Macrocyclic glucagon-like peptide 1 receptor agonists

Abstract

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

Description

[0001] This invention relates to glucagon-like peptide-1 receptor agonists and the therapeutic use of said compounds for the treatment of type II diabetes.

[0002] Glucagon-like peptide-1 (GLP-1) is a member of the incretin family of peptide hormones secreted by enteroendocrine L-cells. GLP-1 induces β-cells to release insulin in a glucose-dependent manner. However, GLP-1 is rapidly metabolized such that only a small percentage of GLP-1 is available for inducing insulin secretion. To compensate for this, GLP-1 receptor (GLP-1R) agonists have been developed to enhance insulin secretion as a treatment for type 2 diabetes.

[0003] Most GLP-1R agonists approved for the treatment of type 2 diabetes are injectable. Patients generally prefer oral medications due to the disadvantages associated with injection, such as inconvenience, pain, and the possibility of injection site irritation.

[0004] WO2018 / 109607 discloses certain benzimidazole derivatives described as GLP-1R agonists. Other GLP-1 agonist compounds are disclosed in WO2019 / 239371, 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, and CN11. Among 3480534, WO2021 / 219019, WO2021 / 244645, WO2021 / 249492, CN113801136, WO2021 / 254470, WO2021 / 259309, WO2022 / 007979, WO2022 / 031994, WO2022 / 028572, WO2022 / 040600, WO2022 / 042691, WO2022 / 068772, WO2022 / 078407, WO2022 / 078380 and WO2022 / 078152.

[0005] However, alternative GLP-1R agonists are needed. Orally administered GLP-1R agonists are particularly needed. Especially important are effective GLP-1R agonists with favorable toxicological and / or pharmacokinetic profiles to support once-daily dosing.

[0006] Accordingly, the present invention provides compounds of the following formula:

[0007]

[0008] Where -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 -;

[0009] R a Each time it appears, it is independently H, halogen, C1-C2 alkyl, OH, or C1-C3 alkoxy;

[0010] R b Each time it appears, it is independently H, halogen, or C1-C2 alkyl;

[0011] yes Where a is the connection point with connection base A; b is the connection point with connection base B;

[0012] X 1 X 2 X 3 and X 4 Independently N, CH or CR1 , where X 1 X 2 X 3 and X 4 No more than two of them are N, and X 1 X 2 X 3 and X 4 No more than two of them are CR 1 ;

[0013] X 5 Is it N, CH or CR? 1a X 6 X 7 and X 8 Independently N, CH or CR 1 , where X 5 X 6 X 7 and X 8 No more than two of them are N, and X 5 X 6 X 7 and X 8 No more than two of them are CR 1a or CR 1 ;

[0014] R 1 Each time it appears independently, it is CN; halogen; C1-C3 alkyl optionally substituted with OH; C1-C3 haloalkyl; C1-C3 alkoxy; C3-C5 cycloalkyl; -SO2C1-C3 alkyl; Each X 9 It is independently CH or N, and there is no more than one X in the ring. 9 It is N, each R e Independently selected from: H, C1-C3 haloalkyl, halogen, C3-C5 cycloalkyl and C1-C3 alkyl optionally substituted with OH, R h It is H, C1-C3 haloalkyl, halogen, C3-C5 cycloalkyl, OH, -NR c R d Or C1-C3 alkyl groups optionally substituted with OH;

[0015] 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is optionally substituted by one or two substituents, the substituents being independently selected from: C1-C3 alkoxy, C3-C5 cycloalkyl, -CH2-C3-C5 cycloalkyl, -SO2C1-C3 alkyl, C4-C5 heterocyclic, -CH2-C4-C5 heterocyclic, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxy, CN, -CONR c Rd -NR c R d Or C1-C3 alkyl groups optionally substituted with OH;

[0016] R 1a CN; halogen; C1-C3 alkyl group optionally substituted with OH; C1-C3 haloalkyl group; or C1-C3 alkoxy group;

[0017] -B- can be -CH2O-, -OCH2-, or -CH2NH-;

[0018] Y 1 Y 2 and Y 7 Independently N, CH or CR 2 , where Y 1 Y 2 and Y 7 No more than one of them is N, and Y 1 Y 2 and Y 7 No more than two of them are CR 2 ;

[0019] Y 3 Y 4 Y 5 and Y 6 Independently N, CH or CR 2 , where Y 3 Y 4 Y 5 and Y 6 No more than two of them are N, and Y 3 Y 4 Y 5 and Y 6 No more than two of them are CR 2 ;

[0020] R 2 Each time it appears, it is independently either a halogen or a methyl group;

[0021] Z 1 Z 2 and Z 3 Independently N, CH or CR 3 Z 1 Z 2 and Z 3 No more than two of them are N, and Z 1 Z 2 and Z 3 No more than two of them are CR 3 ;

[0022] R 3Each occurrence is independently a halogen; a C1-C4 alkyl group; a -OC4-C6 cycloalkyl group optionally substituted with a C1-C2 alkoxy group, OH group, C1-C3 alkyl group, or C1-C3 haloalkyl group; a -OC4-C6 heterocyclic group optionally substituted with a C1-C2 alkoxy group, OH group, C1-C3 alkyl group, or C1-C3 haloalkyl group; or a C1-C4 alkoxy group optionally substituted with one or two substituents selected from: C1-C2 alkoxy group, OH group, -NR group. f R g -CONR c R d CN, halogen, or 5- or 6-membered heteroaryl groups optionally substituted with C1-C3 alkyl groups;

[0023] R 4 yes

[0024] R 5 It is -CO2H,

[0025] R c and R d Each is independently an H or C1-C3 alkyl group;

[0026] R f It is an H or C1-C3 alkyl group; and

[0027] R g It is H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C5 cycloalkyl, C(O)C1-C3 alkyl or C1-C3 alkylC3-C5 cycloalkyl;

[0028] Or its pharmaceutically acceptable salt.

[0029] Formula IX includes all individual enantiomers and their mixtures, as well as racemates.

[0030] In the implementation scheme, compounds of the following formula are provided:

[0031]

[0032] Or its pharmaceutically acceptable salt.

[0033] In the implementation scheme, compounds of the following formula are provided:

[0034]

[0035] Or its pharmaceutically acceptable salt.

[0036] In the implementation scheme, compounds of the following formula are provided:

[0037]

[0038] Or its pharmaceutically acceptable salt.

[0039] In the implementation schemes of formulas V, Va, and VI, Y 4 Y 5 Y 6 and Y 7 Both are CH.

[0040] In the implementation plan, yes In one implementation scheme yes X 1 X 3 and X 4 It is CH; and X 2 It is CR 1 In alternative implementations, yes X 1 It is N; X 2 It is CR 1 And X 3 and X 4 It is CH. In further alternative implementations, yes X 1 X 3 and X 4 It is CH; and X 2 It is N. In a further alternative implementation, yes X 1 and X 4 It is CH; X 2 It is CR 1 And X 3 It is N. In a further alternative implementation, yes X 1 and X 3 It is CH; X 2 It is CR 1 And X 4 It is N. In a further alternative implementation, yes X 1 and X 3 It is CH; and X 2 and X 4 It is CR 1 .

[0041] In the implementation plan, X 1 X 2 X 3 and X4 Only one of them is N.

[0042] In alternative implementation schemes, yes In one implementation scheme yes X 5 X 7 and X 8 It is CH; and X 6 It is CR 1 In alternative implementations, yes X 5 It is N; X 6 It is CR 1 And X 7 and X 8 It is CH.

[0043] In the implementation plan, X 5 X 6 X 7 and X 8 Only one of them is N.

[0044] In the implementation plan, R 1 CN; halogen; C1-C3 alkyl group optionally substituted with OH; C1-C3 haloalkyl group; Each R e Independently selected from: H, C1-C3 alkyl or halogen, and R h It is H or halogen; 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is optionally substituted with a substituent selected from: C1-C3 alkoxy, C3-C5 cycloalkyl, -SO2C1-C3 alkyl, C4-C5 heterocyclic, -CH2-C4-C5 heterocyclic, halogen, -CONR c R d -NR c R d Or optionally, a C1-C3 alkyl group substituted with OH, wherein R c and R d Each is independently an H or C1-C3 alkyl group.

[0045] In the implementation plan, R 1 It is CN, halogen, CF3, -CH2OH, Preferably, R 1 It is CN, Cl, F, CF3, In the implementation plan, R 1CN; halogen; C1-C3 alkyl group optionally substituted with OH; C1-C3 haloalkyl group; Each R e Independently selected from: H or C1-C3 alkyl; 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is optionally substituted with a substituent selected from: C1-C3 alkoxy, C3-C5 cycloalkyl, -SO2C1-C3 alkyl, -CH2-C4-C5 heterocyclic, -CONR c R d Or optionally, a C1-C3 alkyl group substituted with OH, wherein R c and R d Each is independently an H or C1-C3 alkyl group. In the embodiments, R 1 It is CN, halogen, CF3, -CH2OH, Preferably, R 1 It is CN, Cl, F, CF3, In a further implementation scheme, R 1 It is CN, halogen, C1-C3 alkyl, or C1-C3 haloalkyl. In the embodiments, R 1 It is CN, halogen, or CF3. In the implementation scheme, R 1 It is either CN or halogen.

[0046] In one implementation scheme yes X 1 X 3 and X 4 It is CH; X 2 It is CR 1 And R 1 CN; halogen; C1-C3 alkyl group optionally substituted with OH; C1-C3 haloalkyl group; Each R e Independently selected from: H, C1-C3 alkyl or halogen, and R h It is H or halogen; 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is optionally substituted with a substituent selected from: C1-C3 alkoxy, C3-C5 cycloalkyl, -SO2C1-C3 alkyl, C4-C5 heterocyclic, -CH2-C4-C5 heterocyclic, halogen, -CONR c R d -NR c R d Or optionally, a C1-C3 alkyl group substituted with OH, wherein R c and R dEach is independently an H or C1-C3 alkyl group. Preferably, R 1 It is CN, halogen, CF3, -CH2OH, More preferably, R 1 It is CN, Cl, F, CF3,

[0047] In one implementation scheme yes X 1 X 3 and X 4 It is CH; X 2 It is CR 1 And R 1 CN; halogen; C1-C3 alkyl group optionally substituted with OH; C1-C3 haloalkyl group; Each R e Independently selected from: H or C1-C3 alkyl; 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is optionally substituted with a substituent selected from: C1-C3 alkoxy, C3-C5 cycloalkyl, -SO2C1-C3 alkyl, -CH2-C4-C5 heterocyclic, -CONR c R d Or optionally, a C1-C3 alkyl group substituted with OH, wherein R c and R d Each is independently an H or C1-C3 alkyl group. Preferably, R 1 It is CN, halogen, CF3, -CH2OH, More preferably, R 1 It is CN, Cl, F, CF3, In a further implementation plan, X 1 X 3 and X 4 It is CH; X 2 It is CR 1 And R 1 It is CN. In a further implementation, X 1 X 3 and X 4 It is CH; X 2 It is CR 1 And R 1 It is Cl. In a further implementation, X 1 X 3 and X 4 It is CH; X2 It is CR 1 And R 1 It's CF3.

[0048] In alternative implementation schemes, yes X 1 It is N; X 2 It is CR 1 ;X 3 and X 4 It is CH; and R 1 It's CF3.

[0049] In alternative implementation schemes, yes X 1 and X 4 It is CH; X 2 It is CR 1 ;X 3 It is N; and R 1 It's CF3.

[0050] In alternative implementation schemes, yes X 1 and X 3 It is CH; X 2 It is CR 1 ;X 4 It is N; and R 1 It's CN.

[0051] In alternative implementation schemes, yes X 1 and X 3 It is CH; X 2 and X 4 It is CR 1 Furthermore, each R 1 Independently selected from halogens and CN. Preferably, each R 1 It is independently selected from F, Cl and CN.

[0052] In alternative implementation schemes, yes X 5 X 7 and X 8 It is CH; X 6 It is CR 1 And R 1 It is CN or Cl. Specifically, R. 1 It's CN.

[0053] In alternative implementation schemes, yes X 5 It is N; X 6 It is CR 1 ;X 7 and X 8 It is CH; and R 1 It's CN.

[0054] In the implementation scheme, -A- is -CH2CH2CH2O-, -OCH2CH2O-, -CH2CH2OCH2-, -CH2OCH2CH2-, -CH2OCH2-, -CH2CH2O-, -OCH2CH2-, or -CF2CH2OCH2-. In a particular implementation scheme, -A- is -CH2CH2CH2O-, -CH2OCH2-, -CH2CH2OCH2-, CH2OCH2CH2-, or -CF2CH2OCH2-.

[0055] In the implementation plan, -A- is -CHR a CHR a CHR b O-、-CHR b OCHR b -or-OCHR b CHR b O-. In a further implementation, -A- is -CHR a CHR a CHR b O-. In a particular implementation, -A- is -CHR. a CHR a CHR b O-, and R a and R b Each is H. In an alternative implementation, -A- is -CHR. b OCHR b In a particular implementation, -A- is -CHR. b OCHR b -and each R b It is H. In an alternative implementation, -A- is -OCHR b CHR b O-. In a particular implementation, -A- is -OCHR b CHR b O- and each R b It is H. In a particular embodiment, -A- is -CH2CH2CH2O-, -OCH2CH2O-, -CH2CH2OCH2-, -CH2OCH2- or -CH2CH2O-; preferably, A- is -CH2CH2CH2O- or -CH2OCH2-.

[0056] In one embodiment, -B- is -CH2O- or -CH2NH-. In an alternative embodiment, B is -CH2O- or -OCH2-. In a further embodiment, -B- is -CH2O-.

[0057] In the implementation plan, Y 3 It is N or CH. In the implementation plan, Y 3 It is N. In alternative implementations, Y 3 It is CH.

[0058] In the implementation plan, Y 4 It is CH.

[0059] In the implementation plan, Y 5 It is CH.

[0060] In the implementation plan, Y 6 Is it CH or CR? 2 .

[0061] In the implementation plan, Y 3 It is N; and Y 4 Y 5 It is CH; and Y 6 Is it CH or CR? 2 In a further implementation scheme, Y 3 It is N; and Y 4 Y 5 It is CH; and Y 6 It is CH. In a further implementation scheme, Y 3 It is N; and Y 4 Y 5 It is CH; and Y 6 It is CR 2 Preferably R 2 It is F. In an alternative implementation, Y 3 Y 4 Y 5 and Y 6 Both are CH. In a further alternative implementation, Y 3 and Y 6 It is N; and Y 4 and Y 5 It is CH.

[0062] In the implementation plan, Y 1 Is it CH or CR? 2 .

[0063] In the implementation plan, Y 2 It is CH.

[0064] In the implementation plan, Y 7 It is CH.

[0065] In the implementation plan, R 2 It is either F or methyl.

[0066] In the implementation plan, Y 1 Y 2 and Y 7 Both are CH. In alternative implementations, Y 1 It is CR 2 ;Y 2 It is CH; Y 7 It is CH; and R 2 It is F. In a further alternative implementation, Y 1 It is CR 2 ;Y 2 It is CH; Y 7 It is CH; and R 2 It is a methyl group.

[0067] In the implementation plan, Y 1 and Y 2 Both are CH. In alternative implementations, Y 1 It is CR 2 Y 2 It is CH, and R 2 It is F. In a further alternative implementation, Y 1 It is CR 2 Y 2 It is CH, and R 2 It is a methyl group.

[0068] In the implementation plan, Y 4 Y 5 Y 6 and Y 7 Both are CH.

[0069] In the implementation plan, Z 1 Is it CH or CR? 3 .

[0070] In the implementation plan, Z 2 It is CH.

[0071] In the implementation plan, Z 3 It is CH. In alternative implementations, Z 3 It is N.

[0072] In a specific implementation scheme, Z 2 and Z 3 Both are CH.

[0073] In the implementation plan, R 3It is a halogen; optionally substituted with a C1-C3 alkyl group (-OC4-C6 heterocyclic group); or optionally substituted with one or two substituents (C1-C4 alkoxy group), said substituent being selected from: C1-C2 alkoxy, OH, -NR f R g -CONR c R d Or optionally substituted with a C1-C3 alkyl group, 5- or 6-membered heteroaryl; wherein R c and R d Each is independently an H or C1-C3 alkyl group.

[0074] R f It is H or C1-C3 alkyl, and R g It is H, a C1-C3 alkyl group, or a C1-C3 haloalkyl group. In a particular embodiment, R 3 It is a halogenated or optionally substituted C1-C4 alkoxy group, wherein the substituents are selected from: C1-C2 alkoxy, OH, or -NR. f R g , where R f and R g Both are CH3; preferably, R 3 It is F, -OCH3, -OCH2CH2OCH3, OCH2CH2OH or OCH2CH2N(CH3)2.

[0075] In the implementation plan, R 3 It is a halogen, a C1-C4 alkoxy, or a -C1-C3 alkoxy or C1-C2 alkoxy; preferably, R 3 It is F, -OCH3, or -OCH2CH2OCH3. In alternative implementations, R 3 It is a halogen, C1-C2 alkyl, or methoxy group.

[0076] In the implementation plan, Z 1 It is CR 3 And R 3 It is a halogen; optionally substituted with a C1-C3 alkyl group (-OC4-C6 heterocyclic group); or optionally substituted with one or two substituents (C1-C4 alkoxy group), said substituent being selected from: C1-C2 alkoxy, OH, -NR f R g -CONR c R d Or optionally substituted with a C1-C3 alkyl group, 5- or 6-membered heteroaryl; wherein R c and R d Each is independently H or C1-C3 alkyl, R f It is H or C1-C3 alkyl, and R gIt is H, a C1-C3 alkyl group, or a C1-C3 haloalkyl group. In a further embodiment, Z 1 It is CR 3 And R 3 It is a halogenated or optionally substituted C1-C4 alkoxy group, wherein the substituents are selected from: C1-C2 alkoxy, OH, or -NR. f R g , where R f and R g Both are CH3; preferably, R 3 It is F, -OCH3, -OCH2CH2OCH3, OCH2CH2OH, or OCH2CH2N(CH3)2. In one embodiment, Z 1 It is CR 3 And R 3 It is F. In alternative implementations, Z 1 It is CH. In a further alternative implementation, Z 1 It is CR 3 And R 3 It is a methoxy group.

[0077] In the implementation plan, R 5 It is -CO2H. In alternative implementations, R 5 yes

[0078] In the implementation scheme, compounds of the following formula are provided:

[0079]

[0080] Where -A- is -CH2CH2CH2O-, -OCH2CH2O-, -CH2CH2OCH2-, -CH2OCH2CH2-, -CH2OCH2-, -CH2CH2O-, -OCH2CH2-, or -CF2CH2OCH2-;

[0081] yes Where a is the connection point with connection base A; b is the connection point with connection base B;

[0082] X 1 X 2 X 3 and X 4 Independently N, CH or CR 1 , where X 1 X 2 X 3 and X 4 No more than one of them is N, and X 1 X2 X 3 and X 4 No more than two of them are CR 1 ;

[0083] X 5 Is it N or CH, X 6 X 7 and X 8 Independently N, CH or CR 1 , where X 5 X 6 X 7 and X 8 No more than one of them is N, and X 6 X 7 and X 8 No more than one of them is CR 1 ;

[0084] R 1 Each time it appears independently, it is CN; halogen; C1-C3 alkyl group optionally substituted with OH; C1-C3 haloalkyl group; Each R e Independently selected from: H, C1-C3 alkyl or halogen, and R h It is H or halogen; 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is optionally substituted with a substituent selected from: C1-C3 alkoxy, C3-C5 cycloalkyl, -SO2C1-C3 alkyl, C4-C5 heterocyclic, -CH2-C4-C5 heterocyclic, halogen, -CONR c R d -NR c R d Or C1-C3 alkyl groups optionally substituted with OH;

[0085] -B- is either -CH2O- or -CH2NH-;

[0086] Y 1 Is it CH or CR? 2 ;

[0087] Y 3 It is N or CH;

[0088] Y 6 Is it N, CH or CR? 2 ;

[0089] R 2 Each time it appears, it is independently either a halogen or a methyl group;

[0090] Z 1 Is it CH or CR? 3 ;

[0091] Z 3 It is N or CH;

[0092] R 3 It is a halogen; optionally substituted with a C1-C3 alkyl group (-OC4-C6 heterocyclic group); or optionally substituted with one or two substituents (C1-C4 alkoxy group), said substituent being selected from: C1-C2 alkoxy, OH, -NR f R g -CONR c R d Or optionally substituted with C1-C3 alkyl groups of 5- or 6-membered heteroaryl groups;

[0093] R 4 yes

[0094] R 5 It is -CO2H,

[0095] R c and R d Each is independently an H or C1-C3 alkyl group;

[0096] R f It is an H or C1-C3 alkyl group; and

[0097] R g It is H, C1-C3 alkyl, or C1-C3 haloalkyl;

[0098] Or its pharmaceutically acceptable salt.

[0099] In one embodiment of formula VIII, -A- is -CH2CH2CH2O-, -CH2OCH2-, -CH2CH2OCH2-, CH2OCH2CH2-, or -CF2CH2OCH2-.

[0100] In one implementation of formula VIII yes X 1 X 3 and X 4 It is CH; and X 2 It is CR 1 In an alternative implementation of formula VIII, yes X 1 It is N; X 2 It is CR 1 And X 3 and X 4 It is CH. In a further alternative implementation of formula VIII, yes X1 X 3 and X 4 It is CH; and X 2 It is N. In a further alternative implementation of formula VIII, yes X1 and X4 are CH; X2 is CR1; and X3 is N. In a further alternative embodiment of formula VIII, yes X 1 and X 3 It is CH; X 2 It is CR 1 And X 4 It is N. In a further alternative implementation of formula VIII, yes X 1 and X 3 It is CH; and X 2 and X 4 It is CR 1 .

[0101] In one implementation of formula VIII yes X 5 X 7 and X 8 It is CH; and X 6 It is CR 1 In an alternative implementation of formula VIII, yes X 5 It is N; X 6 It is CR 1 And X 7 and X 8 It is CH.

[0102] In one implementation of formula VIII, R 1 It is CN, halogen, CF3, -CH2OH, Preferably, R 1 It is CN, Cl, F, CF3,

[0103] In one implementation of formula VIII yes X 1 X 3 and X 4 It is CH; X 2 It is CR 1 And R 1It is CN, halogen, CF3, -CH2OH, Preferably, R 1 It is CN, Cl, F, CF3,

[0104] In alternative implementations of formula VIII, yes X 1 It is N; X 2 It is CR 1 ;X 3 and X 4 It is CH; and R 1 It's CF3.

[0105] In alternative implementations of formula VIII, yes X 1 X 3 and X 4 It is CH, and X 2 It is N.

[0106] In alternative implementations of formula VIII, yes X 1 and X 4 It is CH; X 2 It is CR 1 ;X 3 It is N; and R 1 It's CF3.

[0107] In alternative implementations of formula VIII, yes X 1 and X 3 It is CH; X 2 It is CR 1 ;X 4 It is N; and R 1 It's CN.

[0108] In alternative implementations of formula VIII, yes X 1 and X 3 It is CH; X 2 and X 4 It is CR 1 And each R 1 Independently selected from halogens and CN. Preferably, each R 1 It is independently selected from F, Cl and CN.

[0109] In alternative implementations of formula VIII, yes X 5 X 7 and X 8 It is CH; X 6 It is CR 1 And R 1 It is CN or Cl. Specifically, R. 1 It's CN.

[0110] In alternative implementations of formula VIII, yes X 5 It is N; X 6 It is CR 1 ;X 7 and X 8 It is CH; and R 1 It's CN.

[0111] In one embodiment of formula VIII, -B- is -CH2O-.

[0112] In one implementation of formula VIII, Y 6 Is it CH or CR? 2 .

[0113] In one implementation of formula VIII, R 2 It is either F or methyl.

[0114] In one implementation of formula VIII, Y 3 It is N, and Y 6 Is it CH or CR? 2 In a further embodiment of formula VIII, Y 3 It is N, and Y 6 It is CH. In a further implementation scheme, Y 3 It is N, and Y 6 It is CR 2 Preferably, R 2 It is F. In an alternative implementation, Y 3 and Y 6 Both are CH. In a further alternative implementation, Y 3 and Y 6 All are N.

[0115] In one implementation of formula VIII, Z 3 It is CH.

[0116] In one implementation of formula VIII, R 3It is a halogenated or optionally substituted C1-C4 alkoxy group, wherein the substituents are selected from: C1-C2 alkoxy, OH, or -NR. f R g , where R f and R g Both are CH3; preferably, R 3 It is F, -OCH3, -OCH2CH2OCH3, OCH2CH2OH or OCH2CH2N(CH3)2.

[0117] In one implementation of formula VIII, R 4 yes

[0118] Some compounds of formula VIII have the following characteristics:

[0119] i. -A- is -CH2CH2CH2O-, -CH2OCH2-, -CH2CH2OCH2-, CH2OCH2CH2-, or -CF2CH2OCH2-;

[0120] ii. yes Where X 1 X 3 and X 4 It is CH, X 2 It is CR 1 And R 1 It is CN, Cl, F, CF3, Or, where X 1 It is N, X 2 It is CR 1- X 3 and X 4 It is CH, and R 1 It is CF3; or, where X 1 X 3 and X 4 It is CH, and X 2 It is N; or, where X 1 and X 4 It is CH, X 2 It is CR 1 X 3 It is N, and R 1 It is CF3; or, where X 1 and X 3 It is CH, X 2 It is CR 1 X 4 It is N, and R 1 It is CN; or, where X 1 and X3 It is CH, X 2 and X 4 It is CR 1 And each R 1 Independently selected from F, Cl, and CN;

[0121] or, yes Where X 5 X 7 and X 8 It is CH, X 6 It is CR 1 And R 1 It is CN or Cl; or, where X 5 It is N, X 6 It is CR 1 X 7 and X 8 It is CH, and R 1 It is CN;

[0122] iii. -B- is -CH2O-;

[0123] iv.Y 1 Is it CH or CR? 2 And R 2 It is F or methyl;

[0124] vY 6 Is it CH or CR? 2 And R 2 It is F;

[0125] vi.Z 3 It is CH;

[0126] vii.Z 1 Is it CH or CR? 3 And R 3 It is F, -OCH3, -OCH2CH2OCH3, OCH2CH2OH, or OCH2CH2N(CH3)2; and

[0127] viii.R 4 yes

[0128] In the implementation scheme, compounds of the following formula are provided:

[0129]

[0130] Or its pharmaceutically acceptable salt.

[0131] In a preferred embodiment, a compound of the following formula is provided:

[0132]

[0133] Or its pharmaceutically acceptable salt.

[0134] In one embodiment of formulas VII and VIIa, X 2 It is CR 1 And R 1 It is CN. In alternative implementations of formulas VII and VIIa, X 2 It is CR 1 And R 1 It's CF3.

[0135] In one embodiment of formulas VII and VIIa, Y 3 It is N. In alternative implementations, Y 3 It is CH.

[0136] In one embodiment of formulas VII and VIIa, Y 1 It is CH. In alternative implementations, Y 1 It is CR 2 And R 2 It is a methyl group.

[0137] In one embodiment of formulas VII and VIIa, R 5 It is -CO2H. In alternative implementations, R 5 yes

[0138] In the implementation scheme, compounds of the following formula are provided:

[0139]

[0140] Where -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-;

[0141] R a Each time it appears, it is independently H, halogen, C1-C2 alkyl or OH;

[0142] R b Each time it appears, it is independently H, halogen, or C1-C2 alkyl;

[0143] yes Where a is the connection point with connection base A; b is the connection point with connection base B;

[0144] X 1 X 2 X 3 and X 4 Independently N, CH or CR 1 , where X 1 X 2 X 3 and X 4 No more than two of them are N, and X 1 X 2 X 3 and X 4 No more than two of them are CR 1 ;

[0145] R 1 CN; halogen; C1-C3 alkyl group optionally substituted with OH; C1-C3 haloalkyl group; C1-C3 alkoxy group; C3-C5 cycloalkyl group; -SO2C1-C3 alkyl group; Each R e Independently selected from: H, C1-C3 alkyl, C1-C3 haloalkyl, halogen, and C3-C5 cycloalkyl; 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is optionally substituted with one or two substituents, wherein the substituents are independently selected from: C1-C3 alkyl, C1-C3 alkoxy, C3-C5 cycloalkyl, -CH2-C3-C5 cycloalkyl, -SO2C1-C3 alkyl, -CH2-C4-C5 heterocyclic, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxy, CN, or -CONR c R d , where R c and R d Each is independently an H or C1-C3 alkyl group;

[0146] -B- can be -CH2O-, -OCH2-, or -CH2NH-;

[0147] Y 1 and Y2 Independently N, CH or CR 2 , where Y 1 and Y 2 Only one of them can be N;

[0148] Y 3 It is N or CH;

[0149] R 2 It is either halogen or methyl;

[0150] Z 1 Is it N, CH or CR? 3 ;

[0151] Z 2 Is it CH or CR? 3 ;

[0152] Z 3 Is it N, CH or CR? 3 ;

[0153] R 3 It is a halogen, C1-C4 alkyl, C1-C4 alkoxy or -C1-C3 alkoxy or C1-C2 alkoxy;

[0154] R 4 yes and

[0155] R 5 Is it -CO2H or

[0156] Or its pharmaceutically acceptable salt.

[0157] In the embodiments, 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 -;

[0158] R a Each time it appears, it is independently H, halogen, C1-C2 alkyl or OH;

[0159] R b Each time it appears, it is independently H, halogen, or C1-C2 alkyl;

[0160] yes Where a is the connection point with connection base A; b is the connection point with connection base B;

[0161] X 1 X 2 X 3 and X 4 Independently N, CH or CR 1 , where X 1 X 2 X 3 and X 4 No more than two of them can be N, and X 1 X 2 X 3 and X 4 No more than two of them can be CR 1 ;

[0162] R 1 It is CN, halogen, C1-C3 alkyl, or C1-C3 haloalkyl;

[0163] -B- can be -CH2O-, -OCH2-, or -CH2NH-;

[0164] Y 1 and Y 2 Independently N, CH or CR 2 , where Y 1 and Y 2 Only one of them can be N;

[0165] Y 3 It is N or CH;

[0166] R 2 It is either halogen or methyl;

[0167] Z 1 Is it N, CH or CR? 3 ;

[0168] Z 2 Is it CH or CR? 3 ;

[0169] Z 3 Is it N, CH or CR? 3 ;

[0170] R 3 It is a halogen, C1-C4 alkyl, C1-C4 alkoxy or -C1-C3 alkoxy or C1-C2 alkoxy;

[0171] R 4 yes and

[0172] R 5 Is it -CO2H or

[0173] Or its pharmaceutically acceptable salt.

[0174] In alternative implementations, compounds of the following formula are provided:

[0175]

[0176] in

[0177] -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 -;

[0178] R a Each time it appears, it is independently H, halogen, C1-C2 alkyl or OH;

[0179] R b Each time it appears, it is independently H, halogen, or C1-C2 alkyl;

[0180] X 1 X 2 X 3 and X 4 Independently N, CH or CR 1 , where X 1 X 2 X 3 and X4 Only one of them can be N, and X 1 X 2 X 3 and X 4 No more than two of them can be CR 1 ;

[0181] R 1 It is either CN or halogen;

[0182] -B- is either -CH2O- or -OCH2-;

[0183] Y 1 and Y 2 Independently N, CH or CR 2 , where Y 1 and Y 2 Only one of them can be N;

[0184] R 2 It is either halogen or methyl;

[0185] Z 1 Is it N, CH or CR? 3 ;

[0186] Z 2 Is it CH or CR? 3 ;

[0187] Z 3 Is it N, CH or CR? 3 ;and

[0188] R 3 It is a halogen, C1-C2 alkyl, or methoxy group;

[0189] Or its pharmaceutically acceptable salt.

[0190] In the implementation scheme, compounds of the following formula are provided:

[0191]

[0192] Or its pharmaceutically acceptable salt.

[0193] In the implementation scheme, compounds of the following formula are provided:

[0194]

[0195] Or its pharmaceutically acceptable salt.

[0196] In a preferred embodiment, a compound of the following formula is provided:

[0197]

[0198] Or its pharmaceutically acceptable salt.

