 1, 4-dioxane (2 mL) and water (0.4 mL)]Dec-5-ene (86 mg,0.60 mmol) and the mixture was heated to 55℃for 36 hours. The mixture was cooled to ambient temperature, concentrated under reduced pressure and the residue was purified by reverse phase chromatography using a gradient of 10 to 90% acn/water (0.1% formic acid to both solvents) to give the title compound (64 mg, 43%) as a white solid. ES/MS (M/z): 769 (M+H).
Preparation 338
2- (4-bromo-5-fluoro-2-methyl-phenyl) acetic acid ethyl ester
1-bromo-2-fluoro-4-iodo-5-methyl-benzene (11 g,34 mmol) and chloro [ (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) -2- (2 '-amino-1, 1' -biphenyl) at RT]To a solution of palladium (II) (XantPhos-Pd-G2, 3.5mg,3.4 mmol) in THF (45 mL) was added (2-ethoxy-2-oxoethyl) zinc (II) (0.50M in THF, 110mL,60 mmol), and in N 2 The mixture was stirred at 65℃overnight. The reaction was quenched by the addition of 1N HCl (100 mL) and the mixture was extracted with EtOAc (3X 100 mL). Combining the organic layers with K 2 CO 3 Aqueous (100 mL) was washed, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0 to 20% etoac/petroleum ether to give the title compound as a pale yellow oil (9.73 g, 98%). ES/MS M/z 274.8 (M+H)
Preparation 339
2- [ 4-bromo-2- (bromomethyl) -5-fluoro-phenyl ] acetic acid ethyl ester
A solution of ethyl 2- (4-bromo-5-fluoro-2-methyl-phenyl) acetate (5.9 g,21 mmol) and N-bromosuccinimide (3.6 g,20 mmol) in ACN (110 mL) was prepared. The solution was pumped through a photochemical reactor consisting of a PFA reaction tube (1/8 "outside diameter, 53mL volume) coiled around a 4100K white bulb (42W, equivalent to 150W) at a flow rate of 1.3mL/min and maintaining the system temperature at 30 to 40 ℃. Once completed, ACN (100 mL) was pumped through the reactor at the same rate. The output mixture was diluted with water (500 mL) and heptane (200 mL). The aqueous layer was extracted with heptane (200 mL) and the combined organic layers were washed with saturated aqueous sodium thiosulfate (2X 100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0 to 10% etoac/hexanes to give 7.0g of the title compound (92% yield, 90% purity). 1 H-NMR(400MHz,CDCl 3 )δ7.59(d,J＝7Hz,1H),7.09(d,J＝9Hz,1H),4.50(s,2H),4.20(q,J＝7.5Hz,2H),3.75(s,2H),1.29(t,J＝7.5Hz,3H).
Preparation 340
2- [ 4-bromo-2- [2- [5- [ (6-chloro-2-pyridinyl) oxymethyl ] -2-cyano-phenyl ] ethoxymethyl ] -5-fluoro-phenyl ] acetic acid ethyl ester
Charging a reaction vessel with 4- [ (6-chloro-2-pyridinyl) oxymethyl]-2- (2-hydroxyethyl) benzonitrile (700 mg,2.4 mmol), 2- [ 4-bromo-2- (bromomethyl) -5-fluoro-phenyl ]]Ethyl acetate (1.3 g,3.2mmol,88 mass%), anhydrous DCM (20 mL) and 2, 6-di-tert-butylpyridine (835 μl,3.61 mmol). The mixture was cooled to 0 ℃ under a nitrogen atmosphere and silver triflate (878) was addedmg,3.38 mmol). The mixture was brought to RT and stirred overnight. By passing throughThe reaction mixture was filtered, the filtrate was concentrated and the residue was purified by silica gel chromatography using a gradient of 20 to 100% dcm/cyclohexane to give the title compound as a colourless waxy solid (369 mg,67wt% purity, 18%). ES-MS M/z 561,563,565 (M+H).
Preparation 341
2- [2- [2- [5- [ (6-chloro-2-pyridinyl) oxymethyl ] -2-cyano-phenyl ] ethoxymethyl ] -5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid ethyl ester
Charging a reaction vessel with 2- [ 4-bromo-2- [2- [5- [ (6-chloro-2-pyridinyl) oxymethyl ] group]-2-cyano-phenyl]Ethoxymethyl group]-5-fluoro-phenyl]Ethyl acetate (340 mg,0.41mmol,67wt% purity), KOAc (140 mg,1.40 mmol), bis (pinacolato) diboron (190 mg,0.73 mmol) and anhydrous 1, 4-dioxane (4 mL). The mixture was bubbled with nitrogen, bis (tricyclohexylphosphine) palladium (II) dichloride (61 mg,0.081 mmol) was added and stirred in a pre-heated bath at 90 ℃ for 5 hours. The reaction mixture was cooled to RT and saturated NaHCO was added 3 Aqueous solution and EtOAc and passingThe mixture was filtered. The aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% etoac/DCM to give the title compound as a yellow waxy solid (275 mg,75wt% purity, 84%). ES-MS M/z 609 and 611 (M+H).
Preparation 342
2-(5 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acidEthyl ester
The reaction vessel was charged with ethyl 2- [2- [2- [5- [ (6-chloro-2-pyridinyl) oxymethyl ] -2-cyano-phenyl ] ethoxymethyl ] -5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate (190 mg,0.23mmol,75wt% purity) and THF (7.8 mL). The mixture was bubbled with nitrogen, then tripotassium phosphate (1.0M in water, 1.2mL,1.2 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (XPhos Pd G2,20mg,0.025 mmol) were added. The mixture was stirred in a preheating bath at 70 ℃ for 30 minutes. The mixture was cooled to RT and water and EtOAc were added. The aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered and the solvent was removed. The residue was purified by silica gel chromatography using a gradient of 0 to 5% etoac/DCM to afford the title compound as a pale brown solid (49 mg,90wt% purity, 42%). ES-MS M/z 447 (M+H).
Preparation 343
2-(5 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
1,5, 7-Triazabicyclo [4.4.0]Dec-5-ene (62 mg,0.44 mmol) was added to 2- (5) 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 Ethyl acetate (72 mg,0.145mmol,90 mass%) in a mixture of ACN (1.5 mL), THF (500 μl) and water (500 μl). By N 2 The mixture was purged and stirred at 50 ℃ for 15 minutes. The organic solvent was removed with a nitrogen stream. EtOAc and aqueous citric acid (5%) were added, the aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered and the solvent removed to afford a white colorThe title compound (65 mg,97%, 91% by mass) was solid. ES-MS M/z 419 (M+H).
Preparation 344
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
To 2- (5) under nitrogen atmosphere 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid (65 mg,0.14mmol,91 mass%) and 4-amino-3- (2-methoxyethoxy) -5- [ [ (2S) -oxetan-2-yl ]Methylamino group]To a solution of methyl benzoate (45 mg,0.145 mmol) in anhydrous DMF (1.4 mL) was added HATU (70 mg,0.18 mmol) and DIPEA (74. Mu.L, 0.42 mmol). The mixture was stirred at RT for 3 hours and diluted with water and EtOAc. The aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered and the solvent was removed. The residue was dissolved in 1, 2-dichloroethane (0.9 mL) and acetic acid (0.9 mL) and concentrated under N 2 The mixture was heated at 60℃for 8 hours. The reaction mixture was cooled to RT, the solvent concentrated under reduced pressure, dried in vacuo at 35-40 ℃ and the residue purified by silica gel chromatography using a gradient of 25 to 100% etoac/DCM to afford the title compound as a white solid (50 mg, 49%). ES-MS M/z 693 (M+H).
Preparation 345
3-fluoro-5- ((1-methylpyrrolidin-3-yl) oxy) -4-nitrobenzoic acid methyl ester
A solution of methyl 3-fluoro-5-hydroxy-4-nitrobenzoate (2.0 g,9.3 mmol), 1-methylpyrrolidin-3-ol (1.13 g,11.2 mmol), triphenylphosphine (2.93 g,11.2 mmol) and DIAD (2.26 g,11.2 mmol) in THF (80 mL) was stirred at RT for 12 h. The reaction mixture was filtered and concentrated and the residue was purified by silica gel chromatography using a gradient of 0 to 10% meoh/DCM to give 1.03g of the title compound (37%). ES-MS M/z 299 (M+H).
Preparation 346
3- ((1-methylpyrrolidin-3-yl) oxy) -4-nitro-5- ((((S) -oxetan-2-yl) methyl) amino) benzoic acid methyl ester
A solution of methyl 3-fluoro-5- (1-methylpyrrolidin-3-yl) oxy) -4-nitrobenzoate (1.03 g,3.45 mmol), [ (2S) -oxetan-2-yl ] methylamine (20 g,8.3 mmol) and TEA (2.1 g,21 mmol) in DMSO (150 mL) was stirred at 80℃for 12 hours. The reaction was diluted with water (50 mL) and extracted with EtOAc (2X 200 mL). The combined organic layers were washed with saturated aqueous NaCl solution (5X 40 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 20% meoh/DCM, followed by reversed phase chromatography using a gradient of 30 to 60% mecn/aqueous ammonium hydroxide (0.05%) to give 520mg of the title compound (41%) as a yellow oil. ES-MS M/z 366 (M+H).
Preparation 347
4-amino-3- ((1-methylpyrrolidin-3-yl) oxy) -5- ((((S) -oxetan-2-yl) methyl) amino) benzoic acid methyl ester
A solution of methyl 3- ((1-methylpyrrolidin-3-yl) oxy) -4-nitro-5- ((((S) -oxetan-2-yl) methyl) amino) benzoate (500 mg,1.37 mmol) and palladium on carbon (10%, 200mg,0.19 mmol) in EtOAc (100 mL) was stirred at RT for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated to give 358mg of the title compound (78%) as a pale yellow solid. ES-MS M/z 336 (M+H).
Preparation 348
4-(2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- ((1-methylpyrrolidin-3-yl) oxy) -5- ((((S) -oxetan-2-yl) methyl) amino) benzoic acid methyl ester
To 2- (5) 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 To a solution of acetic acid (75 mg,0.18 mmol) and HATU (100 mg,0.26 mmol) in DMF (1.8 mL) was added methyl 4-amino-3- ((1-methylpyrrolidin-3-yl) oxy) -5- ((((S) -oxetan-2-yl) methyl) amino) benzoate (67 mg,0.20 mmol) and DIPEA (0.08 mL,0.45 mmol). Stirred at 20℃for 2 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (2X 10 mL). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered and concentrated to give 425mg of the title compound, which was used in preparation 349 without further purification. ES-MS M/z 718 (M+H).
Preparation 349
2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- ((1-methylpyrrolidin-3-yl) oxy) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
4- (2- (5) 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 A solution of methyl (preparation 348,425mg,0.528 mmol) acetamido) -3- ((1-methylpyrrolidin-3-yl) oxy) -5- ((((S) -oxetan-2-yl) methyl) amino) benzoate in 1, 2-dichloroethane (4 mL) and acetic acid (4 mL) was stirred at 55deg.C for 12 hours. ACN (10) with 1:1 toluenemL) was diluted and the solution concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 10% meoh/DCM to give 100mg of the title compound (27%) as a white solid. ES-MS M/z 700 (M+H).
Preparation 350
Ethyl 2- (4-bromo-2- ((2- (((6-bromo-5-fluoropyridin-2-yl) oxy) methyl) -5-cyanophenethyl) methyl) -5-fluorophenyl) acetate
To a solution of 4- [ (6-bromo-5-fluoro-2-pyridinyl) oxymethyl ] -3- (2-hydroxyethyl) benzonitrile (4 g,10.59 mmol), ethyl 2- [ 4-bromo-2- (bromomethyl) -5-fluoro-phenyl ] acetate (8.3 g,21 mmol) and 2, 6-di-tert-butyl-4-methylpyridine (4.45 g,21.2 mmol) in DCM (60 mL) was added silver triflate (8.3 g,32 mmol) at 20deg.C. The reaction was stirred at RT overnight, then the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL. Times.2). The organic layers were combined, washed with saturated aqueous NaCl (60 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0% to 100% dcm/petroleum ether to give the title compound (2.15 g, 25%) ES-MS M/z 625 (m+h) as a pale yellow solid.
Preparation 351
2-(5 4 -cyano-1 6 ,2 3 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid ethyl ester
/>
To a mixture of ethyl 2- (4-bromo-2- ((2- (((6-bromo-5-fluoropyridin-2-yl) oxy) methyl) -5-cyanophenethyl) methyl) -5-fluorophenyl) acetate (2.15 g,2.63 mmol) and cesium fluoride (795 mg,5.18 mmol) in 1, 4-dioxane (230 mL) was added (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1) under nitrogen at RT1' -biphenyl) [2- (2 ' -amino-1, 1' -biphenyl)]Palladium (II) mesylate (XPhos Pd g3,450mg,0.521 mmol) and hexamethylditin (1.34 g,4.05 mmol). The reaction was heated to 110 ℃ with protection from light and stirred for 15 hours, then the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL. Times.3). The organic layers were combined, washed with saturated aqueous NaCl (60 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. By means of preparative HPLC [ column: xtime C18X 40mm,10 μm; mobile phase: 50 to 90% ACN/water (NH containing 3 H 2 O+NH 4 HCO 3 ) Gradient of (2)]The crude residue was purified to give the title compound as a white solid (360.1 mg, 29%). ES-MS M/z 465 (M+H).