[0199] In the implementation scheme, compounds of the following formula are provided:

[0200]

[0201] Or its pharmaceutically acceptable salt.

[0202] In a preferred embodiment, a compound of the following formula is provided:

[0203]

[0204] Or its pharmaceutically acceptable salt.

[0205] In the implementation plan, -A- is -CHR a CHR a CHR b O-. In a further implementation, R a and R b Each is H.

[0206] In the implementation plan, X 1 X 3 and X 4 It is CH, and X 2 It is CR 1 In one implementation, R 1 It is CN. In alternative implementations, R 1 It is Cl.

[0207] In the implementation scheme, -B- is -CH2O-.

[0208] In one implementation, Y 1 and Y 2 Both are CH. In alternative implementations, Y 1 It is CR 2 Y 2 It is CH, and R 2 It is F.

[0209] In the implementation plan, Z 2 and Z 3 Both are CH.

[0210] In the implementation plan, Z 1 Is it CH or CR? 3 In one implementation scheme, Z 1 It is CH. In alternative implementations, Z 1 It is CR 3 And R 3 It is F.

[0211] In the implementation scheme, compounds selected from the following are provided:

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220] Or its pharmaceutically acceptable salt.

[0221] In linker A, the left-hand terminal group is connected to the X ring, and the right-hand terminal group is connected to the Y ring. 1 Y 2 and Y 7 Ring linkage. For example, in the group -CR a R b CR a R b CR b R b In O-, oxygen and Y- 1 Y 2 and Y 7 The ring is linked. In linker B, the left-hand terminal group is linked to the X ring, and the right-hand terminal group is linked to the Y ring. 3 The ring connection.

[0222] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0223] The term "C1-C" n "Alkyl" refers to a straight-chain or branched saturated hydrocarbon containing 1 to n carbon atoms. Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, and tert-butyl. Examples of C1-C3 alkyl groups include, but are not limited to, methyl, ethyl, and propyl. C1-C2 alkyl groups are methyl or ethyl.

[0224] The term "C1-C" n "Halogenated alkyl" refers to a C1-C alkyl group as defined herein that has been substituted with one or more halogens. n Alkyl groups. Examples of C1-C3 haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and pentafluoroethyl.

[0225] The term "C1-C" n "Alkoxy" refers to a straight-chain or branched saturated hydrocarbon containing 1 to n carbon atoms, with a terminal "O", i.e., -O (alkyl). Examples of C1-C4 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy.

[0226] The term "C1-C" n "Haloalkoxy" refers to a C1-C alkoxy group as defined in this paper that has been substituted with one or more halogens. n Alkyl groups. Examples of C1-C3 haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, and pentafluoroethoxy.

[0227] The term "C3-C5 cycloalkyl" refers to a monocyclic saturated carbon ring containing 3 to 5 carbon atoms. Specifically, it refers to cyclopropyl, cyclobutyl, or cyclopentyl.

[0228] The term "C4-C6 cycloalkyl" refers to a monocyclic saturated carbon ring containing 4 to 6 carbon atoms. Specifically, it refers to cyclobutyl, cyclopentyl, or cyclohexyl.

[0229] 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 heteroaryls include, but are not limited to, pyrazoles, triazoles, and thiazoles. Examples of 6-membered heteroaryls include, but are not limited to, pyridines and pyridazines.

[0230] The term "C4-C6 heterocyclic group" refers to a 4, 5, or 6-membered monocyclic saturated ring containing one or more heteroatoms, such as pyrrolidine.

[0231] The term "C4-C5 heterocyclic group" refers to a 4- or 5-membered monocyclic saturated ring containing one or more heteroatoms, such as oxobutane.

[0232] Formula IX encompasses Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, V, Va, Vb, VI, VII, VIIa, and VIIb, and in the following text, such as in the context of treatment methods and therapeutic uses, reference to Formula IX is also considered to refer to each and all of these formulas.

[0233] 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.

[0234] In another embodiment, a method for treating a patient with type 2 diabetes is provided, the method comprising administering a pharmaceutically acceptable composition to the patient requiring treatment, the 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 being.

[0235] In another embodiment, a method for treating a patient with type 2 diabetes is provided, the method comprising administering to the patient requiring 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 being.

[0236] In another embodiment, a method for lowering a patient's blood glucose level is provided, the method comprising administering to a patient requiring 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 being.

[0237] In another embodiment, a method for treating hyperglycemia in a patient is provided, the method comprising administering to the patient requiring 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 being.

[0238] In another embodiment, a method for treating obesity in mammals is provided, the method comprising administering an effective amount of a compound of formula IX or a pharmaceutically acceptable salt thereof to a patient requiring treatment. In a preferred embodiment, the patient is a human.

[0239] In another embodiment, a method for treating a patient with non-alcoholic steatohepatitis (NASH) is provided, the method comprising administering to the 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 being.

[0240] In the implementation plan, a compound of formula IX or a pharmaceutically acceptable salt thereof for treatment is provided.

[0241] In another embodiment, a compound of formula IX or a pharmaceutically acceptable salt thereof is provided for the treatment of type II diabetes.

[0242] In another embodiment, a compound of formula IX or a pharmaceutically acceptable salt thereof for lowering blood glucose levels is provided.

[0243] In another embodiment, a compound of formula IX or a pharmaceutically acceptable salt thereof is provided for the treatment of hyperglycemia.

[0244] In another embodiment, a compound of formula IX or a pharmaceutically acceptable salt thereof is provided for the treatment of obesity.

[0245] In another embodiment, a compound of formula IX or a pharmaceutically acceptable salt thereof for treating NASH is provided.

[0246] In the implementation plan, the use of a compound of formula IX or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of type II diabetes is provided.

[0247] In the implementation plan, the use of a compound of formula IX or a pharmaceutically acceptable salt thereof for the preparation of a medicament for lowering blood glucose levels is provided.

[0248] In the implementation plan, the use of a compound of formula IX or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of hyperglycemia is provided.

[0249] In the implementation plan, the use of a compound of formula IX or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of obesity is provided.

[0250] In the implementation plan, the use of a compound of formula IX or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of NASH is provided.

[0251] Compounds of Formula IX may be used simultaneously, alone, or sequentially in combination with one or more therapeutic agents. Examples of other therapeutic agents include, but are not limited to, metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporters, and pentoxifyllase inhibitors.

[0252] 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 humans.

[0253] As used herein, the term “pharmaceuticalally acceptable salt” refers to a salt of the compounds of the present invention that are considered acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and common methods for their preparation can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use”, P. Stahl et al., 2nd revised edition, Wiley-VCH, 2011, and SMBerge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.

[0254] 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 a diagnosed or treated patient when administered in a single or multiple doses. An effective amount can be readily determined by an attending physician skilled in the art using conventional techniques and by observing results obtained under similar conditions. Factors considered in determining the effective amount or dose of a compound include: whether the compound or a salt thereof is administered; if so, the co-administration of other agents; the patient's body type, age, and general health condition; the extent or severity of the disease; the individual patient's response; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosing regimen; and other relevant factors. The compounds of the present invention are effective at daily doses falling within the range of about 0.01 to about 15 mg / kg body weight.

[0255] The term “treatment” as used in this article refers to reducing, alleviating, or reversing the progression or severity of existing symptoms, conditions, or illnesses such as hyperglycemia, which may include increasing insulin secretion.

[0256] The term "patient" as used in this article includes mammals. Humans are preferred as patients.

[0257] Compounds of Formula IX can be formulated as pharmaceutical compositions administered via any route that makes the compound bioavailable. Such compositions are preferably intended for oral administration. Preferably, the pharmaceutical compositions are formulated as tablets, capsules, or solutions. Tablets, capsules, or solutions may comprise compounds of Formula IX in amounts effective to treat patients requiring treatment. Such pharmaceutical compositions and methods of their preparation are well known in the art (see, for example, “Remington: The Science and Practice of Pharmacy”, edited by A. Adejare, 23). rd Ed., 2020, Elsevier Science.

[0258] Compounds of formula IX and their pharmaceutically acceptable salts may be used for therapeutic purposes according to the present invention, wherein certain configurations are preferred.

[0259] The compounds of the present invention include:

[0260]

[0261]

[0262]

[0263] Or its pharmaceutically acceptable salt.

[0264] Although the invention envisions all individual enantiomers, mixtures thereof, and racemates, compounds of formulas Ia, IIa, IIIa, Va, and VIIa, and their pharmaceutically acceptable salts, are particularly preferred.

[0265] Those skilled in the art can separate or split individual enantiomers at any convenient point in the synthesis of the compounds of the present invention by means of methods such as selective crystallization, chiral chromatography (see, for example, J. Jacques et al., “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, Inc., 1981, and E.L. Leeel and S.H. Wilen, “Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994) or supercritical fluid chromatography (SFC) (see, for example, T.A. Berger; “Supercritical Fluid Chromatography Primer,” Agilent Technologies, July 2015).

[0266] Pharmaceutically acceptable salts of the compounds of the present invention can be formed, for example, by reacting a compound of formula IX with a suitable pharmaceutically acceptable base in a suitable solvent under standard conditions known in the art (see, for example, Bastin, RJ et al.; Org. Process. Res. Dev., 4, 427-435, 2000, and Berge, SM et al.; J. Pharm. Sci., 66, 1-19, 1977).

[0267] Some abbreviations used in this article are defined according to Daub GH 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” refers to tert-butyloxycarbonyl; “cAMP” refers to cyclic adenosine-3',5'-monophosphate; “DCM” refers to dichloromethane or methylene chloride; “DEAD” refers to diethyl azodicarbonate; “DIAD” refers to diisopropyl azodicarbonate; “DIPEA” refers to N,N-diisopropylethylamine; “DMF” refers to N,N-dimethylformamide; “DMSO” refers to dimethyl sulfoxide; “EC” refers to dimethyl sulfoxide; “EC” refers to dimethyl sulfoxide; “DCM ... 50 "" refers to the reagent concentration (absolute EC50) that produces a 50% response to the target activity compared to the predetermined positive control compound. 50"EDC" refers to 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]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide of hexafluorophosphate; "HEK" refers to human embryonic kidney; "HEPES" refers to 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid; "h" refers to one hour or several hours respectively; Ir[dF(CF3)ppy]2(dtbpy))PF6 refers to [4,4'-bis(1,1]... [-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C]iridium(III); "KOAc" refers to potassium acetate; "MeOH" refers to methanol or methyl alcohol; "min" refers to one minute or several minutes; "MTBE" refers to methyl tert-butyl ether; "Pd(dppf)Cl2" refers to [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride; PdCl2(dtbpf) refers to [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium(II) dichloride; "RT" refers to room temperature; "S" refers to [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium(II) dichloride; N "Ar" refers to nucleophilic aromatic substitution; "TBAF" refers to tetrabutylammonium fluoride; "TBS" refers to tert-butyldimethylsilane; "TEA" refers to triethylamine; "TFA" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; "TMAD" refers to tetramethylazodicarbonamide; and "TMSCN" refers to trimethylcyanosilane.

[0268] The compounds of the present invention can be prepared by various procedures, some of which are described in the preparations and examples below. The specific synthetic steps of the various routes can be combined in different ways to prepare the compounds of the present invention or their salts. The products of the following steps can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, preparation, and crystallization. Reagents and raw materials are readily available to those skilled in the art. Individual isomers, enantiomers, and diastereomers can be separated or resolved at any convenient point in the synthesis by methods such as selective crystallization or chiral chromatography (see, for example, J. Jacques et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981 and E.L. Leel and S.H. Wilen, "Stereochemistry of Organic Compounds", Wiley-Interscience, 1994). The following preparations and examples are provided to further illustrate the invention without limiting its scope.

[0269] Option 1

[0270]

[0271] Scheme 1 illustrates the synthesis of intermediates 7, 8, and 9 for preparing the compounds of the present invention. In step 1, the hydroxyl group of intermediate 1 is methylated with iodomethane and a carbonate base at high temperature to give methoxy intermediate 2. In step 2, the ester group of intermediate 2 is then reduced to an alcohol intermediate 3 using NaBH4. In step 3, the alcohol of intermediate 3 is converted to a bromide intermediate 4 using PBr3, and then reacted with TMSCN and TBAF in step 4 to give intermediate 5. In step 5, the cyano group of intermediate 5 is treated with an alcoholic solution of sulfuric acid at high temperature to give ester intermediate 6, and then the methoxy group is demethylated with BBr3 in step 6 to give intermediate 7. Optionally, intermediate 7 can be converted to a borate ester in step 7 using KOAc and Pd(dppf)Cl2 and bis(pinacol)diboron or bis(neopentylethylene glycol)diboron at high temperature to give borate ester 8 or 9, respectively.

[0272] Option 2

[0273]

[0274] Scheme 2 illustrates the synthesis of intermediates 15, 18, 22, and 23, which are also used to prepare the compounds of the present invention. In step 1, bromide 10 is converted to nitrile 11 at high temperature using zinc cyanide and palladium catalyst. In step 2a, nitrile intermediate 11 is converted to ester intermediate 12 at high temperature using an alcoholic solution of thionyl chloride, and then in step 3a, an S-reaction is carried out at high temperature with amine 13 and carbonate base. N In the Ar reaction, fluorine is replaced to give intermediate 14. Then, in step 4a, the nitro group is reduced in methanol under hydrogen atmosphere using a Lindlar catalyst (5% Pd) to give intermediate 15. Intermediate 15 can be reacted with 2-chloroacetyl chloride using a tertiary amine base to give 2-chloromethylimidazolium intermediate 23.

[0275] To obtain the tetrazolium intermediate, in step 2b, intermediate 11 is reacted with amine 13 using an amine base for S-reaction. NAr reaction yields intermediate 16, which is then converted to tetrazolium intermediate 17 at high temperature using tributyltin azide in step 3b. The nitro group is then reduced using a palladium / carbon catalyst at hydrogen pressure (4 bar) in step 4b to yield intermediate 18. Alternatively, intermediate 11 is reacted with tributyltin azide at high temperature in step 2c to yield tetrazolium intermediate 19, which is then protected on the tetrazolium nitrogen with a group such as SEM (trimethylsilylethoxymethyl) in step 3c to yield intermediate 20. In step 4c, an S reaction is carried out with amine 13 and a tertiary amine base. N In the Ar reaction, fluorine is replaced to obtain intermediate 21, and then in step 5c, iron is used to reduce the nitro group in acetic acid at high temperature to obtain the protected tetrazolium intermediate 22.

[0276] Option 3

[0277]

[0278] Scheme 3 illustrates three synthetic routes for preparing intermediate 32 of the compounds of the present invention. In step 1a of the first route, halide intermediate 24 is Heck-coupled with ethyl acrylate at high temperature using palladium acetate and a carbonate base to obtain intermediate 25, followed by olefin reduction at hydrogen (40 psi) in step 2a to obtain intermediate 26. In step 3a, the alcohol group of intermediate 26 is converted to a bromide using PBr3, followed by reaction with intermediate 27 and Ag2CO3 at high temperature to obtain intermediate 29. In step 4a, the ester group is reduced with LiBH4 to obtain intermediate 32.

[0279] In the second route, intermediate 33 (which can be prepared from intermediate 24 using PBr3) is first reacted with intermediate 27 at high temperature using Ag2CO3 in step 1c to obtain intermediate 34. Then, in step 2c, it is coupled at high temperature with bromo-[3-[tert-butyl(dimethyl)silyl]oxypropyl]zinc and palladium catalyst to obtain intermediate 35. Then, in step 3c, deprotection is performed using TBAF to obtain intermediate 32.

[0280] In the third route, in step 1b, intermediate 24 is Sonogashira coupled with tert-butyldimethyl(2-propynyloxy)silane using a palladium catalyst and a tertiary amine base to obtain intermediate 28, which is then photo-extended with intermediate 27 to obtain intermediate 30. In step 3b, deprotection is performed using TBAF, and then in step 4b, the alkyne is hydrogenated using platinum oxide in a hydrogen atmosphere to obtain intermediate 32.

[0281] Option 4

[0282]

[0283] Scheme 4 illustrates 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 high temperature to give intermediate 37. In step 2, it is coupled with propynyl alcohol via Sonogashira coupling to give alkyne intermediate 38. In step 3, the alkyne of intermediate 38 is reduced with a rhodium catalyst at high temperature and hydrogen pressure (90 psi) to give intermediate 39. In step 4, the phthalimide group is reacted with hydrazine at high temperature to give amine 40, and then in step 5, it is reacted with intermediate 41 with DIPEA at high temperature via S... N Ar reaction to obtain intermediate 42.

[0284] Option 5

[0285]

[0286] Scheme 5 illustrates the synthesis of intermediate 47 for preparing the compounds of the present invention. In step 1, intermediate 43 is reacted with (2-bromoethoxy)-tert-butyldimethylsilane using a carbonate base at high temperature. In step 2, the aldehyde of intermediate 44 is reduced using sodium borohydride to give alcohol 45, and then in step 3, it is subjected to a photoelectrophoresis reaction with intermediate 27 to give intermediate 46. In step 4, the tert-butyldimethylsilane is removed using TBAF to give intermediate 47.

[0287] Option 6

[0288]

[0289] As described in Scheme 3, intermediate 32 can be prepared via the alternative route shown in Scheme 6. In step 1a, intermediate 48 is coupled at high temperature with zinc bromo-[3-[tert-butyl(dimethyl)silyl]oxypropyl] and a palladium catalyst to obtain intermediate 49, which is then reduced to alcohol intermediate 50 using lithium aluminum hydride in step 2a. In step 3a, intermediate 50 is reacted with intermediate 27 under photoelectrophoresis conditions to obtain intermediate 32.

[0290] Alternatively, in step 1b, intermediate 24 is reacted with intermediate 27 under photo-extending conditions, or with potassium tert-butoxide and aryl fluoride intermediate 41, to obtain intermediate 34. Steps 2b and 3b are as described in Scheme 3 (root-bank coupling with zinc bromo-[3-[tert-butyl(dimethyl)silyl]oxypropyl], followed by deprotection to obtain intermediate 32).

[0291] Option 7

[0292]

[0293] Scheme 7 illustrates two synthetic routes for preparing intermediate 55 of the compounds of the present invention. In the first route, in step 1a, intermediate 51 is photo-extended with intermediate 8 or 9 to obtain intermediate 52. In step 2a, intermediate 52 is then intramolecularly cross-coupled with a palladium catalyst to form a macrocyclic intermediate 54. In the second route, intermediate 51 is photo-extended with intermediate 7 in step 1b to obtain intermediate 53, and then palladium-catalyzed intramolecular Stille coupling is performed at high temperature in step 2b to obtain intermediate 54. In step 3, the ester group of intermediate 54 is hydrolyzed using an aqueous LiOH solution or a guanidine base in ACN / water to obtain intermediate 55.

[0294] Option 8

[0295]

[0296] Scheme 8 illustrates the synthesis of intermediate 64 for preparing the compounds of the present invention. In step 1, intermediate 56 is reductively coupled with 3-bromo-1-propanol at high temperature to give intermediate 57, and then protected with a TBS group in step 2 to give intermediate 58. Then, in step 3, the ester is reduced with lithium borohydride to give alcohol intermediate 59, and then photo-extruded with intermediate 27 in step 4 to give intermediate 60. In step 5, the TBS protecting group is removed with TBAF to give intermediate 61, and then reacted with intermediate 8 in step 6 with Mitsutnobu to give intermediate 62. In step 7, intermediate 62 is cyclized using a palladium catalyst and potassium phosphate to give intermediate 63, and then hydrolyzed with a guanidine base in aqueous LiOH or ACN / water in step 8 to give acid intermediate 64.

[0297] Option 9

[0298]

[0299] Scheme 9 shows the synthesis of intermediate 77 for preparing the compounds of the present invention, and shows two synthetic routes leading to common intermediate 74.

[0300] In the first route leading to intermediate 74, in step 1a, the acid intermediate 65 is reduced using a borane-dimethyl sulfide complex to obtain alcohol intermediate 66, which is then reacted with sodium hydride and bromide intermediate 67 in step 2a to obtain intermediate 68. In step 3a, ester reduction is performed with lithium borohydride to obtain intermediate 73, which is then subjected to photoelectroplation reaction with intermediate 27 in step 4a to obtain intermediate 74.

[0301] In the second route to intermediate 74, in step 1b, alkyl bromide intermediate 69 is reacted with intermediate 27 using silver carbonate at high temperature to obtain intermediate 70. In step 2b, the ester of intermediate 70 is reduced with lithium borohydride to obtain alcohol 71, which is then reacted with alkyl bromide 72 with potassium tert-butoxide in step 3b to obtain intermediate 74.

[0302] In step 5, intermediate 74 is coupled with ethyl diazonate at high temperature using a palladium catalyst to obtain intermediate 75. In step 6, intramolecular Stille coupling is performed at high temperature using a palladium catalyst to obtain intermediate 76. Alternatively, step 6 is completed by single-pot coupling with bis(neopentylethylene glycol)diboron using a palladium catalyst and potassium pivalate, followed by intramolecular cross-coupling to obtain cyclic intermediate 76. Then, in step 7, intermediate 76 is hydrolyzed with a guanidine base in LiOH aqueous solution or ACN / water to obtain acid intermediate 77.

[0303] Option 10

[0304]

[0305] Scheme 10 illustrates the preparation of intermediate 83 for the preparation of the compounds of the present invention. Two routes leading to the common intermediate 81 are shown. In the first route, intermediate 78 is coupled with 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane at high temperature in step 1a using a palladium catalyst and a carbonate base to obtain intermediate 79. In step 2a, the ester is treated with a reducing agent such as diisobutylaluminum hydride to obtain alcohol 80, which is then reacted with aryl fluoride 41 using a strong organic base such as potassium tert-butoxide to obtain intermediate 81. In the second route, in step 1b, intermediate 34 (see Scheme 3) is first coupled with (E)-1-ethoxyvinyl-2-boronic acid pinacol ester at high temperature using a palladium catalyst and an inorganic base to obtain intermediate 81.

[0306] In step 4, intermediate 81 is treated with HCl in an organic solvent to obtain aldehyde 82, which is then reduced with NaBH4 in step 3 to obtain alcohol intermediate 83. Alternatively, intermediate 81 can be converted to intermediate 83 in one step using mercuric acetate and NaBH4.

[0307] Option 11

[0308]

[0309] Scheme 11 illustrates 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-bank coupling reaction with (2-ethoxy-2-oxoethyl)zinc bromide(II) and a palladium catalyst at high temperature. In step 2, intermediate 85 is subjected to a photochemical bromination reaction with N-bromosuccinimide in a flow reactor to obtain bromide intermediate 86.

[0310] Option 12

[0311]

[0312] Scheme 12 illustrates multiple routes leading to intermediate 92 used in 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 trifluoromethanesulfonate to give intermediate 89. Alternatively, in step 1b, intermediate 83 may first be reacted with alkyl bromide 87 under conditions similar to those in step 1a to give intermediate 88, and then subjected to root-bank coupling with (2-ethoxy-2-oxoethyl)zinc bromide and a palladium catalyst at high temperature in step 1c to give intermediate 89. In step 2a, intermediate 89 undergoes palladium-catalyzed intramolecular Stille coupling at high temperature to give intermediate 91. Alternatively, in step 2b, bromide 89 is converted to borate ester intermediate 90 by cross-coupling with bis(pinacol)diboron, Pd(dppf)Cl2, and potassium acetate at high temperature, and then cyclized in step 2c by intramolecular cross-coupling with a palladium catalyst to form macrocyclic intermediate 91 (steps 2b and 2c can be carried out as a single reaction step). Finally, in step 3, the ester is hydrolyzed using guanidine base in aqueous LiOH or ACN / water to obtain acid intermediate 92.

[0313] Option 13

[0314]

[0315] Scheme 13 illustrates 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 under photo-extending conditions to obtain intermediate 94. In step 2, intermediate 94 is coupled with bromoethanol using nickel and iridium catalysts and irradiated under blue light (456 nm) to obtain intermediate 95. Alternatively, intermediate 95 is prepared in a synthetic route similar to that used in Scheme 10 for the preparation of intermediate 83, starting with intermediate 93 instead of intermediate 78. In step 3, intermediate 95 is reacted with intermediate 96 using 2,6-di-tert-butylpyridine and silver trifluoromethanesulfonate to obtain intermediate 97. In step 4, bromide intermediate 97 is converted to borate ester intermediate 98 by cross-coupling with bis(pinacol)diboron, Pd(dppf)Cl2 and potassium acetate at high temperature. In step 5, intermediate 98 is then intramolecularly cross-coupled with a palladium catalyst to form macrocyclic intermediate 99. Alternatively, intermediate 97 can be converted to intermediate 99 in one step at high temperature using a hexamethyldistin and palladium catalyst via intramolecular Stille coupling. Then, intermediate 99 is hydrolyzed in step 6 using a guanidine base in LiOH aqueous solution or ACN / water to obtain acid intermediate 100.

[0316] Option 14

[0317]

[0318] Scheme 14 illustrates the preparation of intermediate 109 for the preparation of the compounds of the present invention. In step 1, intermediate 101 is subjected to a radical bromination reaction with N-bromosuccinimide at high temperature, followed by reaction with trimethylcyanosilane and TBAF, and then treated with sulfuric acid in an aqueous EtOH solution at high temperature to obtain ester intermediate 102. In step 2, intermediate 102 is coupled with (E)-1-ethoxyethylene-2-boronate pinacol ester using a palladium catalyst and a carbonate base to obtain intermediate 103, which is then converted to alcohol 104 in step 3 using mercuric acetate and sodium borohydride. Separately, in step 4, aldehyde intermediate 43 is first protected, for example, with a SEM group, and then reduced with sodium borohydride to obtain intermediate 105. In step 5, intermediate 105 is subjected to a photoelectroplasty reaction with intermediate 27 to obtain intermediate 106. Intermediates 104 and 106 are coupled via photoelongation to obtain intermediate 107, which 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 (boronization followed by Pd-catalyzed cross-coupling) in scheme 12 to obtain intermediate 108. In step 8, ester hydrolysis is performed using an aqueous LiOH solution or a guanidine base in ACN / water to obtain intermediate 109.

[0319] Option 15

[0320]

[0321] Scheme 15 illustrates 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 high temperature using silver carbonate, and then in step 2a... Ester reduction is performed to obtain intermediate 112. Alternatively, intermediate 34 is carbonylated in step 1b using potassium formate and palladium catalyst to obtain intermediate 111, and then the aldehyde is reduced using NaBH4 in step 2b to obtain intermediate 112. In step 3, the alcohol of intermediate 112 is converted to an alkyl bromide using CBr4 and triphenylphosphine to obtain intermediate 113. In step 4, intermediates 113 and 104 are reacted with silver trifluoromethanesulfonate to obtain intermediate 114. Then, intermediate 114 is intramolecularly cyclized in step 5 in a manner similar to step 2a (one-pot Stille coupling) in scheme 12, or intramolecularly cyclized in steps 5 and 6 in a manner similar to steps 2b and 2c (boration followed by Pd-catalyzed cross-coupling) in scheme 12. In step 7, the obtained ester is hydrolyzed using aqueous LiOH or guanidine base in ACN / water to obtain intermediate 115.

[0322] Option 16

[0323]

[0324] Scheme 16 illustrates the preparation of intermediate 123 for the preparation of the compounds of the present invention. In step 1, intermediate 116 is reacted with methyl bromodifluoroacetate and copper to give intermediate 117, and then in step 2, it is photochemically brominated in a flow reactor using N-bromosuccinimide to give alkyl bromide intermediate 118. In step 3, intermediate 118 is reacted with intermediate 27 at high temperature using a phosphate base to give intermediate 119, and then in step 4, it is reduced with LiBH4 to give alcohol intermediate 120. In step 5, intermediate 120 is treated with NaH and reacted with intermediate 124 to give intermediate 121. In step 6, intermediate 121 is coupled at high temperature with (2-ethoxy-2-oxo-ethyl)zinc bromide and a palladium catalyst to give intermediate 122. Then, intermediate 122 is subjected to intramolecular cyclization in step 7 in a manner similar to step 2a (one-pot Stille coupling) or steps 2b and 2c (boronization followed by Pd-catalyzed cross-coupling) in scheme 12. Ester hydrolysis is then performed in step 8 using an aqueous LiOH solution or a guanidine base in ACN / water to yield intermediate 123.

[0325] Option 17

[0326]

[0327] Scheme 17 illustrates the preparation of borate intermediate 128 for the preparation of the compounds of the present invention. In step 1, intermediate 83 is reacted with alkyl bromide intermediate 125 using silver trifluoromethanesulfonate to give intermediate 126, and then in step 2, intramolecular cyclization is performed in a manner similar to step 2a (one-pot Stille coupling) or steps 2b and 2c (boronization followed by Pd-catalyzed cross-coupling) in Scheme 12. Finally, in step 3, intermediate 127 is coupled with bis(pinacolyl)diboron using a palladium catalyst and potassium acetate at high temperature to give borate intermediate 128.

[0328] Option 18

[0329]

[0330] Scheme 18 shows the preparation of the compounds of the present invention via multiple different routes from intermediate 129 (which includes the general formula of intermediate 128) or intermediate 130 (which includes the general formulas of intermediates 55, 64, 77, 92, 100, 109, 115 and 123).

[0331] To prepare the acid compound of formula IX', in step 1a, intermediate 129 is coupled with chloromethylimidazolium intermediate 23 at high temperature using a palladium catalyst and a phosphate base to obtain intermediate 143. Then, in step 3a, the ester is hydrolyzed at high temperature using an aqueous LiOH solution or a guanidine base in ACN / water to obtain the acid of formula IX'. Alternatively, in step 1c, acid intermediate 130 is coupled with intermediate 15 using an amide coupling agent such as EDC or HATU to obtain intermediate 132. Then, in step 2a, intermediate 132 is cyclized at high temperature with acetic acid to obtain intermediate 143, followed by hydrolysis of the ester as described in step 3a.

[0332] In step 4a, the acid of formula IX' is coupled with cyclopropylmethanesulfonamide using EDC and 4-dimethylaminopyridine to prepare the compound of formula IX'.

[0333] Compounds of formula IX”” are prepared as follows: In step 1b, intermediate 130 is coupled with intermediate 18 (without a tetrazolium nitrogen protecting group, such as SEM) or 22 (with a tetrazolium nitrogen protecting group) using HATU to obtain intermediate 131, and then cyclized with acetic acid at high temperature in step 2b (if necessary, tetrazolium deprotection is performed in step 3b, for example, by removing the SEM group with TBAF) to obtain tetrazolium compounds of formula IX””.

[0334] Option 19

[0335]

[0336] Scheme 19 illustrates the preparation of the compound of formula IX"" of the present invention. Intermediate 133 is subjected to photo-tracing reaction with alcohol intermediate 136 in step 1a to obtain 135, and then reacted with amine 13 and a tertiary amine base at high temperature in step 2. N Ar reaction to give intermediate 138. Alternatively, difluoroaryl intermediate 134 is first reacted with alcohol 136 in step 1b via an S reaction. N The Ar reaction involves first treating the alcohol with NaH, then reacting it with intermediate 134 at high temperature to obtain intermediate 135. A second alternative is to react intermediates 137 and 136 in step 1c in a manner similar to step 1b. N The Ar reaction yields intermediate 138. In step 3, the nitro group of intermediate 138 is reduced, for example, with hydrogen and palladium / carbon to yield aniline intermediate 139. Then, the compound of formula IX" is prepared in three steps from intermediates 139 and 130 in a manner similar to steps 1c, 2a, and 3a in scheme 18. If the "-OR" group depicted in scheme 19 has a protecting group, such as a Boc group on nitrogen or a tert-butyldimethylsilyl group on oxygen, the protecting group can be removed in the final step (e.g., by removing the Boc group using TFA or by removing the tert-butyldimethylsilyl group using TBAF).

[0337] Option 20

[0338]

[0339] Scheme 20 illustrates the preparation of the compounds of the present invention from halide intermediate 140. Intermediate 140 is cross-coupled with optionally substituted 5- or 6-aryl or heteroaryl boronic acids or boronic esters at high temperature using a palladium catalyst and an inorganic base (e.g., Suzuki) to yield 141. Alternatively, 140 can be converted to boronic ester 142, for example at high temperature using tetrahydroxydiboron and a palladium catalyst, to obtain 142 as a boronic acid, which is then cross-coupled with optionally substituted 5- or 6-aryl or heteroaryl halides (e.g., Suzuki) to yield 141. These steps can be performed in protected or unprotected R 5 The process can proceed in the following ways: for example, esters can act as protected functional groups, and they can be hydrolyzed to give R. 5 =-CO2H.

[0340] Preparation and Examples

[0341] exist LC-ES / MS was performed on an HP1200 HPLC system. Electrospray mass spectrometry measurements were performed on a quadrupole mass spectrometer with a mass-selective detector connected to the HPLC (acquired in positive and / or negative modes), with or without ELSD. LC-ES / MS conditions (low pH): Column: NX C 182.0×50mm 3.0μm Gradient: 5-95% B over 1.5 min, followed by 95% B for 0.5 min; Column temperature: 50℃ ± 10℃; Flow rate: 1.2 mL / min; Injection volume: 1 μL; Solvent A: Deionized water containing 0.1% HCOOH; Solvent B: ACN containing 0.1% formic acid; Wavelengths: 200-400 nm and 212-216 nm. If the HPLC is equipped with ELSD, set the evaporator temperature to 45℃, the nebulizer temperature to 40℃, and the gas flow rate to 1.6 SLM. Alternative LC-MS conditions (high pH): Column: Waters C18 column 2.1×50mm, 3.5μm; gradient: 5-95% B over 1.5 min, then 95% B for 0.50 min; column temperature: 50℃ + / -10℃; flow rate: 1.2 mL / min; 1 μL injection volume; solvent A: 10 mM NH4HCO3 pH 9; solvent B: ACN; wavelength: 200-400 nm and 212-216 nm; if ELSD is available: evaporator temperature 45℃, nebulizer temperature 40℃, and gas flow rate 1.60 SLM.

[0342] Preparation 1

[0343] methyl 4-bromo-5-fluoro-2-methoxybenzoate

[0344]

[0345] Iodomethane (5.0 mL, 80.2 mmol) was added to a mixture of methyl 4-bromo-5-fluoro-2-hydroxybenzoate (10.0 g, 40.1 mmol) and potassium carbonate (13.8 g, 100 mmol) in ACN (200 mL). The reaction mixture was stirred at 60 °C for 15 h. 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 10.3 g of the title compound (98%), which was used as crude material for the preparation of 2. 1 H-NMR (400MHz, CDCl3) δ7.60 (d, J = 9Hz, 1H), 7.15 (d, J = 5Hz, 1H), 3.90 (s, 6H).

[0346] Preparation 2

[0347] (4-Bromo-5-fluoro-2-methoxy-phenyl)methanol

[0348]

[0349] Sodium borohydride (10.7 g, 272 mmol) was added to a solution of methyl 4-bromo-5-fluoro-2-methoxybenzoate (14 g, 53.2 mmol) and MeOH (30 mL) in THF (300 mL). The reaction mixture was stirred at 50 °C for 4 h. 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 / hexane to give 11.5 g of the title compound (92%). 1 H-NMR (400MHz, CDCl3) δ7.14 (d, J = 8Hz, 1H), 7.0 (d, J = 6Hz, 1H), 4.63 (s, 2H), 3.85 (s, 3H).

[0350] Preparation 3

[0351] 1-Bromo-4-(bromomethyl)-2-fluoro-5-methoxy-benzene

[0352]

[0353] Phosphorus tribromide (5.6 mL, 59 mmol) was added to a solution of (4-bromo-5-fluoro-2-methoxy-phenyl)methanol (11.5 g, 48.9 mmol) in DCM (200 mL). The reaction was stirred at RT for 1 h. The reaction was quenched by adding ice water (50 mL) and alkalized to pH 7 with a saturated sodium bicarbonate aqueous solution. The organic layer was washed with water (100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 12.5 g of the title compound (86%), which was used as crude material for the preparation of 4. 1 H-NMR (400MHz, CDCl3) δ7.13 (d, J = 8Hz, 1H), 7.03 (d, J = 6Hz, 1H), 4.46 (s, 2H), 3.89 (s, 3H).

[0354] Preparation 4

[0355] 2-(4-bromo-5-fluoro-2-methoxy-phenyl)acetonitrile

[0356]

[0357] A solution of TBAF (1.0 M, in THF, 50 mL, 50 mmol) was added to a solution of 1-bromo-4-(bromomethyl)-2-fluoro-5-methoxybenzene (12.5 g, 42.0 mmol) and TMSCN (6.8 mL, 50.5 mmol) in ACN (250 mL). The reaction was stirred at RT for 4 h. The reaction was concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with saturated sodium chloride aqueous solution (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 8.0 g of the title compound (78%). 1 H-NMR (400MHz, CDCl3) δ7.19 (d, J = 8Hz, 1H), 7.04 (d, J = 5Hz, 1H), 3.86 (s, 3H), 3.64 (s, 2H).

[0358] Preparation 5

[0359] ethyl 2-(4-bromo-5-fluoro-2-methoxy-phenyl)

[0360]

[0361] Concentrated sulfuric acid (25 mL) was added to a solution of 2-(4-bromo-5-fluoro-2-methoxy-phenyl)acetonitrile (8.0 g, 32.8 mmol) in ethanol (100 mL). The reaction mixture was stirred at 80 °C for 18 h. The reaction mixture was neutralized to pH 7 with a saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with DCM (2 × 100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 9.3 g of the title compound (97%), which was used as crude material for the preparation of 6. 1H-NMR (400 MHz, CDCl3) δ 7.02–6.99 (m, 2H), 4.16 (q, J = 7 Hz, 2H), 3.80 (s, 3H), 3.56 (s, 2H), 1.26 (t, J = 7 Hz, 3H).

[0362] Preparation of 6

[0363] ethyl 2-(4-bromo-5-fluoro-2-hydroxy-phenyl)

[0364]

[0365] 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 -78 °C. Boron tribromide (8.0 mL, 84.8 mmol) was added and the mixture was stirred at RT for 2 h. The reaction mixture was cooled to 0 °C and quenched with ice water (40 mL). The solution was alkalized to pH 7 with a saturated aqueous sodium bicarbonate solution. 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 4.0 g of the title compound (84%), which was used as crude material for the preparation of compounds 10, 54, and 60. 1 H-NMR (400MHz, CDCl3) 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).

[0366] Preparation 7

[0367] Methyl 2-(4-bromo-2-hydroxy-5-methyl-phenyl)acetate

[0368]

[0369] The title compound was prepared using methyl 2-(4-bromo-2-methoxy-5-methyl-phenyl)acetate, as described in Preparation 6. ES-MS m / z 259 and 261 (M+H).

[0370] Preparation of 8

[0371] 2-[2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl acetate

[0372]

[0373] 1,4-Dioxane (24 mL) was added to a mixture of methyl 2-(4-bromo-2-hydroxyphenyl)acetate (1.30 g, 5.30 mmol), bis(pinacol)diboron (1.98 g, 7.72 mmol), KOAc (2.23 g, 22.5 mmol), and Pd(dppf)Cl2 (420 mg, 0.57 mmol). The reaction mixture was stirred at 80 °C for 60 hours under a nitrogen atmosphere. The mixture was filtered through a filter pad and washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM, adsorbed onto silica, and rapidly purified by silica gel chromatography using a gradient of 0 to 55% EtOAc / hexane to give 748 mg of the title compound (48%). ES-MS m / z 293 (M+H).

[0374] Preparation 9

[0375] 2-[2-hydroxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl acetate

[0376]

[0377] The title compound was prepared essentially as described in Preparation 8 using methyl 2-(4-bromo-2-hydroxy-5-methyl-phenyl)acetate. It was purified by rapid silica gel chromatography using a gradient of 5 to 80% EtOAc / hexane. ES-MS m / z 304 (MH).

[0378] Preparation 10

[0379] 2-[4-(5,5-dimethyl-1,3,2-dioxaborane-2-yl)-5-fluoro-2-hydroxyphenyl]ethyl acetate

[0380]

[0381] A flask containing ethyl 2-(4-bromo-5-fluoro-2-hydroxyphenyl)acetate (2.43 g, 8.16 mmol), bis(neopentylethylene 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 purged with nitrogen for 5 minutes while stirring. Dichlorobis(tricyclohexylphosphine)palladium(II) (0.31 g, 0.41 mmol) was added and purged with nitrogen for 5 minutes while stirring. The mixture was stirred at 90 °C for 6 hours, then flushed down with 1,4-dioxane (15 mL) and stirred overnight at RT. Diatomaceous earth was added and diluted with MTBE (0.1 L). The mixture was stirred for 30 minutes and then... The sample was filtered through a silica gel pad and washed with MTBE (0.1 L). The filtrate was concentrated under reduced pressure at 50 °C. The residue was dissolved in toluene (0.1 L) and concentrated again at 50 °C. The residue was purified by elution with a 1:1 mixture of EtOAc and heptane through a silica gel pad. The fraction containing the title compound was concentrated to a final volume of 30 mL and stirred at ambient temperature for 1 hour. The solid was collected by filtration, washed with heptane (0.1 L), and dried under reduced pressure at 50 °C for 19 hours to give 1.77 g of the title compound (64%) as a pale orange solid. ES-MS m / z 243 (M+H, for boric acid). 1 H-NMR (400MHz, CDCl3) 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).

[0382] Preparation 11

[0383] ethyl 2-[5-fluoro-2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]

[0384]

[0385] The title compound was prepared essentially as described in Preparation 10 using bis(pinacolyl)diboron, with the mixture stirred at 90°C for 2 hours, followed by stirring at 100°C for 18 hours. The title compound was purified by rapid silica gel chromatography using a gradient of 0 to 50% EtOAc / cyclohexane, and then again by rapid silica gel chromatography using a gradient of 0 to 40% EtOAc / cyclohexane. ES-MS m / z 325 (M+H).

[0386] Preparation 12

[0387] (5-Bromo-4-fluoro-2-iodophenyl)methanol

[0388]

[0389] A borane dimethyl sulfide complex (2 M, in THF, 27 mL, 54 mmol) was added to a solution of 5-bromo-4-fluoro-2-iodobenzoic acid (6.3 g, 18.2 mmol) in 55 mL of THF. The reaction mixture was stirred at RT for 21 hours. The reaction mixture was concentrated and the residue was dissolved in EtOAc. The solution was washed with a saturated aqueous ammonium chloride solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography using a gradient of 10 to 30% EtOAc / heptane to give 5.1 g of the title compound (85%). ES-MS m / z 313 and 315 (M-H2O).

[0390] Preparation 13

[0391] Methyl 3,5-difluoro-4-nitrobenzoate

[0392]

[0393] A solution of thionyl chloride (37 mL, 74 mmol) in MeOH (110 mL) was cooled to -10 °C, and 3,5-difluoro-4-nitrobenzonitrile (2.8 g, 15 mmol) was added. The mixture was stirred at RT for 3 h, and then the temperature was gradually increased to 65 °C over 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in EtOAc (150 mL). The solution was washed with saturated aqueous sodium bicarbonate solution (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 2.24 g of the title compound (66%). 1 H-NMR (400MHz, CDCl3) δ7.78 (d, 2H), 4.0 (s, 3H).

[0394] Preparation 14

[0395] 3-Fluoro-4-nitro-5-[[(2S)-oxetane-2-ylmethyl]amino]methyl benzoate

[0396]

[0397] A mixture of [(2S)-oxetane-2-yl]methylamine (545 mg, 6.13 mmol, CAS 2091328-57-1), methyl 3,5-difluoro-4-nitrobenzoate (1.4 g, 6.1 mmol), and potassium carbonate (1.7 g, 12 mmol) in ACN (14 mL) was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (14 mL) and extracted with EtOAc (3 × 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 1.68 g of the title compound (79%). ES-MS m / z 285 (M+H).

[0398] Preparation 15

[0399] Methyl (S)-3-methoxy-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoate

[0400]

[0401] The title compound was prepared essentially as described in Preparation 14 using methyl 3-fluoro-5-methoxy-4-nitrobenzoate. The residues were purified by silica gel chromatography using a gradient of 5 to 30% EtOAc / DCM to obtain the title compound. ES-MS m / z 296 (M+H).

[0402] Preparation of 16

[0403] 4-Amino-3-fluoro-5-[[(2S)-oxetane-2-ylmethyl]amino]methyl benzoate

[0404]

[0405] A solution of methyl 3-fluoro-4-nitro-5-[[(2S)-oxetane-2-ylmethyl]amino]benzoate (1.68 g, 4.84 mmol) in MeOH (17 mL) was added to a Lindlar catalyst (600 mg, 0.28 mmol) containing 5% palladium. The mixture was stirred at RT for 16 h under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 1.4 g of the title compound (100%), which was used as crude material for the preparation of 86 and 91. ES-MS m / z 255 (M+H).

[0406] Preparation of 17

[0407] 4-Amino-3-methoxy-5-[[(2S)-oxetane-2-yl]methylamino]benzoate

[0408]

[0409] The title compound was prepared using methyl (S)-3-methoxy-4-nitro-5-((oxecyclobutane-2-ylmethyl)amino)benzoate, as described in Preparation 16. The title compound was used in crude form to prepare compounds 89, 93, 99, and 100. ES-MS m / z 267 (M+H).

[0410] Preparation of 18

[0411] 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate

[0412]

[0413] (1-Ethyl-1H-imidazol-5-yl)methylamine dihydrochloride (339 mg, 1.6 mmol) was added 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). The mixture was stirred at 35 °C for 2 h, then at 50 °C for 16 h. The crude reaction mixture was diluted with water and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography using a gradient of 0 to 100% EtOAc / heptane followed by 5% MeOH / DCM to give 395 mg of the title compound (88%). ES-MS m / z 305 (M+H).

[0414] Preparation of 19

[0415] 4-Amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate

[0416]

[0417] 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 °C for 15 minutes. A solution of methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzene (117 mg, 0.38 mmol) in DMF (1 mL) was added. The mixture was stirred at 50 °C for 15 minutes. The reaction was quenched with an aqueous sodium carbonate solution to pH 8, and then... Filtration. The residue was washed with water (2 × 20 mL), and the aqueous layer was back-extracted with EtOAc (2 × 20 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 106 mg of the title compound (100%), which was used as crude material for preparation 95. ES-MS m / z 275 (M+H).

[0418] Preparation 20

[0419] 3-Fluoro-5-methoxy-4-nitrobenzene

[0420]

[0421] DMF (17.8 mL) was added 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). The mixture was stirred at 100 °C for 1.5 h. 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 rapid silica gel chromatography using a gradient of 0 to 15% EtOAc / heptane to give 479 mg of the title compound (89%). ES-MS m / z 197 (M+H).

[0422] Preparation 21

[0423] (S)-3-methoxy-4-nitro-5-((oxetane-2-ylmethyl)amino)benzonitrile

[0424]

[0425] TEA (1.07 mL, 7.7 mmol) and (S)-oxetane-2-ylmethylamine (235 mg, 2.56 mmol) were added to a solution of 3-fluoro-5-methoxy-4-nitrobenzenenitrile (457 mg, 2.3 mmol) in DMF (7 mL). The mixture was stirred overnight at 35 °C. 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 rapid silica gel chromatography using a gradient of 0 to 30% EtOAc / heptane to give 471 mg of the title compound (77%). ES-MS m / z 264 (M+H).

[0426] Preparation 22

[0427] (S)-3-methoxy-2-nitro-N-(oxetane-2-ylmethyl)-5-(1H-tetrazole-5-yl)aniline

[0428]

[0429] Tributyltin azide (1.96 mL, 7.0 mmol) was added to a solution of (S)-3-methoxy-4-nitro-5-((oxetane-2-ylmethyl)amino)benzonitrile (217 mg, 0.82 mmol) in toluene (9.3 mL). The mixture was heated in a microwave oven with stirring to 150 °C for 2.5 h. The crude reaction mixture was filtered through a 10% w / w KF / silica stopper. The mixture was concentrated and the residue was ground with DCM to give 194 mg of the title compound (62%). ES-MS m / z 307 (M+H).

[0430] Preparation 23

[0431] (S)-3-methoxy-N1-(oxetane-2-ylmethyl)-5-(1H-tetrazol-5-yl)phenyl-1,2-diamine

[0432]

[0433] Palladium / carbon (20 mg, 0.009 mmol) was added to a mixture of (S)-3-methoxy-2-nitro-N-(oxetane-2-ylmethyl)-5-(1H-tetrazol-5-yl)aniline (160 mg, 0.42 mmol) and MeOH (3 mL). The mixture was stirred at RT for 8 hours under a hydrogen pressure of 4 bar. The crude reaction mixture was filtered and concentrated to give 120 mg of the title compound (52%), which was used as crude material for the preparation of 96. ES-MS m / z 277 (M+H).

[0434] Preparation 24

[0435] 4-[(6-bromo-2-pyridyl)oxymethyl]-3-iodobenzonitrile

[0436]

[0437] To a mixture of 4-(bromomethyl)-3-iodobenzonitrile (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), 1,4-dioxane (50 mL) was added. The reaction mixture was stirred at 60 °C for 15 hours. The reaction mixture was diluted with EtOAc (50 mL) and filtered through diatomaceous earth. The filtrate was washed with water (2 × 50 mL) and a saturated sodium chloride aqueous solution (50 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography using a gradient elution of 5 to 30% EtOAc / hexane to give 2.8 g of the title compound (76%). ES-MS m / z 415 and 417 (M+H).

[0438] Preparation 25

[0439] ethyl 4-cyano-3-(3-hydroxypropyl)benzoate

[0440]

[0441] The mixture of nickel(II) bromide (167 mg, 0.76 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (210 mg, 0.77 mmol) in anhydrous 1,4-dioxane (40 mL) was stirred at RT for 15 minutes while bubbling under nitrogen. Ethyl 3-bromo-4-cyanobenzoate (2 g, 7.71 mmol), 3-bromo-1-propanol (1.7 mL, 18 mmol), and cobalt(II) phthalocyanine (441 mg, 0.77 mmol) were added. The mixture was stirred at RT for 5 minutes while bubbling under nitrogen. Tetra(dimethylamino)ethylene (2.5 mL, 11 mmol) was added, and the mixture was stirred at RT for another 5 minutes while bubbling under nitrogen. The container was sealed and the mixture was stirred overnight at 85°C. The mixture was cooled to RT and then... Filter and concentrate under reduced pressure. The residue was purified by rapid silica gel chromatography using a gradient of 20 to 50% EtOAc / cyclohexane to give the title compound as a green solid (863 mg, 46%). ES-MS m / z 251 (M+NH4) + ).

[0442] Preparation 26

[0443] 3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-4-cyanobenzoic acid ethyl ester

[0444]

[0445] tert-butyldimethylchlorosilane (615 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 rapid silica gel chromatography using a gradient of 0% to 50% EtOAc / cyclohexane to provide the title compound as a colorless oil (1.24 g, 94%). ES-MS m / z 348 (M+H).

[0446] Preparation 27

[0447] 2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-4-(hydroxymethyl)benzonitrile

[0448]

[0449] Lithium borohydride / THF (2.0 M, 3.9 mL, 7.8 mmol) was added to a solution of ethyl 3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-4-cyanobenzoate (1.24 g, 3.39 mmol) in anhydrous THF (9 mL) at 0 °C under a nitrogen atmosphere. After 5 minutes, the cooling bath was removed, and the mixture was stirred overnight at RT. Most of the reaction solvent was removed by concentration, and citric acid (5%) was carefully added at 0 °C. The aqueous layer was extracted with DCM, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography using a gradient of 10% to 50% EtOAc / cyclohexane to provide the title compound (935 mg, 90%) as a colorless waxy solid. ES-MS m / z 306 (M+H).

[0450] Preparation 28

[0451] 4-[(6-bromo-2-pyridyl)oxymethyl]-3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzonitrile

[0452]

[0453] To a mixture of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-iodobenzonitrile (2.6 g, 6.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.27 g, 0.23 mmol) in 1,4-dioxane (50 mL), bromo-[3-[tert-butyl(dimethyl)silyl]oxypropyl]zinc (0.50 M, in THF, 25 mL, 12.5 mmol) was added. The mixture was stirred at 60 °C for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and then washed with saturated ammonium chloride aqueous solution (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 rapid silica gel chromatography using a gradient elution of 5 to 50% EtOAc / hexane to give 1.07 g of the title compound (37%). ES-MS m / z 461 and 463 (M+H).

[0454] Preparation 29

[0455] 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(3-hydroxypropyl)benzonitrile

[0456]

[0457] 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), TBAF solution (1.0 M, in THF, 2.9 mL, 2.9 mmol) was added. The reaction mixture was stirred at RT for 1 h. The mixture was diluted with EtOAc (50 mL) and washed with saturated ammonium chloride aqueous solution (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 rapid silica gel chromatography using a gradient elution of 5 to 75% EtOAc / hexane to give 0.90 g of the title compound (92%). ES-MS m / z 347 and 349 (M+H).

[0458] Preparation 30

[0459] 4-[(6-bromo-2-pyridyl)oxymethyl]-2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzonitrile

[0460]

[0461] DIAD (915 μL, 4.5 mmol) was slowly added to a solution of triphenylphosphine (1.21 g, 4.61 mmol) in anhydrous THF (15 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred for 30 min, and 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, and the mixture was stirred at RT for 2 h and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography using a gradient of 0 to 30% EtOAc / cyclohexane to provide 1.12 g of the title compound (78%). ES-MS m / z 461 and 463 (M+H).

[0462] Preparation 31

[0463] 4-[(6-bromo-2-pyridyl)oxymethyl]-2-(3-hydroxypropyl)benzonitrile

[0464]

[0465] A TBAF solution (1.0 M, in THF, 2.7 mL, 2.7 mmol) was slowly added to a solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]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 a saturated aqueous solution of NaCl, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography using a gradient of 25 to 50% EtOAc / cyclohexane to provide the title compound as a white solid (790 mg, 89%). ES-MS m / z 347 and 349 (M+H).

[0466] Preparation of 32

[0467] 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-formylbenzonitrile

[0468]

[0469] 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) were added to a solution of 4-formyl-3-hydroxybenzonitrile (3.0 g, 18.8 mmol) in DMF (56 mL). The mixture was stirred at 70 °C for 24 h. 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 rapid silica gel chromatography using a gradient of 0 to 30% EtOAc / heptane to give 5.68 g of the title compound (99%). ES-MS m / z 306 (M+H).

[0470] Preparation of 33

[0471] 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(hydroxymethyl)benzonitrile

[0472]

[0473] A solution of 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-carboxybenzonitrile (450 mg, 1.47 mmol) in MeOH (4.6 mL) was cooled to 0 °C. Sodium borohydride (112 mg, 2.96 mmol) was added and the mixture was stirred at 0 °C for 15 minutes. The mixture was warmed to RT and stirred for 1 hour. The mixture was diluted with water and adjusted to pH 7 with 1 M aqueous HCl solution, and then extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was passed through a silica gel pad to give 350 mg of the title compound (77%). 1 H-NMR (400MHz, CDCl3) δ7.32(d,J=7.7Hz,1H),7.15(d,J=7.7Hz,1H),7.02(d,J=1.0 Hz,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).

[0474] Preparation of 34

[0475] 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzonitrile

[0476]

[0477] DIAD (1.76 mL, 8.94 mmol) was added 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). The mixture was stirred at 50 °C for 4 hours, and then the crude reaction mixture was concentrated. The residue was diluted with EtOAc and then washed with water (3x) and brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography using a gradient of 0 to 20% EtOAc / heptane to give 247 mg of the title compound (47%). ES-MS m / z 463 and 465 (M+H).

[0478] Preparation of 35

[0479] 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-(2-hydroxyethoxy)benzonitrile

[0480]

[0481] The title compound was prepared essentially as described in Preparation 31 using 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzonitrile, with the reaction mixture stirred at RT for 2 hours. The title compound was purified by rapid silica gel chromatography using a gradient of 0 to 20% EtOAc / DCM. ES-MS m / z 349 and 351 (M+H).

[0482] Preparation of 36

[0483] Ethyl (E)-3-[5-chloro-2-(hydroxymethyl)phenyl]prop-2-enoate

[0484]

[0485] Ethyl acrylate (10.3 mL, 94.8 mmol) was added 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). The reaction mixture was stirred at 90 °C for 6 hours under a nitrogen atmosphere. The reaction mixture was filtered and then washed 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 onto silica, and purified by silica gel chromatography using a gradient of 15 to 40% EtOAc / hexane to give 6.14 g of the title compound (32%). ES-MS m / z 258 (M+NH4) + ).

[0486] Preparation of 37

[0487] Ethyl 3-[5-chloro-2-(hydroxymethyl)phenyl]propionate

[0488]

[0489] To the mixture of platinum sulfide / carbon (5%, 220 mg, 0.056 mmol) in EtOAc (20 mL), add ethyl (E)-3-[5-chloro-2-(hydroxymethyl)phenyl]prop-2-enoate (2.21 g, 9.18 mmol) in EtOAc (30 mL). Shake at RT for 1 hour in a Parr shaker under hydrogen pressure of 40 psi. The solution was filtered through a pad and the filtrate was concentrated under reduced pressure to provide 1.91 g of the title compound (86%), which was used as crude material for the preparation of 38 μm ES-MS (m / z 225, M-H₂O).

[0490] Preparation of 38

[0491] Ethyl 3-[2-(bromomethyl)-5-chloro-phenyl]propionate

[0492]

[0493] Phosphorus tribromide (0.80 mL, 8.5 mmol) was added dropwise to a mixture of ethyl 3-[5-chloro-2-(hydroxymethyl)phenyl]propionate (1.90 g, 7.80 mmol) in diethyl ether (40 mL). The mixture was stirred at RT for 1 hour under a nitrogen atmosphere. The reaction was quenched by slow dropwise addition of a saturated aqueous sodium bicarbonate solution (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 provide 2.40 g of the title compound (100%), which was used as crude material for the preparation of 45. ES-MS m / z 322 and 324 (M+NH4). + ).

[0494] Preparation 39

[0495] 4-[(1,3-dioxoisoindoline-2-yl)methyl]-3-iodobenzonitrile

[0496]

[0497] Potassium phthalimide (6, 14 g, 33, 14 mmol) was added to a solution of 4-(bromomethyl)-3-iodobenzonitrile (10 g, 30, 13 mmol) in DMF (100 mL). The reaction mixture was heated at 80 °C for 2 hours, followed by stirring at RT for 16 hours. The solvent was removed, and the solid residue was milled in 500 mL of water for 30 minutes. The white solid was filtered, washed with water, and dried under vacuum at 45 °C for 20 hours to provide the title compound as a white solid (11.5 g, 88%). ES-MS m / z 405 (M+OH) - ).

[0498] Preparation of 40

[0499] 4-[(1,3-dioxoisoindoline-2-yl)methyl]-3-(3-hydroxypropyl-1-ynyl)benzonitrile

[0500]

[0501] To a suspension of 4-[(1,3-dioxoisoindolin-2-yl)methyl]-3-iodobenzonitrile (5.0 g, 11.7 mmol) in THF (50 mL) and TEA (50 mL), 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) were added. The reaction mixture was heated at 40 °C for 3 hours. After cooling to RT, it was diluted with EtOAc (50 mL) and water (50 mL) and passed through... The mixture was filtered. The phase was separated and the aqueous phase was extracted with more EtOAc (2 x 50 mL). The organic matter was combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient from 30% EtOAc / cyclohexane to 100% EtOAc to give 3.2 g (79%) of the title compound as a creamy solid. ES-MS m / z 315 (MH).

[0502] Preparation 41

[0503] 4-[(1,3-dioxoisoindoline-2-yl)methyl]-3-(3-hydroxypropyl)benzonitrile

[0504]

[0505] In 250mL In a miniclave reactor, 1,1'-bis(di-isoindoline-2-yl)methyl]-3-(3-hydroxyprop-1-ynyl)benzonitrile (3 g, 9.48 mmol) was added to a suspension of 4-[(1,3-dioxoisoindoline-2-yl)methyl]-3-(3-hydroxyprop-1-ynyl)benzonitrile (3 g, 9.48 mmol) in MeOH (60 mL) as rhodium tetrafluoroborate (I) (0.34 g, 0.47 mmol). The reactor was purged with hydrogen at 90 psi and heated at 50 °C for 2 hours. The reaction mixture was cooled to RT, the solvent was evaporated, and the residue was purified by using a silica plug with EtOAc as solvent to provide 2.4 g (75%) of the title compound as a light cream-colored solid. ES-MSm / z 321 (M+H).

[0506] Preparation 42

[0507] 4-(aminomethyl)-3-(3-hydroxypropyl)benzonitrile

[0508]

[0509] Hydrazine monohydrate (1.90 mL, 37.6 mmol) was added to a suspension of 4-[(1,3-dioxoisoindoline-2-yl)methyl]-3-(3-hydroxypropyl)benzonitrile (2.4 g, 7.49 mmol) in MeOH (45 mL), and the mixture was stirred at 60 °C for 20 h. The reaction mixture was cooled to RT and the solid was filtered off. The filtrate was evaporated, the residue was diluted with water (30 mL), and extracted with DCM / MeOH 9:1 (3 x 20 mL). The organic compounds were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (880 mg, 49%) as a faint red oil. ES-MS m / z 191 (M+H).

[0510] Preparation 43

[0511] 2-(((5-bromo-4-fluoro-2-iodobenzyl)oxy)methyl)-4-cyanobenzoate

[0512]

[0513] Sodium hydride (60%, in mineral oil, 362 mg, 9.1 mmol) was added to a solution of (5-bromo-4-fluoro-2-iodophenyl)methanol (1.5 g, 4.5 mmol) in THF (24 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min. Methyl 2-(bromomethyl)-4-cyanobenzoate (2.3 g, 9.1 mmol) was added and the mixture was stirred at RT for 1 h. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and a saturated aqueous NaCl solution. 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 rapid silica gel chromatography using DCM to give 2.5 g of the title compound (67%) with a purity of 61% and used for preparation 44 without further purification. ES-MS m / z 504 and 506 (M+H).

[0514] Preparation of 44

[0515] 3-(((5-bromo-4-fluoro-2-iodobenzyl)oxy)methyl)-4-(hydroxymethyl)benzonitrile

[0516]

[0517] 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 at RT for 20 hours, a portion of lithium borohydride (0.5 equivalents) was added, and the mixture was stirred at RT for 2 hours. The reaction mixture was diluted with EtOAc, and the organic layer was washed with water and a saturated aqueous NaCl solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography using a gradient of 0 to 50% EtOAc / heptane to give the title compound. ES-MS m / z 476 and 478 (M+H).

[0518] Preparation of 45

[0519] Ethyl 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-phenyl]propionate

[0520]

[0521] 1,4-Dioxane (40 mL) was added to a mixture of ethyl 3-[2-(bromomethyl)-5-chlorophenyl]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). The reaction mixture was stirred at 40 °C for 15 hours. The filtrate was filtered through a pad and 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 / hexane to give 1.16 g of the title compound (37%). ES-MS m / z 398, 400, and 402 (M+H).

[0522] Preparation of 46

[0523] 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-phenyl]prop-1-ol

[0524]

[0525] Lithium borohydride (2.0 M, in THF, 3.2 mL, 6.4 mmol) was added dropwise to a mixture of ethyl 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-phenyl]propionate (1.16 g, 2.90 mmol) in THF (12 mL). The reaction mixture was stirred at RT for 6 h. Another portion of lithium borohydride (2.0 M, in THF, 2.0 mL, 4.0 mmol) was added. The reaction mixture was stirred at RT for another 17 h. 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 rapid silica chromatography using a gradient elution of 0 to 55% EtOAc / hexane to give 461 mg of the title compound (35%). ES-MS m / z 356, 358 and 360 (M+H).

[0526] Preparation 47

[0527] 4-[[(6-bromo-2-pyridyl)amino]methyl]-3-(3-hydroxypropyl)benzonitrile

[0528]

[0529] To a solution of 4-(aminomethyl)-3-(3-hydroxypropyl)benzonitrile (800 mg, 3.36 mmol) in DMSO (16 mL), 2-bromo-6-fluoropyridine (610 mg, 3.36 mmol) and DIPEA (1.17 mL, 6.72 mmol) were added and the mixture was stirred at 100 °C for 18 hours. The reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with EtOAc (3 x 20 mL). The organic matter was combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient from 30% EtOAc / cyclohexane to 100% EtOAc to provide the title compound (400 mg, 33%) as a thick brown oil. ES-MS m / z 346 and 348 (M+H).