Preparation 352
2-(5 4 -cyano-1 6 ,2 3 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid
2- (5) was purged gently with nitrogen 4 -cyano-1 6 ,2 3 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 A solution of ethyl acetate (345 mg,0.74 mmol) in THF (2.47 mL), water (2.47 mL) and ACN (7.41 mL) was added 1,5, 7-triazabicyclo [ 4.4.0)]Dec-5-ene (320 mg,2.25 mmol). The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated to 45 ℃ and stirred at this temperature for 2 hours, then the reaction was concentrated under reduced pressure to give the title compound (385 mg, 100%) as a white solid, which was used in preparation 353 without further purification. ES-MS M/z 437 (M+H).
Preparation 353
(S)-4-(2-(5 4 -cyano-1 6 ,2 3 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- (2-methoxyethoxy) -5- ((oxetan-2-ylmethyl) amino) Benzoic acid methyl ester
To 2- (5) 4 -cyano-1 6 ,2 3 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 To a solution of acetic acid (preparation 352,250mg,0.48 mmol) and HATU (378 mg,0.97 mmol) in DMF (6 mL) was added 4-amino-3- (2-methoxyethoxy) -5- [ [ (2S) -oxetan-2-yl ]Methylamino group]Methyl benzoate (260 mg,0.75 mmol) and then DIPEA (300. Mu.L, 1.72 mmol) was added to the mixture and the mixture was taken up in N 2 Stirred overnight at 20 ℃. The reaction was diluted with water (20 mL) and extracted with EtOAc (20 mL. Times.2). The organic layers were combined, washed with saturated aqueous NaCl (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.2 g, 100%) as a pale yellow solid, which was used in preparation 354 without further purification. ES-MS M/z 729 (M+H).
Preparation 354
(S)-2-((5 4 -cyano-1 6 ,2 3 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
At N 2 Under RT, (S) -4- (2- (5) 4 -cyano-1 6 ,2 3 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 To a solution of methyl (preparation 353,1.2g,0.49 mmol) acetamido) -3- (2-methoxyethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoate in 1, 2-dichloroethane (5 mL) was added acetic acid (5 mL). The reaction was heated at 55 ℃ and stirred overnight. The reaction was diluted with toluene/ACN 1:1 (5 mL), the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 5% MeOH/DCM The product was obtained as a white solid (270 mg, 35%). ES-MS M/z 711 (M+H).
Preparation 355
(S) -2- (chloromethyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester
A solution of methyl 4-amino-3-fluoro-5- [ [ (2S) -oxetan-2-ylmethyl ] amino ] benzoate (2.0 g,7.9 mmol) and TEA (1.1 mL,7.9 mmol) in 1, 2-dichloroethane (22 mL) was cooled to 0deg.C and 2-chloroacetyl chloride (0.63 mL,7.9 mL) was added. The mixture was stirred at RT for 2 hours. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting residue was dissolved in acetic acid (40 mL) and stirred at 70 ℃ for 2 hours. The crude reaction was concentrated and the residue was purified by silica gel chromatography using a gradient of 0 to 4% meoh/DCM to give 1.76g of the title compound (72%) as a yellow oil. ES-MS M/z 313 (M+H).
Preparation 356
3- (2- ((5-bromo-2-chlorobenzyl) oxy) ethyl) -4- (Ω (6-bromopyridin-2-yl) oxy) methyl) benzonitrile
4- [ (6-bromo-2-pyridinyl) oxymethyl]A solution of 3- (2-hydroxyethyl) benzonitrile (2.3 g,6.8 mmol), 4-bromo-2- (bromomethyl) -1-chloro-benzene (2.7 g,9.5 mmol) and 2, 6-di-tert-butylpyridine (2.2 mL,9.7 mmol) in DCM (36 mL) was cooled to 0deg.C. Silver triflate (3.0 g,11.8 mmol) was added to the reaction mixture and stirred at 0deg.C for 15 min, then at RT for 18 h. To the reaction mixture was added additional silver triflate (0.53 g,2.1 mmol) and stirred at RT for 22 hours. By passing through FiltrationThe crude reaction mixture was concentrated and the residue was purified by silica gel chromatography using a gradient of 0 to 100% dcm/heptane to give 2.3g of the title compound (62%) as a colorless viscous solid. ES-MS M/z 535/537/539 (M+H).
Preparation 357
1 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylheterocyclo-nona-5 4 -carbonitrile
The title compound was prepared as described essentially in preparation 216 using 3- (2- ((5-bromo-2-chlorobenzyl) oxy) ethyl) -4- (((6-bromopyridin-2-yl) oxy) methyl) benzonitrile and purified by silica gel chromatography using a gradient of 0 to 25% etoac/heptane to give the title compound as an off-white solid. ES-MS M/z 377 (M+H).
Preparation 358
1 4 - (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-5 4 -carbonitrile
Will 1 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylheterocyclo-nona-5 4 -carbonitrile (170 mg,0.45 mmol), (S) -1, 2-propanediol (0.2 mL,3 mmol), 2-dicyclohexylphosphino-2 ',4',6' -triisopropylbiphenyl (XPhos, 44mg,0.09 mmol), chloro (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2 ' -amino-1, 1' -biphenyl)]A solution of palladium (II) (XPhos Pd Gen 2,35mg,0.045 mmol), bis (pinacolato) diboron (0.34 g,1.3 mmol) and KOAc (0.13 g,1.3 mmol) in 2-methyltetrahydrofuran (14 mL) was stirred at 80℃for 3 hours. The reaction solution was filtered and concentrated. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 210mg of the title compound (99%), which was taken up in the form of a solid Is used in preparation 359 without further purification. ES-MS M/z 469 (M+H).
Preparation 359
(S)-2-((5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl) -4-fluoro-1- (oxetan-2-yl)Methyl group) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
Will 1 4 - (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-5 4 -carbonitrile (0.12 g,0.26 mmol), (S) -2- (chloromethyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (0.12 g,0.38 mmol), 2-dicyclohexylphosphino-2 ',4',6' -triisopropylbiphenyl (XPhos, 25mg,0.05 mmol), chloro (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2 ' -amino-1, 1' -biphenyl)]A solution of palladium (II) (XPhos Pd Gen 2 20mg,0.025 mmol) and tripotassium phosphate (67 mg,0.31 mmoL) in 2-methyltetrahydrofuran (3 mL) and water (0.3 mL) was stirred at 90℃for 7 hours. The reaction solution was filtered and diluted with EtOAc, washed with water, and the organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 50% etoac/DCM to give 20mg of the title compound (10%) as a yellow solid. ES-MS M/z 619 (M+H).
Preparation 360
(S) -3- (2- (dimethylamino) -2-oxoethoxy) -4-nitro-5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
Sodium hydride/mineral oil (60 wt%,211mg,5.28 mmol) was added to a solution of 2-hydroxy-N, N-dimethylacetamide (730 mg,7.08 mmol) in THF (10 mL) at 0deg.C, then the cooling bath was removed and mixed with stirringThe mixture was allowed to stand for 1 hour. The mixture was cooled again to 0deg.C and 3-fluoro-4-nitro-5- [ [ (2S) -oxetan-2-ylmethyl was added]Amino group]Methyl benzoate (1 g,3.52 mmol). The cooling bath was removed and the mixture was stirred for 48 hours. With saturated NH 4 The reaction was quenched with Cl solution (30 mL) and extracted with EtOAc (3X 50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 60% etoac/petroleum ether to give the title compound (800 mg, 61%) as a yellow oil. ES-MS M/z 368 (M+H).
Preparation 361
(S) -4-amino-3- (2- (dimethylamino) -2-oxoethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
The vessel containing methyl (S) -3- (2- (dimethylamino) -2-oxoethoxy) -4-nitro-5- ((oxetan-2-ylmethyl) amino) benzoate (800 mg,2.13 mmol), pd/C (200 mg,10 wt%) and EtOAc (60 mL) was purged three times with hydrogen. H at one atmosphere 2 The mixture was stirred at ambient temperature for 4 hours. The mixture was filtered and concentrated under reduced pressure. The product was purified by silica gel chromatography using a gradient of 0 to 100% etoac/petroleum ether to give the title compound as a yellow oil (636.4 mg, 88%). ES-MS M/z 338 (M+H).
Preparation 362
(S)-4-(2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- (2- (dimethylamino) -2-oxoethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
1-propanephosphonic anhydride (50 wt% in DCM, 225. Mu.L, 0.378 mmol) was added to 2- (5) at ambient temperature 4 -cyanogen1-hydroxy-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl (S) -4-amino-3- (2- (dimethylamino) -2-oxoethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoate (69 mg,0.20 mmol) in DMF (1 mL) and pyridine (150 μl,1.85 mmol). Stirring was carried out for 20 hours, then additional 1-propanephosphonic anhydride (225. Mu.L, 0.378 mmol) was added. After stirring for an additional 23 hours, the reaction was quenched by the addition of water (2 mL). The mixture was stirred for 10 min, the solid was filtered and collected, then dried in vacuo at 60 ℃ for 2 hours to give the title compound as an off-white solid (75.1 mg, 56%). ES-MS M/z 720 (M+H).
Preparation 363
(S)-2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2- (dimethylamino) -2-oxoethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
(S) -4- (2- (5) 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 A solution of methyl (75 mg,0.104 mmol) acetamido) -3- (2- (dimethylamino) -2-oxoethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoate in acetic acid (3 mL) was stirred at 60℃for 20 hours. Acetic acid was removed in vacuo and the residue was purified by silica gel chromatography using a gradient of 0 to 20% isopropanol/chloroform to give 70mg of the title compound (70% purity, 72%). ES-MS M/z 703 (M+H).
Preparation 364
3- [ (3-ethylimidazol-4-yl) methylamino ] -5-methoxy-4-nitro-benzoic acid methyl ester
TEA (2.2 mL,16 mmol) was addedTo a stirred solution of methyl 3-fluoro-5-methoxy-4-nitro-benzoate (900 mg,3.93 mmol) and (1-ethyl-1H-imidazol-5-yl) methylamine dihydrochloride (900 mg,4.32 mmol) in DMF (20 mL). The mixture was stirred at 60℃for 16 hours. The mixture was cooled to ambient temperature and poured into saturated NH 4 Aqueous Cl (100 mL). The mixture was extracted with DCM (3X 100 mL) and washed with saturated aqueous NaCl solution (3X 50 mL). The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a gradient of 0 to 10% meoh/EtOAc to give the title compound as a yellow oil (800 mg, 61%). ES-MS M/z 335 (M+H).
Preparation 365
4-amino-3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) -5-methoxybenzoic acid methyl ester
Iron (80 mg,14.34 mmol) and NH 4 Cl (768 mg,14.4 mmol) was added to 3- [ (3-ethylimidazol-4-yl) methylamino]A solution of methyl-5-methoxy-4-nitro-benzoate (960 mg,2.87 mmol) in MeOH (30 mL) and water (10 mL). Stirred for 2 hours at 80 ℃, cooled to ambient temperature, then passed throughThe pad was filtered and the pad was washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure and purified by flash chromatography using a gradient of 0 to 15% meoh/EtOAc. Purification was again by silica gel chromatography using a gradient of 0 to 10% meoh/EtOAc to give the title compound as a brown solid (504 mg, 55%). ES-MS M/z 305 (M+H) & gt>
Preparation 366
4-(2-(5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) -5-methoxybenzoic acid methyl ester
1-propane phosphonic anhydride (50 wt% DMF solution, 170. Mu.L, 0.28 mmol) was added to 2- (5) at ambient temperature 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl acetate (76 mg,0.1898 mmol) and methyl 4-amino-3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) -5-methoxybenzoate (63 mg,0.207 mmol) in DMF (600 μl) and pyridine (400 μl,5 mmol). The reaction was stirred at RT for 72 hours, then diluted with EtOAc (100 mL) and saturated NaHCO 3 (100 mL) of the organic material was washed inThe filtrate was filtered and extracted three times with additional EtOAc. The organics were combined, washed twice with saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title product (136 mg) which was used in preparation 367 without further purification. ES-MS M/z 688 (M+H).
Preparation 367
2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -4-methoxy-1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
The use of 4- (2- (5) is substantially as described in preparation 102 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl-acetamido) -3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) -5-methoxybenzoate (preparation 366) in a 1:1 acetic acid:1, 2-dichloroethane mixture as solvent with heating at 70 ℃ for 16 hours to prepare the title compound. The mixture was cooled to RT and concentrated in vacuo. 1:1 EtOAc/toluene was added and concentrated to remove residual acetic acid (twice). The resulting yellow solid was dried in vacuo for 2 hours. By using 90 to 100% EtOAc/DCMThe solid was purified by silica gel chromatography of MeOH to give the title compound as an off-white solid, which was used in example 63 without further purification. ES-MS M/z 670 (M+H).