[0530] Preparation of 48

[0531] 4-[(3-bromophenoxy)methyl]-3-iodobenzonitrile

[0532]

[0533] Add 1,4-dioxane (20 mL) to a mixture of 4-(bromomethyl)-3-iodobenzonitrile (2.0 g, 6.2 mmol), 3-bromophenol (1.10 g, 6.4 mmol), and potassium carbonate (2.6 g, 19.0 mmol). Stir the reaction mixture at RT for 15 hours. Dilute the reaction mixture with EtOAc (100 mL) and pass through... Filtration. The filtrate was washed with water (2 × 50 mL) and a saturated sodium chloride aqueous solution (50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography with gradient elution from 0 to 30% EtOAc / hexane to give 2.4 g of the title compound (93%). 1 H NMR(400.13MHz, CDCl3)δ8.16(d,J=1.5Hz,1H),7.71(dd,J=1.5,8.0Hz,1H),7.6 4(d,J=8.0Hz,1H),7.23-7.17(m,3H),6.92(dt,J=7.5,2.1Hz,1H),5.05(s,2H).

[0534] Preparation 49

[0535] 4-[(3-bromophenoxy)methyl]-3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzonitrile

[0536]

[0537] The title compound was prepared using 4-[(3-bromophenoxy)methyl]-3-iodobenzonitrile, as described in Preparation 28. ES-MS m / z 460 and 462 (M+H).

[0538] Preparation of 50

[0539] 4-[(3-bromophenoxy)methyl]-3-(3-hydroxypropyl)benzonitrile

[0540]

[0541] The title compound was prepared essentially as described in Preparation 29 using 4-[(3-bromophenoxy)methyl]-3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzonitrile. ES-MS m / z 344 and 346 (MH).

[0542] Preparation 51

[0543] 2-Bromo-6-[[2-iodo-4-(trifluoromethyl)phenyl]methoxy]pyridine

[0544]

[0545] Potassium tert-butoxide (0.98 g, 8.6 mmol) was added to a mixture of [2-iodo-4-(trifluoromethyl)phenyl]methanol (2.0 g, 6.6 mmol), 2-bromo-6-fluoropyridine (1.2 g, 6.6 mmol), and 1,4-dioxane (25 mL). The reaction mixture was stirred at 50 °C for 2 hours. The reaction was diluted with EtOAc (100 mL) and... Filtration. The filtrate was washed with water (2 × 50 mL) and a saturated sodium chloride aqueous solution (50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography with gradient elution of 10 to 50% EtOAc / hexane to give 2.0 g of the title compound (66%). ES-MS m / z 458 and 460 (M+H).

[0546] Preparation of 52

[0547] 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)phenyl]propoxy-tert-butyl-dimethyl-silane

[0548]

[0549] The title compound was prepared using 2-bromo-6-[[2-iodo-4-(trifluoromethyl)phenyl]methoxy]pyridine, as basically as described in Preparation 28. The title compound was purified by rapid silica gel chromatography with gradient elution of 0 to 10% EtOAc / hexane. It was used directly in Preparation 53 without further characterization.

[0550] Preparation of 53

[0551] 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)phenyl]prop-1-ol

[0552]

[0553] The title compound was prepared essentially as described in Preparation 29 using 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)phenyl]propoxy-tert-butyl-dimethylsilane. ES-MS m / z 390 and 392 (M+H).

[0554] Preparation of 54

[0555] 2-[4-bromo-2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]propoxy]-5-fluoro-phenyl]ethyl acetate

[0556]

[0557] Tri-n-butylphosphine (0.90 mL, 4.0 mmol) was added to a mixture of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(3-hydroxypropyl)benzonitrile (550 mg, 1.58 mmol) and ethyl 2-(4-bromo-5-fluoro-2-hydroxyphenyl)acetate (0.40 g, 1.4 mmol) in THF (10 mL). A solution of DEAD (40% toluene solution, 1.1 mL, 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 rapid silica gel chromatography using a gradient elution of 5 to 40% EtOAc / hexane to give 1.1 g of the title compound (92%). ES-MS m / z 605, 607, and 609 (M+H).

[0558] Preparation of 55

[0559] 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-phenyl]propoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl acetate

[0560]

[0561] DIAD (0.35 mL, 1.80 mmol) was added dropwise to a mixture of 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-phenyl]prop-1-ol (420 mg, 1.18 mmol), methyl 2-[2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]acetate (422 mg, 1.45 mmol), and triphenylphosphine (460 mg, 1.75 mmol) in THF (8 mL). The reaction mixture was stirred at RT for 1.5 h. The mixture was adsorbed onto silica and purified by rapid silica chromatography using a gradient elution of 0 to 30% EtOAc / hexane to give 306 mg of the title compound (41%). ES-MS m / z 630 and 632 (M+H).

[0562] Preparation of 56

[0563] 2-[2-[3-[2-[[(6-bromopyridin-2-yl)oxy]methyl]-5-cyanophenyl]propoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl acetate

[0564]

[0565] Tri-n-butylphosphine (21 mL, 84 mmol) was added to a mixture of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(3-hydroxypropyl)benzonitrile (14.5 g, 41.9 mmol) and 2-[2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]acetate (18.7 g, 63.9 mmol) in THF (250 mL). The solution was cooled in an ice bath and DIAD (17 mL, 86 mmol) was added dropwise. The reaction mixture was stirred at 45 °C 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 (3 × 25 mL) to give 19.7 g of the title compound (76%). ES-MS m / z 621,623 (M+H).

[0566] Preparation 57

[0567] 2-[2-[3-[2-[[(6-bromo-2-pyridyl)amino]methyl]-5-cyano-phenyl]propoxy]-4-(5,5-dimethyl-1,3,2-dioxaborane-2-yl)-5-fluoro-phenyl]ethyl acetate

[0568]

[0569] Triphenylphosphine (0.30 g, 1.15 mmol) and di-tert-butyl azodicarbonate (0.27 g, 1.15 mmol) were added to a solution of 4-[[(6-bromo-2-pyridyl)amino]methyl]-3-(3-hydroxypropyl)benzonitrile (380 mg, 1.04 mmol) and 2-[4-(5,5-dimethyl-1,3,2-dioxaborane-2-yl)-5-fluoro-2-hydroxyphenyl]ethyl acetate (0.38 g, 1.15 mmol) in THF (5.2 mL). The mixture was stirred at RT for 22 h, the reaction mixture was concentrated, and the residue was purified by silica gel chromatography using a gradient of 10 to 70% EtOAc / cyclohexane to give the title compound (500 mg, 60%) as a pale brown solid. ES-MS m / z 570 and 572 (M+H, for boric acid).

[0570] Preparation of 58

[0571] 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]propoxy]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl acetate

[0572]

[0573] The title compound was prepared essentially as described in Preparation 55 using methyl 4-[(6-bromo-2-pyridinyl)oxymethyl]-3-(3-hydroxypropyl)benzonitrile and methyl 2-[2-hydroxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]acetate. Tri-n-butylphosphine was used instead of triphenylphosphine, DEAD was used instead of DIAD, and dioxane was used as the solvent instead of THF. Purification was achieved by rapid silica gel chromatography using a gradient of 80–100% DCM / hexane. ES-MS m / z 635 and 637 (M+H).

[0574] Preparation 59

[0575] 2-[2-[3-[5-[(6-bromo-2-pyridyl)oxymethyl]-2-cyano-phenyl]propoxy]-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]ethyl acetate]

[0576]

[0577] A solution of di-tert-butyl azodicarbonate (390 mg, 1.7 mmol) in anhydrous THF (2 mL) was slowly added to a solution of triphenylphosphine (435 mg, 1.66 mmol), 4-[(6-bromo-2-pyridyl)oxymethyl]-2-(3-hydroxypropyl)benzonitrile (400 mg, 1.09 mmol), and 2-[5-fluoro-2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]ethyl acetate (480 mg, 83% purity, 1.23 mmol) in anhydrous THF (8 mL) at RT. The mixture was stirred at RT for 1 hour. Triphenylphosphine (170 mg, 0.65 mmol) was added, followed by a slow addition of a solution of di-tert-butyl azodicarbonate (157 mg, 0.65 mmol) in anhydrous THF (2 mL) after 5 minutes. The reaction mixture was concentrated and the residue was purified by rapid silica gel chromatography using a gradient of 10 to 50% EtOAc / cyclohexane to give the title compound as a brown waxy solid (689 mg, 90% purity, 86%). ES-MS m / z 653 and 655 (M+H).

[0578] Preparation of 60

[0579] 2-(4-bromo-2-(2-(2-((((6-bromopyridin-2-yl)oxy)methyl)-5-cyanophenoxy)ethoxy)-5-fluorophenyl)ethyl acetate

[0580]

[0581] Tri-n-butylphosphine (0.91 mL, 3.65 mmol) was added 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-hydroxyphenyl)acetate (506 mg, 1.83 mmol), and TMAD (671 mg, 3.70 mmol) in THF (9 mL). The mixture was stirred at 35 °C for 2 h. The reaction was quenched with MeOH and the crude mixture was concentrated. The residue was purified by rapid silica gel chromatography using a gradient of 0 to 30% EtOAc / heptane to give 876 mg of the title compound (79%). ES-MS m / z 607, 609, and 611 (M+H).

[0582] Preparation of 61

[0583] 3-(((5-bromo-4-fluoro-2-iodobenzyl)oxy)methyl)-4-(((6-bromopyridin-2-yl)oxy)methyl)benzonitrile

[0584]

[0585] The title compound was prepared essentially as described in Preparation 34 using 3-(((5-bromo-4-fluoro-2-iodobenzyl)oxy)methyl)-4-(hydroxymethyl)benzonitrile. The title compound was purified by rapid silica gel chromatography using a gradient of 0 to 10% EtOAc / heptane. ES-MS m / z 631, 633, and 635 (M+H).

[0586] Preparation of 62

[0587] 2-(4-bromo-2-(((2-(((6-bromopyridin-2-yl)oxy)methyl)-5-cyanobenzyl)oxy)methyl)-5-fluorophenyl)ethyl acetate

[0588]

[0589] 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), add 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). Stir the reaction mixture at 70 °C and add ethyl diazoacrylate (2 M, in DCM, 8.5 mL, 17 mmol) in ACN (25 mL) over 10 minutes. Stir at 70 °C for 2 hours. Add a second portion of all reagents (half the initial amount) and heat for another 1.5 hours. Dilute the reaction mixture with EtOAc and wash the organic layer with water. Dry the organic phase over magnesium sulfate, filter, and concentrate under reduced pressure. The residue was purified by rapid silica gel chromatography using a gradient of 0 to 10% EtOAc / heptane to yield 898 mg of the title compound (36%). ES-MS m / z 591, 593, and 595 (M+H).

[0590] Preparation of 63

[0591] 2-[2-[3-[2-[(3-bromophenoxy)methyl]-5-cyano-phenyl]propoxy]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl acetate

[0592]

[0593] The title compound was prepared essentially as described in Preparation 54 using methyl 4-[(3-bromophenoxy)methyl]-3-(3-hydroxypropyl)benzonitrile and methyl 2-[2-hydroxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]acetate, with 1,4-dioxane as the reaction solvent and DEAD in the form of a 40% toluene solution. The title compound was purified by rapid silica gel chromatography using a gradient elution of 80 to 100% DCM / hexane. ES-MS m / z 651 and 653 (M+NH4). + ).

[0594] Preparation of 64

[0595] 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)phenyl]propoxy]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl acetate

[0596]

[0597] The title compound was prepared essentially as described in Preparation 54 using methyl 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)phenyl]prop-1-ol and methyl 2-[2-hydroxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]acetate, with DEAD added to a 40% toluene solution. The title compound was purified by rapid silica gel chromatography using a gradient elution of 85 to 100% DCM / hexane. ES-MS m / z 678 and 680 (M+H).

[0598] Preparation of 65

[0599] 2-(5 4 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 ethyl acetate (-yl)

[0600]

[0601] To a solution of ethyl 2-[4-bromo-2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]propoxy]-5-fluoro-phenyl]acetate (1.1 g, 0.92 mmol) in 1,4-dioxane (40 mL), hexamethyldistin (0.71 g, 2.2 mmol) was added. Tetra(triphenylphosphine)palladium(0) (0.20 g, 0.20 mmol) was added. The reaction mixture was stirred at 90 °C for 60 h. The residue was concentrated under reduced pressure and purified by rapid silica gel chromatography using a gradient elution of 5 to 45% EtOAc / hexane to give 303 mg of the title compound (47%). ES-MS m / z 447 (M+H).

[0602] Preparation of 66

[0603] 2-(5 4 -chloro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 methyl acetate (-yl)

[0604]

[0605] To a mixture of methyl 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-phenyl]propoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]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 Gen2, 28.9 mg, 0.036 mmol), and potassium phosphate (420 mg, 1.94 mmol), THF (48 mL) and water (5.4 mL) were added. The reaction mixture was stirred at 40 °C for 15 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM and adsorbed onto… The compound was rapidly purified by silica gel chromatography using a gradient elution of 0 to 40% EtOAc / hexane to give 152 mg of the title compound (74%). ES-MS m / z 424 and 426 (M+H).

[0606] Preparation of 67

[0607] 2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl acetate (-yl)

[0608]

[0609] To a mixture of methyl 2-[2-[3-[2-[[(6-bromopyridin-2-yl)oxy]methyl]-5-cyanophenyl]propoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]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 Gen2, 1.3 g, 1.6 mmol), and potassium phosphate (28.5 g, 132 mmol), THF (500 mL) and water (52 mL) were added. The reaction mixture was stirred at 45 °C for 2 hours and 15 minutes under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (200 mL) and washed with semi-saturated brine (400 mL). The organic phase was dried over MgSO4, filtered, and 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 (3 × 30 mL) to give 10.7 g of the title compound (82%). ES-MS m / z 415 (M+H).

[0610] Preparation of 68

[0611] 2-(5 4 -Cyano-1 6 -Fluoro-9-oxa-3-aza-2(2,6)-pyridaz-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 ethyl acetate (-yl)

[0612]

[0613] To a solution of ethyl 2-[2-[3-[2-[[(6-bromo-2-pyridyl)amino]methyl]-5-cyano-phenyl]propoxy]-4-(5,5-dimethyl-1,3,2-dioxaborane-2-yl)-5-fluoro-phenyl]acetate (460 mg, 0.57 mmol) in 1,4-dioxacyclohexane (11.5 mL), PdCl2 (dtbpf) (77 mg, 0.11 mmol) and 1 M potassium phosphate aqueous solution (1.73 mL, 1.73 mmol) were added. The mixture was stirred at 70 °C for 2 hours, cooled to RT, and the reaction mixture was diluted with saturated ammonium chloride solution (15 mL) and EtOAc (10 mL). The phase was separated, and the aqueous phase was extracted with EtOAc (2 × 5 mL). The organic matter was combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 30% EtOAc / cyclohexane as the elution system to provide the title compound (125 mg, 49%) as a pale yellow solid. ES-MS m / z 446 (M+H).

[0614] Preparation of 69

[0615] 2-(5 4 -Cyano-1 6 -Methyl-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 methyl acetate (-yl)

[0616]

[0617] The title compound was prepared essentially as described in Preparation 66 using methyl 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]propoxy]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]acetate. It was rapidly purified by silica gel chromatography using a gradient of 0 to 20% EtOAc / DCM. ES-MS m / z 429 (M+H).

[0618] Preparation of 70

[0619] 2-(5 4 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 ethyl acetate (-yl)

[0620]

[0621] To a solution of ethyl 2-[2-[3-[5-[(6-bromo-2-pyridyl)oxymethyl]-2-cyano-phenyl]propoxy]-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]ethyl acetate (650 mg, 90% purity, 0.89 mmol) in 1,4-dioxane (30 mL), PdCl2 (dtbpf) (119 mg, 0.18 mmol) and 1 M potassium phosphate aqueous solution (2.7 mL, 2.7 mmol) were added. The mixture was stirred at 50 °C for 15 min under nitrogen atmosphere, then cooled to RT and diluted with DCM. The solution was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography using a gradient of 10 to 30% EtOAc / cyclohexane to provide the title compound (150 mg, 38%) as a very pale brown solid. ES-MS m / z 447(M+H).

[0622] Preparation 71

[0623] 2-(5 4 -Cyano-1 6 -Fluoro-3,6,9-trioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 ethyl acetate (-yl)

[0624]

[0625] Pd(dppf)Cl2-DCM complex (27 mg, 0.032 mmol) was added to a solution of ethyl 2-(4-bromo-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), and bis(pinacol)diborone (187 mg, 0.72 mmol) in 1,4-dioxane (2.2 mL). The mixture was stirred at 85 °C 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. The residue was added to THF (66 mL), tripotassium phosphate (0.6 g, 3.0 mmol), water (7.3 mL), and a pre-prepared solution of 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). The mixture was stirred at 45 °C for 16 h. The crude mixture was diluted with water and extracted three times with EtOAc (3x). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography using a gradient of 0–30% EtOAc / heptane to give 94 mg of the title compound (32%). ES-MS m / z 449 (M+H).

[0626] Preparation of 72

[0627] 2-(5 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 ethyl acetate (-yl)

[0628]

[0629] The title compound was prepared substantially as described in Preparation 65 using ethyl 2-(4-bromo-2-(((2-((((6-bromopyridin-2-yl)oxy)methyl)-5-cyanobenzyl)oxy)methyl)-5-fluorophenyl)ethyl acetate, with 1.1 eq of hexamethyldistin as a catalyst and Pd(dppf)Cl2-DCM as a catalyst, and stirred at 100 °C for 3.5 h. 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 rapid silica gel chromatography using a gradient of 0 to 80% EtOAc / heptane to give the title compound. ES-MS m / z 433 (M+H).

[0630] Preparation of 73

[0631] 2-(5 4 -Cyano-1 6 -Methyl-3,9-dioxa-1,2(1,3),5(1,2)-triphenylheterocyclic nonafen-1 4 methyl acetate (-yl)

[0632]

[0633] The title compound was prepared substantially as described in Preparation 66 using methyl 2-[2-[3-[2-[(3-bromophenoxy)methyl]-5-cyano-phenyl]propoxy]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]acetate, with the reaction mixture stirred at 40°C for 1 hour. The mixture was rapidly purified by silica gel chromatography using a gradient elution of 0 to 20% EtOAc / DCM to give the title compound. ES-MS m / z 428 (M+H).

[0634] Preparation of 74

[0635] 2-(1 6 -Methyl-5 4 -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 methyl acetate (-yl)

[0636]

[0637] The title compound was prepared substantially as described in Preparation 66 using methyl 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)phenyl]propoxy]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]acetate, stirred at 40 °C for 1 h. The title compound was purified by rapid silica gel chromatography using a gradient elution of 0 to 20% EtOAc / DCM. ES-MS m / z 472 (M+H).

[0638] Preparation of 75

[0639] 2-(5 4 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 -yl)acetic acid

[0640]

[0641] To 2-(5) 4 -Cyano-16 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 1,3,4,6,7,8-hexahydro-2H-pyrimidino[1,2-a]pyrimidin (0.30 g, 2.0 mmol) was added to a mixture of ethyl acetate (290 mg, 0.649 mmol) in ACN:water (5 mL:0.5 mL). The reaction mixture was stirred at RT for 15 hours. The pH of the reaction mixture was adjusted to pH 7 with 1.0 M citric acid aqueous solution and concentrated under reduced pressure to remove volatiles. The residue was diluted with EtOAc (100 mL) and washed with water (50 mL) and saturated NaCl aqueous solution (50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 238 mg of the title compound (88%), which was used as crude material for the preparation of 85 and 86. ES-MS m / z 419 (M+H).

[0642] Preparation of 76

[0643] 2-(5 4 -chloro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 -yl)acetic acid

[0644]

[0645] To 2-(5) 4 -chloro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 Methyl acetate (152 mg, 0.36 mmol) was added to a mixture of ACN (3.6 mL) and THF (3 mL) in an aqueous solution of lithium hydroxide (1.0 M, 1.1 mL, 1.1 mmol). The mixture was stirred at 40 °C for 2 hours. The reaction was quenched with an aqueous solution of citric acid (1.0 M, 2.2 mL) and then diluted with EtOAc. The aqueous layer was removed and extracted with EtOAc (2 × 3 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 150 mg of the title compound (100%), which was used as crude material for the preparation of 87. ES-MS m / z 410 (M+H).

[0646] Preparation of 77

[0647] 2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 -yl)acetic acid

[0648]

[0649] The basic preparation method is as described in 75, from 2-(5) 4 Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by starting with methyl acetate (-yl)-2-ethyl acetate. After the reaction was complete, the mixture 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)

[0650] Preparation of 78

[0651] 2-(5 4 -Cyano-1 6 -Fluoro-9-oxa-3-aza-2(2,6)-pyridaz-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 -yl)acetic acid

[0652]

[0653] To 2-(5) 4 -Cyano-1 6 -Fluoro-9-oxa-3-aza-2(2,6)-pyridaz-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Ethyl ethyl acetate (122 mg, 0.27 mmol) was added to a suspension of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (116 mg, 0.81 mmol) in ACN (3 mL), THF (1 mL), and water (1 mL). The mixture was stirred at 45 °C for 2 hours, cooled to RT, and quenched with 1 M citric acid solution (2 mL). Extraction was performed with EtOAc (3 × 3 mL). The organic matter was 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).

[0654] Preparation 79

[0655] 2-(5 4 -Cyano-1 6 -Methyl-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 -yl)acetic acid

[0656]

[0657] The basic preparation method is as described in 75, using 2-(5) 4 -Cyano-1 6 -Methyl-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 The title compound was prepared from methyl (-yl)acetate. ES-MS m / z 415 (M+H).

[0658] Preparation of 80

[0659] 2-(5 4 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 -yl)acetic acid

[0660]

[0661] The basic preparation method is as described in 78, using 2-(5) 4 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 The title compound was prepared from ethyl acetate (-methyl). ES-MS m / z 419 (M+H).

[0662] Preparation of 81

[0663] 2-(5 4 -Cyano-1 6 -Fluoro-3,6,9-trioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 -yl)acetic acid

[0664]

[0665] The basic preparation method is as described in 75, using 2-(5) 4 -Cyano-1 6 -Fluoro-3,6,9-trioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared from ethyl acetate (-yl) by stirring at 45 °C for 3 h. The reaction was quenched with formic acid to pH 7 and diluted with water. The mixture was extracted three times with EtOAc, followed by three extractions with 3:1 chloroform:isopropanol. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography using a gradient of 10 to 80% EtOAc / DCM to give the title compound. ES-MS m / z 421 (M+H).

[0666] Preparation of 82

[0667] 2-(5 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 -yl)acetic acid

[0668]

[0669] The preparation of 75 basically uses ethyl 2-(5-) 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 The title compound was prepared by stirring at 45 °C for 1 h. The reaction was quenched with formic acid to pH 6-7, and extracted with EtOAc followed by extraction with 3:1 chloroform:2-propanol. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (95%), which was used as crude material for the preparation of 98. ES-MS m / z 405 (M+H).

[0670] Preparation of 83

[0671] 2-(5 4 -Cyano-1 6 -Methyl-3,9-dioxa-1,2(1,3),5(1,2)-triphenylheterocyclic nonafen-1 4 -yl)acetic acid

[0672]

[0673] The basic preparation method is as described in 75, using 2-(5) 4 -Cyano-1 6 -Methyl-3,9-dioxa-1,2(1,3),5(1,2)-triphenylheterocyclic nonafen-1 4 The title compound was prepared by stirring the reaction mixture at 45°C for 1 hour with methyl methyl acetate. The title compound was used as a crude product for the preparation of 99. ES-MS m / z 412 (MH).

[0674] Preparation of 84

[0675] 2-(1 6 -Methyl-5 4 -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 -yl)acetic acid

[0676]

[0677] Basically as described in preparation 75, using 2-(1 6 -Methyl-5 4 -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 The title compound was prepared by reacting methyl acetate (-yl) at 50°C with stirring for 1 hour. The title compound was used as a crude product for the preparation of 100. ES-MS m / z 458 (M+H).

[0678] Preparation of 85

[0679] (S)-4-(2-(5 4 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-((oxetane-2-ylmethyl)amino)benzoate

[0680]

[0681] To 2-(5) 4 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 4-amino-3-[[(2S)-oxetane-2-yl]methylamino]benzoate (crude, 0.170 g, 0.361 mmol) and methyl 4-amino-3-[[(2S)-oxetane-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020 / 263695; 100 mg, 0.423 mmol) in pyridine (3 mL) were added to EDC (125 mg, 0.639 mmol). The reaction mixture was stirred at RT for 15 h. The reaction was quenched with saturated ammonium chloride aqueous solution to pH 6. The mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organics were washed with saturated sodium chloride aqueous solution (10 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 elution of 0 to 50% EtOAc / petroleum ether to give 225 mg of the title compound (71%). ES-MS m / z 637 (M+H).

[0682] Preparation of 86

[0683] (S)-4-(2-(5 4-Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-fluoro-5-((oxetane-2-ylmethyl)amino)benzoate

[0684]

[0685] To 2-(5) 4 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 A mixture of 4-amino-3-fluoro-5-[[(2S)-oxetane-2-ylmethyl]amino]benzoate (238 mg, 0.568 mmol) in DMF (5 mL) was reacted with DIPEA (0.15 mL, 0.86 mmol). HATU (0.20 g, 0.53 mmol) was added. The mixture was stirred at RT for 4 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL) and a saturated aqueous solution of NaCl (50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 0.46 g of the title compound (99%), which was used as crude material for the preparation of 102. ES-MS m / z 655 (M+H).

[0686] Preparation of 87

[0687] (S)-4-(2-(5 4 -chloro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-((oxetane-2-ylmethyl)amino)benzoate

[0688]

[0689] Basically as described in preparation 86, using 2-(5 4 -chloro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 4-(2S)-oxetane-2-yl)methylamino]benzoate (prepared essentially as described in WO 2020 / 263695) was reacted with 4-amino-3-[[(2S)-oxetane-2-yl]methylamino]benzoate, stirred for 16 hours, and then post-processed to prepare the title compound. The title compound was used as a crude substance for the preparation of 104. ES-MS m / z 628 (M+H).

[0690] Preparation of 88

[0691] (S)-4-(2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-((oxetane-2-ylmethyl)amino)benzoate

[0692]

[0693] Basically as described in preparation 86, using 2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl 4-amino-3-[[(2S)-oxetane-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020 / 263695). The crude title compound was obtained without purification and used for the preparation of 105 μL. ES-MS m / z 619 (M+H)

[0694] Preparation of 89

[0695] (S)-4-(2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-methoxy-5-((oxetane-2-ylmethyl)amino)benzoate

[0696]

[0697] Basically as described in preparation 86, using 2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared from methyl 4-(2S)-(2S)-oxetane-2-yl)methylamino]benzoate (Preparation 17). The residues were 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).

[0698] Preparation of 90

[0699] (S)-5-(2-(5 4-Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)diphenylhexacyclic nonafen-14-yl)acetamyl)-6-((oxetane-2-ylmethyl)amino)methyl pyridinecarboxylate

[0700]

[0701] Basically as described in preparation 86, using 2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared using (S)-5-amino-6-((oxocyclobutane-2-ylmethyl)amino)pyridinecarboxylate (0.3 g, 0.75 mmol). The title compound was used in the next step (Preparation 107) without purification. ES-MS m / z 620 (M+H)

[0702] Preparation of 91

[0703] (S)-4-(2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-fluoro-5-((oxetane-2-ylmethyl)amino)benzoate

[0704]

[0705] Basically as described in preparation 86, using 2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared from methyl 4-(2S)-oxetane-2-ylmethyl]amino]benzoate and methyl 4-amino-3-fluoro-5-[[(2S)-oxetane-2-ylmethyl]amino]benzoate. The title compound was used in the next step (Preparation 108) without purification. ES-MS m / z 637 (M+H)

[0706] Preparation of 92

[0707] (S)-4-(2-(5 4 -Cyano-1 6 -Fluoro-9-oxa-3-aza-2(2,6)-pyridaz-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-((oxetane-2-ylmethyl)amino)benzoate

[0708]

[0709] To 2-(5) 4 -Cyano-1 6 -Fluoro-9-oxa-3-aza-2(2,6)-pyridaz-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl 4-amino-3-[[(2S)-oxetane-2-yl]methylamino]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) were added to a solution of 4-amino-3-[[(2S)-oxetane-2-yl]methylamino]benzoate (115 mg, 0.27 mmol), HATU (160 mg, 0.42 mmol), and DIPEA (0.15 mL, 0.86 mmol). The mixture was stirred at RT for 2 h, diluted with water (10 mL), and extracted with EtOAc (4 × 5 mL). The organic compounds were combined, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under vacuum to give the title compound (160 mg, 79%) as a brown solid. ES-MS m / z 636 (M+H).

[0710] Preparation of 93

[0711] (S)-4-(2-(5 4 -Cyano-1 6 -Methyl-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-methoxy-5-((oxetane-2-ylmethyl)amino)benzoate

[0712]

[0713] Basically as described in preparation 86, using 2-(5 4 -Cyano-1 6 -Methyl-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 The title compound was prepared by reacting methyl 4-amino-3-methoxy-5-[[(2S)-oxetane-2-yl]methylamino]benzoate (Preparation 17). The title compound was used as a crude product in the next step (Preparation 103) without purification. ES-MS m / z 663 (M+H).

[0714] Preparation of 94

[0715] (S)-4-(2-(5 4 -Cyano-1 6-Fluoro-3,9-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-((oxetane-2-ylmethyl)amino)benzoate

[0716]

[0717] Basically as described in preparation 86, using 2-(5 4 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl 4-amino-3-[[(2S)-oxetane-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020 / 263695). The title compound was used in its crude form without purification for the preparation of 110. ES-MS m / z 637 (M+H).

[0718] Preparation of 95

[0719] 4-(2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl benzoate (-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate)

[0720]

[0721] Basically as described in preparation 86, using 2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (Preparation 19) with (100 mg, 0.25 mmol) ethyl acetate and (1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate. The reaction mixture was stirred at RT for 18 h, then diluted with water and EtOAc, followed by extraction of the aqueous layer four times 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 111. ES-MS m / z 657 (M+H).

[0722] Preparation of 96

[0723] (S)-2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-14 -N-(2-methoxy-6-((oxetane-2-ylmethyl)amino)-4-(1H-tetrazol-5-yl)phenyl)acetamide

[0724]

[0725] Basically as described in preparation 86, using 2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared from (S)-3-methoxy-N1-(oxetane-2-ylmethyl)-5-(1H-tetrazol-5-yl)phenyl-1,2-diamine. The mixture was stirred at RT for 67 h. 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 residues were purified by rapid silica gel chromatography using a gradient of 0–100% EtOAc / heptane followed by 0–10% MeOH / DCM. ES-MS m / z 659 (M+H).

[0726] Preparation of 97

[0727] (S)-4-(2-(5 4 -Cyano-1 6 -Fluoro-3,6,9-trioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-((oxetane-2-ylmethyl)amino)benzoate

[0728]

[0729] Basically as described in preparation 86, using 2-(5 4 -Cyano-1 6 -Fluoro-3,6,9-trioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl 4-amino-3-[[(2S)-oxetane-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020 / 263695) with stirring at RT for 24 hours. The crude reaction mixture 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 provide the title compound, which was used as a crude substance for the preparation of 112. ES-MS m / z 639 (M+H).

[0730] Preparation of 98

[0731] (S)-4-(2-(5 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 Methyl benzoate (-yl)acetamyl)-3-((oxetane-2-ylmethyl)amino)benzoate

[0732]

[0733] Basically as described in preparation 86, using 2-(5 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 The title compound was prepared by reacting methyl 4-amino-3-[[(2S)-oxetane-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020 / 263695) with stirring at RT for 2 h. The 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 to give the title compound, which was used as crude material for the preparation of 113. ES-MS m / z 623 (M+H).