Preparation 368
(S)-4-(2-(5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- (2-methoxyethoxy) -5- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester
To 2- (5) 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 To a solution of acetic acid (44 mg,0.103 mmol) in DMF (1.2 mL) was added 4-amino-3- (2-methoxyethoxy) -5- [ [ (2S) -oxetan-2-yl]Methylamino group]Methyl benzoate (32 mg,0.103 mmol), HATU (59 mg,0.155 mmol) and DIPEA (0.055 mL,0.32 mmol). The mixture was stirred at RT for 2 hours, then diluted with water (10 mL) and extracted with EtOAc (4×5 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a pale brown solid (80 mg,80% purity, 88% yield). ES-MS M/z 693 (M+H).
Preparation 369
(S)-2-((5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
(S) -4- (2- (5) 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetamido) -3- (2-methoxyethoxy) -5- ((oxetan-2-ylmethyl) amino) benzeneA solution of methyl formate (80 mg,80% purity, 0.092 mmol) in 1, 2-dichloroethane (0.7 mL) and acetic acid (0.7 mL) was heated at 58℃for 6 h. The reaction mixture was cooled to RT, concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 30 to 100% etoac/DCM to afford 25mg (40%) of the title compound as a white solid. ES-MS M/z 675 (M+H).
Preparation 370
(S)-2-((5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
To 2- (5) under nitrogen atmosphere 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) acetic acid (60 mg,0.15 mmol) and 4-amino-3- (2-methoxyethoxy) -5- [ [ (2S) -oxetan-2-yl]Methylamino group]To a solution of methyl benzoate (47 mg, 0.15) in anhydrous DMF (1.5 mL) was added HATU (74 mg,0.19 mmol) and DIPEA (0.08 mL,0.45 mmol). The mixture was stirred at RT for 2.5 hours, then water and EtOAc were added. The aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated. A solution of the residue in 1, 2-dichloroethane (0.9 mL) and acetic acid (0.9 mL) was heated under a nitrogen atmosphere at 60℃for 8 hours. The reaction mixture was cooled to RT, the solvent concentrated under reduced pressure, dried in vacuo at 35-40 ℃ and the residue purified by silica gel chromatography using a gradient of 25 to 100% etoac/DCM as an eluting system to afford the title compound as a white solid (72 mg, 71%). ES-MS M/z 675 (M+H).
Preparation 371
(S)-(1 4 - ((6- (methoxycarbonyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d)]Imidazol-2-yl) methyl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-5 4 -yl) boric acid
Charging (S) -2- ((5) into a reaction vessel 4 -bromo-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (500 mg,0.72 mmol), anhydrous THF (5 mL), and MeOH (10 mL). By N 2 The mixture was bubbled for 10 minutes, and anhydrous ethylene glycol (610 μl,10.9 mmol) and DIPEA (315 μl,1.82 mmol) were added. By N 2 The mixture was bubbled for 5 minutes, and tetrahydroxydiboron (139 mg,1.47 mmol), tricyclohexylphosphine (5 mg,0.018 mmol) and [ (tricyclohexylphosphine) -2- (2' -aminobiphenyl) were added]Palladium (II) methanesulfonate [ P (Cy 3) Pd G3,26mg,0.039 mmol), the vessel was sealed and stirred in a pre-heating bath at 50℃for 2.5 hours. The reaction mixture was concentrated and then saturated NaHCO was added 3 The aqueous solution was stirred for 5 minutes. The solid was filtered off and then washed with water, ACN and MeOH to afford the title compound as a grey solid (500 mg,90wt% purity, 100%). ES-MS M/z 620 (M+H).
Preparation 372
(S)-2-((5 4 - (4-fluoro-1H-imidazol-1-yl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
Charging (S) - (1) into a reaction vessel 4 - ((6- (methoxycarbonyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d)]Imidazol-2-yl) methyl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-5 4 -base) boronic acid (21 mg,0.03mmol,90wt% purity), 4-fluoro-1H-imidazole (14 mg,0.15 mmol), copper (II) acetate (5.8 mg,0.032 mmol), meOH (245 μl) and pyridine (6 μl,0.07 mmol). The reaction vessel was sealed and the suspension stirred at 60 ℃ for 10 hours. EtOAc and aqueous ammonia (28%) were added, the organic layer was separated and the aqueous ammonia (28%), water andthe aqueous saturated NaCl solution was washed, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 20 to 100% etoac/DCM as an elution system to afford the title compound (8 mg, 10%) as a white solid. ES-MS M/z 660 (M+H).
Preparation 373
2- (bromomethyl) -5-chlorobenzoic acid methyl ester
The title compound was prepared as described essentially in preparation 236 using methyl 5-chloro-2-methylbenzoate. The reactor output was stirred with water and aqueous sodium bisulphite, the layers separated and the aqueous phase extracted twice with heptane. The organics were combined, water (3×), saturated NaHCO 3 The aqueous solution was then washed with saturated aqueous NaCl solution. The organics were dried over magnesium sulfate, filtered and concentrated to give the title compound (67.99 g, 87%) as a yellow oil. 1 H NMR(400.21MHz,CDCl 3 )δ7.98(d,J＝2.2Hz,1H),7.49(dd,J＝2.3,8.3Hz,1H),7.43(d,J＝8.3Hz,1H),4.94(s,2H),3.97(s,3H).
Preparation 374
5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl ] benzoic acid methyl ester
A solution of methyl 2- (bromomethyl) -5-chloro-benzoate (20.0 g,67.5 mmol) in toluene (200 mL) was added to a mixture of 6-chloropyridin-2-ol (10.9 g,84.1 mmol) and silver carbonate (14.9 g,54.0 mmol). At N 2 The mixture was heated to 65 ℃ for 48 hours, the reaction vessel was protected from light with aluminum foil, and additional toluene (100 mL) was added. DCM (200 mL) was added to the reaction and the reaction was taken up byPad filtration, rinsing with DCM (100 mL)And (5) washing the pad. The filtrate was concentrated to a volume of 100mL and the first solid material was filtered off. The solid was washed with 1:1 toluene/heptane (50 mL) and heptane (2X 50 mL). To the filtrate was added 100mL of heptane, then the second batch of solid material was filtered off, washed with 1:1 toluene/heptane (50 mL) and heptane (2X 50 mL) as previously described. The filtrate was concentrated and the residue slurried in heptane (200 mL) at 50 ℃ for 30 minutes, then stirred at ambient temperature overnight. The third batch of solids was filtered off and the solids were washed with heptane (2X 50 mL). The first, second and third batches of solid material were combined and dried under reduced pressure at 50 ℃ for 5.5 hours to give the title compound (18.85 g, 89%) as a white solid. ES/MS M/z 312,314 (M+H).
Preparation 375
[ 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl ] phenyl ] methanol
At N 2 Downward 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl]To a mixture of methyl benzoate (14.78 g,46.87 mmol) in THF (75 mL) was added LiBH 4 (2M in THF, 35mL,70 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes, then MeOH (2.9 ml,72 mmol) was added in portions over 1 hour. To the mixture were added EtOAc (5 mL), water (10 mL), HCl (1M aqueous solution, 100 mL) and MTBE (300 mL) and the layers were separated. Separating the layers, using water (50 mL), K 2 CO 3 The organics were washed with aqueous (2M, 50 mL) and saturated aqueous NaCl (50 mL). The organics were dried over magnesium sulfate, filtered and the filtrate concentrated to give the title compound as a waxy solid (13.54 g, 97%). ES/MS M/z 284,286 (M+H).
Preparation 376
2- [ [2- [ (5-bromo-4-fluoro-2-iodo-phenyl) methoxymethyl ] -4-chloro-phenyl ] methoxy ] -6-chloro-pyridine
At N 2 THF (7.5 mL) was added to [ 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl ]]Phenyl group]To a mixture of methanol (0.50 g,1.7 mmol) and 1-bromo-5- (bromomethyl) -2-fluoro-4-iodobenzene (0.89 g,2.1 mmol) was then added potassium tert-butoxide (1M in tert-butanol, 2.2mL,2.2 mmol) in portions. The mixture was stirred at RT for 30 min, then water (30 mL) was added and the mixture was stirred at RT overnight to give the lower phase as a viscous mixture. The supernatant was decanted, water was added and water was decanted. The residue was dissolved in MeOH (55 mL) while heating to 60 ℃ and SiliaMetS Triamine (1 g) was added and heating at 60 ℃ was continued for 3.5 hours. By passing through The reaction was filtered while the pad was hot, the pad was rinsed with hot MeOH (15 mL) and the filtrate was concentrated. The residue was dissolved in MTBE (20 mL), filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 20% etoac/cyclohexane to give the title compound (0.75 g, 68%) as a colorless oil. ES/MS M/z 595,597,599 (M+H).
Preparation 377
2- [ 4-bromo-2- [ [ 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl ] phenyl ] methoxymethyl ] -5-fluoro-phenyl ] acetic acid ethyl ester
At N 2 Bromine- (2-ethoxy-2-oxo-ethyl) zinc (0.4M in THF, 3.4mL,1.4 mmol) was added to 2- [ (5-bromo-4-fluoro-2-iodo-phenyl) methoxymethyl ]]-4-chloro-phenyl]Methoxy group]-6-chloro-pyridine (0.58 g,0.91 mmol) and chloro [ (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) -2- (2 '-amino-1, 1' -biphenyl)]A mixture of palladium (II) (Pd-179,Xantphos Pd G2,45mg,0.045mmol) in THF (1 mL). The reaction mixture was heated to 60 ℃ for 10 hours. The reaction mixture was partitioned between water (15 mL), aqueous citric acid (5 mL), and MTBE. With 5mL portions of water, K 2 CO 3 The organic phase was washed with aqueous solution (2M) and saturated aqueous NaCl solution. Concentrating the organic material toPurified on and by silica gel chromatography using a gradient of 5 to 40% etoac/cyclohexane to give the title compound as a colorless oil (311 mg, 58%). 1 H NMR(400.13MHz,CDCl 3 )δ7.56-7.52(m,2H),7.46-7.44(m,2H),7.32(dd,J＝2.2,8.1Hz,1H),7.07(d,J＝9.0Hz,1H),6.94(d,J＝6.8Hz,1H),6.66(d,J＝7.6Hz,1H),5.36(s,2H),4.66(s,2H),4.57(s,2H),4.11(q,J＝7.1Hz,2H),3.68(s,2H),1.22(t,J＝7.1Hz,3H).
Preparation 378
2-(5 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetic acid ethyl ester
To 2- [ 4-bromo-2- [ [ 5-chloro-2- [ (6-chloro-2-pyridinyl) oxymethyl ]]Phenyl group]Methoxymethyl group]-5-fluoro-phenyl]A mixture of ethyl acetate (0.59 g,1.0 mmol), bis (neopentyl glycol) diboron (0.28 g,1.2 mmol) and potassium pivalate (0.36 g,2.5 mmol) in dry THF (40 mL) was sparged with N 2 After 10 minutes, chloro (2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (X-Phos-Pd-G2, 42mg,0.052 mmol) was added. The reaction mixture was heated at 45℃for 1.5 hours, then at 55℃for 1 hour, then more bis (neopentyl glycol) diboron (46 mg,0.20 mmol) was added and heating continued at 55℃for 45 minutes. Tripotassium phosphate (1.0M in water, 3mL,3.0 mmol) was added and heating was continued for 2 hours at 55deg.C. The reaction mixture was stirred at K 2 CO 3 The layers were partitioned between aqueous (2M, 25 mL) and DCM (100 mL) and separated. The aqueous layer was extracted with DCM (25 mL), and the organics were combined and passed throughAnd (5) filtering. The filtrate was concentrated and the residue was purified by silica gel chromatography using DCM. The product was triturated with a mixture of DCM (5 mL) and heptane (20 mL) and the solid dried in vacuo at 40℃to give a white solid The title compound (144 mg, 32%) as a coloured solid. ES/MS M/z 442,444 (M+H)/(S/S)>
Preparation 379
2-(5 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetic acid
LiOH (1M aqueous solution, 2.1mL,2.1 mmol) was added to 2- (5) 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 Suspension of ethyl acetate (227 mg,0.51 mmol) in a mixture of THF (7 mL) and MeOH (3.4 mL). The mixture was heated at 60℃for 1 hour. The reaction mixture was concentrated and aqueous citric acid (5%) was added. The solid was filtered off, washed with water and dried in vacuo at 40 ℃ to give the title compound (246 mg,90 mass%, 100%) as a white solid. ES-MS M/z 414,416 (M+H).
Preparation 380
(S)-2-((5 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester
To 2- (5) under nitrogen atmosphere 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) acetic acid (246 mg,0.535mmol,90 mass%) and 4-amino-3- (2-methoxyethoxy) -5- [ [ (2S) -oxetan-2-yl]Methylamino group ]To a solution of methyl benzoate (183mg, 0.59 mmol) in anhydrous DMF (6 mL) was added pyridine (492. Mu.L, 6.08 mmol) and 2,4, 6-tripropyl-1,3,5,2,4,6-trioxatriphosphohexane-2, 4, 6-trioxide (1.68M in EtOAc, 800. Mu.L, 1.34 mmol). At the position ofThe mixture was stirred at RT for 30 min, then water was added. The solid was filtered off, washed with water and dried overnight at 40 ℃. A suspension of the solid in 1, 2-dichloroethane (6.4 mL) and acetic acid (6.4 mL) was stirred in N 2 Heated overnight at 60℃under an atmosphere. The reaction mixture was cooled, diluted with EtOAc and water and the solid was filtered off. The organic layer was separated, dried over sodium sulfate, filtered and the organics concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 50% etoac/DCM to afford the title compound (2910 mg, 75%) as a white solid. ES-MS M/z 688,690 (M+H).
Example 1
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Will (S) -2- ((5) 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester, (200 mg,0.257 mmol) and 1,5, 7-triazabicyclo [4.4.0 ]A mixture of dec-5-ene (300 mg,2.11 mmol) in ACN: water (4.0 mL:1.0 mL) was stirred at 60℃for 5 hours. The mixture was adjusted to pH 6 with 1.0M aqueous hydrochloric acid. The whole reaction mixture was purified by C18 reverse phase chromatography eluting with a gradient of 40 to 70% acn/0.225% formic acid in water to give 33mg of the title compound (21%). ES-MS M/z 605 (M+H).
Example 2
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
To (S) -2- ((5 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]To a solution of imidazole-6-carboxylic acid methyl ester (0.24 g,0.38 mmol) in ACN: water (5.0 mL:1.0 mL) was added 1,3,4,6,7,8-hexahydro-2 h-pyrimido [1,2-a ]]Pyrimidine (50 mg,0.40 mmol). Stirred at RT for 15 hours and then at 60℃for 4 hours. The reaction mixture was concentrated to half volume and neutralized to pH 7 with 1M aqueous citric acid. The mixture was diluted with water (100 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 5 to 100% solvent B/solvent a, wherein solvent B was 20% meoh/EtOAc and solvent B was DCM. The product was further purified by C18 reverse phase chromatography using a gradient of 25 to 40% acn/10mM ammonium bicarbonate in water (5% meoh) to give 40mg of the title compound (17%). ES-MS M/z 623 (M+H).
Example 3
(S)-2-((5 4 -chloro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
To (S) -2- ((5 4 -chloro-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]To a mixture of ACN: THF: meOH (0.80 mL:0.50 mL) was added aqueous lithium hydroxide (1.0M, 0.75 mL) methyl imidazole-6-carboxylate (45 mg,0.074 mmol). The mixture was stirred at 40℃for 6 hours and at 55℃for 30 minutes. Adsorbing the mixture toAnd purified by C18 reverse phase chromatography eluting with a gradient of 0 to 100% acn/10mM ammonium bicarbonate in water (5% meoh) to give 22mg of the title compound (49%). ES-MS M/z 596 (M+H).
Example 4
(S)-2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Will (S) -2- ((5) 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (240 mg,0.40 mmol) and 1,5, 7-triazabicyclo [4.4.0 ]A mixture of dec-5-ene (170 mg,1.20 mmol) in 1, 4-dioxane: ACN: water (5:5:1, 11 mL) was stirred at 60℃for 3 hours, at 25℃for 16 hours, and then at 50℃for 72 hours. The mixture was concentrated to one-fourth volume and purified by C18 reverse phase chromatography eluting with a gradient of 10 to 80% acn/10mM ammonium bicarbonate in water (5% meoh) to give 160mg of the title compound (68%). ES-MS M/z 587 (M+H).
Example 5
(S)-2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Will (S) -2- ((5) 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (230 mg,0.28 mmol) and 1,5, 7-triazaBicyclo [4.4.0]A mixture of dec-5-ene (170 mg,1.20 mmol) in 1, 4-dioxane: ACN: water (5:5:1, 11 mL) was stirred at 50℃for 16 hours, 65℃for 4 hours, and then 50℃for 72 hours. The mixture was concentrated to one-fourth volume and purified by C18 reverse phase chromatography eluting with a gradient of 10 to 80% acn/10mM ammonium bicarbonate in water (5% meoh) to give the title compound (170 mg, 72%). ES-MS M/z 617 (M+H).
Example 6
(S)-2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -3- (oxetan-2-ylmethyl) -3H-imidazo [4,5-b]Pyridine-5-carboxylic acid
(S) -2- ((5) was used essentially as described in example 5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -3- (oxetan-2-ylmethyl) -3H-imidazo [4,5-b]Pyridine-5-carboxylic acid methyl ester the title compound was prepared. ES-MS M/z 588 (M+H).
Example 7
(S)-2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester the title compound was prepared. ES-MS M/z 605 (M+H).
Example 8
(S)-2-((5 4 -cyano-1 6 -fluoro-9-oxa-3-aza-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 5 4 -cyano-1 6 -fluoro-9-oxa-3-aza-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester the title compound was prepared in ACN: THF: water (1:1:0.4). The mixture was heated at 50 ℃ for 4 hours, cooled to RT and quenched with 1M citric acid solution. The mixture was extracted three times with EtOAc. The organics were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography using a gradient of 35 to 70% acn/20mM ammonium bicarbonate aqueous solution to give the title compound as a white solid. ES-MS M/z 604 (M+H).
Example 9
(S)-2-((5 4 -cyano-16-methyl-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenz-cyclononatomato-14-yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 5 4 -cyano-1 6 -methyl-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester the title compound was prepared. ES-MS M/z 631 (M+H).
Example 10
(S)-2-((5 4 -cyanogen Base-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 5 4 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester the title compound was prepared. The mixture was heated at 60 ℃ for 2 hours under nitrogen atmosphere, then cooled to RT and quenched with citric acid (5% aqueous). The solid was filtered and then washed with water and ACN to give the title compound as a white solid. ES-MS M/z 605 (M+H).
Example 11
2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Direction 2- ((5) 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ]]To a solution of imidazole-6-carboxylic acid methyl ester (39.7 mg,0.06 mmol) in ACN (0.75 mL), THF (0.19 mL) and water (0.12 mL) was added 1,3,4,6,7,8-hexahydro-2 h-pyrimido [1,2-a ] ]Pyrimidine (35 mg,0.25 mmol). The mixture was stirred at 45℃for 3 hours. Adding further 1,3,4,6,7,8-hexahydro-2 h-pyrimido [1,2-a ]]Pyrimidine (7.5 mg,0.05 mmol) was reacted at 50℃with stirring for 1 hour. The reaction was quenched with formic acid to pH 6-7 and extracted with EtOAc. Dilute with water and extract with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. By using 28 to 64% (1:1 acn: meoh)/(65 mM ammonium acetate in water:ACN 90:10 solution) to afford 11.8mg of the title compound (30%). ES-MS M/z 625 (M+H).
Example 12
(S)-1 4 - ((4-methoxy-1- (oxetan-2-ylmethyl) -6- (1H-tetrazol-5-yl) -1H-benzo [ d)]Imidazol-2-yl) methyl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-5 4 -carbonitrile
(S) -2- (5) 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) -N- (2-methoxy-6- ((oxetan-2-ylmethyl) amino) -4- (1H-tetrazol-5-yl) phenyl) acetamide (56 mg,0.05 mmol) in acetic acid (1.0 mL) was stirred at 65 ℃ for 12 hours. The solution was concentrated and azeotroped with ACN. The residue was purified by C18 reverse phase chromatography using a gradient of 41 to 83% (1:1 acn: meoh)/25 mM ammonium carbonate in water to give 9.4mg of the title compound (28%). ES-MS M/z 641 (M+H).
Example 13
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 6, 9-trioxa-2 (2, 6) -pyridinio-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 1 4 -cyano-1 6 -fluoro-3, 6, 9-trioxa-2 (2, 6) -pyridinio-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester was reacted at 45 ℃ with stirring for 2 hours to prepare the title compound. Upon completion, the reaction was quenched with formic acid to pH 7 and the crude mixture was diluted with water. The mixture was extracted three times with EtOAc. The organic phase is treated withDried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 40% (9:1 DCM: meoh (1% formic acid))/DCM to give the title compound. ES-MS M/z 607 (M+H).
Example 14
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 2 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] ]Imidazole-6-carboxylic acid methyl ester was reacted at 45℃with stirring for 19 hours, then 1, 4-dioxane was added and stirred at 45℃for 23 hours to prepare the title compound. The reaction was quenched with formic acid to pH 6-7 and extracted with EtOAc then with 3:1 chloroform: 2-propanol extraction. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography using a gradient of 30 to 73% (1:1 acn: meoh)/25 mM ammonium carbonate in water to give the title compound. ES-MS M/z 591 (M+H).
Example 15
(S)-2-((5 4 -cyano-1 6 -methyl-3, 9-dioxa-1, 2 (1, 3), 5 (1, 2) -triphenylheterocyclicallyl-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 4 4 -cyano-1 6 -methyl-3, 9-dioxa-1, 2 (1, 3), 5 (1, 2) -triphenylheterocyclicallyl-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester the title compound was prepared. After completion, the reaction mixture was concentrated to one-fourth volume, neutralized with citric acid solution and purified by C18 reverse phase chromatography eluting with a gradient of 10 to 80% acn/10mM ammonium bicarbonate aqueous solution (5% meoh) to give the title compound. ES-MS M/z 630 (M+H).
Example 16
(S) -4-methoxy-2- ((1) 6 -methyl-5 4 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylheterocyclo-nonatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -4-methoxy-2- ((1) was used essentially as described in example 1 6 -methyl-5 4 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylheterocyclo-nonatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester the title compound was prepared using dioxane: ACN: water (6:6:1) as solvent and stirring at 50 ℃ for 2 hours. Upon completion, the reaction mixture was neutralized with citric acid and concentrated. The residue was diluted with EtOAc and washed with water and saturated aqueous NaCl. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel using a gradient of 10 to 80% (20% meoh/EtOAc)/DCM to give the title compound. ES-MS M/z 674 (M+H).
Example 17
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 2 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester the title compound was prepared. The reaction was stirred at 45℃for 4 hours. The mixture was cooled to RT, filtered and the filtrate evaporated. By using 30 to 73% solvent B/solvent A (solvent A= [65mM NH4OAc+ACN (90:10))]The method comprises the steps of carrying out a first treatment on the surface of the Solvent b=acn]) The residue was purified by reverse phase chromatography of a gradient to give the title compound as a white solid. ES-MS M/z 621 (M+H).
Example 18
(S)-2-((5 4 -bromo-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 3 4 -bromo-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester and 2:1thf: meoh were used as solvent to prepare the title compound. Stirred at 65℃for 1.5 hours and 1M KH was added 2 PO 4 An aqueous solution. The reaction was diluted 2.5 times with water and cooled for 45 minutes with stirring. The solid was collected by filtration and washed with 1:3MeOH: water followed by water. The filter cake was dried under reduced pressure at 50 ℃ for 20 hours to give the title compound as a white solid. ES-MS M/z 640 and 642 (M+H).
Example 19
(S)-2-((5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 1 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester the title compound was prepared in 3:1:1acn: thf: water. The mixture was heated at 55 ℃ for 3 hours, cooled to RT and quenched with 5% aqueous citric acid to ph=4-5 to precipitate a white solid. The solid was filtered, washed with water (3 times) and ACN and dried under vacuum overnight at 45 ℃ to give the title compound as a white solid. ES-MS M/z587 (M+H).
Example 20
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 1 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester the title compound was prepared in 3:1:1acn:1, 4-dioxane in water as solvent. The reaction was heated to 60 ℃ for 3 hours, then cooled to RT and quenched with citric acid solution (5% aqueous). Dilute with EtOAc, separate the phases and extract the aqueous phase twice with EtOAc. The organic phases were combined, washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. By SFC [ column: chiralpak 20X 250mm,5 μm; isotonic mobile phase: 35% CO 2 /(MeOH+0.5% dimethylethylamine), 100 bar, flow rate 65mL/min]The residue was purified to give the title compound as a white solid. ES-MS M/z 591 (M+H).
Example 21
(S)-2-((5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 1 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (90 mg,0.14 mmol) the title compound was prepared in 3:1:1 ACN:1, 4-dioxane/water as solvent. The reaction was heated to 60 ℃ for 1 hour, cooled to RT and quenched with aqueous citric acid (5%). The solid was filtered and washed with water and then acetonitrile to provide the title compound as a white solid. ES-MS M/z 587 (M+H).
Example 22
(S) -4-methoxy-2- ((1) 6 -methyl-5 4 - (fluoro) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -4-methoxy-2- ((1) was used essentially as described in example 4 6 -methyl-5 4 - (fluoro) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester was reacted at 50 ℃ with stirring for 2 hours to prepare the title compound. Concentrating the reaction, neutralizing with aqueous citric acid solution, and treating with 10 to 80% ACN/10mM NH 4 HCO 3 Gradient C18 reverse phase chromatography purification of aqueous solution (5% meoh). ES-MS M/z 624 (M+H).
Example 23
2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl) -4-methoxy-1- (oxazol-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Use 2- ((5) as essentially described in example 1 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl) -4-methoxy-1- (oxazol-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid ethyl ester was reacted at 65 ℃ with stirring for 72 hours to prepare the title compound. The mixture was concentrated to one-fourth volume and adjusted to ph=5 using formic acid. The resulting precipitate was collected and purified by using 10 to 80% ACN/10mM NH 4 HCO 3 Gradient elution of aqueous solution (5% meoh) was purified by C18 reverse phase chromatography to give the title compound as a colorless solid. ES-MS M/z 628 (M+H).