[0734] Preparation of 99

[0735] (S)-4-(2-(5 4 -Cyano-1 6 -Methyl-3,9-dioxa-1,2(1,3),5(1,2)-triphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-methoxy-5-((oxetane-2-ylmethyl)amino)benzoate

[0736]

[0737] Basically as described in preparation 85, using 2-(5 4 -Cyano-1 6 -Methyl-3,9-dioxa-1,2(1,3),5(1,2)-triphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl 4-amino-3-methoxy-5-[[(2S)-oxetane-2-yl]methylamino]benzoate (Preparation 17). The title compound was used unpurified for Preparation 114. ES-MS m / z 662 (M+H).

[0738] Prepare 100

[0739] (S)-3-methoxy-4-(2-(1) 6 -Methyl-5 4 -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-5-((oxetane-2-ylmethyl)amino)benzoate

[0740]

[0741] Basically as described in preparation 85, using 2-(1 6 -Methyl-5 4 -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 The title compound was prepared by reacting methyl 4-amino-3-methoxy-5-[[(2S)-oxetane-2-yl]methylamino]benzoate (Preparation 17). The title compound was used as a crude product for Preparation 115 without purification. ES-MS m / z 706 (M+H).

[0742] Preparation 101

[0743] (S)-2-((5 4 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[0744]

[0745] (S)-4-(2-(5) 4 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 A solution of methyl benzoate (220 mg, 0.295 mmol) in acetic acid (3.0 mL) was stirred at 80 °C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 200 mg of the title compound (87%), which was used as crude material in Example 1. ES-MS m / z 619 (M+H).

[0746] Preparation 102

[0747] (S)-2-((5 4 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[0748]

[0749] (S)-4-(2-(5) will be added to acetic acid (5.0 mL). 4 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (0.46 g, 0.56 mmol) was stirred at 55 °C 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 solution 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 / hexane to give 0.24 g of the title compound (67%). ES-MS m / z 637 (M+H).

[0750] Preparation of 103

[0751] (S)-2-((5 4 -Cyano-1 6 -Methyl-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 methyl 4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[0752]

[0753] The basic preparation method is as described in preparation 102, using (S)-4-(2-(5) 4 -Cyano-1 6 -Methyl-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4The title compound was prepared by methyl benzoate (Preparation 93) and 1:1 DCM:acetic acid. It was rapidly purified by silica gel chromatography using a gradient of 5 to 60% EtOAc / DCM. ES-MS m / z 645 (M+H).

[0754] Preparation of 104

[0755] (S)-2-((5 4 -chloro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[0756]

[0757] The basic preparation method is as described in preparation 102, using (S)-4-(2-(5) 4 -chloro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 The title compound was prepared by stirring the reaction mixture at 55°C for 3.5 hours, followed by stirring at 65°C for 2 hours. The mixture was concentrated under reduced pressure and azeotropically reacted with ACN. The residue was dissolved in DCM and adsorbed onto... The sample was purified by silica gel chromatography using a gradient elution of 0 to 100% EtOAc / hexane. ES-MS m / z 610 (M+H).

[0758] Preparation 105

[0759] (S)-2-((5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[0760]

[0761] The basic preparation method is as described in preparation 102, used in a 1:1 dichloroethane:acetic acid mixture (S)-4-(2-(5) 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4The title compound was prepared by (Preparation 88)-(-(oxocyclobutan-2-ylmethyl)amino)methyl benzoate. The residues were 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).

[0762] Preparation of 106

[0763] (S)-2-((5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[0764]

[0765] The basic preparation method is as described in preparation 102, used in a 1:1 dichloroethane:acetic acid mixture (S)-4-(2-(5) 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by methyl methyl 3-((oxocyclobutane-2-ylmethyl)amino)benzoate. The residues were 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).

[0766] Preparation of 107

[0767] (S)-2-((5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

[0768]

[0769] The basic preparation method is as described in preparation 102, used in a 1:1 dichloroethane:acetic acid mixture (S)-5-(2-(5) 4The title compound was prepared by 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).

[0770] Preparation of 108

[0771] (S)-2-((5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[0772]

[0773] The preparation method is basically as described in preparation 102, used in a 1:1 mixture of dichloroethane and acetic acid (S)-4-(2-(5) 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared from methyl benzoate (0.38 g, 0.48 mmol) of (-yl)acetamyl)-3-fluoro-5-((oxetane-2-ylmethyl)amino)benzoate. The residue was purified by silica gel chromatography using a gradient of 5 to 60% EtOAc / DCM to give 0.24 g of the title compound (67%). ES-MS m / z 619 (M+H).

[0774] Preparation 109

[0775] (S)-2-((5 4 -Cyano-1 6 -Fluoro-9-oxa-3-aza-2(2,6)-pyridaz-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[0776]

[0777] (S)-4-(2-(5) 4 -Cyano-1 6-Fluoro-9-oxa-3-aza-2(2,6)-pyridaz-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 A solution of methyl benzoate (160 mg, 0.20 mmol) in 1,2-dichloroethane (1.5 mL) and acetic acid (1.25 mL) was heated at 50 °C for 6 hours. The reaction mixture was cooled to RT, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a 10 to 50% EtOAc / DCM gradient to provide 70 mg (53%) of the title compound as a white solid. ES-MS m / z 618 (M+H).

[0778] Preparation of 110

[0779] (S)-2-((5 4 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[0780]

[0781] The basic preparation method is as described in preparation 109, using (S)-4-(2-(5) 4 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by stirring the reaction mixture at 60 °C for 5.5 h. 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).

[0782] Preparation 111

[0783] 2-((5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazol-6-carboxylic acid methyl ester

[0784]

[0785] Basically as described in preparation 101, using 4-(2-(5) 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl benzoate (1-((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (Preparation 95) with stirring at 65 °C for 5 h, followed by stirring at 80 °C for 17 h. The solution was concentrated and azeotropically reacted with ACN. The residues were 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).

[0786] Preparation 112

[0787] (S)-2-((5 4 -Cyano-1 6 -Fluoro-3,6,9-trioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[0788]

[0789] The basic preparation method is as described in preparation 101, using (S)-4-(2-(5) 4 -Cyano-1 6 -Fluoro-3,6,9-trioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl benzoate (-(oxocyclobutan-2-ylmethyl)amino)benzoate with stirring at 65 °C for 3 h. The reaction was concentrated and azeotropically reacted with ACN. The residue was rapidly purified by silica gel chromatography 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).

[0790] Preparation of 113

[0791] (S)-2-((5 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[0792]

[0793] The basic preparation method is as described in preparation 101, using (S)-4-(2-(5) 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 The title compound was prepared by reacting methyl 3-((oxocyclobutan-2-ylmethyl)amino)benzoate with stirring at 65 °C for 1.5 h. The solution was concentrated and azeotropically reacted with ACN, and the residue was then purified by rapid silica gel chromatography using a gradient of 0 to 60% EtOAc / heptane to give the title compound. ES-MS m / z 605 (M+H).

[0794] Preparation of 114

[0795] (S)-2-((5 4 -Cyano-1 6 -Methyl-3,9-dioxa-1,2(1,3),5(1,2)-triphenylheterocyclic nonafen-1 4 methyl 4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[0796]

[0797] The basic preparation method is as described in preparation 102, used in a 1:1 dichloroethane:acetic acid mixture (S)-4-(2-(5) 4 -Cyano-1 6 -Methyl-3,9-dioxa-1,2(1,3),5(1,2)-triphenylheterocyclic nonafen-1 4 Methyl benzoate (Preparation 99) was prepared from the title compound. ES-MS m / z 645 (M+H).

[0798] Preparation 115

[0799] (S)-4-methoxy-2-((1 6 -Methyl-5 4 -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[0800]

[0801] The preparation method is basically as described in preparation 102, and is used in a 1:1 dichloroethane:acetic acid mixture with (S)-3-methoxy-4-(2-(1) 6 -Methyl-5 4 -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 The title compound was prepared by methyl 5-((oxocyclobutan-2-ylmethyl)amino)benzoate (Preparation 100). 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).

[0802] Preparation of 116

[0803] 2-(4-bromo-2-methylphenyl)acetic acid methyl ester

[0804]

[0805] Thionyl chloride (2.5 mL, 34.3 mmol) was added dropwise to a solution of 2-(4-bromo-2-methylphenyl)acetic acid (5 g, 20.74 mmol) in MeOH (42 mL) at 4 °C over 15 minutes. The reaction was stirred for 3 hours, and then the solvent was evaporated under reduced pressure. Water (50 mL) and a saturated NaHCO3 aqueous solution were added to the residue to bring the solution to pH 7–8, and then the mixture was extracted with EtOAc (3 × 30 mL). The organic compounds were combined, washed with water and a saturated NaCl aqueous solution, dried over MgSO4, 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 the preparation of 117.

[0806] Preparation of 117

[0807] 4-Bromo-2-(bromomethyl)phenylacetic acid methyl ester

[0808]

[0809] 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 °C) equipped with 4 × 370 nm and 4 × 440 nm lamps. The solution was collected over 2 hours, the solvent was evaporated, and water (20 mL) and MTBE (20 mL) were added to the residue. The layers were separated and the aqueous phase was extracted with MTBE (2 × 20 mL). The organic compounds were combined, washed with 20% NaHSO3 aqueous solution, water, and saturated NaCl aqueous solution, dried over MgSO4, 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 (5.1 g, 85% purity, 75% yield) as a white waxy solid. ES-MS m / z338 / 340 / 342(M+NH4 + ).

[0810] Preparation of 118

[0811] methyl 3-fluoro-5-methoxy-4-nitrobenzoate

[0812]

[0813] A solution of sodium formate (25% by mass, in MeOH, 0.33 mL, 1.44 mmol) was added to a solution of methyl 3,5-difluoro-4-nitrobenzoate (0.3 g, 1.38 mmol) in MeOH (4 mL), and the mixture was heated at 65 °C for 2.5 h. The reaction mixture was cooled to RT, and then water was added and extracted with EtOAc (3 × 5 mL). The organic compounds were combined, washed with a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using a gradient of EtOAc / heptane (0 to 10%) to give 245 mg (76%) of the title compound as a yellow oil. ES-MS m / z 230 (M+H).

[0814] Preparation of 119

[0815] ethyl 3-fluoro-5-methoxy-4-nitrobenzoate

[0816]

[0817] Sulfuric acid (2 mL, 3.1 g, 31 mmol) was added to a solution of 3-fluoro-5-methoxy-4-nitrobenzoic acid (0.67 g, 3.1 mmol) in EtOH (10 mL), and the mixture was heated to 80 °C for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 and extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated to give the title compound (0.73 g, 96%), which was used for the preparation of 121 without further purification. ES-MS m / z 244 (M+H).

[0818] Preparation 120

[0819] methyl 3-fluoro-5-(2-methoxyethoxy)-4-nitrobenzoate

[0820]

[0821] Sodium hydride (92 mg, 2.30 mmol) was suspended in THF (10 mL), and then 2-methoxyethanol (0.18 mL, 2.31 mmol) was added and stirred at RT for 30 min. Next, methyl 3,5-difluoro-4-nitrobenzoate (0.5 g, 2.30 mmol) was added and the mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 50 mL). The organic matter was dried over Na₂SO₄, filtered, and concentrated. Purification by silica gel chromatography using a gradient of 0 to 20% EtOAc / heptane yielded the title compound (225 mg, 40%) as a yellow oil. ES-MS m / z 274 (M+H).

[0822] Preparation 121

[0823] Ethyl 3-methoxy-4-nitro-5-(oxazol-2-ylmethylamino)benzoate

[0824]

[0825] The title compound was prepared essentially as described in Preparation 14 using ethyl 3-fluoro-5-methoxy-4-nitrobenzoate (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).

[0826] Preparation 122

[0827] Ethyl 4-amino-3-methoxy-5-(oxazol-2-ylmethylamino)benzoate

[0828]

[0829] Iron powder (0.33 g, 5.8 mmol) and NH4Cl (0.015 g, 0.28 mmol) were suspended in water (4.4 mL), and acetic acid (0.07 mL, 1.18 mmol) was added. The mixture was stirred at 50 °C for 15 minutes, and 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 °C for 20 minutes, cooled to RT, and then... The mixture was filtered and rinsed with EtOAc (100 mL). The organic matter was washed with a saturated NaHCO3 solution (100 mL) and dried over MgSO4. Filtration and concentration were performed to give the title compound (0.11 g, 74%) as a yellow oil, which was used unpurified for the preparation of 169. ES-MS m / z 292 (M+H).

[0830] Preparation 123

[0831] methyl 3-(2-methoxyethoxy)-4-nitro-5-[[(2S)-oxetane-2-yl]-methylamino]benzoate

[0832]

[0833] The title compound was prepared essentially as described in Preparation 14 using methyl 3-fluoro-5-(2-methoxyethoxy)-4-nitrobenzoate and [(2S)-oxetane-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).

[0834] Preparation 124

[0835] 4-Amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetane-2-yl]methylamino]methyl benzoate

[0836]

[0837] The title compound was prepared essentially as described in Preparation 122 using methyl 3-(2-methoxyethoxy)-4-nitro-5-(oxetane-2-yl-methylamino)benzoate. The product was used for the preparation of 170 without further purification. ES-MS m / z 311 (M+H).

[0838] Preparation 125

[0839] 4-[(6-bromo-2-pyridyl)oxymethyl]-3-[(E)-2-ethoxyvinyl]benzonitrile

[0840]

[0841] Under nitrogen bubbling, Cs₂CO₃ (9.5 g, 29 mmol), tetrakis(triphenylphosphine)palladium(O) (835 mg, 0.72 mmol), and (E)-1-ethoxyethylene-2-boronic acid pinacol ester (4.2 mL, 18.8 mmol) were added to a solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-iodobenzonitrile (6 g, 14.45 mmol) in 1,4-dioxane (100 mL). The reaction mixture was heated at 90 °C under nitrogen for 1 day, and then more tetrakis(triphenylphosphine)palladium(O) (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 °C for another 2 days. The mixture was cooled, water (100 mL) was added, and the mixture was extracted with EtOAc (3 × 60 mL). The organic compounds were combined, dried over MgSO4, 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 3.6 g (60% yield) of the title compound as a pale yellow solid. ES-MS m / z 359 / 361 (M+H).

[0842] Preparation 126

[0843] 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-oxoethyl)benzonitrile

[0844]

[0845] To a solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-[(E)-2-ethoxyvinyl]benzonitrile (3.6 g, 8.5 mmol) in THF (54 mL), 4 M HCl / 1,4-dioxane (21 mL, 85 mmol) was added. The mixture was stirred at RT for 20 h. The mixture was concentrated, and water (50 mL) and 2 M sodium carbonate aqueous solution were added to pH 8, followed by extraction with EtOAc (3 × 40 mL). The organic compounds were combined, dried over MgSO4, 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).

[0846] Preparation 127

[0847] 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile

[0848]

[0849] Sodium borohydride (550 mg, 14.53 mmol) was added fractionally to a solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-oxoethyl)benzonitrile (3.9 g, 8.24 mmol) in MeOH (60 mL). The mixture was stirred at RT for 1 h, the solvent was evaporated, DCM (30 mL) and 1 M NaOH solution (10 mL) were added, and the mixture was stirred for 10 min. The phase was separated and the aqueous phase was extracted with more DCM (2 × 5 mL). The organic matter was combined, washed with water and saturated NaCl aqueous solution, dried over MgSO4, 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).

[0850] Preparation 128

[0851] 2-Bromo-4-(hydroxymethyl)benzonitrile

[0852]

[0853] Lithium borohydride / THF (7.7 mL, 15.4 mmol, 2.0 mol / L) was added to a solution of ethyl 3-bromo-4-cyanobenzoate (2 g, 7.71 mmol) in anhydrous THF (20 mL) at 0 °C under nitrogen atmosphere. 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 °C. The aqueous layer was extracted with EtOAc, the organic layers were combined, washed with water and saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 30 to 100% EtOAc / cyclohexane to provide 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).

[0854] Preparation 129

[0855] 2-Bromo-4-[(6-chloro-2-pyridyl)oxymethyl]benzonitrile

[0856]

[0857] The title compound was prepared essentially as described 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).

[0858] Preparation of 130

[0859] 4-[(6-chloro-2-pyridyl)oxymethyl]-2-(2-hydroxyethyl)benzonitrile

[0860]

[0861] Add nickel(II) ethylene glycol dimethyl ether complex (34 mg, 0.15 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (48 mg, 0.17 mmol) to a vial. Purge the vial with nitrogen and add anhydrous 1,2-dimethoxyethane (3 mL). Stir the mixture for 15 minutes.

[0862] To another vial, add Na₂CO₃ (335 mg, 3.13 mmol), 2-bromo-4-[(6-chloro-2-pyridyl)oxymethyl]benzonitrile (502 mg, 1.55 mmol), and (Ir[dF(CF₃)ppy]₂(dtbpy))PF₆ (18 mg, 0.016 mmol). Purge the vial with nitrogen and add anhydrous 1,2-dimethoxyethane (12 mL), 2-bromoethanol (1.1 mL, 15 mmol), tris(trimethylsilyl)silane (740 μL, 2.33 mmol), and the pre-prepared Ni catalyst. Bubble the mixture under nitrogen for 5 minutes and run it through an EvoluChem instrument. TM The sample was irradiated overnight in a photo-redox chamber using a fan-equipped Kessil LED at 456 nm. The solid was filtered off, washed with DCM, and the filtrate was concentrated. The residue was purified by silica gel chromatography using a gradient of 0–10% EtOAc / DCM as the elution system to provide the title compound (190 mg, 42%) as a yellow waxy solid. ES-MS m / z 289, 291 (M+H).

[0863] Preparation of 131

[0864] 2-Bromo-6-[(4-Fluoro-2-iodo-phenyl)methoxy]pyridine

[0865]

[0866] Potassium tert-butoxide (1.20 g, 10.0 mmol) was added to a mixture of (4-fluoro-2-iodo-phenyl)methanol (2.0 g, 7.9 mmol), 2-bromo-6-fluoropyridine (1.4 g, 7.9 mmol), and 1,4-dioxane (25 mL). The reaction mixture was stirred at 60 °C for 16 hours. The reaction was diluted with EtOAc (100 mL) and... Filtration. The filtrate was washed with water (2 × 50 mL) and a saturated sodium chloride aqueous solution (50 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography with a gradient elution of 5 to 50% DCM / hexane to give 2.16 g of the title compound (67%). ES-MS m / z 408 and 410 (M+H).

[0867] Preparation of 132

[0868] 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-fluoro-phenyl]propoxy-tert-butyl-dimethyl-silane

[0869]

[0870] The title compound was prepared using 2-bromo-6-[(4-fluoro-2-iodo-phenyl)methoxy]pyridine, as basically as described in Preparation 28. The title compound was purified by rapid silica gel chromatography with gradient elution of 0 to 10% EtOAc / hexane to obtain an oily substance that was not ionized by ES-MS, which was used directly for Preparation 133 without further identification.

[0871] Preparation of 133

[0872] 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-fluoro-phenyl]prop-1-ol

[0873]

[0874] The title compound was prepared essentially as described in Preparation 29 using 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-fluoro-phenyl]propoxy-tert-butyl-dimethyl-silane (Preparation 132). ES-MS m / z 340 and 342 (M+H).

[0875] Preparation of 134

[0876] 2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-6-(trifluoromethyl)pyridine-3-carboxylic acid methyl ester

[0877]

[0878] The title compound was prepared essentially as described 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).

[0879] Preparation of 135

[0880] [2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-6-(trifluoromethyl)-3-pyridyl]methanol

[0881]

[0882] A mixture of methyl 2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-6-(trifluoromethyl)pyridine-3-carboxylate (2.0 g, 5.3 mmol) and THF (40 mL) was cooled to -10 °C in an ice / salt bath. Lithium aluminum hydride (0.20 g, 5.3 mmol) was added to the mixture, and the mixture was stirred for 1 hour under cooling. The reaction was quenched by dropwise addition of water (1 mL), followed by dilution with EtOAc (50 mL). The resulting mixture was filtered and washed with EtOAc (100 mL). The filtrate was washed with water (100 mL) and a saturated aqueous solution of NaCl (100 mL), and then dried over Na₂SO₄. The mixture was filtered and concentrated to give the title compound (1.66 g, 84%) as a brownish-red oil, which was used for the preparation of 136 without further purification. ES-MS m / z 350 (M+H).

[0883] Preparation of 136

[0884] 3-[3-[(6-bromo-2-pyridyl)oxymethyl]-6-(trifluoromethyl)-2-pyridyl]propoxy-tert-butyl-dimethyl-silane

[0885]

[0886] The title compound was prepared substantially as described in Preparation 51 using [2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-6-(trifluoromethyl)-3-pyridyl]methanol and 2-bromo-6-fluoro-pyridine, with stirring at 60 °C for 16 h. The title compound was purified by rapid silica gel chromatography using a gradient elution of 5 to 50% DCM / hexane. ES-MS m / z 506 and 508 (M+H).

[0887] Preparation of 137

[0888] 3-[3-[(6-bromo-2-pyridyl)oxymethyl]-6-(trifluoromethyl)-2-pyridyl]prop-1-ol

[0889]

[0890] The title compound was prepared essentially as described in Preparation 29 using 3-[3-[(6-bromo-2-pyridyl)oxymethyl]-6-(trifluoromethyl)-2-pyridyl]propoxy-tert-butyl-dimethylsilane. The title compound was purified by rapid silica gel chromatography with gradient elution of 5 to 50% EtOAc / hexane. ES-MS m / z 390 and 392 (M+H).

[0891] Preparation of 138

[0892] (3-Iodo-4-pyridyl)methanol

[0893]

[0894] The mixture of methyl 3-iodopyridine-4-carboxylate (5.0 g, 19 mmol) in THF (40 mL) and MeOH (10 mL) was cooled to -10 °C using an ice / salt bath. Sodium borohydride (1.52 g, 40.2 mmol) was then added and stirred for 1 hour under cooling. The reaction was quenched by dropwise addition of water (1 mL), followed by dilution with EtOAc (50 mL). The resulting mixture was filtered and washed with EtOAc (100 mL). The filtrate was washed with water (100 mL) and a saturated aqueous solution of NaCl (100 mL), and then dried over Na₂SO₄. 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 brownish-red solid. ES-MS m / z 236 (M+H).

[0895] Preparation of 139

[0896] 2-Bromo-6-[(3-iodo-4-pyridyl)methoxy]pyridine

[0897]

[0898] The title compound was prepared essentially as described in Preparation 51 using (3-iodo-4-pyridyl)methanol and 2-bromo-6-fluoropyridine, with stirring at 60 °C for 16 h. 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).

[0899] Preparation of 140

[0900] 3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]propoxy-tert-butyl-dimethylsilane

[0901]

[0902] The title compound was prepared using 2-bromo-6-[(3-iodo-4-pyridyl)methoxy]pyridine, as basically as described in Preparation 28. The title compound was purified by silica gel chromatography using a gradient of 0 to 80% EtOAc / hexane without further characterization for Preparation 141.

[0903] Preparation of 141

[0904] 3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]prop-1-ol

[0905]

[0906] The title compound was prepared essentially as described in Preparation 29 using 3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]propoxy-tert-butyl-dimethylsilane (Preparation 140). The title compound was purified by silica gel chromatography with gradient elution of 5 to 75% (1:4 MeOH:EtOAc) / DCM. ES-MS m / z 322 and 324 (M+H).

[0907] Preparation 142

[0908] 2-[4-bromo-2-[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]phenyl]methyl acetate

[0909]

[0910] To a solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-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), 2,6-di-tert-butylpyridine (0.93 mL, 4.24 mmol) and silver trifluoromethanesulfonate (1.10 g, 4.24 mmol) were added. The mixture was stirred at low temperature for 1 hour, then stirred at RT. After 5 hours, more silver trifluoromethanesulfonate (220 mg, 0.85 mmol) was added. After 20 hours, the mixture was analyzed 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 / z 573 / 575 / 577 (M+H).

[0911] Preparation of 143

[0912] 2-[2-[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl acetate

[0913]

[0914] Under nitrogen atmosphere, methyl 2-[4-bromo-2-[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]phenyl]acetate (630 mg, 0.83 mmol, 75% purity) in anhydrous 1,4-dioxane (8.2 mL) was added with bis(pinacol)diboron (260 mg, 1 mmol) and KOAc (202 mg, 2.01 mmol). After 5 minutes, Pd(dppf)Cl2 DCM complex (40 mg, 0.048 mmol) was added, and the reaction mixture was heated to 80 °C. After 3 hours, the reaction mixture was cooled to RT, and then water (10 mL) and EtOAc (10 mL) were added. The layers were separated, and the aqueous phase was extracted with EtOAc (2 × 5 mL). The organic compounds were combined, washed with water and a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (850 mg, 60% purity) as a brown oil, which was used for the preparation of 150 μL without further purification. ES-MS m / z 621 / 623 (M+H).

[0915] Preparation of 144

[0916] 2-[4-bromo-2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]phenyl]methyl acetate

[0917]

[0918] The preparation was basically as described in Preparation 142, using 4-[(6-chloro-2-pyridyl)oxymethyl]-2-(2-hydroxyethyl)benzonitrile, and an activated [substance] was added to the reaction mixture. The title compound was prepared using molecular sieves. The title compound was purified by silica gel chromatography using a gradient of 50% to 100% DCM / cyclohexane. ES-MS m / z 529, 531, 533 (M+H).

[0919] Preparation of 145

[0920] 2-[2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl acetate

[0921]

[0922] The title compound was prepared essentially as described in Preparation 143 using methyl 2-[4-bromo-2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]phenyl]acetate. After the reaction was complete, the mixture was cooled to RT, saturated NaHCO3 and EtOAc were added, and the mixture was then subjected to... The mixture was filtered. The aqueous layer was separated and the organic layer was washed with water and a saturated aqueous NaCl solution, dried over anhydrous Na₂SO₄, filtered, and the solvent was removed. The residue was purified by silica gel chromatography using a gradient of 0 to 2% EtOAc / DCM, providing the title compound as a colorless waxy solid. ES-MS m / z 577 and 579 (M+H).

[0923] Preparation of 146

[0924] 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-fluoro-phenyl]propoxy]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl acetate

[0925]

[0926] The title compound was prepared essentially as described in Preparation 54 using methyl 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-fluoro-phenyl]prop-1-ol and methyl 2-[2-hydroxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]acetate, with a toluene solution of 40% DEAD. The title compound was purified by rapid silica gel chromatography using a gradient elution of 85 to 100% DCM / hexane. ES-MS m / z 628 and 630 (M+H).

[0927] Preparation of 147

[0928] 2-[2-[3-[3-[(6-bromo-2-pyridyl)oxymethyl]-6-(trifluoromethyl)-2-pyridyl]propoxy]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl acetate

[0929]

[0930] The title compound was prepared essentially as described in Preparation 55 using methyl 3-[3-[(6-bromo-2-pyridyl)oxymethyl]-6-(trifluoromethyl)-2-pyridyl]prop-1-ol and methyl 2-[2-hydroxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-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 rapid silica gel chromatography using a gradient elution of 85 to 100% DCM / hexane. ES-MS m / z 678 and 680 (M+H).

[0931] Preparation of 148

[0932] 2-[2-[3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]propoxy]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl acetate

[0933]

[0934] The title compound was prepared substantially as described in Preparation 55 using methyl 3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]prop-1-ol and methyl 2-[2-hydroxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]acetate in 1,4-dioxane as solvent and stirred 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).

[0935] Preparation 149

[0936] 2-(5 4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl acetate (-yl)

[0937]

[0938] Bis(pinacol)diboron (3.93 g, 15.2 mmol) and KOAc (3.04 g, 30.4 mmol) were added to 2-(5 4 -chloro-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 Methyl 2-(2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)] (0.25 g, 0.31 mmol) was added to a slurry of 1,4-dioxane (0.2 L). The mixture was stirred at 85 °C under positive nitrogen pressure for 2.5 h, then cooled and concentrated under reduced pressure to remove most of the volatiles. The residue was partitioned between DCM (0.15 L) and water (0.15 L), the phases were separated, and the aqueous phase was extracted again with DCM (50 mL). The combined organic phases were washed with 2 M K2CO3 aqueous solution (50 mL), then washed with brine (50 mL), dried over MgSO4, and filtered. The filtrate was concentrated to a volume of 30 mL, and 0.2 L of MeOH was added, followed by concentration to a volume of 60 mL. The mixture was stirred at ambient temperature for 3 hours, and the solid was collected by filtration and washed with 30 mL of MeOH. The filter cake was dried under reduced pressure at 50 °C for 13 hours to give 4.95 g of the title compound (94%) as a gray solid. ES-MS m / z 515 and 516 (M+H).

[0939] Prepare 150

[0940] 2-(5 4 -Cyano-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl acetate (-yl)

[0941]

[0942] The title compound was prepared essentially as described in Preparation 68 using methyl 2-[2-[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]acetate (Preparation 143). ES-MS m / z 415 (M+H).

[0943] Preparation of 151

[0944] 2-(5 4 -Cyano-1 6 -Fluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 ethyl acetate (-yl)

[0945]

[0946] Under a nitrogen atmosphere, a solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile (400 mg, 1.20 mmol), triphenylphosphine (473 mg, 1.80 mmol), and 2-[5-fluoro-2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]ethyl acetate (563 mg, 1.44 mmol) in anhydrous THF (10 mL) was added to a round-bottom flask. The mixture was stirred until the solids dissolved and cooled in an ice bath. A solution of di-tert-butyl azodicarbonate (423 mg, 1.80 mmol) in THF (1.6 mL) was added to the mixture. The ice bath was removed, and the reaction was allowed to stand at RT for 2 hours. THF (26 mL) and potassium phosphate aqueous solution (1 M, 7.2 mL) were added to the reaction mixture, and the mixture was stirred for 5 minutes. Add Pd(dtbpf)Cl2 (80 mg, 0.12 mmol) to the reaction mixture, rinse repeatedly with nitrogen, and heat to 80 °C for 3 hours. Cool the reaction mixture to RT, dilute with EtOAc, and add...

[0947] Stir the mixture for 10 minutes, then... The mixture was filtered through a pad and washed with EtOAc. The filtrate was dried over MgSO4, filtered, and 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 (150 mg, 28.9%) as a white solid. ES-MS m / z 433 (M+H).

[0948] Preparation 152

[0949] 2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 methyl acetate (-yl)

[0950]

[0951] Nitrogen gas was bubbled into a mixture of methyl 2-[2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]acetate (132 mg, 0.20 mmol, 88 mass%), THF (5 mL), and tripotassium phosphate aqueous solution (1.0 M, 1 mL, 1.0 mmol) for 5 minutes. XPhos Pd (crotonyl)Cl (Pd-170 catalyst, CAS No. 1798782-02-1, 6 mg, 0.009 mmol) was added, and the mixture was stirred at 50 °C 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 NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using DCM to provide the title compound as a white solid (51 mg, 61%). ES-MS m / z 415 (M+H).

[0952] Preparation 153

[0953] 2-(5 4 -Fluorine-1 6 -Methyl-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 methyl acetate (-yl)

[0954]

[0955] The title compound was prepared substantially as described in Preparation 66 using methyl 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-fluoro-phenyl]propoxy]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]acetate with stirring the reaction mixture at 40°C for 1 hour under a nitrogen atmosphere. The title compound was purified by rapid silica gel chromatography using a gradient elution of 0 to 20% EtOAc / DCM. ES-MS m / z 422 (M+H).

[0956] Preparation of 154

[0957] 2-(1 6 -Methyl-5 6 -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)-dipyridaza-1(1,3)benzylhexacyclic nonafen-1 4 methyl acetate (-yl)

[0958]

[0959] The title compound was prepared substantially as described in Preparation 66 using methyl 2-[2-[3-[3-[(6-bromo-2-pyridyl)oxymethyl]-6-(trifluoromethyl)-2-pyridyl]propoxy]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyl-2-yl)phenyl]acetate, with stirring at 40 °C for 1 h. 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).