Example 24
(S)-2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 1 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester the title compound was prepared using 5:5:11, 4-dioxane: ACN as solvent, water and stirring at 45 ℃ for 16 hours. The mixture was concentrated to one-fourth volume and adjusted to ph=5 with formic acid. Diluting the mixture with water andthe organics were extracted with chloroform/isopropanol (3:1). The organics were dried over magnesium sulfate, filtered and concentrated. The title compound was purified by flash chromatography eluting with a gradient of 0 to 40% (10% formic acid/MeOH)/DCM. ES-MS M/z 661 (M+H).
Example 25
(S)-2-((5 4 - (hydroxymethyl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Sodium borohydride (5.3 mg,0.14 mmol) was added to (S) -2- ((5) 4 -formyl-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylheterocyclo-nonatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid (30 mg,0.051 mmol) was in slurry in a mixture of MeOH (460. Mu.L) and THF (1 mL). The mixture was stirred for 5 minutes and then warmed to RT. The reaction was stirred for 20 min, then volatiles were removed at RT with a nitrogen stream. Aqueous citric acid (5%) was added and stirred for 5 minutes, the solid was filtered and washed with water and MeOH. The solid was purified by silica gel chromatography using 10% meoh/DCM to provide the title compound (8 mg, 25%) as a white solid. ES-MS M/z 592 (M+H).
Example 26
(S) -4-methoxy-2- ((1) 6 -methyl-5 6 - (trifluoromethyl) -3, 9-dioxa-2 (2, 6), 5 (3, 2) -dipyridyl-1 (1, 3) -phenylheterocyclo-nonatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid; 1,3,4,6,7,8-hexahydro-2H-pyrimido [1,2-a]Pyrimidine
(S) -4-methoxy-2- ((1) was used essentially as described in example 4 6 -methyl-5 6 -(Trifluoromethyl) -3, 9-dioxa-2 (2, 6), 5 (3, 2) -dipyridyl-1 (1, 3) -phenylheterocycloagula-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester was reacted at 45 ℃ with stirring for 16 hours to prepare the title compound. Neutralization with aqueous citric acid, concentration of the mixture, and concentration of the mixture by using 10 to 80% ACN/10mM NH 4 HCO 3 Gradient C18 reverse phase chromatography purification of aqueous solution (5% meoh). ES-MS M/z 675 (M+H).
Example 27
(S) -4-methoxy-2- ((1) 6 -methyl-3, 9-dioxa-2 (2, 6), 5 (4, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -4-methoxy-2- ((1) was used essentially as described in example 4 6 -methyl-3, 9-dioxa-2 (2, 6), 5 (4, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester was reacted at 50 ℃ with stirring for 2 hours to prepare the title compound. Concentrating the reaction, neutralizing with aqueous citric acid solution, and treating with 10 to 80% ACN/10mM NH 4 HCO 3 Gradient C18 reverse phase chromatography purification of aqueous solution (5% meoh). The purified product was redissolved in DCM and neutralized with aqueous citric acid. The organics were washed with water and saturated aqueous NaCl solution. Dried over sodium sulfate, filtered and concentrated to give the title compound. ES-MS M/z 607 (M+H).
Example 28
(S) -1- (oxetan-2-ylmethyl) -2- ((5) 4 - (1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-1 4 -methyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
DMF (0.43 mL) and tripotassium phosphate (1M aqueous solution, 0.13mL,0.13 mmol) were added to the mixture containing (S) -2- ((5) 4 -bromo-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid (30 mg,0.0436 mmol), 1- (oxetan-3-ylmethyl) -4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (19 mg,0.0698 mmol) and 1,1' -bis (di-tert-butylphosphino) ferrocene palladium dichloride (1.4 mg,0.0021 mmol). The vessel was purged with nitrogen, sealed and the mixture was stirred at 60 ℃ for 2 hours. Cooled to ambient temperature and then cooled by using ACN/10mM NH 4 HCO 3 C18 reverse phase chromatography with aqueous solution as eluent directly purified the mixture.
Combined with material from the second, similar reaction, the resulting solid was suspended in 1:1 DCM: etoac and partially concentrated under reduced pressure to remove DCM. The suspension was stirred at ambient temperature for 10 min, then the solid was collected by filtration and washed with EtOAc. Drying under reduced pressure at 50℃for 16 hours gave 28mg of the title compound as a white solid (average value of each of the two reactions: 41%). ES-MS m/z 698.
Example 29
(S)-2-((5 4 - (6-methoxypyridin-3-yl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Will (S) -2- ((5) 4 -bromo-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid (30 mg,0.0436 mmol), 2-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (22 mg,0.094 mmol) and 1,1' -bis (di-tert-butylphosphino) ferrocene dichloridePalladium (3 mg,0.0045 mmol) was added to a glass tube with a stirring rod. The tube was purged with nitrogen and tripotassium phosphate (1M aqueous, 0.13mL,0.13 mmol) and DMF (0.5 mL) were added. The mixture was stirred at 60℃for 16 hours. 1,1' -bis (di-t-butylphosphino) ferrocene palladium dichloride (3 mg,0.0045 mmol) was further added to the reaction and heated at 60℃for 3 hours, followed by heating at 90℃for 16 hours. The mixture was cooled to ambient temperature and then ACN/10mM NH was used 4 HCO 3 C18 reverse phase chromatography with aqueous as eluent directly purified the reaction mixture to give the title compound (4.7 mg, 14%) as a solid. ES-MS m/z 669.
The following examples were prepared essentially as in example 29 using the appropriate boric acid or borate esters.
/>
/>
/>
/>
/>
/>
/>
Example 40
(S)-2-((5 4 - (1-methyl-1H-pyrazol-4-yl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
The title compound was prepared essentially as described in example 29 using 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole, stirring at 60 ℃ for 2 hours and omitting the second addition of catalyst. The crude reaction mixture was loaded onto a Hydrophobic Lipophilic Balance (HLB) resin and reacted with 10mM NH 4 HCO 3 The aqueous buffer was eluted, then with 1:1 DCM: meOH. The fractions containing the title compound were concentrated and then used with ACN/10mM NH 4 HCO 3 The aqueous gradient C18 reverse phase chromatography was further purified. ES-MS m/z 642.
Example 41
(S)-1 4 - ((1- (oxetan-2-ylmethyl) -6- (1H-tetrazol-5-yl) -1H-benzo [ d)]Imidazol-2-yl) methyl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-5 4 -carbonitrile
To (S) -1 4 - ((1- (oxetan-2-ylmethyl) -6- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-tetrazol-5-yl) -1H-benzo [ d)]Imidazol-2-yl) methyl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-5 4 To a solution of formonitrile (100 mg,0.1 mmol) in THF (2 mL) was added TBAF (1M in THF, 0.3mL, 0).3 mmol). The mixture was stirred at 60℃for 16 hours. The reaction was quenched with water and diluted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was suspended in an aqueous ammonia solution and stirred at 50 ℃ for 6 hours. Concentrated under reduced pressure and the solid purified by C18 reverse phase chromatography using a gradient of 30 to 70% acn/ammonium acetate in water to give 93mg of the title compound (10%). ES-MS M/z 611 (M+H).
Example 42
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 6-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
To (S) -2- ((5 4 -cyano-1 6 -fluoro-3, 6-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]To a solution of imidazole-6-carboxylic acid methyl ester (92 mg,0.15 mmol) in ACN (8.4 mL) and water (4.8 mL) was added 1,3,4,6,7,8-hexahydro-2H-pyrimido [1,2-a ]]Pyrimidine (87 mg,0.61 mmol). Stir at 45 ℃ overnight. The mixture was cooled to RT, diluted with water and extracted three times with 3:1 DCM in isopropanol. The organics were combined, washed with water and saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using a gradient of 30% EtOAc/DCM and then 0 to 5% (10:1 MeOH: formic acid)/DCM. By using 41 to 83% [1:1 ACN: meOH ]Reverse phase chromatography of 0.1% aqueous formic acid (pH 3) was again purified to give the title compound (12 mg, 13%) as a white solid. ES-MS M/z 591 (M+H).
Example 43
(S)-2-((5 5 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6), 5 (2, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid diformate
To (S) -2- ((5 5 -cyano-1 6 -fluoro-3, 9-dioxa-2 (2, 6), 5 (2, 3) -dipyridyloxy-1 (1, 3) -phenylheterocyclylalanyl-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]To a suspension of imidazole-6-carboxylic acid methyl ester (66 mg,0.10 mmol) in ACN (1.2 mL), THF (0.3 mL) and water (0.2 mL) was added 1,3,4,6,7,8-hexahydro-2H-pyrimido [1,2-a ]]Pyrimidine (0.032 g,0.23 mmol). The suspension was stirred at 45℃for 6 hours. The mixture was cooled to RT, formic acid was added until ph=4 and extracted with EtOAc (3×5 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 50% solvent B/solvent a (wherein solvent b= (DCM/MeOH/formic acid 9:0.9:0.1) and solvent a=dcm) to give the title compound as an off-white solid (15 mg, 24%). ES-MS M/z 636 (M+H-formate).
Example 44
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
To (S) -2- ((5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (57 mg,0.09 mmol) 1,5, 7-triazabicyclo [4.4.0 ] in a suspension of degassed ACN (0.9 mL), 1, 4-dioxane (0.3 mL) and water (0.3 mL)]Dec-5-ene (38 mg,0.27 mmol). The reaction mixture was heated at 60 ℃ for 2 hours, cooled to RT, 5% aqueous citric acid was added to ph=5, then water (2.0 mL) was added and the mixture was stirred at RT for 15 minutes. Filtering the obtained solidThe body was washed with water (5 mL) and dried under vacuum overnight at 45 ℃. The solid was suspended in MeOH (1.0 mL) and the mixture stirred at RT for 15 min. The resulting solid was filtered, washed with MeOH (0.5 mL), etOAc (1.5 mL) and dried overnight in vacuo at 45 ℃ to give the title compound (19 mg, 34%) as a pale brown solid. ES-MS M/z 635.2/636.2 (M+H).
Example 45
(S)-2-((5 4 -chloro-1 6 ,5 6 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
At 55℃to (S) -2- ((5) 4 -chloro-1 6 ,5 6 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]To a solution of imidazole-6-carboxylic acid methyl ester (245 mg,64% purity, 0.21 mmol) in ACN (2.4 mL), water (0.8 mL) and THF (0.8 mL) was added 1,5, 7-triazabicyclo [4.4.0]Dec-5-ene (210 mg,1.47 mmol). The mixture was stirred at 55 ℃ for 2 hours, cooled to RT, 5% aqueous citric acid was added until ph=4-5, and the white solid precipitated was filtered. The solid was dissolved in ACN/MeOH and purified by preparative HPLC [ column: welch Xtime C18X 30mm X5 μm; mobile phase: 30 to 70% ACN/formic acid aqueous solution (0.225%)]Purification gave the title compound (31 mg, 20%) as a white solid. ES-MS M/z 706 (M+H).
Example 46
(S)-2-((5 5 -cyano-3, 8-dioxa-2, 5 (2, 6) -dipyridyl-1 (1, 3) -phenylheterocycle nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 5 5 -cyano-3, 8-dioxa-2, 5 (2, 6) -dipyridyl-1 (1, 3) -phenylheterocycle nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (63 wt% purity) in a mixture of ACN: THF: water (3:1:1) was reacted under nitrogen at 55 ℃ for 2 hours to prepare the title compound. The mixture was cooled to RT and quenched with aqueous citric acid (5%) then the solid was filtered and washed with water. By means of preparative HPLC [ column: welch Xtime C18X 30mm,5 μm; mobile phase: 25 to 65% ACN/formic acid aqueous solution (0.225%)]Purification gave the title compound as a white solid. ES-MS M/z 662 (M+H).
Example 47
(S)-2-((5 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 2 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester in 10:5:3acn:1, 4-dioxane as solvent: the title compound was prepared by stirring the reaction mixture in water at 55 ℃ for 6 hours 30 minutes. Concentrating the crude reaction mixture to And by using 10 to 73% ACN/NH 4 HCO 3 Gradient C18 reverse phase chromatography purification of aqueous solution (10 mM with 5% meoh) afforded the title compound. ES-MS M/z 688 (M+H).
Example 48
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
To (S) -2- ((5 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]To a mixture of imidazole-6-carboxylic acid (15 mg,0.022 mmoL), potassium ferrocyanide trihydrate (14.5 mg,0.039 mmoL), XPhos Pd (crotyl) Cl (Pd-170, 5.5mg,0.008 mmoL) and KOAc (5.6 mg,0.056 mmoL) was added 1, 4-dioxane (1.0 mL) and water (0.4 mL). The mixture was stirred at 90℃for 4 hours. Concentrating the reaction mixture toAnd by using 10 to 73% ACN/NH 4 HCO 3 Gradient C18 reverse phase chromatography purification of aqueous solution (10 mM with 5% meoh) afforded 8.2mg of the title compound (55%). ES-MS M/z 679 (M+H).
Example 49
(S)-2-((5 4 -cyano-2 3 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] ]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 45 4 -cyano-2 3 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 Methyl) -4-)(2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester the title compound was prepared. By means of preparative HPLC [ column: welch Xtime C18X 25mm,5 μm; mobile phase: 25 to 70% ACN/TFA aqueous solution (0.1%)]And (5) purifying. The organic solvent was removed under reduced pressure and the residual aqueous solution was lyophilized to give the title product as a white solid. ES-MS M/z 679 (M+H).
Example 50
(S)-2-((5 4 -cyano-6, 6-difluoro-3.8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Will (S) -2- ((5) 4 -cyano-6, 6-difluoro-3.8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (61 mg,0.086 mmol) was dissolved in ACN (1 mL), 1, 4-dioxane (0.3 mL) and water (0.3 mL). 1,5, 7-Triazabicyclo [4.4.0 ] is added to the solution]Dec-5-ene (0.04 g,0.28 mmol) and the mixture was stirred at ambient temperature for 18 hours. Thereafter, the reaction was quenched with 1N HCl (to pH 5) and extracted with EtOAc. The organics were dried over magnesium sulfate, filtered and concentrated. Reversed phase HPLC [ column: phenomenex Kinetex EVO C18 100X 30mm,5 μm; mobile phase: 23 to 58% ACN/NH 4 HCO 3 Aqueous solution (10 mM 5% MeOH)]The material was purified to give the title compound as a white solid (14.5 mg, 24.1%). ES-MS (M/z) 697.4 (M+H).
Example 51
(S)-2-((5 4 -cyano-3, 8-dioxa-2 (2, 4) -pyrimidinyl-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 2 4 -cyano-3, 8-dioxa-2 (2, 4) -pyrimidinyl-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester as starting material the title compound was prepared using 5:2:1acn:1, 4-dioxane, water as solvent and heating the reaction to 40 ℃ for 21 hours. After completion, the reaction was cooled to ambient temperature and quenched with 5% aqueous citric acid to bring the pH to 4. The resulting precipitate was filtered and the solid was washed with water. The collected solids were dried under reduced pressure to give the title compound. ES/MS M/z 618 (M+H).
Example 52
(S) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -2- ((5) 6 - (trifluoromethyl) -3, 8-dioxa-2 (2, 6), 5 (3, 4) -dipyridyl-1 (1, 3) -phenylheterocyclo-nonatomato-1 4 -methyl) -1H-benzo [ d ] ]Imidazole-6-carboxylic acid
(S) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -2- ((5) is used essentially as described in example 2 6 - (trifluoromethyl) -3, 8-dioxa-2 (2, 6), 5 (3, 4) -dipyridyl-1 (1, 3) -phenylheterocyclo-nonatomato-1 4 -methyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester and 2.8:1:1acn: thf as solvent were reacted with water at 45 ℃ for 2 hours to prepare the title compound. The reaction was quenched with 1M aqueous citric acid to bring the pH to 4.5. The resulting colorless solid was filtered and dried in vacuo. Purification by reverse phase chromatography on a C18 column using a gradient of 42% to 75% acn/formic acid in water (0.225%) gave the title compound. ES/MS M/z 705 (M+H).
Example 53
(S)-2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenylHeterocyclic nine-tomato-1 4 -yl) methyl) -4- (2- (2-methyl oxazol-4-yl) ethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
(S) -2- ((5) was used essentially as described in example 5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2- (2-methyl oxazol-4-yl) ethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester and using a 3:1:1acn: thf: water mixture as solvent, the reaction was stirred at 35 ℃ for 6 hours to prepare the title compound. After completion, the mixture was concentrated and the residue was dissolved in minimum DMSO. The DMSO solution was filtered and passed through a preparative HPLC [ column: welch Xtime C18X 30mm,5 μm; mobile phase: 10 to 45% ACN/NH 4 HCO 3 Gradient of (10 mM) aqueous solution]The filtrate was purified to give the title compound as a white solid. ES/MS M/z 712 (M+H).
Example 54
(S)-2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -4- (2- ((2, 2-trifluoroethyl) amino) ethoxy) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
To (S) -4- (2- ((tert-butoxycarbonyl) (2, 2-trifluoroethyl) amino) ethoxy) -2- ((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]To a solution of imidazole-6-carboxylic acid (preparation 311,75mg,0.058 mmol) in toluene (7 mL) was added silica gel (750 mg) and the mixture was heated to 120℃for 18 hours. The mixture was cooled to ambient temperature, filtered and concentrated in vacuo. By means of preparative HPLC [ column: xtimate C18 100X 30mm,10 μm; mobile phase: gradient of 35 to 65% ACN/formic acid aqueous solution (0.2%)]The residue was purified to give the title compound (2.5 mg, 5.7%) as a colorless solid. ES/MS M/z 728.6 (M+H).
Example 55
(S) -4- [ 2-hydroxyethoxy ]]-2-((5 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
To a solution of (S) -4- [2- [ tert-butyl (dimethyl) silyl ] oxyethoxy ] -2- ((54-chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenz-cyclonona-14-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (62 mg,0.079 mmol) in THF (5 mL) and MeOH (2 mL) was added LiOH (10 mg,0.42 mmol) dissolved in water (2 mL) and heated to 45 ℃ for 1.5 hours. More LiOH (12 mg,0.050 mmol) dissolved in water (1 mL) was added and heated at 45 ℃ for an additional hour, cooled to ambient temperature and concentrated under reduced pressure. The crude material was suspended in water (20 mL) and the pH was adjusted to 5 with 1N HCl. The solid was filtered, collected and dried under reduced pressure. Purification by C18 reverse phase chromatography eluting with 30-60% ACN/10mM ammonium bicarbonate in water (5% MeOH) afforded the title compound (7.5 mg, 14%). ES/MS (M/z): 656.4 (M+H).
Example 56
(S)-2-((5 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2- (dimethylamino) ethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
To (S) -2- ((5 4 Chloro-3, 8-dioxa-2 (2, 6) dioxetanes Pyridino-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2- (dimethylamino) ethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (89 mg,0.12 mmol) 1,5, 7-triazabicyclo [4.4.0 ] in a nitrogen sparge mixture of ACN (2 mL), 1, 4-dioxane (1 mL) and water (0.22 mL)]Dec-5-ene (60 mg,0.42 mmol). The reaction mixture was heated at 60℃for 16 hours. The mixture was cooled to ambient temperature, concentrated under reduced pressure and the residue was purified by reverse phase chromatography using a gradient of 10 to 80% ACN/water (0.1% formic acid added to both ACN and water) to give the title compound (42 mg, 48%) as a colourless solid. ES/MS M/z 683 (M+H).
Example 57
(S)-2-((5 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2- (methylamino) ethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
To (S) -4- (2- ((tert-butoxycarbonyl) (methyl) amino) ethoxy) -2- ((5) in DCM (2 mL) 4 -chloro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]To imidazole-6-carboxylic acid (12.3 mg,0.016 mmol) was added TFA (0.1 mL,1 mmol). The mixture was stirred at ambient temperature for 15 min, then the reaction was concentrated under reduced pressure and the residue was purified by reverse phase chromatography using a gradient of 10 to 90% acn/water (0.1% formic acid added to both solvents) to give the title compound (2.2 mg, 21%). ES/MS (M/z): 669 (M+H).
Example 58
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
1,5, 7-Triazabicyclo [4.4.0]Dec-5-ene (29 mg,0.20 mmol) was added to (S) -2- ((5) 4 -cyano-1 6 -fluoro-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]A degassed suspension of imidazole-6-carboxylic acid methyl ester (50 mg,0.069 mmol) in a mixture of ACN (1.4 mL), 1, 4-dioxane (0.5 mL), and water (0.5 mL). At N 2 The mixture was heated at 60 ℃ for 1.5 hours, cooled to RT and quenched with aqueous citric acid (5%). The solid was filtered and washed with water then ACN to afford the title compound (34 mg, 70%) as a colorless solid. ES-MS M/z 679 (M+H).
Example 59
2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- ((1-methylpyrrolidin-3-yl) oxy) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Will 2- ((5) 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- ((1-methylpyrrolidin-3-yl) oxy) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (90 mg,0.12 mmol) and 1,5, 7-triazabicyclo [4.4.0]A solution of dec-5-ene (55 mg,0.39 mmol) in a nitrogen sparge mixture of 1, 4-dioxane (0.4 mL), water (0.4 mL) and ACN (0.4 mL) was stirred at 25℃for 6 hours. The mixture was adjusted to pH 7 with formic acid and concentrated. By using 6 to 46% mecn/aqueous ammonium hydroxide (0.04%) +nh 4 HCO 3 The residue was purified by reverse phase chromatography (10 mM) gradient to give 30.5mg of the title compound (35%). ES-MS M/z 686 (M+H).
Example 60
(S)-2-((5 4 -cyano-1 6 ,2 3 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
To (S) -2- ((5 4 -cyano-1 6 ,2 3 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (250 mg,0.16 mmol) in THF (1.17 mL), water (1.17 mL) and ACN (3.51 mL) were added 1,5, 7-triazabicyclo [ 4.4.0)]Dec-5-ene (150 mg,1.06 mmol). The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated to 45 ℃ and stirred at this temperature for 2 hours. The reaction was quenched with 1M aqueous citric acid to ph=4.5, then the colorless solid was filtered and dried under reduced pressure. By preparative HPLC (column: welch Xtime C18X 25mm,5 μm); mobile phase: the solid was purified to give the title compound (53.9 mg, 49%) ES-MS M/z 697 (M+H) as a colorless solid.
Example 61
(S)-2-((5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Will (S) -2- ((5) 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -methyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (20 mg,0.03 mmol) and 1,3,4,6,7, 8-hexahydro-2H-pyrimido [1,2-A]A solution of pyrimidine (20 mg,0.1 mmol) in ACN (6 mL) and water (4 mL) was stirred at 45℃for 7 hours. The pH was adjusted to 6 with formic acid and extracted with 3:1 chloroform isopropanol. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 10% (meoh+10% formic acid)/DCM to give 4mg of the title compound (20%). ES-MS M/z 605 (M+H).
Example 62
(S)-2-((5 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2- (dimethylamino) -2-oxoethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Will (S) -2- ((5) 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2- (dimethylamino) -2-oxoethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] ]A solution of imidazole-6-carboxylic acid methyl ester (50 mg,0.0356 mmol) and trimethyltin hydroxide (34 mg,0.178630 mmol) in 1, 2-dichloroethane (1 mL) was stirred at 80℃for 16 h. The temperature was increased to 90 ℃ for 7 hours, then to 100 ℃ for 72 hours. Additional trimethyltin hydroxide (34 mg,0.178 mmol) was added and heated to 105 ℃ for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. 15% aqueous citric acid (1 mL) was added to form a gum, which was slowly filtered on a sintered funnel. The gum was washed with water (2 mL) and dried in a vacuum oven at 60 ℃. By means of preparative HPLC [ column: phenomenex Kinetex EVO C18 250X 30mm,5 μm; mobile phase: 0 to 100% ACN/NH 4 HCO 3 Gradient of (10 mM+5% MeOH) aqueous solution]The crude product was purified to give the title compound as a colourless solid (12.5 mg, 51%). ES-MS M/z 688 (M+H).
Example 63
2-((5 4 -cyano-3, 9-dioxa-2(2, 6) -Pyridinza-1 (1, 3), 5 (1, 2) -Diphenyl-heterocycle Jiuzhan-1 4 -yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -4-methoxy-1H-benzo [ d ]]Imidazole-6-carboxylic acid
Sparging 1,5, 7-triazabicyclo [4.4.0 ] using nitrogen]A solution of dec-5-ene (28 mg, 0.197mmol) in a mixture of ACN (0.4 mL), 1, 4-dioxane (0.4 mL) and water (0.15 mL) for 10 min. 2- ((5) is added to the reaction vessel 4 -cyano-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -4-methoxy-1H-benzo [ d ]]An anaerobic solution of imidazole-6-carboxylic acid methyl ester (44 mg,0.065 mmol). The mixture was stirred at ambient temperature for 24 hours. The reaction mixture was partitioned between EtOAc and 0.1M aqueous HCl. The organic layer was separated and washed with saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure. By means of preparative HPLC [ column: phenomenexEVO C18.times.30mm, 5. Mu.m; mobile phase: gradient of 14 to 48% ACN/formic acid aqueous solution (0.1%)]The residue was purified to give the title compound (8.2 mg, 19%). ES-MS M/z 655 (M+H).
Example 64
(S)-2-((5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
To (S) -2- ((5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (23 mg,0.033 mmol) 1,5, 7-triazabicyclo [4.4.0 ] in a suspension of degassed ACN (0.5 mL), THF (0.2 mL) and water (0.2 mL) ]Dec-5-ene (15 mg,0.11 mmol). The mixture was heated to 55 ℃ for 3 hours, then cooled to RT and 5% aqueous citric acid was added to make ph=4-5. The resulting solid was filtered, washed with water (3 times) and ACN, and then dried under vacuum overnight at 45 ℃ to give the title compound (15 mg, 63%) as an off-white solid. ES-MS M/z 661 (M+H).
Example 65
(S)-2-((5 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
1,5, 7-Triazabicyclo [4.4.0]Dec-5-ene (26 mg,0.18 mmol) was added to (S) -2- ((5) 4 -cyano-3, 8-dioxa-2 (2, 6) -pyrido-1, 5 (1, 3) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (45 mg,0.067 mmol) in a degassed suspension in a mixture of ACN (1.4 mL), 1, 4-dioxane (0.5 mL) and water (0.5 mL). At N 2 The mixture was heated at 60 ℃ for 1.5 hours, cooled to RT and quenched with aqueous citric acid (5%). The solid was filtered and washed with water then ACN to afford the title compound (26 mg, 59%) as a white solid. ES-MS M/z 661 (M+H).