[0960] Preparation of 155

[0961] 2-(1 6 -Methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridaza-1(1,3)-benzene-1-cyclononafen-1 4 methyl acetate (-yl)

[0962]

[0963] The title compound was prepared substantially as described in Preparation 66 using methyl 2-[2-[3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]propoxy]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]acetate with stirring at 40 °C for 1 h. 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).

[0964] Preparation of 156

[0965] 2-(5 4 -bromo-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 -yl)acetic acid

[0966]

[0967] Add MeOH (20 mL) and water (5 mL) to a 2-(5) 4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4A mixture of methyl acetate (4.45 g, 8.55 mmol) and copper bromide (5.73 g, 25.7 mmol) was added. The mixture was stirred at 80 °C for 30 hours. The mixture was cooled to ambient temperature, and a 30% aqueous solution of NH4OH was added and diluted with water to a final volume of approximately 0.5 L. The mixture was stirred for 0.5 hours, and the solid was collected by filtration and washed with a 10% aqueous solution of NH4OH (0.1 L), followed by washing with water (0.1 L). THF (0.14 L), MeOH (70 mL), and a 1M aqueous solution of LiOH (35 mL) were added to the moist solid, and the mixture was stirred at 60 °C for 3.5 hours. A 1M aqueous solution of KH2PO4 (0.1 L) was added to the mixture, and then diluted with water to a final volume of approximately 1 L. The mixture was allowed to cool naturally with stirring for 1 hour, and the solid was collected by filtration and washed with a 1:4 solution of water:MeOH (0.2 L) and water (0.1 L). The filter cake was dried under reduced pressure at 50 °C for 16 hours to give 3.66 g of the title compound (92%) as a grayish-white solid. ES-MS m / z 454 and 456 (M+H).

[0968] Preparation of 157

[0969] 2-(5 4 -Cyano-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 -yl)acetic acid

[0970]

[0971] The basic preparation method is as described in 78, using 2-(5) 4 -Cyano-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared from methyl (-yl)acetate. ES-MS m / z 401 (M+H).

[0972] Preparation of 158

[0973] 2-(5 4 -Cyano-1 6 -Fluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 -yl)acetic acid

[0974]

[0975] The basic preparation method is as described in 78, using 2-(5) 4 -Cyano-1 6-Fluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 The title compound was prepared from ethyl acetate (-methyl). ES-MS m / z 418 (M+H).

[0976] Preparation 159

[0977] 2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 -yl)acetic acid

[0978]

[0979] The basic preparation method is as described in 78, using 2-(5) 4 -cyano-3,8-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 The title compound was prepared from methyl (-yl)acetate. ES-MS m / z 401 (M+H).

[0980] Preparation of 160

[0981] 2-(1 6 -Methyl-5 4 -(fluorine)-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 -yl)acetic acid

[0982]

[0983] Basically as described in preparation 75, using 2-(1 6 -Methyl-5 4 -(fluorine)-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl ethyl acetate at 50 °C with stirring for 1 hour. The title compound was used without purification for the preparation of 168. ES-MS m / z 408 (M+H).

[0984] Preparation of 161

[0985] Methyl 2-(1 6 -Methyl-5 6 -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)-dipyridaza-1(1,3)benzylhexacyclic nonafen-1 4 -yl)acetic acid

[0986]

[0987] Basically as described in preparation 75, using 2-(1 6 -Methyl-5 6 -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)-dipyridaza-1(1,3)benzylhexacyclic nonafen-1 4 The title compound was prepared by reacting methyl acetate (-yl) at 50 °C with stirring for 1 hour. The title compound was used to prepare 171 without further purification. ES-MS m / z 459 (M+H).

[0988] Preparation of 162

[0989] 2-(1 6 -Methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridaza-1(1,3)-benzene-1-cyclononafen-1 4 -yl)acetic acid

[0990]

[0991] Basically as described in preparation 75, using 2-(1 6 -Methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridaza-1(1,3)-benzene-1-cyclononafen-1 4 The title compound was prepared by reacting methyl acetate (-yl) with stirring at 50 °C for 1 h. The title compound was used to prepare 172 without further purification. ES-MS m / z 391 (M+H).

[0992] Preparation of 163

[0993] (S)-4-(2-(5 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 Methyl benzoate (-yl)acetamyl)-3-methoxy-5-((oxetane-2-ylmethyl)amino)benzoate

[0994]

[0995] Basically as described in preparation 86, using 2-(5 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4The title compound was prepared by reacting methyl 4-amino-3-methoxy-5-[[(2S)-oxetane-2-yl]methylamino]benzoate with stirring for 16 hours. The title compound was used in the next step (Preparation 173) without purification. ES-MS m / z 653 (M+H).

[0996] Preparation of 164

[0997] (S)-4-(2-(5 4 -bromo-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-((oxetane-2-ylmethyl)amino)benzoate

[0998]

[0999] Add DMF (33 mL) and pyridine (6 mL) to 2-(5 4 -bromo-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 A mixture of 4-amino-3-[[(2S)-oxetane-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020 / 263695; 1.75 g, 7.41 mmol) was stirred for 30 min. 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphazenecyclohexane-2,4,6-trioxide (1.68 mol / L, in EtOAc, 10 mL, 16.8 mmol) was added and the mixture was stirred for 50 min. The reaction mixture was diluted with water to a final volume of 0.2 L and stirred for 20 min. The solid was collected by filtration and washed with water (0.1 L). The filter cake was dried under reduced pressure at 50 °C for 24 h to give 4.64 g of the title compound (99%) as a pale pink solid. ES-MS m / z 672 and 674 (M+H).

[1000] Preparation of 165

[1001] (S)-4-(2-(5 4 -Cyano-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-((oxetane-2-ylmethyl)amino)benzoate

[1002]

[1003] Basically as described in preparation 86, using 2-(5 4 -Cyano-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl 4-amino-3-[[(2S)-oxetane-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020 / 263695). The title compound was used in the next step (Preparation 175) without purification. ES-MS m / z 619 (M+H).

[1004] Preparation of 166

[1005] (S)-4-(2-(5 4 -Cyano-1 6 -Fluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 Methyl benzoate (-yl)acetamyl)-3-((oxetane-2-ylmethyl)amino)benzoate

[1006]

[1007] Basically as described in preparation 86, using 2-(5 4 -Cyano-1 6 -Fluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 The title compound was prepared by reacting methyl 4-amino-3-[[(2S)-oxetane-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020 / 263695). The title compound was used as a crude substance for the preparation of 176 μm ES-MS m / z 623 (M+H).

[1008] Preparation of 167

[1009] (S)-4-(2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-((oxetane-2-ylmethyl)amino)benzoate

[1010]

[1011] Basically as described in preparation 86, using 2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4The title compound was prepared by reacting methyl 4-amino-3-[[(2S)-oxetane-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020 / 263695). The title compound was used as a crude substance for the preparation of 177. ES-MS m / z 619 (M+H).

[1012] Preparation of 168

[1013] (S)-3-methoxy-4-(2-(1) 6 -Methyl-5 4 -(fluorine)-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-5-((oxetane-2-ylmethyl)amino)benzoate

[1014]

[1015] Basically as described in preparation 86, using 2-(1 6 -Methyl-5 4 -(fluorine)-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared from methyl 4-amino-3-methoxy-5-[[(2S)-oxetane-2-yl]methylamino]benzoate (Preparation 160). The title compound was used unpurified for the preparation of 178. ES-MS m / z 656 (M+H).

[1016] Preparation of 169

[1017] 4-(2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 ethyl 3-((oxazol-2-ylmethyl)amino)benzoate

[1018]

[1019] Basically as described in preparation 85, using 2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting ethyl 4-amino-3-methoxy-5-(oxazol-2-ylmethylamino)benzoate (Preparation 122). The title compound was used unpurified for Preparation 179. ES-MS m / z 674 (M+H).

[1020] Preparation of 170

[1021] (S)-4-(2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-(2-methoxyethoxy)-5-((oxetane-2-ylmethyl)amino)benzoate

[1022]

[1023] Basically as described in preparation 85, using 2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetane-2-yl]methylamino]benzoate (Preparation 124). The title compound was used for preparation 180 without further purification. ES-MS m / z 693 (M+H).

[1024] Preparation of 171

[1025] (S)-3-methoxy-4-(2-(1) 6 -Methyl-5 6 -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)-dipyridaza-1(1,3)benzylhexacyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-5-((oxetane-2-ylmethyl)amino)benzoate

[1026]

[1027] The preparation method is basically as described in 86, using methyl 2-(1 6 -Methyl-5 6 -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)-dipyridaza-1(1,3)benzylhexacyclic nonafen-1 4 The title compound was prepared from methyl 4-amino-3-methoxy-5-[[(2S)-oxetane-2-yl]methylamino]benzoate (for preparation 161). The title compound was used to prepare 183 without further purification. ES-MS m / z 707 (M+H).

[1028] Preparation of 172

[1029] (S)-3-methoxy-4-(2-(1) 6 -Methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridaza-1(1,3)-benzene-1-cyclononafen-1 4 Methyl benzoate (-yl)acetamyl)-5-((oxetane-2-ylmethyl)amino)benzoate

[1030]

[1031] Basically as described in preparation 86, using 2-(1 6 -Methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridaza-1(1,3)-benzene-1-cyclononafen-1 4 The title compound was prepared from methyl 4-amino-3-methoxy-5-[[(2S)-oxetane-2-yl]methylamino]benzoate (Preparation 162). The title compound was used in the next step (Preparation 184) without further purification. ES-MS m / z 639 (M+H).

[1032] Preparation of 173

[1033] (S)-2-((5 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 methyl 4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1034]

[1035] The basic preparation method is as described in preparation 102, using (S)-4-(2-(5) 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 The title compound was prepared by reacting methyl benzoate (from Preparation 163) with (-yl)acetamoxy-5-((oxetane-2-ylmethyl)amino)benzoate under heating at 65 °C for 9 h. The mixture was cooled to RT and the solvent was evaporated under reduced pressure, with ACN 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).

[1036] Preparation of 174

[1037] (S)-2-((5 4 -bromo-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1038]

[1039] The basic preparation method is as described in preparation 102, using (S)-4-(2-(5) 4 -bromo-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by methyl 3-((oxocyclobutane-2-ylmethyl)amino)benzoate using a 1:1 acetic acid:2-chlorotoluene solvent. The reaction mixture was stirred at 60 °C for 32 h under positive nitrogen pressure. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM, concentrated onto diatomaceous earth, and purified by silica gel chromatography using a gradient of 0-50% EtOAc / DCM to give the title compound as a white solid. ES-MS m / z 654 and 656 (M+H).

[1040] Preparation of 175

[1041] (S)-2-((5 4 -Cyano-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1042]

[1043] The basic preparation method is as described in preparation 102, using (S)-4-(2-(5) 4 -Cyano-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl benzoate (-(oxocyclobutan-2-ylmethyl)amino)benzoate in a 1:11,2-dichloroethane:acetic acid solvent at 50 °C for 5 h. The reaction mixture was cooled to RT, the solvent was concentrated under reduced pressure, and the residue was 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).

[1044] Preparation of 176

[1045] (S)-2-((5 4 -Cyano-1 6 -Fluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1046]

[1047] The basic preparation method is as described in preparation 102, using (S)-4-(2-(5) 4 -Cyano-1 6 -Fluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 The title compound was prepared by heating methyl 3-((oxocyclobutan-2-ylmethyl)amino)benzoate in a 1:11,2-dichloroethane:acetic acid solvent at 52 °C for 4 hours. The reaction was cooled to RT and the solvent was removed 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. ES-MS m / z 605 (M+H).

[1048] Preparation of 177

[1049] (S)-2-((5 4 -cyano-3,8-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1050]

[1051] The basic preparation method is as described in preparation 102, using (S)-4-(2-(5) 4 -cyano-3,8-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl benzoate (-(oxetane-2-ylmethyl)amino)benzoate in a 1:11,2-dichloroethane:acetic acid solvent at 60 °C for 5 h. The reaction mixture was cooled to RT, the solvent was concentrated under reduced pressure, and the residue was 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).

[1052] Preparation of 178

[1053] (S)-4-methoxy-2-((1 6 -Methyl-5 4 -(fluorine)-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1054]

[1055] The basic preparation method is as described in preparation 102, using (S)-3-methoxy-4-(2-(1) 6 -Methyl-5 4 -(fluorine)-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by methyl 5-((oxobutan-2-ylmethyl)amino)benzoate in a 1:1 dichloroethane:acetic acid mixture. The title compound was purified by silica gel chromatography using a gradient of 80 to 100% DCM / hexane. ES-MS m / z 638 (M+H).

[1056] Preparation of 179

[1057] 2-((5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 ethyl 4-methoxy-1-(oxazol-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylate

[1058]

[1059] Basically as described in preparation 101, using 4-(2-(5) 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared from ethyl 3-((oxazol-2-ylmethyl)amino)benzoate in acetic acid. The reaction mixture was concentrated and the title compound was precipitated from heptane without further purification for use in Example 23. ES-MS m / z 656 (M+H).

[1060] Preparation of 180

[1061] (S)-2-((54 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 4-(2-methoxyethoxy)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1062]

[1063] The basic preparation method is as described in preparation 101, using (S)-4-(2-(5) 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared from methyl methyl((oxetane-2-ylmethyl)amino)benzoate 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).

[1064] Preparation of 181

[1065] (S)-2-((5 4 -formyl-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1066]

[1067] In a Schlenk tube, add bis(acetonitrile)palladium(II) dichloride (11 mg, 0.042 mmol) and butyl di-1-adamantylphosphine (48 mg, 0.13 mmol). Purge the tube with nitrogen (3× vacuum / nitrogen circulation) and add 4-methylmorpholine (3 mL, 27.24 mmol). While stirring, purge the tube again with nitrogen (5× vacuum / nitrogen circulation). Close the tube and stir at ambient temperature for 1 hour. In a glass pressure vessel, add (S)-2-((5 4 -bromo-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4Methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (290 mg, 0.42 mmol) and 4-methylmorpholine (9 mL, 81.73 mmol, 100% by mass). The mixture was capped with a diaphragm and bubbled with nitrogen while stirring. After 30 minutes, the catalyst suspension was transferred to a pressure vessel and purged three times with syngas to 80 psi, then re-primed with syngas to 80 psi. The mixture was stirred and heated overnight at 105 °C. The reaction mixture was cooled to RT and the solvent removed. The residue was partitioned between DCM (20 mL) and a 2 M aqueous solution of K₂CO₃ (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (10 mL). The organic layers were combined, washed with a saturated aqueous solution of NaCl (10 mL), filtered, and concentrated to give 320 mg of orange residue. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc / DCM to give the title compound (250 mg, 89%) as a white solid. ES-MS m / z 604 (M+H).

[1068] Preparation of 182

[1069] (S)-2-((5 4 -formyl-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4 -1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid

[1070]

[1071] Add 1 M LiOH aqueous solution (1.25 mL, 1.25 mmol) to (S)-2-((5 4 -formyl-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylhexacyclic nonafen-1 4Methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (0.25 g, 0.37 mmol, 90% by mass) was in a stirred suspension of THF (5 mL) and MeOH (2.5 mL). The reaction vessel was sealed and stirred at 60 °C for 2 h. The reaction was quenched with 1 M K₂HPO₄ aqueous solution (5 mL), diluted with water to a volume of 60 mL, and the mixture was stirred overnight at ambient temperature. The pH of the reaction was adjusted to 4 by adding 5% citric acid aqueous solution, diluted with saturated NaCl aqueous solution (50 mL), and extracted with DCM (50 mL), followed by three extractions with 1:4 isopropanol:DCM (50 mL, 25 mL, 25 mL). The extracts were combined and concentrated under reduced pressure at 50 °C. The residue was dissolved in 1:1 DCM:MeOH, concentrated onto diatomaceous earth, and then purified by silica gel chromatography using a gradient of 0 to 20% MeOH / DCM. The appropriate fraction was concentrated under reduced pressure at 50 °C to obtain 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 °C for 21 h to give the title compound (125 mg, 51%) as a white solid. ES-MS m / z 590 (M+H).

[1072] Preparation of 183

[1073] (S)-4-methoxy-2-((1 6 -Methyl-5 6 -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)-dipyridaza-1(1,3)benzylhexacyclic nonafen-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1074]

[1075] The basic preparation method is as described in preparation 102, using (S)-3-methoxy-4-(2-(1) 6 -Methyl-5 6 -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)-dipyridaza-1(1,3)benzylhexacyclic nonafen-1 4 The title compound was prepared by methyl 5-((oxocyclobutan-2-ylmethyl)amino)benzoate in a 1:1 DCM:acetic acid solvent. 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).

[1076] Preparation of 184

[1077] (S)-4-methoxy-2-((1 6 -Methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridaza-1(1,3)-benzene-1-cyclononafen-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1078]

[1079] The basic preparation method is as described in preparation 102, using (S)-3-methoxy-4-(2-(1) 6 -Methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridaza-1(1,3)-benzene-1-cyclononafen-1 4 Methyl benzoate (Preparation 172) was prepared in a 1:1 dichloroethane:acetic acid 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).

[1080] Preparation of 185

[1081] 5-(3-Fluoro-4-nitro-phenyl)-1H-tetrazole

[1082]

[1083] Tributyltin azide (2 mL, 7 mmol) was added to a solution of 3-fluoro-4-nitrobenzonitrile (470 mg, 2.8 mmol) and TMSCN (4.5 mL, 33 mmol) in toluene (9 mL), and the mixture was heated in a microwave reactor at 150 °C for 2 h. The reaction was quenched with a saturated aqueous solution of NaHCO3 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 586 mg of the title compound (99%). ES-MS m / z 210 (M+H).

[1084] Preparation of 186

[1085] 2-[[5-(3-fluoro-4-nitro-phenyl)tetrazole-1-yl]methoxy]ethyl-trimethyl-silane

[1086]

[1087] Sodium hydride (60%, in mineral oil, 180 mg, 4.5 mmol) was added to a solution of 5-(3-fluoro-4-nitro-phenyl)-1H-tetrazole (860 mg, 4.1 mmol) in 12 mL of THF at 0 °C. 2-(chloromethoxy)ethyl-trimethylsilane (0.79 mL, 4.5 mmol) was added to the mixture and the mixture was 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. The residue was purified by silica gel chromatography eluting with heptane:EtOAc (8:2) to give 240 mg of the title compound (17%). ES-MS m / z 377 (M+H).

[1088] Preparation of 187

[1089] Fumaric acid; [(2S)-oxetane-2-yl]methylamine

[1090]

[1091] [(2S)-oxetane-2-yl]methylamine (3.6 wt%, in EtOH, 1500 g, 620 mmol) and fumaric acid (72 g, 620 mmol) were mixed at 25 °C under nitrogen atmosphere 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-d4)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).

[1092] Preparation of 188

[1093] 2-Nitro-N-[[(2R)-oxetane-2-yl]methyl]-5-[1-(2-trimethylsilylethoxymethyl)tetrazole-5-yl]aniline

[1094]

[1095] A solution of fumaric acid, [(2S)-oxetane-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 h. 2-[[5-(3-fluoro-4-nitro-phenyl)tetrazole-1-yl]methoxy]ethyl-trimethylsilane (240 mg, 0.7 mmol) was added, and the mixture was stirred at 35 °C 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. The residue was purified by silica gel chromatography eluting with heptane:EtOAc (1:1) to give 200 mg of the title compound (70%). ES-MS m / z 429 (M+Na).

[1096] Preparation of 189

[1097] N2-[[(2R)-oxetane-2-yl]methyl]-4-[1-(2-trimethylsilylethoxymethyl)tetrazole-5-yl]phenyl-1,2-diamine

[1098]

[1099] A mixture of iron (100 mg, 2 mmol), ammonium chloride (7 mg, 0.1 mmol), and acetic acid (30 μL, 0.5 mmol) in water (3 mL) was stirred vigorously at 50 °C for 15 minutes. Then, 2-nitro-N-[[(2R)-oxetane-2-yl]methyl]-5-[1-(2-trimethylsilylethoxymethyl)tetrazole-5-yl]aniline (100 mg, 0.2 mmol) was added to DMF (1 mL), and the mixture was stirred at 50 °C for 1 hour. The reaction mixture was filtered, quenched with water, and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 98 mg of the title compound (99%). ES-MS m / z 377 (M+H).

[1100] Preparation of 190

[1101] (S)-2-(5 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 -N-(2-((oxetane-2-ylmethyl)amino)-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazole-5-yl)phenyl)acetamide

[1102]

[1103] To 2-(5) 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 HATU (142 mg, 0.37 mmol) was added to a solution of N2-[[(2R)-oxetane-2-yl]methyl]-4-[1-(2-trimethylsilylethoxymethyl)tetrazole-5-yl]phenyl-1,2-diamine (98 mg, 0.26 mmol) and TEA (104 μL, 0.75 mmol) in DMF (2 mL). The mixture was stirred at RT for 1 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 to give 190 mg of the title compound (99%). LC-MS retention time = 2.17 min.

[1104] Preparation of 191

[1105] (S)-1 4 -((1-(oxetane-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)-pyridaz-1(1,3),5(1,2)diphenylhexacyclic nonafen-5 4 -formonitrile

[1106]

[1107] The basic preparation method is as described in preparation 102, using (S)-2-(5) 4 -Cyano-3,9-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting acetamide with a solution of 1:11,2-dichloroethane and acetic acid at 85 °C for 16 h. 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).

[1108] Preparation of 192

[1109] 1-Bromo-4-(bromomethyl)-2-fluoro-5-iodobenzene

[1110]

[1111] N-bromosuccinimide (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); then 2,2'-azobis(2-methylpropionitrile) (1.26 g, 7.54 mmol) was added and the mixture was heated at 85 °C for 5 h. After cooling to room temperature, a saturated NaHCO3 solution (300 mL) was added and the mixture was extracted with DCM (200 mL). The organic compounds 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 16.04 g (54% yield) of the title compound. 1 H NMR (400.13MHz, CDCl3) δ8.05 (d, J = 6.8 Hz, 1H), 7.29 (d, J = 9.00, 1H), 4.51 (s, 2H).

[1112] Preparation of 193

[1113] 2-(4-bromo-5-fluoro-2-iodo-phenyl)acetonitrile

[1114]

[1115] To a solution of 1-bromo-4-(bromomethyl)-2-fluoro-5-iodobenzene (16.04 g, 40.74 mmol) and TMSCN (7.24 mL, 53 mmol) in ACN (110 mL), TBAF (1 M, in THF, 53 mL, 53 mmol) was slowly added. The reaction was heated at 40 °C for 3 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in EtOAc (150 mL) and washed with saturated NaCl aqueous solution (3 × 50 mL). The organic matter 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 15% EtOAc / heptane to give the title compound (10.34 g, 69%) as an orange oil. ES-MS m / z 340 / 342 (M+H).

[1116] Preparation of 194

[1117] Ethyl 2-(4-bromo-5-fluoro-2-iodo-phenyl)

[1118]

[1119] Sulfuric acid (24 mL) was added 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. The reaction mixture was heated at 80 °C for 18 hours. The mixture was cooled to RT, alkalized to pH > 7 by adding saturated aqueous NaHCO3 solution, and extracted with DCM (3 × 50 mL). The organic matter was combined, washed with water and saturated aqueous NaCl solution, 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 8.88 g (75%) of the title compound as a white solid. ES-MS m / z 387 / 389 (M+H).

[1120] Preparation of 195

[1121] 2-[4-bromo-2-[2-ethoxyvinyl]-5-fluoro-phenyl]ethyl acetate

[1122]

[1123] Tetra(triphenylphosphine)palladium(0) (1.3 g, 1.1 mmol), Cs₂CO₃ (7.4 g, 23 mmol), and 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (3.3 mL, 15 mmol) were added to a solution of 2-(4-bromo-5-fluoro-2-iodo-phenyl)ethyl acetate (4.37 g, 11.31 mmol) in 1,4-dioxane (80 mL). The mixture was heated at 90 °C for 5 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic compounds 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 2.51 g (67%) of the title compound as a yellow oil. ES-MS m / z 331 / 333(M+H).

[1124] Preparation of 196

[1125] Ethyl 2-[4-bromo-5-fluoro-2-(2-hydroxyethyl)phenyl]

[1126]

[1127] Mercuric acetate (6.3 g, 19 mmol) was added to a solution of ethyl 2-[4-bromo-2-[2-ethoxyvinyl]-5-fluoro-phenyl]acetate (2.51 g, 7.59 mmol) in THF (45 mL) at 0 °C and stirred at 0 °C for 2 h. Simultaneously, sodium borohydride (520 mg, 13.75 mmol) was added to a solution of K₂CO₃ (60 g) in water (56 mL), and this mixture was added to the previous reaction with the starting material. The reaction was stirred at RT for 40 min, then diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic compounds 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 (1.31 g, 40% yield) as a colorless oil. ES-MS m / z 305 / 307 (M+H).

[1128] Preparation of 197

[1129] 4-Formyl-3-hydroxybenzonitrile

[1130]

[1131] Boron tribromide (100 g, 399.16 mmol) was added fractionally to a solution of 4-cyano-2-methoxybenzaldehyde (13 g, 79.86 mmol) in DCM (480 mL) at -10 °C. The reaction mixture was stirred at RT for 3 days, cooled to 0 °C, and water (21 mL) was slowly added. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3 × 100 mL). The organic compounds were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residues were purified by silica gel chromatography using a gradient of 0 to 20% EtOAc / heptane to give 7.61 g (65%) of the title compound. ES-MS m / z 148 (M+H).

[1132] Preparation of 198

[1133] 4-Formyl-3-(2-trimethylsilylethoxymethoxy)benzonitrile

[1134]

[1135] 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-hydroxybenzonitrile (4 g, 27.18 mmol) in DCM (68 mL) and diethyl ether (30 mL). The reaction mixture was stirred at RT for 3 hours. The reaction mixture was diluted with saturated aqueous NH4Cl solution and extracted with DCM (3 × 50 mL). The organic compounds were combined, washed with water and saturated aqueous NaCl solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residues were 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).

[1136] Preparation of 199

[1137] 4-(hydroxymethyl)-3-(2-trimethylsilylethoxymethoxy)benzonitrile

[1138]

[1139] Sodium borohydride (1.6 g, 42 mmol) was added fractionally 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 0 °C. The reaction mixture was stirred for 1 hour, then water (50 mL) was added and the mixture was extracted with EtOAc (3 × 50 mL). The organic compounds were combined, washed with water and a saturated aqueous solution of NaCl, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 5.55 g (97%) of the title compound. ES-MS m / z 280 (M+H).

[1140] Preparation of 200

[1141] 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-trimethylsilylethoxymethoxy)benzonitrile

[1142]

[1143] Sodium hydride (60%, in mineral oil, 500 mg, 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 the reaction was heated at 60 °C for 3 hours. The reaction was cooled to ambient temperature, diluted with water (50 mL), and extracted with EtOAc (3 × 50 mL). The organic compounds were combined, washed with water and saturated NaCl aqueous solution, 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 3.18 g (77%) of the title compound. 1 H NMR (400.13MHz, CDCl3) 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).

[1144] Preparation of 201

[1145] 4-[(6-bromo-2-pyridyl)oxymethyl]-3-hydroxybenzonitrile

[1146]

[1147] Carbon tetrabromide (364 mg, 1.1 mmol) was added to a solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-trimethylsilylethoxymethoxy)benzonitrile (3.18 g, 7.31 mmol) in 2-propanol (75 mL). The reaction mixture was heated at 80 °C 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).

[1148] Preparation of 202

[1149] 2-[4-bromo-2-[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenoxy]ethyl]-5-fluoro-phenyl]ethyl acetate

[1150]

[1151] Add DEAD diluted in THF (1 mL) to a solution of ethyl 2-[4-bromo-5-fluoro-2-(2-hydroxyethyl)phenyl]acetate (519 mg, 1.70 mmol), 4-[(6-bromo-2-pyridyl)oxymethyl]-3-hydroxybenzonitrile (500 mg, 1.64 mmol), and triphenylphosphine (645 mg, 2.46 mmol) in THF (17 mL). Stir the reaction mixture at RT overnight. After 14 hours, at 0 °C, add more DEAD diluted in THF (1 mL) (40% in toluene, 0.53 mL, 1.36 mmol). After standing at RT for 20 hours, dilute the reaction mixture with water (25 mL) and extract with EtOAc (3 × 10 mL). Combine the organics, filter, and concentrate under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 10 to 30% EtOAc / heptane to give 444 mg (44%) of the title compound as a white solid. ES-MS m / z 591 / 593 / 595 (M+H).

[1152] Preparation of 203

[1153] 2-(5 4 -Cyano-1 6 -Fluoro-3,6-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 ethyl acetate (-yl)

[1154]

[1155] In two separate batches, nitrogen gas was bubbled through a solution of ethyl 2-[4-bromo-2-[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenoxy]ethyl]-5-fluoro-phenyl]acetate (299 mg, 0.50 mmol) in 1,4-dioxane (10 mL), followed by the addition of hexamethyldistin (0.16 mL, 0.76 mmol) and a Pd(dppf)Cl2 DCM complex (100 mg, 0.12 mmol). The reaction mixture batches were heated at 100 °C for 3 hours. The two batches were cooled to RT and combined. The mixture was diluted with water and extracted three times with EtOAc. The organic matter was combined, washed with water and a saturated aqueous solution of 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 (90 mg, 41%) as a white solid. ES-MS m / z 433(M+H).

[1156] Preparation of 204

[1157] 2-(5 4 -Cyano-1 6 -Fluoro-3,6-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 -yl)acetic acid

[1158]

[1159] The basic preparation method is as described in 75, using 2-(5) 4 -Cyano-1 6 -Fluoro-3,6-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 The title compound was prepared by reacting ethyl acetate (-yl) with the mixture at 45°C for 3 hours. Formic acid was added to the mixture to pH 5-6, the mixture was diluted with water, and extracted three times with 3:1 DCM:isopropanol. The organic compounds were combined, washed with water and a saturated aqueous solution of 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).

[1160] Preparation of 205

[1161] (S)-4-(2-(5 4 -Cyano-1 6 -Fluoro-3,6-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 Methyl benzoate (-yl)acetamyl)-3-((oxetane-2-ylmethyl)amino)benzoate

[1162]

[1163] To 2-(5) 4 -Cyano-1 6 -Fluoro-3,6-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 44-amino-3-[[(2S)-oxetane-2-yl]methylamino]benzoate (48 mg, 0.20 mmol) was added to a solution of 4-amino-3-[[(2S)-oxetane-2-yl]methylamino]benzoate (48 mg, 0.20 mmol) in DMF (2 mL) along with 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 organic compounds were combined, washed with water and saturated NaCl aqueous solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (200 mg, >100%), which was used for the preparation of 206 without further purification. ES-MS m / z 623 (M+H).

[1164] Preparation of 206

[1165] (S)-2-((5 4 -Cyano-1 6 -Fluoro-3,6-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 methyl 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1166]

[1167] Add acetic acid (6 mL) to (S)-4-(2-(5) 4 -Cyano-1 6 -Fluoro-3,6-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic octafan-1 4 Methyl benzoate (205, 200 mg, 0.32 mmol) was prepared and stirred at 65 °C for 2 h. The mixture 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 20% EtOAc / DCM to give 92 mg (47%) of the title compound. ES-MS m / z 605 (M+H).

[1168] Preparation of 207

[1169] Ethyl 3-amino-5-bromo-pyridine-2-carboxylate

[1170]

[1171] Sulfuric acid (52 mL, 927 mmol) was slowly added to a solution of 3-amino-5-bromopyridin-2-carboxylic acid (15 g, 65.66 mmol) in 8 M ethanol / water (197 mL). The reaction was heated at 80 °C for 18 h. The mixture was cooled to RT, and then NaOH (2 M aqueous solution) was slowly added until pH = 8, and the mixture was extracted with EtOAc (3 × 100 mL). The organic compounds were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (13.93 g, 86%) as a pale yellow solid. ES-MS m / z 245 / 247 (M+H).

[1172] Preparation of 208

[1173] (3-amino-5-bromo-2-pyridyl)methanol

[1174]

[1175] Lithium borohydride (3.75 g, 172 mmol) was added in portions to a solution of ethyl 3-amino-5-bromo-pyridine-2-carboxylate (13.93 g, 56.84 mmol) in THF (230 mL) and MeOH (23 mL) at 0 °C. The reaction mixture was stirred at RT for 1 h. A saturated solution of NaHCO3 was added and the mixture was extracted with EtOAc (5 x 100 mL). The organic compounds were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. ACN was added to the residue, and the resulting slurry was filtered. The solid was washed with ACN and then dried under vacuum to give 9.87 g (81%) of the title compound as a beige solid. ES-MS m / z 203 / 205 (M+H).

[1176] Preparation 209

[1177] (5-bromo-3-iodo-2-pyridyl)methanol

[1178]

[1179] 4-Methylbenzenesulfonic acid hydrate (27.81 g, 146.2 mmol) was added to a suspension of (3-amino-5-bromo-2-pyridyl)methanol (9.87 g, 48.63 mmol) in ACN (170 mL). The mixture was stirred for 10 minutes and then cooled to 0 °C. Sodium nitrite (6.72 g, 97.4 mmol) in water (20 mL) was added to the mixture, followed by potassium iodide (20.48 g, 123.4 mmol) in water (20 mL). The reaction was stirred at 0 °C for 10 minutes and then at RT for 2 hours. A saturated aqueous solution of NaHCO3 was added to the mixture, and the mixture was extracted with EtOAc (3 x 100 mL). The organic matter was combined, washed with a 5% aqueous solution of sodium bisulfite, water, and a saturated aqueous solution of NaCl, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solid obtained by grinding with ACN was then filtered and vacuum dried to give the title compound (10.31 g, 61%) as a slightly brown solid. ES-MS m / z 314 / 316 (M+H).

[1180] Preparation of 210

[1181] [5-Bromo-3-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]-2-pyridyl]methanol

[1182]

[1183] Bis(triphenylphosphine)palladium(II) dichloride (2.64 g, 3.73 mmol), cuprous iodide (0.71 g, 3.76 mmol), and TEA (31 mL, 225 mmol) were added to a (5-bromo-3-iodo-2-pyridyl)methanol solution (11.78 g, 37.53 mmol) under nitrogen atmosphere at RT. Tert-butyldimethyl(2-propynyloxy)silane (10 mL, 48 mmol) was added, and the reaction was heated at 40 °C for 20 h. The reaction was cooled to RT, water and brine were added, and the mixture was extracted three times with EtOAc. The organic compounds 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 9.03 g (67%) of the title compound as a brown oil. ES-MS m / z 356 / 358 (M+H).

[1184] Preparation of 211

[1185] 5-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]-6-(hydroxymethyl)pyridine-3-carboxynitrile

[1186]

[1187] Zinc cyanide (2.09 g, 17.85 mmol) was added under nitrogen to a solution of [5-bromo-3-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]-2-pyridyl]methanol (9.03 g, 25.26 mmol) in DMF (180 mL), followed by the addition of tetrakis(triphenylphosphine)palladium(0) (2.93 g, 2.54 mmol). The reaction was heated at 100 °C for 2 h. The mixture was cooled to RT, water and a saturated aqueous NaCl solution were added, and the mixture was extracted three times with EtOAc. The organic compounds 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 4.6 g (60%) of the title compound as a brown oil. ES-MS m / z 303 (M+H).

[1188] Preparation of 212

[1189] 6-[(6-bromo-2-pyridyl)oxymethyl]-5-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]pyridine-3-carboxylonitrile

[1190]

[1191] The title compound was prepared essentially as described in Preparation 34 using 5-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]-6-(hydroxymethyl)pyridin-3-carboxynitrile. 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).

[1192] Preparation of 213

[1193] 6-[(6-bromo-2-pyridyl)oxymethyl]-5-(3-hydroxyprop-1-ynyl)pyridine-3-carboxynitrile

[1194]

[1195] 1 M TBAF / THF (16.1 mL, 16.1 mmol) was added to a solution of 6-[(6-bromo-2-pyridinyl)oxymethyl]-5-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]pyridine-3-carboxylonitrile (6.15 g, 13.42 mmol) in THF (40 mL). The mixture was stirred at RT for 7 hours. A saturated aqueous solution of NaHCO3 was added and the mixture was extracted three times with EtOAc. The organic matter was combined, washed with water and a saturated aqueous solution of 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 3.04 g (66%) of the title compound as a colorless oil. ES-MS m / z 344 / 346 (M+H).

[1196] Preparation of 214

[1197] 6-[(6-bromo-2-pyridyl)oxymethyl]-5-(3-hydroxypropyl)pyridine-3-carboxynitrile

[1198]

[1199] Platinum oxide (0.06 g, 0.26 mmol) was added to a solution of 6-[(6-bromo-2-pyridinyl)oxymethyl]-5-(3-hydroxyprop-1-ynyl)pyridine-3-carboxynitrile (0.65 g, 1.88 mmol) in MeOH (18 mL) and two drops of acetic acid. Hydrogen gas was introduced into the reaction vessel (15 psi), and the mixture was stirred at RT for 5 hours. The reaction was filtered through a pad and washed with MeOH and EtOAc. The filtrate was evaporated under vacuum 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).

[1200] Preparation of 215

[1201] 2-[4-bromo-2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-3-pyridyl]propoxy]-5-fluoro-phenyl]ethyl acetate

[1202]

[1203] The title compound was prepared essentially as described in Preparation 60 using 6-[(6-bromo-2-pyridinyl)oxymethyl]-5-(3-hydroxypropyl)pyridine-3-carboxylonitrile (1.01 g, 2.9 mmol), with the removal of the MeOH quenching step, to give the title compound as a white solid. ES-MS m / z 606 / 608 (M+H).

[1204] Preparation of 216

[1205] 2-(5 5 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridaza-1(1,3)-benzene-1-cyclononafen-1 4 ethyl acetate (-yl)

[1206]

[1207] Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 75.2 mg, 0.094 mmol) was added to a mixture of ethyl 2-[4-bromo-2-[3-[2-[(6-bromo-2-pyridinyl)oxymethyl]-5-cyano-3-pyridinyl]propoxy]-5-fluoro-phenyl]acetate (0.75 g, 1.23 mmol), cesium fluoride (203 mg, 1.33 mmol), and hexamethyldistin (321 mg, 0.98 mmol) in 1,4-dioxane (55 mL) under nitrogen atmosphere. The reaction mixture was heated at 100 °C for 18 hours. The mixture was cooled to RT and subjected to... The sample was filtered through a pad and washed with EtOAc (2 × 100 mL) and MeOH (2 × 100 mL). The filtrate was evaporated and the residue was purified by silica gel chromatography using a 0–50% EtOAc / heptane gradient to give 0.27 g (49%) of the title compound as a pale yellow solid. ES-MS m / z 448 (M+H).

[1208] Preparation of 217

[1209] 2-(5 5 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridaza-1(1,3)-benzene-1-cyclononafen-1 4 -yl)acetic acid

[1210]

[1211] To 2-(5) 5 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridaza-1(1,3)-benzene-1-cyclononafen-1 4Ethyl 1,3,4,6,7,8-hexahydro-2H-pyrimidino[1,2-a]pyrimidinium (0.075 g, 0.54 mmol) was added to a mixture of ACN (3.2 mL), THF (0.8 mL), and water (0.5 mL). The suspension was heated at 45 °C for 2 hours. The mixture was cooled to RT, formic acid was added until pH = 4, and the mixture was extracted with EtOAc (3 × 5 mL). The organic compounds were combined, washed with water and saturated NaCl aqueous solution, 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).

[1212] Preparation of 218

[1213] (S)-4-(2-(5 5 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridaza-1(1,3)-benzene-1-cyclononafen-1 4 Methyl benzoate (-yl)acetamyl)-3-methoxy-5-((oxetane-2-ylmethyl)amino)benzoate

[1214]

[1215] To 2-(5) 5 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridaza-1(1,3)-benzene-1-cyclononafen-1 4 4-amino-3-methoxy-5-[[(2S)-oxetane-2-yl]methylamino]benzoate (0.077 g, 0.29 mmol) in a solution of 4-amino-3-methoxy-5-[[(2S)-oxetane-2-yl]methylamino]benzoate (0.077 g, 0.29 mmol) in DMF (1.3 mL) was reacted with DIPEA (0.13 mL, 0.74 mmol) and HATU (0.16 g, 0.40 mmol). The reaction mixture was stirred at RT for 16 h. A saturated aqueous solution of NaHCO3 was added and the mixture was extracted with EtOAc (2 × 40 mL). The organic compounds 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 for the preparation of 219 without further purification. ES-MS m / z 668 (M+H).

[1216] Preparation 219

[1217] (S)-2-((5 5 -Cyano-1 6-Fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridaza-1(1,3)-benzene-1-cyclononafen-1 4 methyl 4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1218]

[1219] The basic preparation method is as described in preparation 102, using (S)-4-(2-(5) 5 -Cyano-1 6 -Fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridaza-1(1,3)-benzene-1-cyclononafen-1 4 The title compound was prepared by reacting methyl benzoate (((oxocyclobutane-2-ylmethyl)amino)benzoate (Preparation 218) with heat at 100 °C for 2 hours. After completion, the reaction was cooled to RT, ACN was added, and the mixture was evaporated. This process was repeated three times to ensure the 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).

[1220] Preparation of 220

[1221] 4-[(6-chloro-2-pyridyl)oxymethyl]-3-iodobenzonitrile

[1222]

[1223] A mixture of 4-(bromomethyl)-3-iodobenzonitrile (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 °C for 20 h. More 6-chloropyridin-2-ol (1.61 g, 12.4 mmol) and silver carbonate (3.5 g, 13 mmol) were added, and the mixture was stirred at 70 °C for 5 h. The mixture was cooled to RT and filtered through a silica gel stopper using DCM as the eluent to give the title compound (24.6 g, 107%) as a pale yellow solid. ES-MS m / z 371.0 / 373.0 (M+H).

[1224] Preparation of 221

[1225] 4-[(6-chloro-2-pyridyl)oxymethyl]-3-formyl-benzonitrile

[1226]

[1227] To a mixture of 4-[(6-chloro-2-pyridinyl)oxymethyl]-3-iodobenzonitrile (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), 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, 775 mg, 1.29 mmol], and tri-tert-butylphosphonium tetrafluoroborate (360 mg, 1.22 mmol) were added, and the mixture was stirred and heated at 75 °C for 23 hours. The mixture was cooled to RT and filtered through a silica gel stopper using DMF as the eluent. The filtrate was cooled to 0°C, and 1N HCl (120 mL) was added and stirred at 0°C for 15 minutes. The reaction mixture was diluted with water (200 mL) and stirred at RT for 30 minutes. 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).

[1228] Preparation of 222

[1229] 4-[(6-chloro-2-pyridyl)oxymethyl]-3-(hydroxymethyl)benzonitrile

[1230]

[1231] A solution of 4-[(6-chloro-2-pyridinyl)oxymethyl]-3-formylbenzonitrile (1.0 g, 3.67 mmol) in MeOH (20 mL) was cooled to 0 °C and sodium borohydride (290 mg, 7.26 mmol) was added in portions. The mixture was stirred at RT for 30 minutes and then cooled to 0 °C. Water (25 mL) was added to the mixture, followed by a 5% aqueous citric acid solution to pH 5, and then more water (50 mL) was added. The reaction mixture was stirred at RT for 30 minutes. 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).

[1232] Preparation of 223

[1233] 3-(bromomethyl)-4-[(6-chloro-2-pyridyl)oxymethyl]benzonitrile

[1234]

[1235] A solution of 4-[(6-chloro-2-pyridyl)oxymethyl]-3-(hydroxymethyl)benzonitrile (870 mg, 3.17 mmol) and triphenylphosphine (932 mg, 3.52 mmol) in DCM (20 mL) was cooled to 0 °C. Carbon tetrabromide (920 mg, 2.77 mmol) was added, and the reaction mixture was stirred at RT for 30 min. The reaction mixture was filtered through a silica gel stopper using DCM as the 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).

[1236] Preparation of 224

[1237] 2-[4-bromo-2-[2-[[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]methoxy]ethyl]-5-fluoro-phenyl]ethyl acetate

[1238]

[1239] 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-pyridyl)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 trifluoromethanesulfonate (2.60 g, 10.0 mmol) was added fractionally, and the reaction mixture was stirred at RT for 2 hours. The mixture was filtered, and the solid was 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 (480 mg, 34%) as a yellow solid. ES-MS m / z 561 / 563 (M+H).

[1240] Preparation of 225

[1241] 2-[2-[2-[[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]methoxy]ethyl]-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]ethyl acetate

[1242]

[1243] Under nitrogen bubbling, dichlorobis(tricyclohexylphosphine)palladium(II) (30 mg, 0.04 mmol) was added to a mixture of ethyl 2-[4-bromo-2-[2-[[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]methoxy]ethyl]-5-fluoro-phenyl]acetate (150 mg, 0.27 mmol), bis(pinacol)diboron (60 mg, 0.23 mmol), and KOAc (54 mg, 0.54 mmol) in 1,4-dioxane (2.5 mL), and the reaction mixture was stirred at 90 °C for 30 min. The reaction mixture was cooled to RT, concentrated under reduced pressure, and the residue was purified by filtration through a silica-stoppered filter using a gradient of 0 to 100% EtOAc / DCM as eluent to give the title compound (101 mg, 65%) as a pale white solid. ES-MS m / z 609 / 611 (M+H).

[1244] Preparation of 226

[1245] 2-(5 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 ethyl acetate (-yl)

[1246]

[1247] To a mixture of ethyl 2-[2-[2-[[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]methoxy]ethyl]-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]acetate (160 mg, 0.26 mmol) in THF (9.0 mL), 1 N tripotassium 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 PdG2, 21 mg, 0.03 mmol) were added, while nitrogen was bubbled through the mixture, and the reaction was stirred at 70 °C for 30 min. The reaction mixture was cooled to RT, and then MTBE (25 mL) and water (25 mL) were added. The separated phase was extracted with MTBE (3 × 20 mL) from the aqueous phase. The organic phases were combined, washed with water and a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0–100% EtOAc / DCM as eluent to give the title compound (45 mg, 34%) as a white solid. ES-MS m / z 447.0 (M+H).

[1248] Preparation of 227

[1249] 2-(5 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 -yl)acetic acid

[1250]

[1251] Under nitrogen bubbling, towards 2-(5) 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Ethyl ethyl acetate (91 mg, 0.24 mmol) was added in portions to a mixture of ACN (2.7 mL), THF (0.90 mL), and water (0.90 mL), followed by the addition of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (96 mg, 0.67 mmol) and stirred at 45 °C for 1 h. The reaction mixture was cooled to RT, and water (5 mL) and a 5% aqueous citric acid solution were added to adjust the pH to 5. 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).

[1252] Preparation of 228

[1253] (S)-4-(2-(5 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-2-methoxy-5-((oxetane-2-ylmethyl)amino)benzoate

[1254]

[1255] To 2-(5) 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4Methyl 4-amino-3-methoxy-5-[[(2S)-oxetane-2-yl]methylamino]benzoate (50 mg, 0.19 mmol), HATU (96 mg, 0.25 mmol), and DIPEA (0.1 mL, 0.60 mmol) were added to a solution of 4-amino-3-methoxy-5-[[(2S)-oxetane-2-yl]methylamino]benzoate in DMF (2.5 mL). The mixture was stirred at RT for 2 hours, and then water (10 mL) and EtOAc (10 mL) were added. The phase was separated and the aqueous phase was extracted with EtOAc (3 × 10 mL). The organic compounds were combined, washed with 2 M Na₂CO₃ aqueous solution, water, and saturated NaCl aqueous solution, 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).

[1256] Preparation 229

[1257] (S)-2-((5 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1258]

[1259] (S)-4-(2-(5) 4 -Cyano-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (prepared as 228, 190 mg, 0.28 mmol) in 1,2-dichloroethane (3.0 mL) and acetic acid (1.5 mL) was heated at 60 °C for 6 hours. The reaction mixture was cooled to RT, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc / DCM to give the title compound (58 mg, 31%) as a white solid. ES-MS m / z 649.2 / 650.2 (M+H).

[1260] Preparation 230

[1261] 2-Bromo-4-chloro-6-fluoro-benzaldehyde

[1262]

[1263] Isopropyl magnesium chloride (2M THF solution, 94 mL, 188 mmol) was added dropwise to a solution of 1,2-dibromo-5-chloro-3-fluorobenzene (50 g, 170 mmol) in heptane (130 mL) and THF (210 mL) at -45 °C, while maintaining the internal reaction temperature at -40 °C to -45 °C. The mixture was stirred at -40 °C for 30 min, then DMF (66 mL, 853 mmol) was added dropwise and stirred at -20 °C for 1 h. The reaction mixture was warmed to 0 °C, 1 N HCl was added to pH = 7, and the mixture was extracted with EtOAc (3 × 300 mL). The organic matter was combined, washed with water and a saturated aqueous solution of 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).

[1264] Preparation of 231

[1265] (2-bromo-4-chloro-6-fluoro-phenyl)methanol

[1266]

[1267] Sodium borohydride (5.16 g, 134 mmol) was added to a solution of 2-bromo-4-chloro-6-fluorobenzaldehyde (22.70 g, 89.88 mmol) in MeOH (240 mL) at 0 °C. The mixture was stirred at RT for 2 h. After cooling to 0 °C, 1 N HCl was added to pH 7, most of the solvent was concentrated, and the mixture was extracted with EtOAc (3 × 150 mL). The organic compounds were combined, washed with water and a saturated aqueous solution of 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).

[1268] Preparation of 232

[1269] 1-Bromo-2-(bromomethyl)-5-chloro-3-fluorobenzene

[1270]

[1271] Phosphorus tribromide (7.51 mL, 79.2 mmol) was added dropwise to a solution of (2-bromo-4-chloro-6-fluoro-phenyl)methanol (22.3 g, 79.2 mmol) in DCM (220 mL) at 0 °C. The reaction mixture was brought 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-d6) δ7.75 (t, J = 2Hz, 1H), 7.63 (dd, J = 9.5, 2Hz, 1H), 4.70 (d, J = 2Hz, 2H).

[1272] Preparation of 233

[1273] 2-[(2-bromo-4-chloro-6-fluoro-phenyl)methoxy]-6-chloro-pyridine

[1274]

[1275] Silver carbonate (180 g, 653 mmol) was added to a solution of 1-bromo-2-(bromomethyl)-5-chloro-3-fluorobenzene (34.1 g, 107 mmol) and 2-chloro-6-hydroxypyridine (57 g, 431 mmol) in ACN (1000 mL). The reaction mixture was stirred at 40 °C for 36 h. The mixture was cooled to RT, filtered, and the filtrate was 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).

[1276] Preparation of 234

[1277] 2-Chloro-6-[[4-Chloro-2-[(E)-2-ethoxyvinyl]-6-fluoro-phenyl]methoxy]pyridine

[1278]

[1279] Under nitrogen atmosphere, 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (11.8 mL, 55.4 mmol) was added to a mixture of 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (11.8 mL, 55.4 mmol), followed by tetra(triphenylphosphine)palladium(0) (6.13 g, 5.0 mmol). The reaction was heated to 90 °C for 12 hours, followed by the addition of more 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (5.4 mL, 25 mmol) and tetra(triphenylphosphine)palladium(0) (3.1 g, 2.5 mmol). The mixture was stirred at 90°C for 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 organic compounds 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).

[1280] Preparation of 235

[1281] 2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]-3-fluoro-phenyl]ethanol

[1282]

[1283] Mercuric acetate (37.53 g, 117.8 mmol) was added to a solution of 2-chloro-6-[[4-chloro-2-[(E)-2-ethoxyvinyl]-6-fluoro-phenyl]methoxy]pyridine (12.7 g, 35.3 mmol) in THF (280 mL) and water (280 mL) at 0 °C, and the mixture was stirred at 0 °C for 3 h. A 50% aqueous solution of K₂CO₃ (190 mL) and sodium borohydride (6 g, 158.59 mmol) were added to the mixture at 0 °C, and the mixture was stirred at 0 °C for 3 h. Water (200 mL) was added to the mixture, and the mixture was extracted with EtOAc (3 × 500 mL). The organic compounds 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 25% EtOAc / petroleum ether to give the title compound (9.46 g, 78%) as a colorless oil. ES-MS m / z 316(M+H).

[1284] Preparation of 236

[1285] 1-Bromo-5-(bromomethyl)-2-fluoro-4-iodobenzene

[1286]

[1287] A solution of 5-bromo-4-fluoro-2-iodotoluene (50.2 g, 156 mmol) and N-bromosuccinimide (29.2 g, 164 mmol) in ACN (0.8 L) was prepared. The solution was pumped through a photochemical reactor maintained at 40 °C and controlled by four Kessil PR160–370 nm (40 W) lasers and four Evoluchem ionomers. A coiled PFA reaction tube (1 / 8” od, 52 mL volume) surrounded by a 450 nm (30 W) lamp array was used at a flow rate of 2 mL / min to 3 mL / min. After completion, ACN (60 mL) was pumped through the reactor at the same rate. The reactor effluent was stirred and 20% sodium bisulfite aqueous solution (0.2 L) was added, followed by water to a final volume of 2 L. The resulting slurry was stirred at ambient temperature for 30 min. The solid was collected by filtration and washed with water (0.5 L). The filter cake was dissolved in a mixture of EtOAc (0.1 L) and heptane (0.4 L), and the organic layer was washed with 50 mL of water, saturated NaHCO3 aqueous solution, and saturated NaCl aqueous solution, then dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure at 50 °C to give 35.19 g of the title compound (53%, 93% purity) as a cream-colored solid. 1 H-NMR (400MHz, CDCl3) 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).

[1288] Preparation of 237

[1289] 2-[[2-[2-[(5-bromo-4-fluoro-2-iodo-phenyl)methoxy]ethyl]-4-chloro-6-fluoro-phenyl]methoxy]-6-chloro-pyridine

[1290]

[1291] Silver trifluoromethanesulfonate (8.30 g, 32 mmol) was added to a solution of 2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]-3-fluoro-phenyl]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. The reaction mixture was filtered, diluted with water (100 mL), and extracted with EtOAc (3 × 100 mL). The organic compounds 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).

[1292] Preparation of 238

[1293] 2-[4-bromo-2-[2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]-3-fluoro-phenyl]ethoxymethyl]-5-fluoro-phenyl]ethyl acetate

[1294]

[1295] Zinc bromide (2-ethoxy-2-oxoethyl) was added to a mixture of 2-[[2-[2-[(5-bromo-4-fluoro-2-iodophenyl)methoxy]ethyl]-4-chloro-6-fluorophenyl]methoxy]-6-chloropyridine (1.49 g, 1.94 mmol) and chloro[(4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (Xantphos-Pd-G2, 0.2 g, 0.2 mmol) in THF (7 mL) at nitrogen atmosphere. The mixture was heated at 65 °C for 2 hours in a microwave reactor. The mixture was cooled to RT, saturated NH4Cl aqueous solution (30 mL) was added, then diluted with water (30 mL) and extracted with EtOAc (3 × 50 mL). The organic compounds 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 0.57 g (45%) of the title compound as a colorless oil. ES-MS m / z 588 / 590 (M+H).

[1296] Preparation 239

[1297] 2-(5 4 -Chloride-1 6 5 6 -difluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 ethyl acetate (-yl)

[1298]

[1299] Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 176 mg, 0.21 mmol) was added 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(pinacol)diboron (0.8 g, 3 mmol) in THF (85 mL) under nitrogen atmosphere. The reaction was heated at 55 °C for 4 hours. Tripotassium phosphate (1.42 g, 6.57 mmol) in water (6.57 mL) was added to the reaction mixture, and the mixture was heated at 55 °C for 2 hours. The mixture was cooled to RT, water (30 mL) was added, and the mixture was extracted with EtOAc (3 × 100 mL). The organic compounds were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residues were purified by silica gel chromatography using a gradient of 0 to 15% EtOAc / petroleum ether to give the title compound (308 mg, 27%) as a beige solid. ES-MS m / z 474 (M+H).

[1300] Preparation 240

[1301] 2-(5 4 -Chloride-1 6 5 6 -difluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 -yl)acetic acid

[1302]

[1303] Basically as described in preparation 227, using 2-(5 4 -Chloride-1 6 5 6 -difluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared from ethyl acetate (M+H). ES-MS m / z 446 (M+H).

[1304] Preparation of 241

[1305] (S)-4-(2-(5 4 -Chloride-1 6 5 6 -difluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-14 Methyl benzoate (-yl)acetamyl)-3-(2-methoxyethoxy)-5-((oxetane-2-ylmethyl)amino)benzoate

[1306]

[1307] Under nitrogen gas, towards 2-(5 4 -Chloride-1 6 5 6 -difluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetane-2-yl]methylamino]benzoate (242 mg, 0.70 mmol) and DIPEA (0.28 mL, 1.62 mmol) were added to a solution of 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetane-2-yl]methylamino]benzoate in DMF (5.4 mL). The mixture was stirred at RT for 2 hours, then water (10 mL) was added and extracted with EtOAc (3 × 25 mL). The organic compounds were combined, washed with water and saturated NaCl aqueous solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (594 mg, 34% purity) as a white solid, which was used for the preparation of 242 without further purification. ES-MS m / z 738 (M+H).

[1308] Preparation 242

[1309] (S)-2-((5 4 -Chloride-1 6 5 6 -difluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 4-(2-methoxyethoxy)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1310]

[1311] The basic preparation method is as described in preparation 102, using (S)-4-(2-(5) 4 -Chloride-1 6 5 6 -difluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4The title compound was prepared by reacting methyl benzoate (-(2-methoxyethoxy)-5-((oxetane-2-ylmethyl)amino)benzoate in a 1:11,2-dichloroethane:acetic acid solvent at 60 °C for 6 h. The reaction mixture was cooled to RT, the solvent was evaporated under reduced pressure, and EtOAc / toluene (1:1) was added to the concentrate to aid in the removal of acetic acid. The residue was purified by silica gel chromatography using a gradient of 0 to 5% MeOH / DCM to give the title compound (64% purity) as a pale yellow solid. ES-MS m / z 720 (M+H).

[1312] Preparation of 243

[1313] 2-Bromo-6-(bromomethyl)nicotinamide

[1314]

[1315] A solution of 2-bromo-6-methylnicotinamide (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 dimensions = 15 m, 15 mL, flow rate = 1 mL / min, 25 °C) equipped with a 440–460 nM, 200 W lamp. The reaction solvent was evaporated and the residue was partitioned between water and DCM. The organic layer was separated, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed. The residue was dissolved in THF (400 mL), and diethyl phosphite (8.63 mL, 65.8 mmol) and DIPEA (17.8 mL, 99.0 mmol) were added at 0 °C under N2 for 0.5 h. The reaction mixture was warmed to RT and stirred overnight to obtain a black solution. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, washed with a saturated aqueous NaCl solution, 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 provide the title compound as a white solid (28.45 g, 84%). ES-MS m / z 275, 277, 279 (M+H).

[1316] Preparation of 244

[1317] 2-Bromo-6-[(6-chloro-2-pyridyl)oxymethyl]pyridine-3-carboxylonitrile

[1318]

[1319] Silver carbonate (10.5 g, 37.3 mmol) was added to a solution of 2-bromo-6-(bromomethyl)nicotinamide (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 °C 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 provide the title compound as a white solid (957 mg, 91 wt% purity, 42%). ES-MS m / z 324, 326, 328 (M+H).

[1320] Preparation of 245

[1321] 6-[(6-chloro-2-pyridinyl)oxymethyl]-2-[(E)-2-ethoxyvinyl]pyridine-3-carboxynitrile

[1322]

[1323] 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (13.5 mL, 63.4 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM complex (4.7 g, 5.65 mmol) were added to a mixture of 2-bromo-6-[(6-chloro-2-pyridinyl)oxymethyl]pyridine-3-carboxylonitrile (20.4 g, 56.6 mmol, 91 wt% 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 °C 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 provide the title compound as a yellow solid (15.7 g, 83 wt% purity, 73%). ES-MS m / z 316, 318 (M+H).

[1324] Preparation of 246

[1325] 6-[(6-chloro-2-pyridyl)oxymethyl]-2-(2-hydroxyethyl)pyridine-3-carboxynitrile

[1326]

[1327] The title compound was prepared essentially as described in Preparation 235 using 6-[(6-chloro-2-pyridinyl)oxymethyl]-2-[(E)-2-ethoxyvinyl]pyridine-3-carboxynitrile. After the reaction was complete, 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, 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 provide the title compound as a pale yellow solid. ES-MS m / z 290, 292 (M+H)

[1328] Preparation 247

[1329] 2-[4-bromo-2-[2-[6-[(6-chloro-2-pyridyl)oxymethyl]-3-cyano-2-pyridyl]ethoxymethyl]phenyl]methyl acetate

[1330]

[1331] The title compound was prepared substantially as described in Preparation 224 using 6-[(6-chloro-2-pyridinyl)oxymethyl]-2-(2-hydroxyethyl)pyridine-3-carboxynitrile and methyl 2-[4-bromo-2-(bromomethyl)phenyl]acetate, stirred overnight at 40 °C. After the reaction was complete, ACN was removed under reduced pressure, the residue was diluted with water and extracted with EtOAc. The organic matter was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC [column: Phenomenex Luna C18 250 × 50 mm, 10 μm; mobile phase: 40 to 85% ACN / formic acid aqueous solution (0.225%)] to provide the title compound as a pale yellow waxy solid. ES-MS m / z 530, 532, 534 (M+H).

[1332] Preparation 248

[1333] 2-(5 5 -cyano-3,8-dioxa-2,5(2,6)-dipyridaza-1(1,3)-benzene-1-cyclononaza-1 4 methyl acetate (-yl)

[1334]

[1335] The title compound was prepared substantially as described in Preparation 216 using methyl 2-[4-bromo-2-[2-[6-[(6-chloro-2-pyridyl)oxymethyl]-3-cyano-2-pyridyl]ethoxymethyl]phenyl]acetate as the 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 the catalyst, and heated to 110°C overnight. After the reaction was complete, the reaction mixture was concentrated, water was added, and the mixture was extracted three times with EtOAc. The combined organic matter was dried over sodium sulfate, filtered, and concentrated. The residue was purified by HPLC [column: Welch Xtimate C18 150×40 mm, 10 μm; mobile phase: 40 to 80% ACN / formic acid aqueous solution (0.225%)] to provide the title compound as a white solid. ES-MS m / z 416(M+H).

[1336] Preparation 249

[1337] 2-(5 5 -cyano-3,8-dioxa-2,5(2,6)-dipyridaza-1(1,3)-benzene-1-cyclononaza-1 4 -yl)acetic acid

[1338]

[1339] The basic preparation method is as described in 78, using 2-(5) 5 -cyano-3,8-dioxa-2,5(2,6)-dipyridaza-1(1,3)-benzene-1-cyclononaza-1 4 The title compound was prepared from methyl methyl acetate. Upon completion of the reaction, the organic solvent and water, along with an aqueous solution of citric acid (1M), were removed to bring the pH to 5-6. 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).

[1340] Preparation 250

[1341] (S)-4-(2-(5 5 -cyano-3,8-dioxa-2,5(2,6)-dipyridaza-1(1,3)-benzene-1-cyclononaza-1 4 Methyl benzoate (-yl)acetamyl)-3-(2-methoxyethoxy)-5-((oxetane-2-ylmethyl)amino)benzoate

[1342]

[1343] Basically as described in preparation 86, using 2-(5 5-cyano-3,8-dioxa-2,5(2,6)-dipyridaza-1(1,3)-benzene-1-cyclononaza-1 4 The title compound was prepared by reacting methyl 4-(2-(2-methoxyethoxy)-5-[[(2S)-oxetane-2-yl]methylamino]benzoate with stirring at RT overnight. The reaction mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with water and a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered, and concentrated under vacuum to give the title compound as an orange waxy solid with a purity of 54 wt%. ES-MS m / z 694 (M+H).