Example 66
(S)-2-((5 4 - (4-fluoro-1H-imidazol-1-yl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Aqueous LiOH (1M, 120. Mu.L, 0.12 mmol) was added to (S) -2- ((5) 4 - (4-fluoro-1H-imidazol-1-yl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid methyl ester (30 mg,0.045 mmol) was suspended in a mixture of MeOH (300. Mu.L) and THF (600. Mu.L) and stirred at 60℃for 12 hours. The reaction mixture was concentrated and aqueous citric acid (5%) was added. The solid was filtered off, washed with water, ACN and MeOH to afford the title compound (11 mg, 47%) as a pale brown solid. ES-MS M/z 646 (M+H).
Example 67
(S)-2-((5 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Aqueous LiOH (1M, 1.6mL,1.6 mmol) was added to (S) -2- ((5) 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] ]Imidazole-6-carboxylic acid methyl ester (284 mg,0.39 mmol) was suspended in a mixture of THF (8.5 mL) and MeOH (4.3 mL). The mixture was heated at 60℃for 3 hours. The reaction mixture was concentrated, aqueous citric acid (5%) was added, and the solid was filtered off and washed with water and ACN. The solid was dried in vacuo at 40 ℃ to give the title compound as a white solid (284 mg, 100%). ES-MS M/z 674,676 (M+H).
Example 68
(S)-2-((5 4 -cyano-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Charging (S) -2- ((5) into a reaction vessel 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid (61 mg,0.087 mmol), potassium ferrocyanide trihydrate (57 mg,0.135 mmol), KOAc (19 mg,0.19 mmol) and chloro (crotyl) (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) palladium (II) (Pd-170, XPhos Pd (crotyl) Cl,6.2mg,0.009 mmol)]. By N 2 The reaction mixture was purged and DMF (1.7 mL) and water (0.9 mL) were added. Again using N 2 The mixture was purged for 5 minutes, the vessel was sealed and stirred overnight at 90 ℃. The mixture was cooled to RT, aqueous citric acid (5%) was added, the solid filtered off and washed with water and ACN. By means of preparative HPLC [ column: XBridge C18 x 150mm,5 μm, mobile phase: 30 to 50% ACN/NH 4 HCO 3 Gradient of aqueous solution (20 mM, pH 9)]The solid was purified to provide the title compound (9 mg, 16%) as a white solid. ES-MS M/z 665 (M+H).
Example 69
(S) -N- ((cyclopropylmethyl) sulfonyl) -2- ((5 4 -fluoro-1 6 -methyl-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4-methoxy-1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxamide
To (S) -4-methoxy-2- ((1) 6 -methyl-5 4 - (fluoro) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]To a solution of imidazole-6-carboxylic acid (100 mg,0.16 mmol) in DCM (2 mL) was added 4-dimethylaminopyridine (20 mg,0.16 mmol)Cyclopropylmethylsulfonamide (35 mg,0.26 mmol), TEA (0.1 mL,0.7 mmol), and N 2 The mixture was gently purged for 10 minutes. EDC (50 mg,0.26 mmol) was added to the reaction mixture, stirred at RT overnight, and then heated at 40℃for 4 hours. The reaction was quenched with aqueous citric acid (5%) and diluted with DCM. The phases were separated and the aqueous layer was extracted twice with DCM. The organic phases are combined, washed with saturated aqueous NaCl, dried over sodium sulfate, the solid filtered off and the solvent removed under reduced pressure. By means of preparative HPLC [ column: xbridge C18X 19mm,5 μm, mobile phase: 50 to 80% ACN/NH 4 CO 3 Gradient of aqueous solution (20 mm, ph=9)]The residue was purified to give the title product (28 mg, 23.6%) ES-MS M/z 741 (M+H) as a white solid.
Example 70
(S)-2-((5 4 -cyano-1 6 ,5 6 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Use of (S) -2- ((5) as described essentially in example 68 4 -chloro-1 6 ,5 6 -difluoro-3, 8-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid was used as starting material and a 2.5:1 mixture of 1, 4-dioxane: water was used as solvent and the reaction was heated to 90 ℃ for 4 hours to prepare the title compound. By means of preparative HPLC [ column: c18 100X 30mm,5 μm; mobile phase: gradient of 15 to 85% ACN/formic acid aqueous solution (0.225%)]Purification gave the title compound as a white solid. ES-MS M/z 697 (M+H).
Example 71
(S)-2-((5 4 - (3-fluoro-4-oxopyridin-1 (4H) -yl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocycleJiuqian-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] ]Imidazole-6-carboxylic acid
Charging (S) -2- ((5) into a reaction vessel 4 -bromo-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid (51 mg,0.079 mmol), 3-fluoropyridin-4-ol (14 mg,0.12 mmol), cuprous iodide (I) (1.6 mg,0.008 mmol) and K 2 CO 3 (22 mg,0.156 mmol). By N 2 The reaction vessel was purged, and then anhydrous DMSO (80. Mu.L) and 2, 6-tetramethyl-3, 5-heptanedione (7. Mu.L, 0.033 mmol) were added. The reaction mixture was stirred at 120℃for 9 hours. The mixture was cooled to RT, aqueous citric acid (5%) was added, and the solid was filtered off and washed with water. By means of preparative HPLC [ column: XBIdge C18X 150mm,5 μm; mobile phase: 30 to 60% ACN/NH 4 HCO 3 Gradient of aqueous solution (20 mM, pH 9)]Purification provided the title compound (10 mg, 18%) as a white solid. ES-MS M/z 673 (M+H).
Example 72
(S)-2-((5 4 - (4-methyl-1H-imidazol-1-yl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Anhydrous DMSO (0.06 mL) is added to (S) -2- ((5) 4 -bromo-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid (20 mg,0.031 mmol), 4-methylimidazole (10 mg,0.119 mmol), tripotassium phosphate (13 mg,0.059 mmol), N 1 ,N 2 Bis (furan-2-ylmethyl) oxamide (3 mg,0.012 mmol) and cuprous (I) oxide (5mg,0.034 mmol) of the mixture. The reaction vessel was purged with argon, sealed and heated to 120 ℃ with stirring for 19 hours. The reaction mixture in DCM (20 mL) was mixed with a second mixture prepared under similar conditions with bis (tetrabutylammonium iodide) cuprous (I) iodide (7 mg, 0.006mmol) instead of cuprous (I) oxide. Water (5 mL), 2-propanol (5 mL), aqueous citric acid (5%, 5 mL) and saturated aqueous NaCl solution (20 mL) were added, and the mixture was then shaken and the phases were separated. The aqueous phase was extracted with 4:1 DCM:2-propanol (50 mL in two). The aqueous phase pH was adjusted to 3 using aqueous tripotassium phosphate and extracted again with 4:1 dcm:2-propanol (15 mL). The organic extracts were combined and concentrated under reduced pressure. By using 30 to 60% ACN/NH 4 HCO 3 The residue was purified by reverse phase chromatography (10 mm, ph=9) gradient of aqueous solution to give the title compound (6 mg, 15%) as a solid. ES-MS M/z 642 (M+H).
Example 73
(S)-2-((5 4 - (1H-imidazol-1-yl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Anhydrous DMSO (0.20 mL) is added to (S) -2- ((5) 4 -bromo-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid (30 mg,0.046 mmol), imidazole (13 mg,0.189 mmol), tripotassium phosphate (20 mg,0.091 mmol), N 1 ,N 2 In a mixture of bis (furan-2-ylmethyl) oxamide (5 mg,0.02 mmol) and cuprous (I) oxide (3 mg,0.02 mmol). The vessel was purged with argon, sealed and then heated to 120 ℃ with stirring for 20 hours. Transfer reaction mixture to MeOH washed strong anion exchange resin cartridgeSAX), and sequentially with 7:3 MeOH/water, meOH, DCM and 1:1 DCM: meOH (3% acetic acid). The fractions containing the title compound were combined and concentrated under reduced pressure. The residue was dissolved in DMSO and then purified by using 30 to 60% ACN/NH 4 HCO 3 (10 mm, ph=9) gradient of aqueous solution. The appropriate fractions were concentrated under reduced pressure. The solid residue was triturated in 1:1 DCM: etOAc (4 mL) and the mixture was partially concentrated to remove DCM. The suspension was centrifuged to remove the supernatant, and the residue was dried under reduced pressure at 50 ℃ for 24 hours to give 9.4mg of the title compound as a white solid (29% yield). ES-MS M/z 628 (M+H).
Example 74
(S) -1- (oxetan-2-ylmethyl) -2- ((5) 4 - (4-oxopyridin-1 (4H) -yl) -3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo nona-tomato-1 4 -methyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Anhydrous DMSO (80. Mu.L) and 2, 6-tetramethyl-3, 5-heptanedione (7. Mu.L, 0.033 mmol) are added to (S) -2- ((5) 4 -bromo-3, 9-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyl heterocyclo-nona-tomato-1 4 -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid (50 mg,0.078 mmol), 4-hydroxypyridine (10 mg,0.102 mmol), copper (I) iodide (1.6 mg,0.008 mmol), and K 2 CO 3 (22 mg,0.156 mmol) in a nitrogen purge. The vessel was sealed and stirred at 120℃for 16 hours. The mixture was cooled to RT, aqueous citric acid (5%) was added, and the solid was filtered off and washed with water. By means of preparative HPLC [ column: XBIdge C18X 150mm,5 μm; mobile phase: 25 to 55% ACN/NH 4 HCO 3 Gradient of aqueous solution (20 mm, ph=9)]The solid was purified, then the solid product was washed with MeOH and ACN to give the title compound (11 mg, 18%) as a colorless solid. ES-MS M/z 655 (M+H).
Example 75
(S)-2-((1 6 -fluoro-5 4 - (1-methyl)-6-oxo-1, 6-dihydropyridin-3-yl) -3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -diphenyloctatomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid
Charging (S) -2- ((5) into a reaction vessel 4 -chloro-1 6 -fluoro-3, 7-dioxa-2 (2, 6) -pyrido-1 (1, 3), 5 (1, 2) -dibenzo-octatomato-1 4 -yl) methyl) -4- (2-methoxyethoxy) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]Imidazole-6-carboxylic acid (61 mg,0.087 mmol), 1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (43 mg,0.174 mmol) and chloro (crotyl) (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) palladium (II) (Pd-170, XPhos Pd (crotyl) Cl,6.2mg,0.009 mmol). By N 2 The vessel was purged, DMF (860. Mu.L) and aqueous tripotassium phosphate (1M, 260. Mu.L, 0.26 mmol) were added and the mixture was stirred at 90℃for 2.5 hours. The mixture was cooled to RT, aqueous citric acid (5%) was added, the solid filtered off and washed with water and ACN. By means of preparative HPLC [ column: xbridge C18, 19X 150mm,5 μm; mobile phase: 30 to 60% ACN/NH 4 HCO 3 (20 mM, pH=9)]The solid was purified to afford the title compound (9.5 mg, 14%) as a pale brown solid. ES-MS M/z 747 (M+H).
Biological detection
Human GLP-1 receptor HEK293 cell cAMP detection
Determination of GLP-1 receptor functional Activity Using cAMP formation in HEK293 clone cell lines expressing human GLP-1R (NCBI accession No. NP-002053) at expression densities of 581+ -94 (n=6) and 104+ -12 (n=5) fmol/mg protein (using [ use ] 125 I]GLP-1(7-36)NH 2 Homologous competition binding assay). In a 20. Mu.l assay volume (final DMSO concentration 0.5%) 1 XGlutaMAX was supplemented TM (Gibco Cat#35050), 0.1% bovine casein (Sigma C4765-10 ML), 250. Mu.M IBMX (3-isobutyl-1-methylxanthine, acros Cat# 228420010) and 20mM HEPES (Gibc)hGLP-1R receptor expressing cells were treated with compound (20-point concentration response curve in DMSO, 2.75-fold Labcyte Echo direct dilution, 384 well plate Corning Cat # 3570) in DMEM (Gibco Cat # 31053) of o Cat # 15630. After incubation at 37 ℃ for 30 minutes, the increase in intracellular cAMP was quantified using CisBio cAMP Dynamic HTRF assay kit (62 AM4 PEJ). Briefly, by adding cAMP-d2 conjugate (10. Mu.L) in cell lysis buffer followed by antibody anti-cAMP-Eu 3+ Cryptates (also in cell lysis buffer) (10 μl), detect intracellular cAMP levels. The resulting competitive assay (competitive assay) was incubated at room temperature for at least 60 minutes, then using a PerkinelmerThe instrument detects at 320nm excitation and at 665nm and 620nm emissions. Envision units (emission at 665nM/620nM 10,000) are inversely proportional to the amount of cAMP present and converted to nM cAMP per well using a cAMP standard curve. The amount of cAMP (nM) generated in each well was converted to human GLP-1 (7-36) NH 2 Percent of maximum response observed. Using the maximum percent response vs. added compound concentration, the relative EC was deduced by nonlinear regression analysis 50 Value and highest percentage (percentage top) (E max ) Fitting to a four parameter logistic equation. EC when testing the compounds of examples 1-80 in the above cAMP assay using HEK293 cells expressing 581 and 104fmol/mg GLP-1R 50 And E is max The data are shown in tables 1 and 2, respectively. These data indicate that the compounds of examples 1-80 are agonists of the human GLP-1 receptor.