[1344] Preparation of 251

[1345] (S)-2-((5 5 -cyano-3,8-dioxa-2,5(2,6)-dipyridaza-1(1,3)-benzene-1-cyclononaza-1 4 methyl 4-(2-methoxyethoxy)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1346]

[1347] The basic preparation method is as described in preparation 109, using (S)-4-(2-(5) 5 -cyano-3,8-dioxa-2,5(2,6)-dipyridaza-1(1,3)-benzene-1-cyclononaza-1 4 The title compound was prepared by stirring at 60 °C for 6 hours under a nitrogen atmosphere with methyl benzoate (54 wt% purity) of (-(oxetane-2-ylmethyl)amino)benzoate (54 wt% purity). Purification by silica gel chromatography using a gradient of 0 to 6% MeOH / DCM yielded the title compound as an orange waxy solid with a purity of 63 wt%. ES-MS m / z 676 (M+H).

[1348] Preparation of 252

[1349] 2-Chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)benzoate

[1350]

[1351] To a solution of methyl 5-(bromomethyl)-2-chlorobenzoate (25 g, 95 mmol) in 1,4-dioxane (600 mL), 6-chloropyridin-2-ol (14.2 g, 110 mmol) and silver carbonate (53.2 g, 193 mmol) were added. The mixture was stirred at 60 °C for 23 hours. The reaction suspension was filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure to give 29.4 g of the title compound (99%), which was used for the preparation of 253 without further purification. ES-MS m / z 312,314 (M+H).

[1352] Preparation of 253

[1353] (2-Chloro-5-(((6-chloropyridin-2-yl)oxy)methyl) Phenyl Methanol

[1354]

[1355] A solution of methyl 2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)benzoate (from preparation 252, 22 g, 71 mmol) in THF (200 mL) was cooled to 0 °C, and then added dropwise. (60 wt%, in toluene, 30 mL, 92 mL). The mixture was stirred at 0 °C for 10 min, and then the reaction was quenched with EtOAc (10 mL). The mixture was stirred at RT for 2 h, and then the reaction was diluted with water (200 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 20.7 g of the title compound (100%), which was used for the preparation of 254 without further purification. ES-MS m / z 284, 286 (M+H).

[1356] Preparation of 254

[1357] 2-((3-(bromomethyl)-4-chloro) benzyl )Oxy-6-chloropyridine

[1358]

[1359] A solution of (2-chloro-5-((((6-chloropyridin-2-yl)oxy)methyl)phenyl)methanol (from Preparation 253, 1.5 g, 5.3 mmol) and triphenylphosphine (2.0 g, 7.5 mmol) in DCM (35 mL) was cooled to 0 °C. Carbon tetrabromide (1.9 g, 5.7 mmol) was added, and the reaction mixture was stirred at 0 °C for 10 min, followed by stirring at RT for 30 min. The reaction solution was filtered through a silica gel pad and washed with DCM. The filtrate was concentrated under reduced pressure to give 1.8 g of the title compound (100%), which was used for Preparation 255 without further purification. ES-MS m / z 345 / 347 / 349 (M+H).

[1360] Preparation of 255

[1361] 2-(4-bromo-2-(2-((2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)benzyl)oxy)ethyl)-5-fluorophenyl)ethyl acetate

[1362]

[1363] The title compound was prepared essentially as described 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], with the reaction mixture stirred at RT for 1 hour and 15 minutes. The reaction mixture was filtered and concentrated under reduced pressure, and then purified by silica gel chromatography using a gradient of 0 to 20% EtOAc / hexane to give the title compound. ES-MS m / z 570 / 572 / 574 (M+H).

[1364] Preparation 256

[1365] 2-(2-(2-((2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)benzyl)oxy)ethyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)ethyl acetate

[1366]

[1367] 1,4-Dioxane (15 mL) was added 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(pinacol)diboron (480 mg, 1.87 mmol), KOAc (450 mg, 4.5 mmol), and dichlorobis(tricyclohexylphosphine)palladium(II) (225 mg, 0.30 mmol). The mixture was stirred at 90 °C for 5 hours, then Pd(dppf)Cl2 (125 mg, 0.17 mmol) was added and the mixture was stirred at 90 °C for 15 hours. The crude mixture was filtered through a silica gel pad and washed with EtOAc. The filtrate was concentrated under reduced pressure to give the title compound, which was used for the preparation of 257 without further purification. ES-MS m / z 536 (M+H, for boric acid).

[1368] Preparation 257

[1369] 2-(5 4 -Chloride-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 ethyl acetate (-yl)

[1370]

[1371] A solution of potassium phosphate (1.6 g, 7.4 mmol) in water (5 mL) was added to a solution of ethyl 2-(2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)benzyl)oxy)ethyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)acetate (from preparation 256,925 mg, 1.5 mmol) and XPhos Pd G2 (145 mg, 0.18 mmol) in THF (50 mL). The reaction mixture was stirred at 60 °C for 1.5 h. The crude reaction mixture was diluted with EtOAc (50 mL) and a 1:1 water:saturated NaCl aqueous solution (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 / hexane to yield 140 mg of the title compound (20%). ES-MS m / z 456 (M+H).

[1372] Preparation 258

[1373] 2-(5 4 -Chloride-1 6-Fluoro-3,7-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 -yl)acetic acid

[1374]

[1375] The basic preparation method is as described in 75, using 2-(5) 4 -Chloride-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting ethyl acetate (-methyl) with a solvent of 3:3:1 ACN:1,4-dioxane:water and heating at 50 °C for 1 hour and 20 minutes. The reaction mixture was diluted with water and quenched with 1 M citric acid aqueous solution. The precipitate was collected by filtration and washed with water to obtain the title compound. ES-MS m / z 428 (M+H).

[1376] Preparation 259

[1377] (S)-4-(2-(5 4 -Chloride-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-(2-methoxyethoxy)-5-((oxetane-2-ylmethyl)amino)benzoate

[1378]

[1379] Basically as described in preparation 86, using 2-(5 4 -Chloride-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetane-2-yl]methylamino]benzoate with 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetane-2-yl]methylamino]benzoate under RT stirring for 17 h. The reaction mixture 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).

[1380] Preparation 260

[1381] (S)-2-((5 4 -Chloride-1 6-Fluoro-3,7-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 methyl 4-(2-methoxyethoxy)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1382]

[1383] The basic preparation method is as described in preparation 109, using (S)-4-(2-(5) 4 -Chloride-1 6 -Fluoro-3,7-dioxa-2(2,6)-pyridaza-1,5(1,3)-diphenylheterocyclic nonafen-1 4 The title compound was prepared from (-(2-methoxyethoxy)-5-((oxetane-2-ylmethyl)amino)benzoate)methyl benzoate (from Preparation 259). The title compound was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc / hexane to obtain the title compound. ES-MS m / z 702 (M+H).

[1384] Preparation of 261

[1385] 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-iodobenzonitrile

[1386]

[1387] Two batches were prepared on the same scale as follows: Na₂CO₃ was added to a solution of 4-(bromomethyl)-3-iodobenzonitrile (22.4 g, 62.6 mmol) in acetone (340 mL) and water (340 mL). Both batches were stirred overnight at 80 °C, and then combined. The mixture was concentrated to remove acetone, and the solid was filtered off and washed with water. The solid was dried under vacuum and then stirred in DCM (70 mL) for 30 minutes. The solid was filtered, washed with DCM, and dried under vacuum to give 4-(hydroxymethyl)-3-iodobenzonitrile (23.6 g, 72%) as a white solid. 1 H-NMR (400MHz, DMSO-d6) 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).

[1388] Under nitrogen atmosphere at 0 °C, potassium tert-butoxide (1 M, in THF, 43 mL, 43 mmol) was added to a solution of 4-(hydroxymethyl)-3-iodobenzonitrile (11.5 g, 43.5 mmol) and 2-bromo-3,6-difluoropyridine (7.08 g, 35.8 mmol) in 1,4-dioxane (80 mL). The reaction mixture was stirred at 0 °C for 1 h, then stirred at RT for 7 h. The reaction mixture was diluted with saturated NH4Cl aqueous solution (50 mL), then water (100 mL) was added and the mixture was extracted with EtOAc (250 mL × 3). The organic layers were combined, washed with saturated NaCl aqueous solution (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).

[1389] Preparation of 262

[1390] 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-[(E)-2-ethoxyvinyl]benzonitrile

[1391]

[1392] The title compound was prepared basically as described in Preparation 245 using 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-iodobenzonitrile as the starting material and K₂CO₃ as the base, and heated to 90 °C for 1.5 h. 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 a saturated aqueous NaCl solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification was achieved by silica gel chromatography using a gradient of 0 to 60% EtOAc / petroleum ether to give the title compound as a white solid. ES-MS m / z 377 (M+H).

[1393] Preparation of 263

[1394] 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-(2-oxoethyl)benzonitrile

[1395]

[1396] The title compound was prepared essentially as described in Preparation 126 using 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-[(E)-2-ethoxyvinyl]benzonitrile, stirred at RT for 20 hours. After completion, the reaction mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with a saturated aqueous NaCl solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow solid, which was used for Preparation 264 without further purification. ES-MS m / z 349, 351 (M+H).

[1397] Preparation of 264

[1398] 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile

[1399]

[1400] Sodium borohydride (3.59 g, 93.9 mmol) was added to a solution of 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-(2-oxoethyl)benzonitrile (from preparation 263, 8.54 g, 22.0 mmol) in MeOH (80 mL) at 0 °C, and the reaction mixture was stirred at RT for 4 h. The reaction was quenched with a saturated aqueous NH4Cl solution 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 × 3). The organic layers were combined, washed with a saturated aqueous NaCl solution (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).

[1401] Preparation of 265

[1402] 2-(4-bromo-2-((2-(((6-bromo-5-fluoropyridin-2-yl)oxy)methyl)-5-cyanophenethoxy)methyl)phenyl)methyl acetate

[1403]

[1404] The title compound was prepared substantially as described in Preparation 224 using 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile and methyl 2-[4-bromo-2-(bromomethyl)phenyl]acetate as starting materials, with 2,6-di-tert-butyl-4-methylpyridine used instead of 2,6-di-tert-butylpyridine, and the reaction was stirred overnight at RT to prepare the compound. After completion, the reaction mixture was concentrated, and then water was added and extracted three times with EtOAc. The organic layers were combined, washed with a saturated aqueous NaCl solution, dried over sodium sulfate, filtered, and concentrated. Purification was achieved by silica gel chromatography using a gradient of 0 to 100% DCM / petroleum ether to give the title compound as a pale yellow oil. ES-MS m / z 592 (M+H).

[1405] Preparation of 266

[1406] 2-(5 4 -Cyano-2 3 -Fluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl acetate (-yl)

[1407]

[1408] 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-cyanophenethoxy)methyl)phenyl)acetate as the starting material, with (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate (XPhos Pd G3) as the catalyst, and the reaction mixture was protected 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 a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification was achieved by silica gel chromatography using a gradient of 0 to 33% EtOAc / petroleum ether to give the title compound as a brown solid. ES-MS m / z 433 (M+H).

[1409] Preparation of 267

[1410] 2-(5 4 -Cyano-2 3 -Fluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 -yl)acetic acid

[1411]

[1412] The basic preparation method is as described in 78, using 2-(5) 4 -Cyano-2 3 -Fluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared from methyl 2-(m-2-)acetate. After completion, the reaction was quenched with 1M citric acid aqueous solution 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 for the preparation of 268 without further purification. ES-MS m / z 419 (M+H).

[1413] Preparation of 268

[1414] (S)-4-(2-(5 4 -Cyano-2 3 -Fluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Methyl benzoate (-yl)acetamyl)-3-(2-methoxyethoxy)-5-((oxetane-2-ylmethyl)amino)benzoate

[1415]

[1416] Basically as described in preparation 86, using 2-(5 4 -Cyano-2 3 -Fluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetane-2-yl]methylamino]benzoate with stirring at RT overnight. After completion, the reaction mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a pale brown oil, which was used for the preparation of 269 without further purification. ES-MS m / z 711 (M+H).

[1417] Preparation 269

[1418] (S)-2-((5 4 -Cyano-2 3 -Fluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4methyl 4-(2-methoxyethoxy)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1419]

[1420] The basic preparation method is as described in preparation 102, using (S)-4-(2-(5) 4 -Cyano-2 3 -Fluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl benzoate (Preparation 268) with 1:11,2-dichloroethane:acetic acid at 55 °C for 5 hours. After the reaction was complete, the solvent was removed under reduced pressure, and then 1:1 EtOAc:toluene was added to the residue and the mixture was concentrated under vacuum. The title compound was purified by silica gel chromatography using a gradient of 0 to 6% MeOH / DCM to give the compound as an orange oil. ES-MS m / z 693 (M+H).

[1421] Preparation 270

[1422] 2-(5-cyano-2-methyl-phenyl)-2,2-difluoro-acetic acid methyl ester

[1423]

[1424] 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). Methyl bromodifluoroacetate (6 mL, 51.9 mmol) was added to the slurry, and the mixture was stirred at 30 °C under nitrogen for 18 hours. Then, 100 mL of saturated NaHCO3 aqueous solution was added, followed by 100 mL of EtOAc. The mixture was filtered, and the solid was washed with EtOAc (3 × 50 mL). The filtrate was then separated, and the organic layer was washed with saturated NH4Cl aqueous solution. The organic matter was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0–25% EtOAc / hexane) to give the product as a clear crystalline solid (3.3 g, 73%). 1 H NMR (DMSO-d6) 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).

[1425] Preparation 271

[1426] 2-[2-(bromomethyl)-5-cyano-phenyl]-2,2-difluoro-acetic acid methyl ester

[1427]

[1428] Methyl 2-(5-cyano-2-methyl-phenyl)-2,2-difluoro-acetate (4.4 g, 20 mmol) and N-bromosuccinimide (4 g, 22.47 mmol) were dissolved in ACN (100 mL). This solution was placed twice under a 4100 K white light bulb at flow conditions (1.0 mL / min; 72 ft 1 / 8” outer diameter reaction tube, wound around a beaker; maintained at 30 °C). After this treatment, the reaction solution was concentrated to dryness, and the residue was then purified by silica gel chromatography (0–10% EtOAc / hexane) to give the product (3.7 g, 62%) as a clear, viscous oil. 1 H NMR (DMSO-d6) 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).

[1429] Preparation 272

[1430] 2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoroacetic acid

[1431]

[1432] Methyl 2-[2-(bromomethyl)-5-cyano-phenyl]-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 the mixture was heated to 60 °C for 2 hours. The reaction was then quenched with 1 N HCl (to pH ~6) and extracted with EtOAc. The combined organic matter was dried over magnesium sulfate, filtered, and concentrated to give a product (7.8 g, 100%) as a viscous brown oil. ES-MS m / z ( 79 Br / 81 Br)382.8 / 384.8[M+H] + .

[1433] Preparation of 273

[1434] 2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro-acetic acid methyl ester

[1435]

[1436] 2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro-acetic acid (7.8 g, 20 mmol) was stirred in MeOH (100 mL). Concentrated sulfuric acid (0.1 mL, 2 mmol) was added and the mixture was heated to reflux for 30 hours. The reaction mixture was concentrated to dryness, and the residue was then purified by silica gel chromatography (0-100% EtOAc / hexane) to give the product (8 g, 99%) as a white crystalline solid. ES-MS m / z ( 79 Br / 81 Br)396.8 / 398.8[M+H] + .

[1437] Preparation of 274

[1438] 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(1,1-difluoro-2-hydroxy-ethyl)benzonitrile

[1439]

[1440] 2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro-acetic acid methyl ester (8 g, 20.14 mmol) was dissolved in THF (100 mL). Lithium borohydride (0.88 g, 40.4 mmol) was added to this solution, and the mixture was stirred at ambient temperature under nitrogen for 2 hours. The reaction was then quenched with saturated NH4Cl solution and extracted with EtOAc. The organic matter was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc / hexane) to give a product (4.7 g, 63%) as a viscous, transparent oil. ES-MS m / z ( 79 Br / 81 Br)368.8 / 370.8[M+H] + .

[1441] Preparation of 275

[1442] 3-[2-[(5-bromo-2-iodo-phenyl)methoxy]-1,1-difluoro-ethyl]-4-[(6-bromo-2-pyridyl)oxymethyl]benzonitrile

[1443]

[1444] 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(1,1-difluoro-2-hydroxy-ethyl)benzonitrile (4.5 g, 12 mmol) was dissolved in THF (60 mL) and DMF (10 mL). Sodium hydride (0.6 g, 15 mmol; 60% by mass, in mineral oil) was added to this solution and stirred at ambient temperature under nitrogen for 5 minutes. Then 4-bromo-2-(chloromethyl)-1-iodobenzene (4.8 g, 14 mmol) was added and stirring continued at ambient temperature under nitrogen for 18 hours. Subsequently, the reaction was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The organic matter was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0–30% EtOAc / hexane) to give a product (3.9 g, 48%) as a viscous, transparent oil. ES-MS m / z ( 79 Br / 81 Br)663.0 / 665.0[M+H] + .

[1445] Preparation 276

[1446] 2-[4-bromo-2-[[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro-ethoxy]methyl]phenyl]ethyl acetate

[1447]

[1448] 3-[2-[(5-bromo-2-iodo-phenyl)methoxy]-1,1-difluoro-ethyl]-4-[(6-bromo-2-pyridyl)oxymethyl]benzonitrile (3.9 g, 5.9 mmol) and [(4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XantPhos Pd G3, 0.6 g, 0.6 mmol)] were dissolved in THF (30 mL). Zinc bromide (2-ethoxy-2-oxo-ethyl) bromide (0.5 M, in diethyl ether) (18 mL, 9.0 mmol) was added to this solution, and the mixture was heated to 60 °C for 18 hours under nitrogen. The reaction was then cooled to ambient temperature, quenched with a saturated aqueous solution of NaHCO3, and extracted with EtOAc. The organic matter was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc / hexane) to give a product (1.6 g, 44%) as a viscous light brown oil. ES-MS m / z ( 79 Br / 81 Br)623.2 / 625.2[M+H] + .

[1449] Preparation of 277

[1450] 2-(5 4 -Cyano-6,6-difluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 ethyl acetate (-yl)

[1451]

[1452] Ethyl 2-[4-bromo-2-[[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro-ethoxy]methyl]phenyl]ethyl acetate (1.6 g, 2.9 mmol) was dissolved in 1,4-dioxane (30 mL). KOAc (0.64 g, 6.39 mmol) and bis(pinacol)diborone (0.8 g, 3.09 mmol) were added to this solution, and nitrogen was bubbled through the solution for 10 minutes. Then, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM complex (0.11 g, 0.132 mmol) was added, and the mixture was heated to 80 °C for 18 hours under nitrogen. The reaction mixture was then cooled to ambient temperature, diluted with a saturated aqueous NaCl solution, and extracted with EtOAc. The organic matter was dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 1,4-dioxane (50 mL) and water (3 mL), and tripotassium phosphate (1.4 g, 6.5 mmol) was added, followed by chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 0.1 g, 0.125 mmol). The mixture was heated to 60 °C for 2 hours. The reaction was then cooled to ambient temperature, quenched with a saturated aqueous NH4Cl solution, and extracted with EtOAc. The organic matter was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0–50% EtOAc / hexane) to give the product as a white solid (249 mg, 21%). ES-MS (m / z) 465.2 (M+H).

[1453] Preparation 278

[1454] (S)-2-((5 4 -Cyano-6,6-difluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl 4-(2-methoxyethoxy)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[1455]

[1456] 2-(5) 4 -Cyano-6,6-difluoro-3,8-dioxa-2(2,6)-pyridaza-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 Ethyl ethyl(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]dec-5-ene (0.23 g, 1.62 mmol) was added to this solution, and the mixture was stirred at ambient temperature for 2 hours. The reaction was then quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc. The organic matter was dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in DMF (2 mL), and methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetane-2-yl]methylamino]benzoate (0.055 g, 0.18 mmol), DMF (0.09 mL, 0.5 mmol), and HATU (0.09 g, 0.24 mmol) were added, and the mixture was stirred at ambient temperature for 18 hours. The reaction was then quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc. The organic matter was 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 50 °C for 18 hours. The mixture was concentrated to dryness, and the residue was purified by silica gel chromatography (0-100% EtOAc / hexane) to give the title compound (61 mg, 52.5%) as a grayish-white solid. ES-MS (m / z) 711.4 (M+H).

[1457] Preparation 279

[1458] 4-[(2-chloropyrimidin-4-yl)oxymethyl]-3-iodobenzonitrile

[1459]

[1460] Cs₂CO₃ (42.5 g, 130 mmol) and 4-(bromomethyl)-3-iodobenzonitrile (21.04 g, 65.35 mmol) were added to a solution of 2-chloropyrimidin-4-ol (8.50 g, 65.1 mmol) in DMF (150 mL). The reaction mixture was stirred at ambient temperature for 16 hours. The crude reaction mixture was poured into water, and the precipitate was collected by filtration. The solid 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 used for preparation 280 without further purification. ES / MS m / z 372 (M+H).

[1461] Preparation 280

[1462] 4-[(2-chloropyrimidin-4-yl)oxymethyl]-3-[(E)-2-ethoxyvinyl]benzonitrile

[1463]

[1464] Add tripotassium phosphate (40 mL, 80 mmol, 2 M aqueous solution), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (7.5 mL, 35 mmol), and bis(triphenylphosphine)palladium(II) dichloride (953 mg, 1.36 mmol) to a solution of 4-[(2-chloropyrimidin-4-yl)oxymethyl]-3-iodobenzonitrile (10.1 g, 27.2 mmol) in THF (150 mL), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (7.5 mL, 35 mmol), and bis(triphenylphosphine)palladium(II) dichloride (953 mg, 1.36 mmol) to the solution. Pinacol was injected with nitrogen for 15 min, and then stirred at 55 °C for 4 h. 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 / hexane to give the title compound (5.97 g, 70%). ES / MS m / z ( 35 Cl / 37 Cl)315 / 317[M+H + .

[1465] Preparation of 281

[1466] 4-[(2-chloropyrimidin-4-yl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile

[1467]

[1468] Hydrochloric acid (46 mL, 184 mmol, 4 M dioxane solution) was added to a solution of 4-[(2-chloropyrimidin-4-yl)oxymethyl]-3-[(E)-2-ethoxyvinyl]benzonitrile (5.75 g, 18.2 mmol) in THF (85 mL). The mixture was stirred at ambient temperature for 2.5 h. The reaction was concentrated under reduced pressure, and the residue was diluted with DCM. The mixture was adjusted to pH 8 with a saturated aqueous NaHCO3 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), cooled to 0 °C in an ice bath, and then sodium borohydride (1.28 g, 33.7 mmol) was gradually added. The mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with a 1 M NaOH aqueous solution, and the solution was further diluted with water and DCM, and then 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 / hexane to give the title compound (2.86 g, 44%). ES / MS m / z ( 35 Cl / 37 Cl)289 / 291[M+H + .

[1469] Preparation of 282

[1470] 2-[4-bromo-2-[2-[2-[(2-chloropyrimidin-4-yl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]phenyl]methyl acetate

[1471]

[1472] A solution of 4-[(2-chloropyrimidin-4-yl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile (200 mg, 0.69 mmol) in anhydrous DCM (4.6 mL) was cooled to 0 °C in an ice bath. Methyl 2-[4-bromo-2-(bromomethyl)phenyl]acetate (556 mg, 1.73 mmol) was added, followed by 2,6-di-tert-butylpyridine (0.31 mL, 1.38 mmol) and silver trifluoromethanesulfonate (354 mg, 1.38 mmol). The mixture was stirred at 0 °C for 1 hour, and then stirred at ambient temperature for 16 hours. The reaction mixture was filtered through a diatomaceous earth pad, and the pad was washed 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 / hexane to give the title compound (128 mg, 35%). ES / MS m / z ( 79 Br / 81 Br)529 / 531[M+H] + .

[1473] Preparation of 283

[1474] 2-[2-[2-[2-[(2-chloropyrimidin-4-yl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl acetate

[1475]

[1476] To a solution of methyl 2-[4-bromo-2-[2-[2-[(2-chloropyrimidin-4-yl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]phenyl]acetate (566 mg, 0.715 mmol) in 1,4-dioxane (7.5 mL), bis(pinacol)diboron (222 mg, 0.86 mmol), KOAc (177 mg, 1.80 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex (30 mg, 0.036 mmol) were added. The solution was purged with nitrogen for 10 min and then heated to 80 °C. The mixture was stirred for 19 h. The reaction was cooled to ambient temperature and filtered through a silica gel stopper, which was washed with DCM. The filtrate was concentrated under reduced pressure to obtain the title compound, which was used for the preparation of 284 without further purification. ES / MS m / z ( 35 Cl / 37 Cl)496 / 498[M+H] + (As boric acid)

[1477] Preparation of 284

[1478] 2-(5 4 -cyano-3,8-dioxa-2(2,4)-pyrimidin-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 methyl acetate (-yl)

[1479]

[1480] Add tripotassium phosphate (0.68 mL, 0.68 mmol, 1 M aqueous solution) to a solution of methyl 2-[2-[2-[2-[(2-chloropyrimidin-4-yl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]acetate (preparation 283, 130 mg, 0.225 mmol) in THF (5.6 mL). Inject the solution with nitrogen for 10 minutes, then add chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.9 mg, 0.011 mmol) and continue inhalation for another 5 minutes. Heat the solution at 50 °C 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 0-40% gradient of EtOAc / hexane to give the title compound (21 mg, 22%). ES / MS m / z 416 (M+H).

[1481] Preparation of 285

[1482] 2-(5 4 -cyano-3,8-dioxa-2(2,4)-pyrimidin-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 -yl)acetic acid

[1483]

[1484] Basically as described in preparation 217, using 2-(5 4 -cyano-3,8-dioxa-2(2,4)-pyrimidin-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4 The title compound was prepared by reacting methyl acetate (-methyl) at ambient temperature with stirring for 2 hours. After completion, the reaction was quenched with a 5% aqueous citric acid solution to bring the pH to 4, and the mixture was then diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with a saturated aqueous NaCl solution. The organic phases were dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting solid was milled with water to obtain the title compound. ES / MS m / z 402 (M+H).

[1485] Preparation of 286

[1486] (S)-4-(2-(5 4 -cyano-3,8-dioxa-2(2,4)-pyrimidin-1(1,3),5(1,2)-diphenylheterocyclic nonafen-1 4Methyl benzoate (-yl)acetamyl)-3-methoxy-5-((oxetane-2-ylmethyl)amino)benzoate

[1487]

[1488] Basically as de...

Claims

1. A compound of the following formula or a pharmaceutically acceptable salt thereof: where -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 Each time it appears, it is independently H, halogen, C1-C2 alkyl, OH, or C1-C3 alkoxy; R b Each time it appears, it is independently H, halogen, or C1-C2 alkyl; yes or , where a is the connection point with connection base A; b is the connection point with connection base B; X 1 X 2 X 3 and X 4 Independently N, CH or CR 1 , where X 1 X 2 X 3 and X 4 No more than two of them are N, and X 1 X 2 X 3 and X 4 No more than two of them are CR 1 ; X 5 Is it N, CH or CR? 1a X 6 X 7 and X 8 Independently N, CH or CR 1 , where X 5 X 6 X 7 and X 8 No more than two of them are N, and X 5 X 6 X 7 and X 8 No more than two of them are CR 1a or CR 1 ; R 1 Each time it appears independently, it is CN; halogen; C1-C3 alkyl optionally substituted with OH; C1-C3 haloalkyl; C1-C3 alkoxy; C3-C5 cycloalkyl; -SO2C1-C3 alkyl; , or , where each X 9 It is independently CH or N, and there is no more than one X in the ring. 9 It is N, each R e Independently selected from: H, C1-C3 haloalkyl, halogen, C3-C5 cycloalkyl and C1-C3 alkyl optionally substituted with OH, R h It is H, C1-C3 haloalkyl, halogen, C3-C5 cycloalkyl, OH, -NR c R d Or C1-C3 alkyl groups optionally substituted with OH; 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is optionally substituted by one or two substituents, the substituents being independently selected from: C1-C3 alkoxy, C3-C5 cycloalkyl, -CH2-C3-C5 cycloalkyl, -SO2C1-C3 alkyl, C4-C5 heterocyclic, -CH2-C4-C5 heterocyclic, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxy, CN, -CONR c R d -NR c R d Or C1-C3 alkyl groups optionally substituted with OH; R 1a CN; halogen; C1-C3 alkyl group optionally substituted with OH; C1-C3 haloalkyl group; or C1-C3 alkoxy group; -B- can be -CH2O-, -OCH2-, or -CH2NH-; Y 1 Y 2 and Y 7 Independently N, CH or CR 2 , where Y 1 Y 2 and Y 7 No more than one of them is N, and Y 1 Y 2 and Y 7 No more than two of them are CR 2 ; Y 3 Y 4 Y 5 and Y 6 Independently N, CH or CR 2 , where Y 3 Y 4 Y 5 and Y 6 No more than two of them are N, and Y 3 Y 4 Y 5 and Y 6 No more than two of them are CR 2 ; R 2 Each time it appears, it is independently either a halogen or a methyl group; Z 1 Z 2 and Z 3 Independently N, CH or CR 3 Z 1 Z 2 and Z 3 No more than two of them are N, and Z 1 Z 2 and Z 3 No more than two of them are CR 3 ; R 3 Each occurrence is independently a halogen; a C1-C4 alkyl group; a -OC4-C6 cycloalkyl group optionally substituted with a C1-C2 alkoxy group, OH group, C1-C3 alkyl group, or C1-C3 haloalkyl group; a -OC4-C6 heterocyclic group optionally substituted with a C1-C2 alkoxy group, OH group, C1-C3 alkyl group, or C1-C3 haloalkyl group; or a C1-C4 alkoxy group optionally substituted with one or two substituents selected from: C1-C2 alkoxy group, OH group, -NR group. f R g -CONR c R d CN, halogen, or 5- or 6-membered heteroaryl groups optionally substituted with C1-C3 alkyl groups; R 4 yes , or ; R 5 It is -CO2H, or ; R c and R d Each is independently an H or C1-C3 alkyl group; R f It is an H or C1-C3 alkyl group; and R g It is H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C5 cycloalkyl, C(O)C1-C3 alkyl or C1-C3 alkylC3-C5 cycloalkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula: 。 3. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein... yes .

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X 1 X 3 and X 4 It is CH, X 2 It is CR 1 And R 1 It is CN, Cl, F, CF3, , , , , , or .

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X 1 It is N; X 2 It is C(CF3); and X 3 and X 4 It is CH.

6. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X 1 X 3 and X 4 It is CH; and X 2 It is N.

7. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X 1 and X 4 It is CH; X 2 It is C(CF3); and X 3 It is N.

8. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X 1 and X 3 It is CH; X 2 It is C(CN); and X 4 It is N.

9. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X 1 and X 3 It is CH; X 2 and X 4 It is CR 1 And each R 1 It is independently selected from F, Cl and CN.

10. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein... yes .

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein X 5 X 7 and X 8 It is CH, and X 6 It is C(CN).

12. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein X 5 It is N; X 6 It is C(CN); and X 7 and X 8 It is CH.

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein -A- is -CH2CH2CH2O-, -CH2OCH2-, -CH2CH2OCH2-, CH2OCH2CH2- or -CF2CH2OCH2-.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein -B- is -CH2O-.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 and Y 7 Both are CH.

16. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Y 1 It is CR 2 Y 2 It is CH, Y 7 It is CH, and R 2 It is F.

17. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Y 1 It is CR 2 Y 2 It is CH, Y 7 It is CH, and R 2 It is a methyl group.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Y 3 It is N; and Y 4 Y 5 It is CH; Y 6 It is CH or CF.

19. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Y 3 Y 4 Y 5 and Y 6 Both are CH.

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein Z 1 Is it CH or CR? 3 And R 3 It is F, -OCH3, -OCH2CH2OCH3, OCH2CH2OH or OCH2CH2N(CH3)2.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein Z 2 It is CH.

22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Z 3 It is CH.

23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 5 It is -CO2H.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent or excipient.

25. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23 in the preparation of a medicament for the treatment of type II diabetes.

26. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23 in the preparation of a medicament for lowering blood glucose levels.

27. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23 in the preparation of a medicament for treating hyperglycemia.

28. The use according to any one of claims 25 to 27, wherein the compound is administered orally.

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