TABLE 1 relative EC of intracellular cAMP response of HEK293 cell lines with GLP-1R expression density of 581fmol/mg 50 And E is max
/>
/>
TABLE 2 relative EC of intracellular cAMP response of HEK293 cell lines with a GLP-1R expression density of 104fmol/mg 50 And E is max
/>
/>
EC 50 Nm=geometric mean, post-SEM (delta method), number of observations in parentheses.
E max The%=arithmetic mean, post-plus ± SEM, the number of observations in parentheses, for GLP-1 (7-36) NH at hGLP-1R 2 The maximum response percentage of (2)
GLP-1R CHO Cell beta-inhibitor protein recruitment assay
The activated G protein-coupled receptor may interact with the β -arrestin family of signaling proteins. The efficacy of the compounds for GLP-1R induced inhibition protein recruitment was determined using the PathHunter enzyme fragment complementation method (von Degenfeld et al, FASEB J.,2007 (14): 3819-26 and Hamdouchi et al, J.Med chem.,2016 59 (24): 10891-10916) essentially as described. CHO-K1 cells expressing Pro-Link labeled human GLP-1R and enzyme receptor labeled β -arrestin-2 can be obtained from discover rx and prepared as frozen cells ready for detection. Test compounds were dissolved in DMSO and serially diluted using an Echo acoustic dispenser (LabCyte). The assay medium was PathHunter cell assay buffer (discover Rx) containing 0.1% w/v hydrolyzed casein (Sigma). Will be 100n L test compound solution was dispensed into 10. Mu.L of assay medium in 384 well plates, and then 10. Mu.L of cells were added to the assay medium to obtain 5000 cells per well. The plates were incubated at 37℃at 5% CO 2 Incubate for 90 minutes in incubator and add 10 μl PathHunter detection reagent (discover rx) and incubate the plate at RT for 60 minutes. The luminescence signal is measured. Fitting a compound concentration-response curve to a four-parameter logistic model to calculate EC 50 And the highest percentage (E max ) Efficacy of the form. The percent stimulation was data normalized using DMSO and GLP-1 (7-36) as minimum and maximum controls (Campbell et al Assay Guidance Manual 2017). The efficacy of the sample compounds to stimulate GLP-1R induced β -arrestin recruitment is reported in table 3.
TABLE 3 relative EC of hGLPLR-induced beta-arrestin-2 recruitment 50 And E is max
Examples EC 50 nM(SEM，n) E max ％(SEM，n)
1 213(36.7，n＝9) 42.9(1.85，n＝9)
2 133(6.65，n＝7) 52.7(1.78，n＝7)
3 320(29.4，n＝7) 34(2.44，n＝7)
12 ＞49500(n＝1) 9.47(1.44，n＝7)

Claims (51)

1. A compound of the formula:
wherein-A-is-CR a R b CR a R b CR b R b O-、-OCR b R b CR a R b CR a R b -、-OCR b R b CR b R b O-、-CR a R b CR b R b OCR b R b -、-CR b R b OCR b R b CR a R b -、-CR b R b OCR b R b -、-CR a R b CR b R b O-or-OCR b R b CR a R b -；
R a At each occurrence independently H, halogen, C 1 -C 2 Alkyl, OH or C 1 -C 3 An alkoxy group;
R b at each occurrence independently is H, halogen or C 1 -C 2 An alkyl group;
is->Wherein a is the point of attachment to linker A; b is the point of attachment to linker B;
X 1 、X 2 、X 3 and X 4 N, CH or CR independently 1 Wherein X is 1 、X 2 、X 3 And X 4 Not more than two of which are N, and X 1 、X 2 、X 3 And X 4 Not more than two of them are CR 1 ；
X 5 Is N, CH or CR 1a ，X 6 、X 7 And X 8 N, CH or CR independently 1 Wherein X is 5 、X 6 、X 7 And X 8 Not more than two of which are N, and X 5 、X 6 、X 7 And X 8 Not more than two of them are CR 1a Or CR (CR) 1 ；
R 1 Independently at each occurrence is CN; halogen; c optionally substituted by OH 1 -C 3 An alkyl group; c (C) 1 -C 3 A haloalkyl group; c (C) 1 -C 3 An alkoxy group; c (C) 3 -C 5 Cycloalkyl; -SO 2 C 1 -C 3 An alkyl group;wherein each X 9 Is independently CH or N, and no more than one X in the ring 9 Is N, each R e Independently selected from: H. c (C) 1 -C 3 Haloalkyl, halogen, C 3 -C 5 Cycloalkyl and optionally OH-substituted C 1 -C 3 Alkyl, R h Is H, C 1 -C 3 Haloalkyl, halogen, C 3 -C 5 Cycloalkyl, OH, -NR c R d Or C optionally substituted by OH 1 -C 3 An alkyl group;
a 5-or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is optionally substituted with one or two substituents independently selected from: c (C) 1 -C 3 Alkoxy, C 3 -C 5 Cycloalkyl, -CH 2 -C 3 -C 5 Cycloalkyl, -SO 2 C 1 -C 3 Alkyl, C 4 -C 5 Heterocyclyl, -CH 2 -C 4 -C 5 Heterocyclyl, halogen, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, CN, -CONR c R d 、-NR c R d Or C optionally substituted by OH 1 -C 3 An alkyl group;
R 1a is CN; halogen; c optionally substituted by OH 1 -C 3 An alkyl group; c (C) 1 -C 3 A haloalkyl group; or C 1 -C 3 An alkoxy group;
-B-is-CH 2 O-、-OCH 2 -or-CH 2 NH-；
Y 1 、Y 2 And Y 7 N, CH or CR independently 2 Wherein Y is 1 、Y 2 And Y 7 Not more than one of them is N, and Y 1 、Y 2 And Y 7 Not more than two of them are CR 2 ；
Y 3 、Y 4 、Y 5 And Y 6 N, CH or CR independently 2 Wherein Y is 3 、Y 4 、Y 5 And Y 6 Not more than two of which are N, and Y 3 、Y 4 、Y 5 And Y 6 Not more than two of them are CR 2 ；
R 2 Independently at each occurrence is halogen or methyl;
Z 1 、Z 2 and Z 3 N, CH or CR independently 3 Wherein Z is 1 、Z 2 And Z 3 Not more than two of which are N, and Z 1 、Z 2 And Z 3 Not more than two of them are CR 3 ；
R 3 Independently at each occurrence, is halogen; c (C) 1 -C 4 An alkyl group; optionally by C 1 -C 2 Alkoxy, OH, C 1 -C 3 Alkyl or C 1 -C 3 haloalkyl-substituted-OC 4 -C 6 Cycloalkyl; optionally by C 1 -C 2 Alkoxy, OH, C 1 -C 3 Alkyl or C 1 -C 3 Haloalkylsubstituted-OC 4 -C 6 A heterocyclic group; or C optionally substituted by one or two substituents 1 -C 4 Alkoxy, said substituents being selected from: c (C) 1 -C 2 Alkoxy, OH, -NR f R g 、-CONR c R d CN, halogen or optionally C 1 -C 3 Alkyl-substituted 5-or 6-membered heteroaryl;
R 4 is that
R 5 is-CO 2 H、
R c And R is d Each independently is H or C 1 -C 3 An alkyl group;
R f is H or C 1 -C 3 An alkyl group; and is also provided with
R g Is H, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 3 -C 5 Cycloalkyl, C (O) C 1 -C 3 Alkyl or C 1 -C 3 Alkyl C 3 -C 5 Cycloalkyl groups.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:
4. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:
5. a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein
Is->
6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein X 1 、X 3 And X 4 Is CH and X 2 Is CR (CR) 1 。
7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R 1 Is CN, cl, F, CF 3 、
8. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein X 1 Is N; x is X 2 Is CR (CR) 1 ；X 3 And X 4 Is CH.
9. Root of Chinese characterThe compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R 1 Is CF (CF) 3 。
10. The compound of claim 5, wherein X 1 、X 3 And X 4 Is CH; and X is 2 Is N.
11. The compound of claim 5, wherein X 1 And X 4 Is CH; x is X 2 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And X is 3 Is N.
12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein R 1 Is CF (CF) 3 。
13. The compound of claim 5, wherein X 1 And X 3 Is CH; x is X 2 Is CR (CR) 1 ；X 4 Is N.
14. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R 1 Is CN.
15. The compound of claim 5, wherein X 1 And X 3 Is CH; and X is 2 And X 4 Is CR (CR) 1 。
16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently selected from F, cl and CN.
17. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein
Is->
18. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein X 5 、X 7 And X 8 Is CH and X 6 Is CR (CR) 1 。
19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R 1 Is CN.
20. The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein X 5 Is N; x is X 6 Is CR (CR) 1 The method comprises the steps of carrying out a first treatment on the surface of the And X is 7 And X 8 Is CH.
21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein R 1 Is CN.
22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein-a-is-CH 2 CH 2 CH 2 O-、-CH 2 OCH 2 -、-CH 2 CH 2 OCH 2 -、CH 2 OCH 2 CH 2 -or-CF 2 CH 2 OCH 2 -。
23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein-B-is-CH 2 O-。
24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein Y 1 、Y 2 And Y 7 Are CH.
25. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein Y 1 Is CR (CR) 2 ，Y 2 Is CH, Y 7 Is CH and R 2 Is F.
26. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein Y 1 Is CR (CR) 2 ，Y 2 Is CH, Y 7 Is CH and R 2 Is methyl.
27. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Y 3 Is N; and Y is 4 、Y 5 Is CH; and Y is 6 Is CH or CR 2 。
28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein Y 6 Is CH.
29. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein Y 6 Is CR (CR) 2 And R is 2 Is F.
30. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Y 3 、Y 4 、Y 5 And Y 6 Are CH.
31. The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein Z 1 Is CH or CR 3 。
32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein Z 1 Is CR (CR) 3 And R is 3 Is F, -OCH 3 、-OCH 2 CH 2 OCH 3 、OCH 2 CH 2 OH or OCH 2 CH 2 N(CH 3 ) 2 。
33. A compound or according to claim 31Pharmaceutically acceptable salts thereof, wherein Z 1 Is CH.
34. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein Z 2 Is CH.
35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein Z 3 Is CH.
36. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R 5 is-CO 2 H。
37. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R 5 Is that
38. The compound of claim 1, selected from the group consisting of:
/>
or a pharmaceutically acceptable salt thereof.
39. A pharmaceutical composition comprising a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.
40. A method of treating type II diabetes in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof.
41. A method of lowering blood glucose levels in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof.
42. A method of treating hyperglycemia in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof.
43. The method of any one of claims 40-42, wherein the compound is administered orally.
44. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, for use in therapy.
45. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes.
46. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, for use in lowering blood glucose levels.
47. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, for use in the treatment of hyperglycemia.
48. A compound or pharmaceutically acceptable salt thereof for use according to any one of claims 44 to 47, wherein the compound is administered orally.
49. Use of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of type II diabetes.
50. Use of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for lowering blood glucose levels.
51. Use of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hyperglycemia.
CN202280036421.2A 2021-05-20 2022-05-19 Macrocyclic glucagon-like peptide 1 receptor agonists Pending CN117355517A (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US63/191034 2021-05-20
US202163254564P 2021-10-12 2021-10-12
US63/254564 2021-10-12
EP21383172.0 2021-12-21
PCT/US2022/029958 WO2022246019A1 (en) 2021-05-20 2022-05-19 Macrocyclic glucagon-like peptide 1 receptor agonists

Publications (1)

Publication Number Publication Date
CN117355517A true CN117355517A (en) 2024-01-05

Family

ID=89371512

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202280036421.2A Pending CN117355517A (en) 2021-05-20 2022-05-19 Macrocyclic glucagon-like peptide 1 receptor agonists

Country Status (1)

Country Link
CN (1) CN117355517A (en)

Similar Documents

Publication Publication Date Title
US10221162B2 (en) Triazole agonists of the APJ receptor
US10391082B2 (en) Protein kinase inhibitors
CN108137541B (en) Pyridone dicarboxamides for use as bromodomain inhibitors
EP2374802B1 (en) Kynurenine production inhibitor
EP4271672A1 (en) Carboxy-benzimidazole glp-1r modulating compounds
EP3902796B1 (en) (pyridin-2-yl)amine derivatives as tgf-beta r1 (alk5) inhibitors for the treatment of cancer
US20230339886A1 (en) Rev-erb agonists for the treatment of th17-mediated inflammatory disorders
KR20230173166A (en) Macrocyclic glucagon-like peptide 1 receptor agonist
CN117355517A (en) Macrocyclic glucagon-like peptide 1 receptor agonists
TWI843104B (en) Glucagon-like peptide 1 receptor agonists
JP7515049B2 (en) (Pyridin-2-yl)amine derivatives as TGF-beta R1 (ALK5) inhibitors for the treatment of cancer - Patents.com
WO2024102625A1 (en) Glucagon-like peptide 1 receptor agonists
EA043088B1 (en) (PYRIDIN-2-YL)AMINE DERIVATIVES AS TGF-BETA R1 (ALK5) INHIBITORS FOR THE TREATMENT OF MALIGNANT NEOPLASMS

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination